Grail Inc Aktie

Hi, everyone. So I'm Evie Koslosky, the life science tools and diagnostics analyst here at Goldman Sachs. I'm joined here by Aaron Freidin, the CFO of GRAIL. So thank you so much for joining us.

Yes. Thanks for having us.

Maybe to kick us off, start by helping investors get oriented with the story, a quick overview of kind of how you're building out the multi-cancer early detection market and sort of what you're most focused on right now?

Yes, definitely. So we're really excited about what we've built over the last 10 years. Multi-cancer early detection was just an idea but now we've got a product in the market. We've got lots of interventional data. We've got RTP data that we released at ASCO, really showing that this technology works, really the capability to pick up cell-free DNA circulating good blood from tumors at a very, very high specificity, low false positive rate and then tell people where the cancer is coming from. And so we've always been built for population scale. We've got a lab in RTP that can run over 1 million samples, the low false positive rate and so on. And we're now moving forward toward FDA approval and broad access. So really, really big milestones coming up that we're excited to come to achieve.

Great. And then last weekend, at ASCO, you mentioned that you had the full data readout from NHS-Galleri. Maybe talk through at a high level sort of those results versus the original headline and how you think about that?

Yes, definitely. So the full data readout is probably still coming. I mean you got to think about it, it's 140,000 people over 3 years in a randomized controlled trial. What we covered at ASCO were really the primary endpoints and some of the secondary endpoints and what we press released earlier. So we're really excited that we showed a Stage IV reduction essentially between the control arm and the intervention arm. In the second year, it was more than 20%. The third year, it was more than 26%. That's a pretty massive decrease in Stage IV cancer, which is really metastatic cancer, cancer that you really don't treat with curative intent. It's more palliative care.

So the oncology community was actually very excited and supportive of the data that we presented. And clinical utility isn't just one thing, right? This isn't a Stage III drug trial, where it didn't actually have a clinical output outcome and it hit some secondary endpoints that said the drug wasn't toxic. This is really the test of the implementation of an MCED test in 140,000 people in RCT. So beyond the stage shift, we found more Stage I and II cancers than the control arm. And if you like go a layer deeper, we actually found more Stage I and II cancers in the screening arm and the control arm than total cancers found by screening in the control arm.

So I mean that's a pretty dramatic story to talking about what the current standard of care screening is, which if you think about it makes sense. I mean, standard of care in the U.S. only finds about 14% of cancers. In PATHFINDER 2, we found 3 to 6x more cancers depending on how you compare to USPSTF or just standard of care. So other clinical utility endpoints, I mean, emergency room presentations, right, big decrease there, more than 25% and so on. So this clinical utility package, this clinical utility story was pretty impressive. And it will support national coverage decisions. It will support NHS decisions and so on going forward.

Yes. I think the other thing that was interesting that came out of the data was the Stage III and IV increase in the first year, but then the subsequent declines in years 2 and 3. So maybe talk through that. It kind of implies that with longer follow-up, you could potentially see that kind of decrease further over time. But maybe talk about sort of potential extension of this data another 12 months and any implications there from the cost standpoint.

Yes, definitely. So we are extending the lookout period by 12 months. So there will be no more Galleri tests, right? But we're not going to be giving another test. But what we'll do is we'll allow the data to mature in the control arm essentially because what you're doing with the Galleri test is you're finding cancer in people that you don't have cancer. So they're getting a test, it's not showing up clinically. And then in the original study analysis, we just cut that data off after 12 months. But there are people in the control arm who have cancer that isn't being found because it hasn't presented clinically.

So after another 12 months go by, more of those cancers will show up. And we believe that there's -- that will happen because there's just far more cancers in the intervention arm than in the control arm. You'd expect those things to be balanced because it was an RCT where it was randomized and balanced between those 2 things. So we would expect that to happen over that period of time.

And then also, you pointed out another really important part, that first year, you're essentially sweeping out all the cancer that's existing in the population in the screening arm. So those are a bunch of people who didn't know they had cancer. There wasn't another clinical way to find it and so on. But when you look at the second and third year, those people have been swept out. And then that's where you see the reductions in Stage IV and also starting to see in Stage III. And over more time, if we would have ran the study for another year, done another intervention, I think that type of data will be modeled and you can -- we'll be looking at it here eventually. But we're definitely going to be in probably the first part of next year, we'll have a follow-up on the additional 12 months, and we'll see what the numbers look like there.

Okay. Maybe taking a step back in the primary endpoint -- from the primary endpoint, and you still saw a 20% reduction in Stage IV. I guess, have you done any sort of analysis on like how this could translate into cost savings for a single payer system like NHS?

Yes. So the NHS will be doing a cost analysis. It's in I think sometime in '28 or '29 with mortality analysis and so on. So yes, we will be looking at that. And then I think other single-payer systems will see a lot of value in that. CMS, U.S. payers. We've got the REACH/Galleri study, where we're doing something similar to HS, where it's a 3 time point 5,000-person study in the Medicare population. They'll have data in the U.S. population when they do an NCD as well. So we think all that put together will give them a very robust data package to make an NCD.

Yes. And then the go/no-go decision on Galleri rollout in the U.K. was kind of contingent on these results. I guess any update on that and how you're thinking about driving scale there?

Yes. So they've just got access to the data. They've seen it, and they're excited by it. So I think no government makes a decision very quickly. We've always expected that to happen over an extended period of time. And there were multiple endpoints that they wanted to look at. One was the primary endpoint, but there were also others. So we'll be working with them to see what the next steps are. And once we have an idea what those are, we'll share that.

Great. And then you also mentioned the 25% reduction in the emergency presentation. Maybe talk through how you think that will impact the decision from like current physicians right now in their ordering practices and any sort of demand you would expect on the back of some of this data?

Yes. I mean one of the things that we heard loud and clear from ASCO and physician sense is they don't -- they're looking for things to do to not treat people with palliative care and treat with curative intent. So a reduction in emergency room presentation is very exciting to them. And we'll see. We're training our sales force now. We would have expanded our sales force. They're all getting trained on the ASCO data currently, and they'll go out and hit the streets, and we'll see what the receptivity is like.

Great. Yes. And actually, my next question was on the sales force. I guess, when would you expect maybe to see an influx in volumes on the back of this...

Toward the...

And is that included in your current guide?

Yes. Our 22% to 32% guide includes that.

Great. And then I guess going to the FDA status, you completed the final module of the PMA in January. You have the breakthrough device designation. And I guess timing should really be any day now. I guess what are your conversations with the agency now and sort of is still convenient at home?

Yes. We've been working with the FDA for quite a while now as a breakthrough device, first MCED test that they're looking at. So a lot of foundation building, a lot of understanding of the technology and so on. They've looked at all of our studies that we've done to date under an IDE, which means they looked at the study, they looked at the SAP, they looked at the results. So they're very familiar with our capabilities and the way we've built our studies. We've submitted our final module of the PMA in January of '26.

And we're in an iterative review process with them. They get lots of questions. We have lots of responses. And to date, the clock hasn't stopped. So this is an iterative review process. What we're waiting for now is to really understand if they're going to have an AdCom. We should find out here shortly. Some of those -- their normal time lines are starting to run out if they're not going to have an AdCom. But we're really excited and confident with our submission. And if there's an AdCom, let's have one. If there's not, let's move forward.

Yes. Yes. And on the AdCom, like is there anything you think would be the sticking point for the panel or really the focus for them?

Again, without an MCED test being looked at before, I'm not going to probably give you a satisfying answer. I'd say they did an MCED advisory panel in 2023. It then was really about the space or the application of the technology, but it was very -- it was not the types of questions you would expect on a specific data submission. So if they have an AdCom, I'd expect the AdCom to be focused on the data submission, the data we submitted.

But I think it can be often challenging to keep AdCom members focused on that because our package doesn't include the clinical utility data from NHS. It's just the first year data. I'm sure people want to talk about years 2 and 3. So we'll see. But again, I think either way, from the first Advisory Committee, we took all that feedback. We incorporated it in our PMA submission. We've incorporated the feedback from -- sorry, their feedback in everything we've done to date. So we feel good about where we're at.

Great. And then how do you think about the initial label? I mean, will it be broad in kind of asymptomatic adults, 50-plus or maybe more specific to cancer types or maybe even like a risk-adjusted?

So I think if you look at what we've put together from a data package perspective, right, it's all asymptomatic people with no suspicion of cancer between the ages of 50 and 80. So having a label different than that would be hard to understand. I could see the label not including every cancer we find because if the FDA says, well, you only found 2 of this cancer and you found 20 of these, then we'll give you the 20 and not the 2 or however they end up doing that.

But at the end of the day, we've been reassured that we'll be able to return all results. So whether it's in the label or whether it's on the second page, a physician, a clinician, a patient will be able to actually act on the report.

And as far as where you could restrict would be by age, so maybe 80 of our data, maybe somebody says, well, but 60 to 80 is higher use or high utilization. That's generally not an FDA call. That would be more of a payer call. But the thing that we're most assured by is that we'll be able to return all results because if we can do that, then I think it's an easy clinical commercial story.

Yes. Yes, that was my next question was sort of if it is a more restricted label, what are the economics? It seems like not much has changed or maybe...

Right. I mean I think payers once we get to those conversations may have different views. But at the end of the day, if the test works to finding cancer that you have, whether it's 47 cancers are in the label and 57 or we found over 150 different types of cancer at this point across our studies. You don't know what cancer the person has. And so what you not pay for or not treat 1 that's just rare I mean like something like annual cancer is very, very rare. You have to have a study of more than 1 million people to get like 20 cases. You're never going to do that. So we'll see how it ends up.

Yes. And then if you were to be screening a narrow population like high-risk individuals, I guess, how would you think about your ability to scale and kind of get the unit economics necessary if it's a narrower patient population?

I mean -- so I think I always have to remember at GRAIL and dealing with this population, it's 100 million people in the U.S. Right now, we did 56,000 tests last quarter. So we're in a very low penetration into that population. And that's even before you go globally. So we've got a lab that can do more than 1 million tests. We're going to be able to get to our 50% to 60% margins at lower ASPs closer to what CMS would reimburse the test for per the legislation once we get to scale on the system we have. And so I think we can get to the economics without with reimbursement, we get there faster with it. But given the international opportunity and this growing self-pay market, we'll see.

Yes. Actually, I wanted to ask about that. So reimbursement, maybe walk us through some of the moving pieces there. How critical is it to the business model? And yes, you kind of answered it, but is the sulfate market enough to kind of drive profitability with scale over time?

So I wouldn't go as far as, I would start with -- I don't think any screening company has really demonstrated profitability sometimes even with broad reimbursement. So -- but we do know that we're different than a lot of them. This is just a blood test that happens annually. So the cost to sell, we believe is going to be more efficient and more effective than other screening tests that aren't blood-based or taken annually.

But the other side of that equation is who does cholesterol testing. Well, is it going to be that, right? Is it just going to be automatic every year because there's 70 million people that show up to get a physical every year. It's just another checkbox. Maybe eventually, but how that happens, what we have to invest in, in building awareness to get to that level, those are the things that or stopping me from saying we'll be profitable by, that thing. But all I know is we've got over $800 million in the bank, and we've got the capital to really invest in more faster if we're seeing an inflection if we're seeing demand get out ahead of our capabilities. And that would really be from a sales force perspective because we've got the lab.

Yes. And then you mentioned your strategy outside the U.S. I guess, any time line you can provide on getting reimbursement there? I mean we talked a little bit about the NHS but you're also working with Samsung. So I guess, how difficult is it to get coverage in other markets? And are there any major differences in how we should think about getting covered internationally versus domestically?

Yes. So a lot of international markets will, one, look to the FDA, right? They don't just rubber stamp what the FDA does. But having FDA approval is a faster path, a smaller implementation study to do. And so we think once the FDA approval, that will open up more of those markets. But then you would likely have to see some sort of depending on the geography of partnership like Samsung in Korea, and if that goes well, it expands into Japan and then some sort of geo geographic clinical study, small.

We're not talking about anything near like what we did at the adjustor even with PATHFINDER because those are really robust strong data sets. So we do have several countries knocking on the door asking us to look at that type of an implementation, but it makes sense to tie it all around getting an FDA approval to speed up that process when it happens and then also the dissemination of the NHS data. So we'll really be growing more focused internationally once those things are broadly out.

Okay, okay. And when we think about CMS coverage, kind of what aspects of the NHS-Galleri test or trial do you think best convey the clinical utility?

So the stage reduction, Stage IV reduction, for sure. The III and IV starts to reduce after the second and third year, the significant increase in Stage I and II cancers found, Stage 1 and 2 cancers or you treat those and they're generally treated with surgery, radiation and so on. the decrease in the emergency room presentation and so on. So those are the things that are really going to drive CMS that they're going to look at is saying when they make their coverage decision.

Yes. And then I guess, you've seen some early adopters in the private space for the Galleri test in terms of payers. After the ASCO data, does that change in the conversations with some of those private players, either small ones or even larger ones as we kind of wait for FDA or CMS? Or is the NHS data just enough to start like pilot programs there?

The commercial payers in the U.S. have been pretty clear that you've got to have an FDA approval, with FDA approval and then with the ASCO data, then those conversations will start to happen. And at the same time, Medicare will be moving along. We know payers like to also follow Medicare. We'll also be leading into the USPSTF path and then it knows where this possible rapid development goes.

Yes. You mentioned NSX, I guess there's a lot of legislation legislative consideration is also the rapid pathway which you mentioned, maybe talk to the puts and takes of these and how we should think about them and we're thinking about the timing of coverage?

Yes. So coverage is generally a long process, as we all know. But I think there's an overwhelming sense, especially after ASCO and other on this FDA path that it's a when, not if now for an MCED, like they will be covered eventually. And how we get there, I think there's multiple paths and there's probably multiple time lines. something like rapid happens, getting to reimbursement will be faster than if you have to get to USPSTF. I don't no one's really even sure what USPSTF is going to look like in a year or 2 or now. So I think it's important, though, for the business given that we've built this large self-pay market, we lean into that. And then these international opportunities are kind of disconnected other than from the FDA approval standpoint to further ramp into a more profitable company.

Yes. Yes. So FDA approval takes longer than what you expect. I guess, could you move into some of these international markets without that? Or would you really need to see the FDA approval first?

So we've got -- we're in international markets now through distributor models which are kind of like building in Canada and Israel, some other countries kind of like the way we started in the U.S., where they've got their concierge or their medical tourism. They've got wealthy individuals who can pay for the test. So we're leaning into that. We're taking advantage of that where these distributors have sold these tests before and we can really do it in a capital-efficient way, where we basically are just running the test and they're managing everything else. So we'll continue to do those. But when you step back and you're going to like, are you in millions of people doing that? Probably by the time we will have FDA approval before we're getting to the millions of people through that type of test deployment.

Yes, yes. Touching on some of the self-pay. I mean, it's obviously you had the majority of your test right now. Maybe walk through the various channels and where you're finding particular success there.

So physicians' offices, not just concierge doctors, but we see continued drive there, continued growth there. That's really where our rep sales reps are focused. And it's not a strategy of blanketing the whole U.S. with the reps. We're really focused in metropolitan areas and where we're finding success. There's a lot of white space out there because we were the only people educating and building awareness up until a couple of quarters ago. and it's an expensive proposition. But now there's more awareness being built. We've just expanded our sales force by about 30 territories, and we'll continue to grow there, really driven by PCPs.

The other trend in health care is the consumerization of health care and some of these digital health platforms. So Function Health has been a partner for a couple of years now, and they're a great partner. They continue to drive growth. We've recently announced the pins and herbs loop and others, we'll see how that translates. It's a new thing for us. Those launches are built into our guide as it is but each of them kind of have a captive audience of potentially millions of people who are health seekers, like one of the biggest heart of cells is finding patients who want that. So we'll see how that goes but I think the digital health channel is potentially a large opportunity to expand the self-pay market.

Yes, yes. And maybe talk about some of these direct-to-consumer marketing plans. How much do you expect or how are you balancing this spend in your P&L planning?

So the digital health partners are a very efficient way for us to sell and grow, right, because it's the their marketing dollars. Again, we're running the test, they've got the captive patient and so on. So it's definitely an area that we would continue to lean into given how capital efficient it is. And then on the other spectrum, you can have self-insured employers that can be a little bit more costly to sell tests into because they've got benefits manager, you've got to manage.

They've got to get the test out to their people. usually have to do blood draw events to get a bolus of people because I mean people are at work, they don't want to go to a doctor's office, so you just bring the commodity to them. And then you got PCPs, you're somewhere in between. You've got those that are like Eric Sue or Dr. Friedman, who were on our panel, advisory panel. They were on the -- Dr. Sue was on the ASCO Investor Day, where they're prescribing the test to just about everybody in their office. That's an easier one. And there's others that are more dabblers where you've got to talk to them more often.

Yes. That is something I wanted to touch on like kind of how do you think about same-store sales within some of the brick-and-mortar physicians driving that? I guess, what would it take to get a doctor to order this test more often?

I mean, I think, like any other adoption curve, like there's going to be those true believers, right, who are going to be early, early adopters and then the more milestones we achieve to like derisk I think the decision of a physician to prescribe the test more will adopt. So FDA approval that will likely open up a whole another group of physicians. It's interesting because 1 out of 100 people, they're going to find a cancer in. So that's just the incidence of cancer. We do know that when they find a cancer and they find a cancer early, they become believers, and they prescribe more. But if it takes you 100 to find a cancer, there's a lot of time in there to actually not think this works.

So we've got a lot of programs around putting physicians together to talk to each other who find cancers and what do they do with it and so on. And I think you're also seeing through like Farber and Mayo some of these other well-respected oncology centers, they're creating their own MCED clinics, where they're publishing on their own data. They've got PPVs of like 70% to 80% because they're looking for the cancer until they find it. It's just -- we find test cancer molecularly and imaging isn't perfect. So is there really -- is it really a false positive? Or is it just a later positive?

Yes, yes. Kind of the same question for patients. At $900 a test, do you see patients coming back for repeat testing? Or is it typically like a onetime thing for them?

No. I mean this last quarter, I think more than 30% of the tests have been repeat tests in the last 18 months. So you could take the test annually, but I mean I never take my physical exactly 12 months after, so we use 18 months. And then just for comparatively, like Cologuard, I think their retest rate is just around 30% for a fully reimbursed FDA-approved test after 10 years. So I think it really speaks -- I mean, Cologuard is a great test. It speaks more towards the form factor of a blood-based test and the ability to pick up cancers, not a cancer.

Yes, definitely. You also have the Epic integration. Maybe if we look at kind of past integration like Quest and athena, how much volume uplift did you get from these within ordering physicians? Or should we expect a similar uplift in Epic?

So we're excited about Epic. We're in the middle of that implementation process. I'd expect that to go live by the end of the quarter -- I mean, by the end of the year. So I wouldn't expect that to be a significant impact this year. But I think as we you're talking about like early adopters and how do we expand. So this makes the physicians who are bought in very easy to order.

I don't think we're at a point because it's not an FDA-approved test that is fully reimbursed that just having Epic is going to make a physician go from, I'm not going to order this to order it. I think physicians are a little more thoughtful than just having an easy button. But I think once we have crossed that threshold of FDA approval and so on, then it just becomes much easier to order. We've seen definitely a good uptake from Quest and Athena. Epic is a completely bigger and different beast. And so we're excited to see where that goes.

Awesome. And then maybe turning to competition. The MCED market is obviously -- has a really large patient population. But how are you thinking about increasing competition in the MCED stage with more launches and then also maybe single cancer screening? And just talk through kind of what you're seeing there?

Yes. I mean we've been the only people in this space for a while. And where we welcome others into it. There's over 100 million people. This doesn't need to be a winner take all market. We're very proud of where we're at, though, in that position being the market leader. We're also the only company that has interventional data, clinical data. We're the only company that has data in the intended use population, which is a symptomatic people. We're the only company that has randomized controlled data. We're the only company that showed a Stage IV shift.

So like our data package is just so much higher quality and built in the intended population versus case-controlled study that we think we're pretty differentiated there. But people building awareness, people educating on MCED, we more than welcome that. We're really comfortable with where we're at, and we're continually looking at what is new, what could we do differently, how could we -- how are we going to improve the test.

We've already that it once. We reduced our cost pretty significantly with the same performance. So we've shown that we can take the data in our system and our commercial data and make the test better. We're going to continue to do that. And I think we've ran close to 1 million total samples now between clinical and commercial studies. So we like where we're at.

Yes. Yes. Do you think that, that data differentiation is something that a lot of the self-pay kind of consumers will understand as they look to who the provider is going to be?

So that's a great question. I think the more awareness we build and the more we are successful in showing physicians in explaining the difference. I think that kind of gets you there. We'll see how many tests somebody like a digital health partner offers or are they going to offer 5 MCED tests or they can offer 1. So we'll see how that all rolls out. I mean, as you guys all know, you're investors in this space and you're an analyst in the space. People like to compare all sorts of data that probably isn't comparable, and it can cause confusion. But at the end of the day, we've got RCP data shows clinical utilities kind of everything kind of understands that.

Yes. Yes. Maybe touching on the financials a bit and on profitability. I guess, how do you think about the OpEx line items moving forward? You recently hired more reps, but then you completed the NHS study. So kind of maybe the moving pieces there?

Yes. So I think we'll burn about $300 million this year, no more than that, and we see cash into 2030. So the growth, the increase in margins, growth in revenue will start to contribute to the bottom line. Sales and marketing will be the area that we do invest in. The R&D are different than we are now. I mean, primarily the majority of the costs in prior years, the testing. That's the most expensive part of it. This is a pretty affordable follow-up stuff. And our innovation and R&D programs, we continue to invest in, but they're not 70,000-person clinical trials.

Yes. Yes, absolutely. You mentioned the cash runway into 2030. I guess maybe talk us through the bridge to EBITDA breakeven eventually, like what revenue scale would be required to kind of get you there?

So we haven't gotten that specific yet. We've got a lab that's capable to do more than 1 million tests. And with all those variables we talked about earlier is about how efficient that can be, how efficiently you can sell will drive whether you get there or not. I also think that what happens internationally because selling in the U.S. is a lot more expensive than selling internationally. If something were to happen with the NHS or any other single payer system, that's not a sales force. They send out text messages and people show up to the doctor.

And so our gross margins will be less because the test price will be less, but the cost to sell is close to 0. And so our operating margins will be pretty healthy. So I hate to not answer your question directly, but there's just -- I just know it all and be wrong. There's a lot of variables.

And I guess thinking about your revenue guide for the year, the 22% to 32% for Galleri. You grew 37% in 1Q. I guess how should we think about the cadence throughout the year and why the implied step down?

Yes. So we will be looking at guidance again. We'll see how this quarter goes. We asked the data going out sales force expansion and so on. We'll see how those things -- this transition period works. We were excited by the growth in Q1. Q2 volumes were already higher than Q1 from last year. So the growth is going to be a little bit different. But we still believe we're in that 20% to 30% range. But we, of course, will look at our guidance as we go through the quarter.

Okay. Great. And the upside/downside levers there, sales force I think are on the upside or the downside?

I mean, like any -- there is upside, if it all goes well, there's downside if it doesn't because there's disruption from your existing territories and so on and so on. How is that transitory? Is it permanent? Those are the types of things that you figure out.

Yes, yes. I guess you just have a couple of minutes left. So what do you feel is the most underappreciated part of the GRAIL story? What are you most looking forward to in the few years ahead?

Yes. I mean I think we spent a lot of time talking about NHS-Galleri, right, in clinical utility. Some of the big criticisms we get are, it's not ready for prime time. And I go, I don't know, we just kind of showed a pretty substantial Stage 4 shift in a 2-year period in an RCP. I think these other people have said, you could add up like the last 15 years of therapeutic innovation, and it's nowhere near that. This is ready now, and it's saving lives now. And we're very proud of the data we have. We've been very transparent with it. And we're excited to see where it goes. I think the biggest takeaway I have is the test is saving lives today and saving thousands of lives.

Great. All right. We'll leave it at that. Thank you so much, yes.

Thanks, Evie.

Good day, everyone. Welcome to the GRAIL ASCO 2026 Analyst Call. [Operator Instructions] At this time, I'd like to now turn the call over to Bob Ragusa, Chief Executive Officer. Please go ahead, sir.

Thank you for joining us this evening. We're excited to be hosting this call from the American Society of Clinical Oncology Annual Meeting, where we presented the results from 2 of our large interventional trials this weekend in scientific forums.

I'm joined on the call today by Dr. Josh Ofman, our President and CEO Elect; Harpal Kumar, our Chief Scientific Officer; Andy Partridge, our Chief Growth Officer; and 3 leading physicians in the MCED space. Dr. Mylynda Massart; Dr. Nima Nabavizadeh; and Dr. Eric Sue.

with that, I'll now pass it over to Josh.

Thank you, Bob. As many of you know, GRAIL was founded over a decade ago with the vision of reducing the burden of cancer through population scale, multi-cancer early detection screening. Now the goal of cancer screening is really to find cancer in individuals before the cancers have spread, when interventions are more effective and are potentially curative.

When we find cancers before they metastasize, outcomes are improved, treatments are less toxic, costs are lower and the entire experience for the patient, their families and their caregivers can be meaningfully improved. Now unfortunately, today, there's absolutely nothing acceptable about the status quo in cancer screening. Most cancers are simply not screened for at all. In the United States, we find about 14% of cancers with our current screening programs and 70% to 80% of all the cancer deaths are from cancers that we are not looking for at all. Finding more cancer earlier before metastatic spread can make a meaningful difference in cancer control, in patient outcomes and the public health. This is not the type of situation that warrants extreme conservatism. It warrants urgency, action and groundbreaking technology that can make a difference and they can be implemented safely. The results of our randomized controlled NHS-Galleri trial of 140,000 individuals were presented Saturday morning by Dr. Charles Swanton and the results of our 35,000 patient PATHFINDER 2 study were presented this morning by Dr. Karthik Giridhar. The results of these studies demonstrate the many clinically meaningful benefits that Galleri has to offer for population health. We now know that across these studies, Galleri has detected more than 150 distinct types of cancer. Much more than the 50 that we identified with our original study. This is truly remarkable. The NHS-Galleri study is the first time any MCED has demonstrated the ability to generate a stage shift and how cancers are detected. This is truly a historic moment. Additional data points from the study such as an increase in cancer detection rates and a decrease in emergency presentation adds substantially to our clinical utility evidence base. In fact, the NHS-Galleri randomized controlled trial in that study, Galleri found more early-stage cancers than all screen detected cancer found in the National Health Services screening program in the control group, groundbreaking indeed.

In addition, performance metrics such as PPV and safety in both studies continue to be strong and consistent across all populations and all of our other studies. We're extremely proud to share these data with you all. I believe that with the rapidly evolving treatment landscape, combined with the paradigm shift of MCEDs being added to standard of care screening, that we have the opportunity to actually eradicate the scourge and human toll of metastatic diagnoses in our lifetimes. And these data that you're going to hear about tonight are the most significant advancements toward that goal that we have ever seen.

I'll now pass it to Harpal to walk through the findings. Following the data presentation, Andy will lead a panel discussion with our physician experts. Over to you, Harpal.

Thank you, Josh. And first of all, a huge thank you to the patients, physicians and institutions that participated in these studies. It really is an incredibly exciting time, and there's a lot of data, so I'll get right to it. As Josh mentioned, we read out 2 large studies this weekend. The NHS-Galleri trial, the first and only randomized controlled study of an MCED test was designed to demonstrate population level impact through the reduction of late-stage cancer diagnosis and increased cancer detection within England's National Health Service.

The trial evaluated annual screening with the Galleri test in addition to standard of care screening over 3 years in more than 142,000 demographically representative participants aged 50 to 77% compared to standard of care screening alone. The PATHFINDER 2 study is the largest MCED interventional study in North America in an intended use population with no clinical sufficient of cancer.

This study evaluated performance of single MCED test in a population of approximately 35,000 individuals aged 50 and above. And these studies add further to the broad evidence we've generated for Galleri. Yesterday morning, the results of the NHS-Galleri trial were presented by Dr. Charlie Swanton. NHS-Galleri is the largest first and indeed only randomized controlled clinical utility trial of an MCED test to date. Approximately 142,000 individuals participated in the study. Consented participants aged 50 to 77 years with no cancer diagnosis or treatment in the last 3 years and no clinical suspicion of cancer gave a blood sample and will then randomized one-to-one into the intervention or controlled arm at their initial study visit. The MCED test was performed on samples from intervention arm participants and those with a positive MCED test were unblinded and referred to established NHS urgent referral for diagnostic testing. All subsequent workup and treatment occurred outside the trial. Participants received routine NHS care and no white [ glove ] attention. Cancer outcomes were passively collected using national registry data sets for all participants. Participants were invited to return for 2 more annual blood samples and both arms had high retention rates across the 3 screening rounds. The 2 arms were very well balanced and generally reflective of the U.K. demographics of the target age group. The trial enrolled from more deprived groups and those with lower education status which is typically underrepresented in research. Follow-up for the first 2 rounds were approximately 12 months each, a median follow-up for the third screening round was 17 months.

Given the urgent need for improved cancer detection, this screening trial was designed to rigorously assess the benefit of MCED testing in as short a time as possible. We agreed with NHS England on a pragmatic clinical utility endpoint of a reduction in the combined incidence rate of Stage III and IV cancers after 3 annual screening rounds with just 12 months of follow-up after the last blood draw.

The primary endpoint was assessed as an incidence ratio, which compares the frequency of cancer diagnosis between the intervention and control arms and account for different links of follow-up times. This was done in a prespecified set of 12 cancer types responsible for 2/3 of cancer deaths in the U.S. and U.K. and in all routinely stage cancers, including and excluding prostate cancer. The primary endpoint of a reduction in Stage III and IV cancers was not met. And we'll talk about what we see here -- what we saw here in just a minute. As we use Stage III and IV reduction will not be the only relevant measure of clinical utility, the study included several prespecified secondary end points such as the reduction in Stage IV cancer, increased Stage I and II diagnoses and MCED test performance. We saw a clinically significant reduction in Stage I cancers of more than 20% in the incident rounds, an increase of 16% in Stage I and II cancers detected and strong performance and safety metrics for Galleri. We also evaluated the overall number of cancers detected as compared with the controlled arm and the impact on incidence of clinically diagnosed cancers and emergency presenting cancers.

With the addition of MCED testing to standard of care screening, we observed a fourfold increase in screen detective cancers and a substantial decrease in cancers detected through emergency presentation. The totality of this data provides very strong evidence that adding Galleri to standard of care screening can identify more cancers through screening and enables a state shift at a population level.

Now we shared back in February that the primary endpoint was not met. If a screening program works, what you would expect to see is a large increase in late-stage cancers detected in the first screening round as you sweep up those late-stage cancers that are already prevalent but undiagnosed in the population. In subsequent rounds, you would then expect to see a reduction in late-stage cancers as the effect of the screening intervention becomes apparent. And this is exactly what we saw. When we look in the further detail of the data by screening round, we can see that there was a very large increase in cancer detected in the first or prevalent screening round. And as I'll show you in a minute, these are predominantly Stage III cancers. Overall, there was a 19% increase in Stage III and IV cancers during that prevalent round. There was a trend towards fewer Stage III and IV cancers in the incident screening rounds, growing to 12% in the third round, but cumulatively not quite enough to overcome the large prevalent round effect. The confidence intervals are broad here and not great enough, as I say, to overcome the large increase in Stage III and IV cancers observed in the prevalent screening round. It's important to note though that the incident rounds that is excluding the prevalent round, most closely resemble what we might expect in the steady-state screening program. When we separate the stages we see a substantial decrease in stage IV cancers, but this was outweighed by an overall increase in the number of Stage III cancers, particularly in the prevalent screening round. We believe the Stage 3 increase was driven in part by a number of Stage IV cancers being shifted to earlier stages, including at Stage III and the fact that many more cancers overall were found earlier through screening in the intervention arm, while the equivalent cancers may not yet have been diagnosed in the controlled arm. And we would expect more of these cancers, what do we expect to see more of these as yet undiagnosed late-stage cancers being found in the controlled arm with longer follow-up. In addition, the trial has revealed just how much undiagnosed and uninvestigated Stage III cancer is already prevalent in the population before any screening commences. Finding these cancers earlier means we can start treating those patients with the agency needing and in many cases, with the opportunity of curative intent. If we break down the 14% reduction in Stage IV diagnosis by screening rounds, we see that the reduction in Stage IV increases with each screening round. As I touched on earlier, the prevalent round detects undiagnosed cancers already present in the population at the time of initial screening while subsequent incident rounds detect cancers that develop or progress between screening rounds and become detectable. Thus, as I mentioned earlier, the incident rounds most closely approximate the likely steady-state impact of an annual screening program.

Overall, in this prespecified secondary endpoint, a 14% reduction in Stage IV cancers was observed. These results were nominally statistically significant. In the incident rounds, there is a significant reduction of more than 22% in the second round, reaching nearly 27% in the third. Importantly, while this slide shows the results for the 12 prespecified cancers, we saw reductions of greater than 20% in the incident rounds for all cancers, which is a remarkable decrease at a population level. The reduction in Stage IV cancers is clinically meaningful. While it varies by cancer, for most of the 12 prespecified deadly cancers evaluated, a diagnosis at Stage III improved survival rates dramatically compared to a diagnosis of Stage IV. You can see here that survival rates for Stage III and IV alongside the reductions that were found in the study for each of these cancer types. For example, for colorectal cancers, where we saw a 34% reduction in Stage IV, 5-year survival is 64% at Stage III compared with around 11% at Stage IV. And not shown on this chart, in prostate cancer, we saw a 25% reduction in stage IV diagnoses, where 5-year survival is 97% at Stage III but only 53% at Stage IV. Along with the decrease in Stage IV cancer incidents, we also observed a 16% increase in stage I and II cancers for the 12 prespecified cancer types after 3 screening rounds in the intervention versus the controlled arm.

And as you can see, overall, there were about 90 more cancers diagnosed at Stage I or II. A large part of this increase was in colorectal cancer with the rest split between upper GI, ovary and heme cancers with large increases in individual cancer types typically diagnosed very late such as ovarian, esophageal, pancreatic and liver cancers.

Shifting to test performance, another secondary endpoint, the aggregate performance metrics were robust. Over 3 screening rounds, 1,801 participants or 0.91% had a positive MCED test results and 937 of those were diagnosed with cancer for a positive predictive value or PPV of 52%. The high specificity of 99.55% means a false positive rate of just 0.45%. The negative predictive value was almost 99%. Episode sensitivity overall was around 30% and around 55% in the 12 prespecified cancers. Cancer signal detection accuracy was greater than 90%.

The safety profile is also strong, focusing first on false positives across 3 screening rounds in the 70,000 participant intervention arm, there were 864 false positives. This means there was a positive Galleri test but the subsequent workup in the system did not find the cancer. Now 303 of these false positive tests were in the first screening round on which we have 2 years of follow-up. In 54 of these cases, the participant was ultimately diagnosed with the cancer during the course of the study. In cases where the test was called a false positive, and the participant was later diagnosed with cancer, the CSO prediction was correct, more than 80% of the time. There were a very small number of phlebotomy related adverse events and no related serious adverse events were reported. We have always stated that for MCEDs, it's the cancer detection yields that best reflects the overall sensitivity of the MCED in totality as opposed to cancer-by-cancer sensitivities.

The Galleri MCED has the unique feature of a single specificity that we optimize for, unlike single cancer screening tests that optimize sensitivity. So in terms of overall cancer detection yield, the addition of MCED screening to existing NHS screening programs led to an approximate fourfold increase in screen-detected cancers. Many of these cancers were detected in Stage I or Stage II. In fact, more Stage I and II cancers were detected by Galleri than all cancers at whatever stage detected by all standard of care screening in the controlled arm. This large increase in screen detected cancers meant an overall 21% reduction in cancers that they needed to be detected through clinical presentation.

And further, the addition of MCED screening decreased the number of cancers detected through emergency presentations by more than 25%. And as you may know, cancers detected in the emergency room represents some of the poorest outcomes and most costly cases. Of the 937 cancers detected by Galleri, roughly 70% were in stages I to III and roughly 40% in stages I to II and roughly 20% at Stage I. Roughly 60% of the cancers detected have no current screening paradigm, which increases to more than 70% when we consider that lung screening was only just being introduced at that time. And in fact, most lung cancer cases are in individuals who are not actually eligible for lung cancer screening. Now the ends get smaller for less prevalent cancers but you can see the breakdown of cancers by stage here. And these findings demonstrate the opportunity for a transformational shift in cancer detection. Moving us to a more comprehensive, proactive approach. Multi-cancer early detection provides an opportunity to reshape screening and detect more cancers when there's an opportunity for cure.

Now I'll spend just another minute or 2 on the data that was presented this morning on our PATHFINDER 2 study. We presented data on the first 25,000 patients from this study at ESMO in October last year. And this morning presented the data from the full, nearly 36,000 participant study. In this study, participants with the positive results underwent targeted diagnostic evaluation guided by the predicted CSO. If no cancer was diagnosed during the targeted evaluation, participants received a protocol-dictated diagnostic PET-CT. The study's primary objectives were to evaluate safety and performance of the MCED test in an intended use population.

Participant population was representative across age, sex, race and ethnicity, which is important as we sought to assess performance of the MCED test in the intended use population. The full results of the study show the positive predictive value of the MCED test was 60.3%. Specificity was 99.6%, an and CSO detection accuracy was greater than 90%. And the high CSO accuracy facilitated efficient targeted evaluation. Episode sensitivity for cancers diagnosed in the 12 months following the MCED test was robust, especially in prespecified clinically relevant cancer subgroups where we saw sensitivity of up to 70%. More than half of the new cancers detected by Galleri was Stage I or II and more than 70% of these have no USPSTF A or B recommended screening. Approximately 70% of the new cancers detected by Galleri were detected at stages I to III when treatment with curative intent is more often possible. Overall, 6.5x as many cancers were detected through screening when MCED was used in addition to USPSTF grade A and B screening recommendations and 3x as many when used in addition to B and C screening recommendations. Galleri demonstrated a favorable safety profile. Screening with a Galleri test at a very low false positive rate and a low rate of invasive procedures. 85% of diagnostic procedures were noninvasive. There were 5 study-related adverse events reported during diagnostic evaluation and only in those with cancer diagnosis. Anxiety temporarily increased for participants with a positive MCED test and subsequent cancer diagnosis and returned to baseline by 12 months as has been observed for other screening tests. At the time of the analysis, 5 study related AEs were reported during diagnostic evaluation. And as I said, only occurred in those with the cancer diagnosis and none are serious. In these data sets this weekend, we saw clear evidence of strong performance for Galleri. Across the 2 studies, which included almost 180,000 participants together, we see consistent evidence that Galleri is able to detect cancers that standard of care is not finding today. This is the first demonstration of clinical utility via stage shift for an MCED test. In a randomized study, we demonstrated a greater than 20% reduction in Stage IV cancers, a double-digit increase in Stage I and II cancers and a 25% reduction in cancers diagnosed after emergency presentation.

In the 2 studies presented this weekend, we saw that adding Galleri to standard of care, increase the number of cancers detected by screening by between 4x nd 6.5x. Today, the standard of care finds only about 6% of cancers in the U.K. and around 14% of cancers in the U.S. Adding Galleri to the standard screening programs could increase this figure to greater than 50% in the U.S. This is a substantial improvement on current practice and enables detection of cancers that don't have screening options today. The consistent performance that we see between studies enables confident real-world use of Galleri. Multiple studies have now demonstrated a very low false positive rate and a high PPV in intended use populations. And the high accuracy of Galleri's cancer signal origin results enable efficient patient-centered care. The Galleri multi-cancer early detection or MCED test, which identifies a shared cancer signal has detected over 150 distinct types of cancer including many deadly cancers that currently lack screening options such as pancreatic, ovarian, liver and bile duct cancers. The Galleri test is the only MCED test clinically proven through a randomized controlled trial to increase early cancer detection and reduce Stage IV diagnoses, enabling more patients to have curative treatment. The totality of this data adds to the growing body of clinical evidence for Galleri. We are really excited about this data and the impact it shows that we can have on cancer care. With the addition of a simple blood test to standard of care screening, we now have the opportunity to reduce metastatic cancer diagnosis, enabling many more patients to have the opportunity of treatment with curative intent as well as the associated reduced financial burden, reduced toxicity and reduced emotional burden on patients and their families.

I'll now pass it to Andy to introduce our physician participants to discuss this data.

Thank you, Harpal. I'm joined this evening as Bob outlined by 3 physicians, Dr. Mylynda Massart; Dr. Eric Sue; and Dr. Nima Nabavizadeh. I'm going to invite each of them to briefly introduce themselves and describe their medical practice.

Thank you. Good evening. I am Dr. Mylynda Massart, and I'm an associate professor at the University of Pittsburgh and Family Medicine position at UPMC. And I run a primary care precision medicine clinic where I have introduced multi-cancer early detection screening since it was released out to the market. And I would like to pass it off to my colleague.

Thank you. Thanks, Mylynda. Nima Nabavizadeh here. I'm a radiation oncologist at the Oregon Health & Science University in Portland, Oregon, and I also lead our early detection and clinical research team. Early Detection has been a priority for our cancer institute for quite some time, and we have been, I would say, super enrollers on the prospective studies from GRAIL PATHFINDER, PATHFINDER 2, as well as the REACH study. Furthermore, early detection is certainly important, but it's also important professionally as a radiation oncologist, in that we have nonsurgical curative treatment options available for patients with early-stage cancers.

So certainly, early detection is near and dear to what I do and the patients that I see.

I'm Eric Sue, I'm an internal medicine physician in private practice in Los Angeles. I have now done 1,277 Galleri screens in 3.5 years and have had 6 true positive Galleri tests. I think it's incredible stuff. I think it's only going to get better.

So maybe Eric, we'll start with you. You're actually presenting actually on Monday, your experience with the Galleri test in your practice here at ASCO. How long have you been offering Galleri to your patients? And who do you recommend it for?

Sorry, I only learned of Galleri cancer screening in September 2022. I only learned a bit because one of my patients asked me about it. I've never heard of it before. We reached out to GRIAL and asked them to present the information to us. And when you hear all of the information that you've heard today, it sounds really incredible. I have to be honest, my first question was, is this going to be the next Theranos where it's a lot of smoke, but is the technology actually there? But here I am 1,277 Galleri screenings later with 62 positives, I do think we're there. And it's something that I like to talk to essentially all of my patients about it that I think everyone deserves to know that something like this is available.

If I'm having a conversation with a young and healthy patient who may not need Galleri cancer screening, but maybe perhaps they would want their parents to consider something like this. So it's really a daily conversation that something like this is available. It's a blood test. They can screen for over 50 different kinds of cancer. It's being described as a liquid biopsy as a [ snapshot ] in time where if it's negative, you've got a 99% certainty of having any of those 50 different kinds of cancer at that moment in time, which can be some piece of mind. It is technically recommended for anyone over the age of 50 because that's when everyone's risk of cancer increases. But particularly if you have an known family history of some kinds of cancer and you consider doing it on an annual basis not as a replacement for any current cancer screening guidelines like, annual [indiscernible] females, starting at age 40 or periodic colonoscopy starting at age 45, but it's meant to be as an adjunct to try to give ourselves the best chance to identifying any 1 of these cancers most of which we don't have any way to screen for. And if the overall risk of false positive is 0.5%, which is unheard of in the cancer-screening world. If you did get a positive Galleri test, we now get the positive predictive value and actually meaning you've cancer with 60%. So I tell patients that a positive doesn't mean you have cancer but it certainly raises the question and that a positive test tells you what kind of cancer with now 91% accuracy, and it tells you what to look. If you take that look and you don't find anything, maybe it was a false positive. And under that scenario, the plan is to repeat the Galleri screening 1 to 2 months later, which then the company pays for. If it's positive again, and you look for cancer again and perhaps identify something, and that first has to appears to have been a true positive or may have been at a preclinical stage with the conventional studies we have available to detect cancer, couldn't find anything or short term follow-up we were and potentially at a very early and very treatable stage, I tell patients I really believe that we may be on the frontier of what we're going to be able to achieve from an early cancer detection standpoint, fascinating stuff.

Thank you, Eric. I encourage anyone here at ASCO to go and talk to Eric at his poster on Monday. Mylynda, how have you been incorporating Galleri into your practice? And how did you first hear about it and decide to incorporate Galleri?

Yes. So I first heard about it actually when our Executive Health wanted to implement this testing for their patients. And because it's a new and emerging precision medicine technology, they were a little bit nervous and so they came to our precision medicine clinic to have additional backup and to have genetic counselors available and clinicians familiar with genomic technology and overall screening.

So we became very excited to be able to support that project and then also be able to start informing our own patients about the opportunity to have this added to their gold standard USPSTF cancer screening. In my precision medicine clinic, I do care for many high-risk patients, both not just by age over 50, but by those who we were positive for hereditary cancer risk variants, those who have had significant family history, but may not have a genetic risk that's been sound and other individuals with exposures or chronic illnesses that make them at higher risk for cancer. And so this has been a great adjunct that we have been able to educate our patients about. We normally tell them about the opportunity if there are new patients, and we're picking that family history for the first time and reviewing what type of screening they are current with. Sometimes we will bring it up if a patient comes in for an appointment and shares a new diagnosis in the family or just a concern in general about cancer. And then always with every annual wellness visit, where that's where primary care always is addressing any proactive health screening, including cancer screening at relevant ages.

Thanks so much Mylynda. Nima, as a principal investigator in the PATHFINDER study, you followed a large number of patients on Galleri. What have you learned through this process? And any specific patient examples come to mind?

Yes, absolutely. So yes, like I mentioned, we've been rolling on PATHFINDER, PATHFINDER 2 and the REACH study and have nearly worked up 100 patients with signal positive findings at OHSU. And given our clinical trial system, those are largely centralized within our clinical trial team. And we have plenty of examples here. I was invited just a couple of months ago at the American Association of Cancer Research to speak on this topic and I was invited by the BLOODPAC Consortium to speak on this topic. And the message that I was trying to relate to the PAC room was the strong value in the cancer signal origin result that comes from the signal positive finding. And I was leading to the investigators and the other test developers in the room to really work on this because my experience of working with the Galleri test and seeing the CSO finding is that it's incredibly helpful. I'm a radiation oncologist. I examined imaging all the time. I use it as part of my treatment plan and indeterminate findings are all over the place. And for a patient who has a signal positive finding, who has a potential and what radiologists may call an indeterminate finding, but then that matches the cancer signal origin, especially with a positive predictive value of 60%, it allows evidence for me to sit down with my specialist colleagues to potentially go the extra mile to try to really further adjudicate and identify what's going along with this indeterminate finding. And a good example here is a patient who had a signal positive for gastroesophageal cancer, and they had previously many years ago, had a gastric bypass surgery. And with the gastric bypass surgery, basically, it excludes the bottom portion of your stomach from your esophagus. So we provided the cancer signal origin specified workup, which is an upper endoscopy and the endoscopist is only able to access the first 1/3 of the stomach or so. It was normal. And before deeming this patient a false positive, we obtain a whole body imaging, whole body imaging with the PET-CT revealed some subtle lividity in the bypass portion of stomach that was inaccessible with routine outpatient endoscopy. And I think in the absence of the cancer signal origin finding, that subtle lividity would have been kind of put aside, going to extra distance to biopsy that area is a big deal. And I sat down with my gastroenterologists, we looked at the imaging. I explained the cancer signal origin and the PPV of the testThat portion of the stomach was able to be biopsy but had to be in the operating room under general anesthesia using this very long endoscope that goes into the small bowel and back into the bypass portion of the stomach. And it was a biopsy-proven gastric cancer, early-stage gastric cancer. And without that cancer signal origin, we would have completely overlooked it, and this patient would have presented with Stage IV cancer. Another example is a patient who had an anorectal signal and underlying signal positive work up and with that, you automatically go to endoscopy with the lower endoscopy and that patient came back positive for an early-stage anal cancer. And this is important because, certainly, this is a curative treatment option. And because it was found early stage in an asymptomatic, nonsymptomatic situation, this patient is able to receive less radiation, less chemotherapy, much less side effects with fantastic survival. And interestingly, when the colorectal surgeon, they refer the patient to who called me back with the result of the biopsy, you relayed the result. But then the second question was, how can I get this test? He is totally shocked by the sensitivity of this test to pick up that early-stage anal cancer.

Thanks, for sharing your experience with the CSOs. It's something we hear commonly from physicians, also from patients and of course, this is something that the FDA advisory panel on MCEDs was something that the FDA felt was an important component of any MCED.

Eric, I want to want you to think about the current status quo of screening in relation to what we saw both in NHS Galleri, where we saw 4x more cancers identified through screening in the intervention arm compared to the control arm and also what we saw in PATHFINDER 2. What is this impact to you as both the physician and to your patients when you think about the current status quo?

Sure. I mean when you understand the status quo with 5 current cancer screening guidelines, we're only able to capture 29% of the cancers that people are dying from, leaving 71% of the cancer that people are dying from that we had with no available cancer screening [indiscernible] for. And what really struck me about hearing all of this information that was presented this weekend.

When you look at PATHFINDER 1, which is GRAIL's initial real-world interventional trial in the midst of the pandemic and enrolled 6,600 patients. They saw a twofold increase in the cancers detected when compared to standard of care. And now we're hearing that with PATHFINDER 2, there is a threefold increase in overall cancers detected when compared to standard of care. And that with NHS Galleri, we've now seen a fourfold increase in cancer detected when compared to standard of care. We are literally witnessing the power and potential of MCED testing when performed at scale. And we now have evidence showing that annual Galleri cancer screening can reduce Stage IV cancers by year 2, by 22%. And by year 3, by 26%. And so by shifting cancers for away from metastatic presentation and closer to earlier-stage detection, we're creating so many more opportunities to intervene when curative treatment needs to be possible. And most importantly, where the opportunity to reduce cancer mortality is the greatest. And that's, I think, what's really stood out to me this weekend.

Mylynda, what were your reflections after seeing the presentations this weekend. What did you find most compelling about NHS-Galleri and some PATHFINDER 2 study results?

Yes. It was really reflecting all weekend after listening to each of the presentations. And last night, I was really thinking that -- as a scientist, I have reviewed this data over the last 4 years as it continues to emerge and evolve. And I have really seen the established scientific validity of this screening. And as a primary care provider, my heart has been very heavy for the patients that I have lost over the last 20 years of practice. And I now have hope for a different future. and a future where we can actually screen and catch more than just 5 cancers with an opportunity for treatment with curative intent, which is transformative in my life span. As a patient, I am convinced that I am here today because my melanoma was diagnosed at Stage I in 2018. And I myself have added this to my screening regimen every single year to ensure that I have the best opportunity to keep that going. And as a family member, I got to see my own step mom diagnosed with Stage IV glioblastoma in the emergency room after a sudden onset seizure while she was out for a walk after dinner one night with my brother. And he then dropped out of college and took care of her until her passing and never return back to university.

And so this -- all of this data and reflecting on all of these experiences from these different perspectives truly gives me hope that we will actually see a profound difference in the future for our ability to screen, detect, treat and support patients and their families from cancer.

Mylynda, thanks so much for sharing those personal experiences. That's what brought all GRAIL employees to GRAIL. And that's what keeps us focused on the mission that we have. Nima, you've heard Eric and Mylynda talk about the decrease in Stage IV. What are the benefits for your patients on shifting the diagnosis to earlier stages. When you think about this from a radiation oncologist perspective?

It gives them a shot for curative treatment and that's what people are seeing me in my clinic for. They understand that a lot of these cancers are really aggressive. And they're aware of that. They've been told that, all their research shows that. But what patients are looking fo is some hope and a shot to cure this cancer. And that's really what happens in the Stage III situation. I see patients in my clinic from the stage I situation to stage IV situation, and in the Stage IV setting, largely our discussions are in regards to what can we do to treat your cancer to help with symptoms or improve your quality of life. The conversation is not in the sense of what can we do to cure this cancer. But in the radiation oncology world, we're typically brought in and involved to treat these Stage III cancers. And over the last decade or so, there have been a multitude of advancements in the Stage III scenario, particularly with the progression in immunotherapy and the addition of that to standard of care, surgery and radiation has really moved the needle for what was previously thought to be really, really bad aggressive cancer. A great example of that being Stage III lung cancer. Furthermore, the treatment intensity and toxicity, as I mentioned with that anal cancer patient is far fewer and far less once you're able to bring the stage down from stage IV.

Eric, you talked a little bit about the positive predictive value of Galleri. How does that compare to other screening tests that you currently use? And how do you describe the benefits of a higher PPV with Galleri to your patients?

So when I was first introducing Galleri to patients, I was working with PATHFINDER 1 information. And at that time, the positive predictive value was 43.1%. Oftentimes, people would hear that and say, so if I do this test, I get a positive test, I have a less than 1 or 2 chance of actually having cancer. That's not great. But I really want to do this test and subject myself to that potential of going down that rabbit hole and not being found to have cancer. But then I mentioned, well, what's the positive predictive value of an abnormal mammogram and actually, meaning, someone has breast cancer, 4.4%. What's the positive predictive value of a positive Cologuard stool test, which is being used as potentially an alternative to colonoscopies and is fully covered by all insurance and Medicare and actually meaning someone has colon cancer, 3.7%. So 43.1% positive predictive value of a positive Galleri test and actually meaning someone has cancer is in order of magnitude better than what we're doing a standard of care. And now we're dealing with the totality of the PATHFINDER 2 trial data that, that positive predictive value is 60%. And with NHS in the prevalent screening round that the positive predictive value is 58%. So again, in order of magnitude, better than what we're doing as standard of care. Nothing like this around anywhere.

Thank you. Mylynda, I'll ask you the last question before we open it up to Q&A. In the U.S. and also in the U.K., a substantial proportion of patients are diagnosed with cancer in the emergency room. In the NHS-Galleri study, we observed a substantial reduction in ER diagnoses in the intervention arm with Galleri. Can you describe what it means to a patient and their family to be diagnosed with cancer in the ER?

Yes. I -- So not only did I share the story of my stepmother, but I am a hospice Medical Director and have been for 17 years. And seeing patients diagnosed with a very advanced cancer in the ER is incredibly dramatic to both the patients and to their family. They often have very poor outcomes and very little time to make decisions. And it's incredibly stressful to make those types of decisions in that environment.

In our country, we always think that we need to treat, treat, treat. And that is true, if someone has an earlier stage detection. But when it comes to presenting that symptomatic in the emergency room, most of the time, it's incredibly late stage and diffusely metastatic. And so they are not great options, and that's when I get called in to meet with those families. And I think it's devastating. So I think more than anything, what I've heard from patients over the years is hope is critical. And so not only does early detection prevent those types of traumatic events, but it allows us to finally detect cancer with intent to treat successfully, and that is what hope is all about, and that's really a gift.

Mylynda, Nima and Eric, thanks for sharing your perspectives and really bringing to life what Galleri means in your medical practices and what it means to your patients and brought to life what these NHS-Galleri and PATHFINDER 2 results mean when we actually implement the Galleri tests within medical practices.

I'm now going to open it up to questions on the line. So over to you, moderator, please.

[Operator Instructions] Our first question comes from Subbu Nambi with Guggenheim.

Harpal and Josh, I want to give you an opportunity to address the points brought by discussions yesterday regarding 2 points. One, catching the Stage IV may not improve outcomes; and two, detecting cancer in stage I and II that are already screened by standard of care and that catching rare cancers may not be cost-effective. What would be your discussing -- discussion points?

Subu. This is Josh. Let me take the first -- the second one first about cost effectiveness. So again, most of what Galleri finds are cancers that are not detected by current screening. In fact, almost 3/4 of the cancers we find are cancers other than what is found by mammography or colonoscopy or low-dose CT or PSA testing. So that's really not an issue. As it relates to cost effectiveness, we've already demonstrated and published numerous cost effectiveness analyses that shows that given our current set of assumptions, Galleri is a highly cost-effective intervention. Those are being rerun now with the latest data, and we're highly confident that they will remain a very cost-effective intervention. Good value for money and as cost effective as any of the single cancer screening tests.

In terms of your first question, again, this is a very common thought that it just may not be important to find cancers in their earlier stages. That's very curious to me to hear people say that. Clinical practice other than for prostate and thyroid cancer, which are very slow growing, is to aggressively treat all early cancers. That's what happens when they are found incidentally. That's what happens when they are found through symptoms. That is what happens when they were found through MCED screening. So it's curious to hear oncologists say things like we just don't know if it's a benefit to find cancer early. To me, that raises very fundamental questions about whether it would be ethical to not treat patients with early cancer, I don't believe it is. And so I think we have to just look at how clinical practice is delivered today. When we find cancers early, they can be offered with treatment options that very frequently in Stage I through III provide the opportunity for curative intent.

Yes, I will just add 1 point, which is I think we need to look at the data. The data says it all. I gave the example, and I'll quote it again, a Stage IV colorectal cancer has a 5-year survival rate of 11%. And the Stage III colorectal cancer has a 5-year survival of 64%. I challenge anyone to say that's not meaningful. I just don't -- I fundamentally don't accept the premise that finding that cancer at Stage III rather than Stage IV is not beneficial for the patient.

No, I hear you, but then when you cite CRC, people argue that there are better sensitivity tests already out there. So why do we need this multi-center test -- another multi-cancer test altogether adding to the cost?

Well, I think the fundamental point is because of the situation that we have today, which is that we're only finding 14% of cancers through all of our existing screening programs in the U.S. That leaves the other 86% that are not currently being found through screening. What the PATHFINDER 2 study showed was that we have the opportunity to find 60% of cancer through screening. So it's extraordinarily additive. We've been very clear from the beginning that this should be complementary to existing single cancer screening, not a replacement for those. But the complementarity is, I think, very strongly demonstrated when we can go from 14% of cancers detected through screening to 60% of cancer detected through screening.

And Subu, just last point is that while we're not suggesting colorectal cancer was used by Harpal as an example of the benefits of finding cancers in earlier stages than in their metastatic state. The survival cliff across most solid tumors is now between Stage III and Stage IV. 10 to 15 years ago, it was between Stage II and Stage III. That has dramatically changed due to the treatment landscape evolution. I would also challenge any of the academics who like to say things like we're just not sure we should be treating early cancers, to ask any patient who's diagnosed with an early cancer if they would like to forgo treatment. They're unlikely to find any patient who would agree with that.

Josh and Harpal, I just want you to hear your thoughts on this. Recognizing that reimbursement is predicated on FDA approval, do you come out of the ASCO better or worse with regards to FDA and by extension CMS?

Well, it's a really provocative question. I don't know the answer to that question. I think that we feel that the evidence space has been quite solidified by the database -- data that's been presented at this meeting. Again, the FDA will be looking at our package that we submitted to them, which includes the first year of the NHS-Galleri trial and all of PATHFINDER 2. They're going to be focused on clinical validation and clinical performance. And we don't believe that they're going to be particularly focused on clinical utility and stage shift. We do think that CMS and payers will be quite interested in stage shift and I think you've already heard from Harpal, how compelling do you think these data are.

Our next question will come from Dan Brennan with TD Cowen.

Great. Maybe just following up on one Subbu's question. There's a lot of discussion about where the benefit to Galleri is, obviously, unscreened cancers screens out, although the data looks encouraging in particularly CRC and lung. But I'm just wondering from the NHS-Galleri data, how would you rank order the unscreened cancers where you think Galleri shows the biggest benefit? I know you've got slides selling Stage I and Stage II shift and Stage IV shift as well by cancer types, I'm interested in that. And then as a follow-up to that, if in fact, the FDA were not to approve Galleri label with lung or CRC, how would that impact the value of Galleri from a clinical utility and health economic basis?

Maybe I'll take the second question and then give it over to Harpal. On the second one, we have been fairly reassured as best we can that irrespective of what the label looks like, we're going to be able to return every result that we find to -- back to the doctors and their patients. We will continue to find interval colon cancer, interval lung cancer, interval breast cancer, you see that throughout our studies. So we don't think the labeling, whatever it may end up looking like is going to particularly impact the overall value proposition because we will be able to return all those results. And as we've stated, we found over 150 different types of unique cancers already through these [ VOWST ] studies. And I'll turn it over to Harpal to get through the first question.

Dan, thank you. It's an extraordinarily hard question to answer when you ask me to rank order where I see the benefit. Because actually, the reality is we're looking at so many different types of cancer, which have very different levels of aggressiveness, of prognosis, of incidents in the population. And so to say that an ovarian cancer is more important than a colorectal cancer, it's more important than an anal cancer is something I struggle with. We want to show benefit across as many patients as possible. I think we've demonstrated that this multi-cancer test really is that, it's multi-cancer. And to the point about is it really useful to detect additional colorectal or lung cancers when we already have screening programs. I would make a couple of points, which is those screening programs miss the majority of those cancers. And so colorectal screening in the U.S., fantastically effective though it is find about 25% of colorectal cancers. There's another 75% that it's not finding. Lung screening is not available to the majority of people who end up with a lung cancer diagnosis. So there is huge complementarity here. And even in breast cancer, we're finding interval cancers between screening rounds, the mammography program misses. So I just -- I hesitate with the notion of rank ordering. I think there's benefit really across the board here.

Yes, if I can add 1 comment. This is Nima. In the state of Oregon, only 10% and we've looked at this at the Oregon Health and Science University, only 10% of people that are at high risk and eligible for a low-dose CT screening are actually getting it within the state. And there's a multitude of factors there in regards to access and stigma, Oregon's a very rural state. You've to be close to a CT scanner to get these exams. And furthermore, even for more common screening practices like mammograms, I mean, very recently, we had a signal positive breast cancer in a patient who skipped out on early mammograms because they were worried about the radiation exposure from the mammogram. And the Galleri test here identified the early-stage breast cancer in this patient. So I commend GRAIL in providing these results irregardless of the cancer signal and irregardless of the other screening techniques that are available for these patients because not everybody is getting them.

Great. And then maybe just on the data, just as a follow-up on the 2 parter. You mentioned that you think there's going to be a lot of late-stage cancers that are going to show up in the control arm just given the dynamics of what you saw. So I'm just wondering kind of how we might see that come out over what time frame? Like when will that get reported? Will it get reported? And then b, the study was run at 3 years. And feedback from experts reflected like a screening study like this probably needed to be run a lot longer in order to catch the full extent of it. So the performance of the assay was improving at year 2, it's improving at year 3. Is there any way to think about like at what point it would [ asymptote ]. I don't know if that will be something you guys can do. Obviously, the study stopped, right? So this -- it would be all modeled out. But I'm just wondering kind of the trajectory that you saw at year 3, kind of what would that imply like if we play it out further?

Yes. So let me -- so on your first question, which is a further follow-up, I think we've said a couple of times now that we want to continue to follow up the NHS-Galleri population for at least another 12 months. We are hopefully close to getting that agreed with the NHS. Assuming we do, then that data should be available, analyzed by, I would hope, Q1, Q2 next year. And in terms of where and when we will present it, that's still to be determined. But that's roughly speaking, the time line that we would expect to have that information on.

Your second question, which is we did all this very quickly. Yes, we did. And as you rightly point out, most screening studies historically have followed up for a lot longer before they report any results. Indeed, most screening studies historically didn't even prespecify endpoints. They waited until they had an endpoint before they reported one. We chose not to do that because, frankly, it's not a very good scientific way to do this kind of work, and we want to do things properly. And actually, the more important point is that we wanted to get to results quickly because thousands of people are dying from cancer every day. And I pushed my team, we as a company have pushed to get to results as quickly as possible so we can help the clinical community start saving lives.

[Operator Instructions] Your next question comes from Kyle Mikson of Canaccord.

Mulitpart question on NHS trial. It does seem logical that there would have been a bolus of cancer that happened in the prevalent round with I guess, Stage III being funded by far. If you foresaw or expected this, I think Harpal, you mentioned that, did you try to deprioritize or remove the prevalent round from the primary endpoint during those initial kind of trial design discussions? I know it's a tough question, but just more context would be interesting.

And then secondly, given this round was the most problematic, but it's the only NHS trial fees provided to the FDA. Can you try to provide supplemental data from the instant rounds to the FDA? Even they focus on safety and performance, they might kind of have to look a little bit quickly [indiscernible] possibly for this.

Yes, interesting question. I mean, the challenge with it is once you prespecify a primary endpoint, it's really not appropriate to change it when you see the data. And so I understand the question. I understand where it comes from, but it just wouldn't scientifically have been the right thing to do, and we would have been criticized very heavily for doing so. What we've tried to do is to present the results transparently, completely openly, recognizing that, that meant that the primary endpoint wasn't met but I think the fact that we're able to show the data in the granular way that we've done so and showing the difference that the incident rounds make, is really the important point here because people can then see it for themselves and make their own decisions. We think it's profoundly important we're seeing the substantial Stage IV reductions in the incident screening rounds.

And Kyle, maybe I'll add one thing. You heard Dr. Swanton say yesterday, that this study was designed almost 8 years ago with some assumptions about what we would see in the prevalent round based on the best available knowledge at that time, which was very little. And that -- those estimates were off, and there was just quite a lot more Stage IIIvcancer than was ever anticipated. And had that been anticipated, perhaps the study would have been designed to be to have longer new screening rounds or things like that, but nobody knew that. And so to Harpal's point, it would not have been appropriate to have changed anything based on what we had prespecified. And I think Swanton made that point quite clearly yesterday.

I think it is -- sorry, just to add one quick comment. It is just worth reiterating. One of the things that we've learned in this study is just how much undiagnosed late-stage cancer exists in the population. We had no idea that was the case because it's never been studied before. Now we know. And it will give us huge insights into how we think about both the prevalence of cancer but also what we might do about it going forward.

And Kyle, Harpal's point is whatever the primary endpoint was, it doesn't dictate what you actually observed in the trial. And to Harpal's point, what was observed in that trial is now being made clear to everybody. And that's what's really important, and we think will be the legacy of this trial and of this meeting.

This is Mylynda. I wanted to just add that as a primary care provider, I think it's really interesting that folks frame this as a failure. To me, I see from the scientific viewpoint that it just means that 3 years wasn't long enough. And so when I explain that to my patients, then I might say, we need to do annual screening for 4 years to actually feel confident as opposed to 3 years, which is not a reflection on the technology or a reflection on the ability to capture cancers earlier, but really a reflection on how we will eventually see population shift. And that is -- to me, that's a -- still a pretty valuable information that we've learned from the science. And even more excitingly, I get to counter that with even in that time frame, we may catch 4x more cancer and catch cancers that we've never been able to screen for before.

Our next question will come from Catherine Schulte of Baird.

If I just think about NHS-Galleri, you showed reduction in Stage IV, reduction in combined Stage III and IV by the third round of screening. An increase in early-stage diagnosis and increase in overall cancers detected. And yes, there are still some questions out there about clinical utility. Do you think at some point, you're just going to have to show mortality data. This is obviously a very high bar. But do you have any plans to evaluate that and maybe absent mortality data, just -- what do you think is the metric that should be viewed as the best measure of success for instant tests, given what you know today?

Well, it's a very thought provoking question, and I'll look to Harpal and our experts to comment as well. I'll tell you that I don't believe a true mortality study is going to ever be done for MCED. So I think while people like to talk about that, that has been the standard for single cancer screening. I don't believe that's an appropriate standard for a multi-cancer screening test. Underneath that request, the presupposition is that we don't know that it's a good thing to find early cancer, and I just completely disagree with that premise. We know quite a lot about finding early cancer. We've done it for all the cancers that we screened for. We know that it's done in clinical practice every day, and Harpal has already talked about the mortality differences between these different stages that we see at the population level. So I think that study is not going to get done. It's really important to remember that we have agreed to explore mortality in NHS-Galleri, but NHS-Galleri was neither designed or powered to show a mortality benefit. I'm going to let Harpal talk about how we're going to do that in a minute. But your bigger question is what is the right endpoint. I don't think there is a single right end point. This is about how do we best address the screening unmet need we have right now to find cancers in the population, to find more cancers in the population through screening and to find them at stages that are not metastatic where people have the opportunity for curative intent. My view is the most important thing we can do in MCED studies going forward is to show a reduction in metastatic disease. I believe that we are on the precipice of seeing an eradication of the diagnosis of these dread full cancers when they're already metastasized in our lifetime. And these data that Harpal has just presented to you are the best data available to give the hope that, that is actually going to happen. So I don't think there's any one magic bullet here. I think it's going to be a lot about all the endpoints that Harpal has been describing, but the most important of which will be a pure reduction in the diagnosis of metastatic disease. Harpal?

I'm going to agree and disagree with what Josh just said. Just for some entertainment value. First of all, I fully agree. You have to look at the totality of the evidence. There isn't one single way of determining the utility of a multi-cancer screening test. I'm not really going to disagree. But what I would say is if I were forced to pick one, I would say the most important thing is to be able to find cancers at a time when we have treatment options available that might be curative. At the end of the day, that is what matters. We want to be able to do something about these cancers. And if we can find them at a stage when the answer to that is yes, that is what's meaningful to patients. It's what is meaningful for health systems and it's what's important to populations. So finding cancers before we run out of treatment options or even better, finding cancers at a stage where we can develop better treatment options for the future. That's what I'm focused on. Having said all of that, yes, as Josh alluded to, we are going to look at different ways of exploring mortality from NHS-Galleri. Some of that will simply be passive follow-up of the individuals, where we'll compare the number of people who had died in the 2 arms at time points into the future. As Josh importantly pointed out, that's not powered, but we will look at it and we'll report it. There is another analysis we'll be doing, which I'm not going to describe in detail here, but it's what's called a nested mortality analysis, which we would hope to have some time in the 2028 time frame and we'll report on that when we have it.

Mylynda again, I just wanted to I also just to this from the primary care perspective, the utility also has to be about feasibility of acceptability, right? So if we continue to think that we need to expand cancer screening and include cancers beyond our current 5 that we're able to screen for, it's not feasible to do that on a single organ basis. As a primary care provider, you would spend all of your time then trying to track down and get patients to achieve their cancer screening. And it wouldn't be acceptable to the patients either. It also would have a dramatic increase in the rate of false positives, which would lead to also some significant consequences. And so I think we also have to think about the utility in these terms as well.

It's a great point. Maybe one way of reframing that is what is the alternative to using an MCED for population screening. It would be to continue to develop more single cancer screening tests and as all of you have heard us say before, those false positive rates accumulate in individuals. So a 50-year-old female who's getting a mammography, a colon cancer screening test, a cervical screening test and let's say they're a smoker and they get low-dose, CT the lungs, that individual female would have a false positive rate in excess of 40%. No one would ever recommend a test like that to a woman nor would anybody ever approve a test like that. Now imagine a world with 5 more single cancer screening tests. It is untenable, not feasible and there would be major safety concerns associated with that. So in our view, there is no alternative to really screening for multiple cancers beyond the 5 that we have now without an MCED test.

Our next question will come from Puneet Souda with Leerink Partners.

Congrats on completing presenting the largest trial in early detection. This is a multiparter question. It's rather simple. The first part is really simple. Look, but it's an important one in terms of clinical adoption, so asking both management and physicians on the panel. What do you think the reaction and prescription behavior of an average primary care physician in the U.S. like was on February 19, when the headline for primary endpoint not meeting came about versus the detailed data cuts that you're providing today? Would this additional data details change that prescription beaver versus February? And do you think you have to ask FDA on changing the marketing materials since you're already engaged with them?

And lastly, for Harpal and just maybe for Josh, you've learned a lot through this trial, what would you different -- do differently if you had to redo this trial again?

Thanks for your question. So I'll take the first one. So as I outlined on our last earnings call, we are certainly hearing from physicians, they're getting a lot of questions from patients following not just our press release, but some of the negative headlines that appeared in some of the media. We haven't been able to address those questions that physicians have had in a really meaningful way. I'm personally excited that we're going to be training all of our teams, both our medical teams and our sales teams on the detailed data that we presented here at ASCO on PATHFINDER 2 and NHS-Galleri because going forward, we're going to be able to answer those questions. And as you've seen, the data are simply remarkable and we believe they're going to be transformative. So I think they're going to have a positive impact on prescribing going forward. But I really shouldn't be the one speculating on that. We have 3 physicians on our panel now. So I'm going to ask them what has been their experience with their patients following the press release and negative media coverage. And what do each of you think is going to happen going forward now. Eric?

Sure. So I got plenty of e-mails and phone calls following the headlines 3 months ago, cancer screening fails major trial. And I thought they were really unfortunate headlines because I think what they threaten to do is render the entirety of this massive landmark never before tried trial, that's completely meaningless to render everything else GRAIL has done in the last 5 years, that's completely meaningless. And what I tell patients and colleagues is that what the NHS trial has shown and I can tell them even more based on this weekend. It's a greater than 20% reduction in Stage IV diagnosis by years 2 and years 3, I saw a fourfold increase in overall cancer detection rate when compared to standard of care and a substantial increase in Stage I and II cancers at 16%, when those cancers would have otherwise gone undiagnosed. None of these are trivial things. These are all things we should want in a cancer screening tool. And I would say that for physicians who are already ordering Galleri, I think that this data is going to stop them and prevent them from ordering it more. I think that there are plenty of questions about other competitors in the space who are oftentimes marketing to physicians and consumers alike, when the other competitors, I don't think have any real-world interventional prospective trials that prove what they are showing in the case control trial data actually works in the real world intended patient use population. And that's everything that GRAIL has done in the last 5 years. So I remain hugely optimistic about the potential of multi-cancer early detection, and GRIAL just submitting a premarket approval advocation on the FDA on January 29, soon thereafter, being the President signing into law of Medicare Multi-Cancer Early Detection and Screening Coverage Act, establishing a pathway for Medicare reimbursement if and when multi-cancer early detection testing becomes FDA approved. So we're heading in a direction where this maybe come recognized as a valuable tool, when we understand again that the status quo is far from perfect and potentially covered by Medicare, after which product insurance companies might follow along as they ordinarily do. And this may become much more widely available to everyone that we believe deserve access to something like this.

I guess all that, I mean, I think for anybody to look at this trial and say that it was a flop is completely disingenuous and they're not paying attention and they're reading a single sentence from the primary endpoint. In my practice work, having worked with the technology, I know it's been working. I know it picked up early-stage cancers that patients would have otherwise known about, and the richness and the granularity of the data in regards to the incidents and prevalence rounds of the screening are quite remarkable and just so excited to see another year or 2 or a follow-up and that's because really, the data is actually incredibly encouraging.

And I think the challenge for GRIAL is how to disseminate this information to the lay press in a lay way and who could do that with because a trial failed is probably more clickbait than a trial failed, but there's actually some really encouraging signals that we need to wait for and look at that I think is more challenging. So...

So yes. I completely agree with my colleagues. And I think all that I would add is it's the wrong headline. It's just absolutely the wrong headline, and it doesn't do service to our patients and our communities and our populations to not focus instead on all of the incredible science and things that were learned from this trial and the opportunity to touch 4x as many cancers as we've been taking with standard of care thus far.

And then finally, on the question about the FDA. Right now, we're not thinking about changing any of our materials prior to the FDA approval. Obviously, when the FDA does improve Galleri, which we obviously hope it will, we will have to relook at what the label is and what our marketing materials are, but we wouldn't do anything like that until at that time.

And then Harpal, I'll ask you the final question he asked about what have we learned? And is there anything we would have done differently?

Well, we've learned a huge amount, and we're continuing to learn, and we will continue to learn because this is an enormous data set. We definitely learned some things. We've learned that. As I touched on earlier, there's a huge amount of undiagnosed relatively late-stage cancer in the population. That's quite a sobering insight actually that we've discovered from this trial. And now that we know that now that everyone knows that. I think that will have implications for if there are future trials, how they should be thought about. I'm not going to say we should have done the design in a different way that it wouldn't be appropriate to do that with the benefit of hindsight. But I would -- what I would say is a trial has to be designed in the context of what you know today. And what we know today is that the treatment landscape is very different now from what it was 10 years ago. We can treat many, many Stage III cancers now, which wasn't possible 10 years ago. And the fact that we can do that means that actually finding cancers before they reach Stage IV is a really fantastic opportunity for transforming cancer outcomes.

And that is the primary endpoint for the Medicare REACH study, which was designed just a few years ago. It's much more of a focus on remediating Stage IV disease and finding cancer before it's metastasized. So hopefully, that answers all your questions.

Our next question will come from Kallum Titchmarsh from Morgan Stanley.

Just given what's been covered already, it's a bit more holistic and longer-term one, it's clear that there are some cancers where not enough ctDNA is being shared at an optimal point in time for Galleri detection. But do you think there's something you could do technologically to drive better early detection, some point down the line in those cancers, you're perhaps missing on these trials. And maybe just talk us through the direction of R&D from this point onwards.

That's a terrific question. I think I can say a few thoughts on things about that, and then ask Harpal as well. I think, obviously, our R&D efforts are squarely focused on how do we continue to improve the performance of Galleri on many dimensions. One thing that's very careful that we have to navigate is that what we don't want to do is get into the area of overdiagnosis where we're finding cancers that are shedding very little bits of DNA and we're diagnosing those. That is one of the biggest concerns right now about the safety of cancer screening is that we are over diagnosing indolent disease. And we've published now twice from the CCGA study that those cancers with indolent disease that we do not detect have remarkable survival at every stage, much greater than would be predicted based on the SEER data and that the cancers that we do find that are shedding measurable amounts of DNA are the ones that need treatment and that need to be acted upon and so we know that. So while we want to continue to improve our limits of detection. We want to continue to improve our sensitivity. And we have several programs designed to do that. We need to be very careful not to get into this area of overdiagnosis because that is a real safety concern. Harpal?

Yes. I'll be brief, but I think I'll make a few quick points. The first, just to reiterate what Josh has just said, which is, we could just change our specificity, and we could find a lot more cancer today, but we would be doing that at the expense of having many, many more false positives. And so there's 2 balances to be struck. One is avoiding substantially more false positives because we don't think that's a good thing either for individuals or for health systems; and two, avoiding other diagnosis. So that's the first point I'd make. Second point I'd make is that, as Josh just touched on, we do nevertheless have a number of research programs underway where we will be looking at improving sensitivity in those cancers, we do want to detect. And it is interesting, when we look at the detail that most of the ones we're missing are ones where we do have current screening programs or where they are already being found at Stage I. And so the opportunity to find the many earlier in Stage I doesn't actually exist. And so those are most of the ones we're missing, but that's not to say we catch everything else. We don't. And so we will -- we do have a number of programs addressed at that. The third point I want to make is just an important one that we don't spend much time talking about, which is that actually the effectiveness of a screening test is as much about what happens after the screening test. If the diagnostic workup isn't done properly, the cancer might be missed, right? But it's still there. The test might have found it. But if the diagnostic workup isn't done properly, that is a missed opportunity to find that cancer. And we know that, that happens not just in the NHS, but in the U.S. as well. And so one of the things I think is going to be really important going forward is the effectiveness of the subsequent workup that providers undertake when they have a positive test. And what we've seen over time is that as physicians, as providers get more comfortable with the Galleri test, they realize just how strong the PPV is and therefore, the importance of properly working up a positive test when they find one.

And it's a hugely important point. I'll amplify it with 2 facts both in the SYMPLIFY trial in symptomatic individuals and what we saw in NHS-Galleri, cancers that were deemed false positives in the first year were subsequently found in the next year or 2 in both of these trials at the predicted site by our test. And that signals that either 1 of 2 things happen. Either the cancer was present and missed by the workup, either imaging missed it, endoscopy missed it or it was too early to find by our conventional tests. And so I think Harpal's point is critically important, and that will improve over time as well.

Okay. Well, with that, I really want to thank everybody for their participation. I want to thank our experts. Andy, I want to thank you and Harpal, and thank you very much for our panelists. We really appreciate hearing from you and how these data impact your practice and your thoughts about it.

Again, the goal of all of this, multi-cancer lead detection is to find more cancers earlier when they're more treatable and potentially curable so that patients have the chance to live longer and more productive lives. So again, the NHS-Galleri trial provides this wealth of data that we will be studying for years to come and really the opportunity to reduce the burden of metastatic disease. PATHFINDER 2 accentuates those data and further confirms the performance. And we really appreciate all the questions, and thank you for your attention. And with that, we'll close the evening. Thank you so much.

There are no further questions at this time. Thank you for joining. You may now disconnect.

[Audio Gap] Our digital health channels. It's been great to see there despite some of the NHS headlines, the growth persisted and so on. So really excited to be there. For the rest of the year, we've got -- we've announced we're going to implement Epic by the end of the year. We continue to see momentum from some of our other integrations, whether it's Quest or Athenahealth and the pull-through is there. So it's great to see...

Maybe let's -- you mentioned NHS. -- let's just dive right into that. That was sort of the big update that happened during the quarter. A lot to parse apart there. Has that impacted any of your customers or in your conversations around demand? So has that had any impact on the business as you see it in terms of like volume?

Yes. So I'd say that the headline came out and physicians who are orderers, physicians who are prospective orderers ask more questions. It was pretty clear though that those who saw beyond the headline and saw some of the clinical utility measures such as Stage IV reduction, increase in Stage I and II, decreased emergency room presentations, 4x more cancers found than the standard of care, like they got it. That all being said, everyone wants to see the data at ASCO. It's one of those SEC disclosure type things where you've got data in-house, you've got to say something vague, to not protect your -- I mean, to not ruin your ASCO presentation. So everybody wants to see the ASCO data, and that will be coming out here at the end of the month.

Okay. Any way you can frame that? I know it's not ASCO yet, but we are getting the same question sort of any way you can frame out like what the various scenarios are what the various outcomes are and sort of like where it could go from there?

Yes. I mean I think what you'll see is all the underlying data beyond the headline, right, the qualitative headline, the cancers by stage, how many were there, were in each of the years, where we really made -- what all the details are behind those clinical utility metrics. And so our field team, we've expanded that. We've expanded our salespeople. We've expanded our medical sales team. They're all being hired and trained up. So by the time ASCO hits, they can hit the ground running with updated materials, education for physicians and so on. So we're excited to finally have the data out there because it really is -- this data has never been seen before. It's a randomized controlled trial of 140,000 people, 3 tests over the period of the 3 years, 3 time points. And really see just how our test, how a multi-cancer test can detect cancer very efficiently when it's sitting alongside standard of care. Standard of care only catches 14% of cancers. So there's a whole lot that people aren't testing for.

Okay. And what about the -- going back to NHS, what are the next steps there?

With the NHS? Yes. So, we're -- we've got -- we have an agreement with them, right, as part of this whole trial thing. There was a series of clinical utility endpoints to look at, and we've met some of those. So we'll have a discussion. But like anything with NHS or any other government agency, that's always going to be balance of politics, budget and then data. So we'll have those discussions. Those discussions will happen probably over the next 12 months or so. There's a lot going on with NHS right now. I think they're consolidating the way that they run the NHS with the government. So -- but we are -- we do talk to them. And of course, we look forward to working with them on how and if this gets implemented in their population.

Okay. Is there anything that will come out at ASCO that you think could impact those conversations or...

No. I mean I think at this point, I believe they have the data. The key people there have been read in. As I said, I think they've got a lot going on outside of our study.

Okay. Fair enough. In terms of the NHS data and what you presented at ASCO and how that impacts the FDA, that was a big debate point with what would be considered, what would be considered. What gives you confidence that, that's not going to be interpreted as an incremental negative in terms of the data package?

Yes. So we've been in breakthrough with them since 2018. We've designed our study package for them. We've submitted all that in January of this year. They've accepted the review package, and we're in a review process with them now. The part of the NHS-Galleri trial that was going to them is the first year data, which was not the primary endpoint, right? It's the performance data, which we've now repeated in multiple studies, interventional studies, case-controlled studies, really something that no one else in the space has done. No one else has interventional data or prospective data.

So we're confident that the package is the package. That's what they're reviewing. Could there be an AdCom? Could there be other people who want to talk about the clinical utility metrics? I'm sure that will -- that may happen. We'll see how that goes. But what the FDA said they're going to be looking at the benefits and harms of the test, and the test performance. I think the NHS data, the clinical utility will be more impactful on like CMS or payers. I would say just on that, we also have the REACH study with CMS and FDA, where the primary endpoint of that study is a Stage IV shift, which is kind of what we've shown in the NHS data. So we have a path there as well.

Okay. All right. Maybe since you mentioned REACH, let's go to that. Can you give us an update on the timing for that? When we can expect the next update there?

Yes. It's continually enrolling. It's going to be over 3 years, 3 blood draws for the population. I believe the final readout is sometime in early 2031-ish, somewhere in there. But the CMS, the intention is to have interim data for them to look at in their population that will sit alongside the NHS data and real-world evidence that we've gathered. We've done over 0.5 million commercial tests at this point. And that will give them a large package to review to make a decision on coverage. Of course, CMS has never reviewed a multi-cancer early detection test before. So we don't -- they haven't stated publicly where the bars are at. But I imagine kind of like with the FDA over 7 years of 8 years of working with them on a breakthrough, they'll get -- they'll form an opinion, the more we work together, the more that they understand how the test works and what the benefits are.

Okay. In terms of that FDA review timelines, the ongoing conversations. Is there a timeline you can share with us sort of like how that's going to play out?

Yes. I mean I think what the FDA has said publicly is if there's no AdCom, it's a 180-day review. If there is an AdCom, it's 320 days. At this point, we don't know if there's going to be an AdCom. We're preparing for one, just so we're ready if it happens. But that's the package was submitted at the end of January. So you can all do the math from there if it fits in their stated timelines. But we're working with them iteratively right now. And when we have something to update, we will.

Okay. Okay. All right. And just to be clear, there has been no change in conversation. There has been no change in tone since NHS came out.

No. No.

Maybe let's pivot to sort of like the commercial performance and what you're seeing in the market outside of NHS and the FDA process. You talked about Epic. You talked about Quest a little bit. Can you expand a little bit more on sort of where you're seeing the benefits?

Yes. So right now, our channels, it's really a self-pay test, 70% of it is self-pay, really driven by brick-and-mortar physicians' offices, where we've seen an expansion of physicians ordering the test and also existing order -- physicians order the test more. Things like those tools like Athena, Quest, Epic will really help there. The digital health, I don't know what revolution, whatever you want to call it, that's happening where consumers are really driving their own healthcare through things like Function, Everlywell, Hims & Hers. That's a new opportunity, and it's been an opportunity that's shown to be fruitful. It's still early days for some of those partners. We've been with function for a while. We just launched with Hims & Hers. So we'll really see how that expands over time. But if you think about it, that's like a captive health seeker who's signed up to care about how they feel, how they're living.

And so one of the harder parts of finding a patient is addressed. These are people who want to know -- want to live longer, want to know what their health is. And generally, they have -- they'll invest in that. They'll spend their own money on it. And so the more and more people in the U.S. are combining these digital health platforms with standard care. I think there's like something just under 4 billion apps -- digital health apps have been downloaded in the last year. Of course, there's some of those are multiple apps for the same person. But it's a good opportunity, and it's really just more proof that there's this large self-pay opportunity, large pre-reimbursement market as we work toward the broader access, right? Because GRAIL has been built for population health from day 1, making sure that there's a low false positive rate that, it's easy for physicians to implement and that it can be affordable. The whole plan is to get the price of the test down.

The MCED legislation that was passed that set reimbursement at just about $500, a little bit more than $500, and that's what our current version is built to be able to support margins in the 50% to 60% range at. So we think it's well positioned. And the investment that we're making now and the traction we're seeing in this pre-reimbursement space with these partners with the physicians who are adopting is very fruitful and will help on the broad access side.

You talked a lot about the digital health and some of the newer channels. What about more traditional channels like Quest or the traditional healthcare provider? Is that gaining traction in the market? How much of that is about educating the channel themselves given sort of the new market opportunity here?

Yes. So as I said, the brick-and-mortar, so we started in concierge medicine back in 2021 when we launched whatever it was. Now concierge is not a large part of the business. It's physician practices in areas where there's real champions who physicians really see the benefit of the test. At the end of the day, 1 out of 100 people will have cancer. The physicians who find a cancer, we've found order the test a hell of a lot more than the ones who take a lot longer to find a cancer. So commercially, we try to connect these physicians so they can listen to each other and talk to each other.

Yes, your brick-and-mortar physicians' offices continue to grow and expand. I think we added 1,300 physicians last quarter, if I remember correctly. And that's really driven by market awareness. So any of these things -- any of the medical education that we do, any of the social media advertising that we do and then these physician groups that we put together, that's really how awareness is driven on the physician side. Patients can go to physicians as well and ask for it. But what we find is that the physician doesn't know about the test, they're not likely to prescribe it. So I think now there's other market players in there like Exact's out there now and so on.

That's actually driving more awareness. They've got over 1,000 reps, I believe. We've got 150-ish. But what we've found is the more people out there, and we've been waiting for this, helping build the market, add credibility to it, educate people on what an MCED test is, the easier it's going to be. We're really confident with the position that we're in from a data perspective and our experience that this is helpful to us. There being more players out there educating.

The physicians that you're adding, I mean, are you seeing any improvement in terms of attach rate, how much they're reordering? Is that sort of compounding over time?

Yes. I mean I think our -- what we call our retest rate, so the people who've come back for another test after getting a first test is over 30% now, which we're really happy with, given that it's a self-pay test. It's not reimbursed. I think for comparison, other screening tests, other stool-based screening tests have about a 30% retest rate after a decade of reimbursement. So it just shows this can be a really highly compliant, highly adhered to technology because it's blood-based. So yes, but we see that.

You mentioned on other players coming into the market and sort of the expanding MCED landscape and a lot of that is sort of bringing market awareness. Still very early, obviously, but are you seeing any change in conversation in terms of competitive landscape or what the alternative tests are?

No. I mean, as I said, we've -- we're the only company that's got interventional data, prospective data, and not just case-control data. Like we can actually tell you what -- how this test performs in a population of this room or people who are actually asymptomatic for cancer. Really, no one else can do that. We've also submitted our FDA approval and no one else has done that. So they're building awareness to the space, which is, again, helpful. It's educating more doctors. It's expanding the reach of awareness to physicians.

So I think that landscape will evolve. We'll see what -- if we have an FDA approval, what that does to the landscape. But we're excited about the position we're in. That being said, we're always looking at what we can do to improve the quality of the test, to improve the delivery of the test and so on. So we're not just resting on our laurels that we've got like the winning technology, and we're done at this point. So we'll continue to monitor and pay attention. But for now, it's a bit of a tailwind.

I mean a lot of the debate we've heard is sort of having a one-off test versus the cancer care continuum, right? A lot of the other vendors and a lot of other players in advanced molecular diagnostics, they'll have therapy selection. They'll have MRD, they'll have recurrence monitoring. How do you feel that sets you up in the competitive landscape in terms of conversations with physicians, with channel?

Yes. So some of those are to PCPs, some of those are to oncologists, right? But at the end of the day, back in 2024, we've focused the company on MCED when we did our restructuring. But we have MRD capabilities. We've got therapy selection capabilities. We have recurrence capabilities. Those are all investments that we would need to make at the right time to move things forward to like clinical studies. I've always -- I mean, I'm the CFO here. I'm not the scientist, but I've always said that if you can find cancer in people who don't know they have cancer, you don't know have cancer, you're probably going to be pretty good about finding people who you know have cancer.

And so if you get the top of that funnel, then the rest of that funnel is going to be easier to penetrate. But right now, winning in the MCED space, creating the MCED space is where we're investing. I've also always said as a CFO that if we failed at MCED but one at MRD, we'd be the most expensive MRD company ever funded. There are probably much faster ways to do that than we would have. But yes, that's -- given the position that we're in now, FDA approval and NHS data read out. We financed ourselves last year. We've got about $830 million on the balance sheet. Now is the time that we can start thinking about what we do with those other product applications if it's the right time to get back into them.

Okay. You touched on reimbursement a couple of times and obviously, the cash pay nature of the business. So how critical is that for you going forward? Do you have various scenarios mapped out depending on how the reimbursement decisions go? And where ASPs shake out over the next couple of years?

Yes, definitely. I mean from broad access, which is what we've been built for, we're talking about running millions of tests, like our lab in RTP just with the infrastructure that it has today can already run over 1 million tests, and it can be expanded significantly from there in the same footprint of that building. So there's a couple of different paths to reimbursement or broad access. They're global, right? There's international and there's the U.S. Of course, we're working internationally with NHS. We've worked with Samsung. So there's ways to get to broad access globally that are actually kind of independent of what's happening in the U.S. We've got the infrastructure to kind of service both.

And domestically, for reimbursement, we've talked about REACH leading to a CMS. We've talked about the MCED legislation that passed, which would allow CMS to start covering the test in 2029 upon a positive national coverage decision. And then there's always new developments that are happening with legislation or on the hill. So there's a new push for the rapid legislation or rapid rules, which would allow essentially FDA and CMS to work faster together, essentially to drive reimbursement for FDA breakthrough approved devices faster than the normal timelines. So there's all sorts of positive ways that you could get to reimburse reimbursement faster.

The offset of that is the reimbursement takes longer. But we're -- I think we've demonstrated, we're demonstrating a growing self-pay market, a growing pre-reimbursement market in the U.S. Things like Samsung and some of the things that we're doing, got a distributor in Canada. We've got one in Israel. We'll see what that looks like. But we're still talking 1 million -- couple of million tests there pre-reimbursement for now, get into like the 40 million test range with broad access, which is what we're built for. But it's -- we're definitely aware and conscious of running the business pre-reimbursement longer if we need to. versus getting to broad access in the proposed timelines.

Okay. I mean the other side of that coin is COGS and the cost structure, making some progress there. Can you talk about road map there for the next couple of years and how that can help offset reimbursement if it doesn't play out as favorably?

Yes, definitely. So as I said, the version we have now is going to be capable of supporting a lower cost at scale, right? With the lab infrastructure we have now can run more than 1 million tests. And so if you look at our last 2 or 3 quarters, you can see how many tests we've ran and you can see us growing into that fixed cost leverage and you see margin improvement. That will just continue to happen. We're nowhere near running 1 million tests a year right now.

And so we can definitely be bringing the price down. We've kind of built the model now and the business now to at like the MCED legislation rates of around $500-plus a test to support a 50% to 60% margin, right? And that's what the version we have today. And we're always looking at things that we can do, have development efforts to bring the cost down further or to -- and/or improve the performance of the test. So we're going to continue to drive this cost down because it's -- we think it should be accessible to everybody. We do think -- we do appreciate it's going to be a large line item, a budget line item. It might be cost effective. Who knows, it might even be cost neutral someday, but it's going to be a large budget item. And so the more we can bring that down, the better we think, for people and for systems who are going to want to adopt it.

And is that operational efficiency? Is that scale? Is that new platforms, new technologies?

Scale and probably some technology changes.

In terms of sequencing workflow or...

I mean test format, the sequencing workflow, regions and so on and so on.

Okay. Any questions from the audience? All right. We'll keep going. You talked about cash balance and the raise and sort of being well positioned there. What are your investment opportunities or investment priorities in 2026 and '27. You did a little bit of a commercial expansion so far. Can you just talk about the road map there and the timing for contribution?

Yes. So the goal is to have those batches of expansion, those people up and running after ASCO and contributing to growth by the Q3, Q4. As far as other investment opportunities, I mean, the whole point of the raise was to give us the flexibility to intercept the demand that we believe will come from things like NHS data being out there and understood, the FDA approval and so on.

So we may make further investments into people. We've invested in Epic, right? There's other tools that we'll do to wrap around the ordering process, the reporting process that should make things easier as well. And alluding to like investing in the next versions of the test and so on. We may make some decisions to go into things outside of screening. But right now, we're still focused on MCED. I don't like doing early victory dances and I think investing in things outside of that right now would be a little too early.

Is there an argument of, let's chat post ASCO, let's chat post FDA decision, maybe let's chat post CMS and then that will determine, are we going after, are we going right here?

Yes. I mean I think we'll learn a lot after ASCO. We'll learn a lot after FDA approval. And those two things are not very far away right now. I don't see myself waiting for CMS to make any of those decisions.

Okay. Okay. I mean maybe a couple of big picture ones. We've got about 5 minutes left. You've been talking about population scale screening for a while. You touched on a couple of the barriers there. It's been a long road, certainly, sort of like what do you think has been the biggest factor holding you back, and the biggest factor holding back broader adoption of population scale MCED? Is it reimbursement? Is it awareness? Is it test accuracy and sensitivity? -- why is it -- it's been a long road if you go back to GRAIL's founding in 2016?

I wouldn't put performance as a barrier. It's just an understanding of a new technology. Like the FDA, as I said, we've been working with them for 8 years. The FDA didn't have a plan on how to approve MCED tests. CMS doesn't have a plan on how to improve MCED tests. There's just physicians. Physicians -- the first thing most people think about is a single cancer test. Well, this is not a single cancer test. Most folks don't realize that when you do your standard of care screening, as I said, that detects about 14% of cancers in the population. That probably -- that surprises most people when you talk about it. So it's just so new and paradigm changing that you've got to do a lot of education, show a lot of data, show that consistently, right, be transparent about it and do a lot of work to show that this can work and it works consistently.

And so the barriers haven't really been performance. I mean, as we've demonstrated, I mean, with a false positive rate of less than 0.5%, if you can find 4x more cancers than the standard of care, that's a pretty powerful tool. You just have to believe in the tool. You have to believe that that's accurate. So ASCO data hopefully shows that, FDA approval shows that. And then we move into the economic discussions with CMS and other large payers on affordability and on the economics of reimbursement.

I mean to that point, in terms of how paradigm shifting it is, that kind of speaks to some of the other players in the space are starting with a single test and sort of using that to piggyback into more of an MCED approach. There's a lot of debate on like the pros and cons of those 2 methods. I mean, does that kind of speak to maybe this is not the way to go after, maybe the paradigm shift at FDA and CMS is too much of a hurdle?

I don't believe that. The world has single cancer tests. Developers develop single cancer tests, where there's already reimbursement. So you have another colorectal cancer tests, another breast cancer test. That's why companies choose those things. When we were founded, we did a bake-off of multiple technologies, methylation, mutations, fragment, so on and so on to find multiple cancers. And so we picked that to find MCED. We didn't take a technology that we already had and then shoehorn it into something else. It's simple, companies go after single cancer screening tests because they're already reimbursed. I don't think that's paradigm changing at all. That drives more people into compliance with things like colonoscopy. We're trying to find, as I said, the 86% of cancers that people aren't looking for. And that's where you find a paradigm shift.

Okay. I don't know if there's any -- we got a question...

You talked about preparing your sales force for the upcoming commercialization. Can you talk about what you're doing with oncologists to kind of prepare for that outcome?

I'll just repeat the question for the webcast. The question was preparing the sales force. What can you do to prepare oncologists?

Yes. So right now, the primary orders of this are PCPs. Oncologists, as you guys know, work for so many months, they already have a cancer. We do engage oncologists because they are KOLs and they're thought leaders. Oncologists that we've engaged are -- they're excited about the data at ASCO. I've actually never heard more oncologists say positive things about GRAIL than after the ASCO release went out because oncologist knows that a reduction in Stage IV cancers of that amount is a very important thing. Physicians don't and oncologists specifically would rather treat people with Stage I, II or III cancer than Stage IV cancer.

There's a large mortality cliff between Stage III and Stage IV right now for many cancers due to the advances in cancer therapies. But we have forums, symposiums, we show up at ASCO, AACR and ESMO and so on. We have a lot of publications out there. The oncology community is an important community, but they're not the orderers of the test right now. So we're trying to tackle the 500,000-person PCP sale physicians that are out there and educate the oncologists as well, which is, again, back to the competition. We were doing this by ourselves for multiple years, which is very expensive. Now there's other people out there helping do it, which is nice. I hope that answers your question.

We've got about a minute left. So maybe just we'll end with our usual closing question of what do you think is most underappreciated or most misunderstood about GRAIL? A lot to choose from, I'm sure.

Yes. I mean just -- again, the opportunity in front of us to find more than 14% of cancers by adding one test with a very low false positive rate, right? So you're going to make the whole cancer detection system extremely more efficient than it is today. The cost of finding a cancer goes way down. And it's probably the best shot we have at finding -- bending the cancer mortality curve, adding single cancer tests, you already have about a 40% false positive rate as a person getting 4 annual screens. That's just not sustainable. If you multiply that by all the cancers that are out there, you're going to have to start testing an individual for cancers, not an individual for all -- for a single cancer. So what cancer does that individual have versus looking for prostate cancer or looking for colon cancer. And our technology does that. It just all it cares about is finding cancer that then tells you where it's at.

Okay. Well, on that note, we're going to wrap it there. Thanks, everyone for joining. Aaron, thanks for being here.

Thank you for having me, Mike.

Looking forward to ASCO. Sounds like you must attend.

Yes, definitely. It's going to be a good time.

Thanks, everyone.

Thank you.

Good day, ladies and gentlemen, and welcome to the GRAIL First Quarter 2026 Earnings Call. [Operator Instructions] Please be advised that this conference call is being recorded. GRAIL Investor Relations, please begin.

Thank you, and thank you all for joining us today. On the call are Bob Ragusa, our Chief Executive Officer; Aaron Freidin, our Chief Financial Officer; Josh Ofman, President; Sir Harpal Kumar, Chief Scientific Officer and President, International; and Andy Partridge, Chief Commercial Officer.

I'll remind you that we'll be making forward-looking statements based on current expectations. It's our intent that all statements other than statements of historical fact, including statements regarding our anticipated financial results and commercial activity will be covered by the safe harbor provisions for forward-looking statements under federal securities laws. Forward-looking statements are subject to risks and uncertainties. Actual events or results may differ materially from those projected or discussed. All forward-looking statements are based upon currently available information, and GRAIL assumes no obligation to update these statements.

To better understand the risks and uncertainties that could cause actual results to differ, we refer you to the documents that GRAIL files with the SEC, including the Risk Factors section on GRAIL's most recent annual report on Form 10-K, and the quarterly report on Form 10-Q, which we plan to file for the first quarter of 2026.

This call will also include a discussion of GAAP results and certain non-GAAP financial measures, including adjusted gross profit and adjusted EBITDA, which excludes certain specified items. Our non-GAAP financial measures are intended to supplement your understanding of GRAIL's financials. Reconciliations of the non-GAAP measures to most directly comparable GAAP financial measures are available in the press release issued today, which is posted to our website.

And with that, we turn to Bob.

Good afternoon, everyone, and thank you for joining us to review first quarter results. I will take a moment to highlight recent achievements before turning it over to Josh for an update on our clinical programs and recent and upcoming data, then over to Aaron to cover financials.

This quarter, we saw continued strong commercial momentum with expanding physician adoption, increasing engagement across health systems and growth in test volumes. GRAIL sold over 56,000 Galleri tests in the first quarter, a 50% increase in volume year-over-year. Total Galleri screening revenue was $39.8 million, up 37% over the prior year.

We are making important strides to enhance provider and patient awareness of MCED. We continue to grow our partnerships with health systems, which educate physicians and engage the community. We are seeing growing deployment of Galleri in leading systems, including Dana-Farber, Rush, OHSU and Cleveland Clinic and Duke. We are seeing major health systems, including Community Health at Intermountain investing in new and expanded employee benefit coverage of Galleri.

We are continuing to deepen our work with existing digital health partners, which enable outreach to curated memberships. We have also recently added additional partners such as WHOOP.

Also, our employer relationships continue to expand as experience with Galleri grows. We've invested in the ease of access through our previously announced partnerships with Quest to integrate into their ordering systems and our recently announced collaboration with the Epic electronic health record platform.

Integration through Epic Aura will allow health systems and their HCPs to order the Galleri test directly at the point of care, receive structured results and manage patient follow-up within their existing native EHR and with their existing clinical workflows. Integration will provide standardized implementation and quicker onboarding for health systems adopting Galleri. Integrations are beginning now.

In January, we announced that we completed our FDA PMA submission, which has been accepted by the FDA for review. The PMA for Galleri is focused on test performance and safety results from the first approximately 25,000 participants in the PATHFINDER 2 study with 1-year follow-up and the prevalence screening round only of the NHS-Galleri trial.

The submission also includes a bridging analysis to compare performance of the version Galleri used in the clinical trials to the updated version that has been submitted to the FDA for premarket approval. We announced in February our planned expansion of the field sales and medical teams. We expect the majority of the new sales personnel will be onboarded and trained by midyear. We believe this expansion will enable us to continue to drive commercial momentum.

Finally, we're looking forward to the upcoming data presentations for our 140,000 participant NHS-Galleri trial and the 35,000 participant PATHFINDER 2 study at the 2026 American Society of Clinical Oncology Annual Meeting later this month. We're excited to share data from the studies and begin to incorporate the learnings in our educational and sales initiatives.

Following our data presentations at ASCO, we are planning to hold an analyst call on Sunday evening, May 31. Stay tuned for details on the analyst call in the coming weeks.

And with that, I'll ask Josh to provide an update on our clinical programs.

Thanks, Bob. At GRAIL, we're very excited about the comprehensive data we've been generating to demonstrate the value proposition for Galleri. This technology has been validated through robust studies, including those in intended use populations.

More than 174,000 individuals are included in studies supporting our PMA submission to the FDA, and we're seeing consistent results through hundreds of thousands of commercial and clinical study tests. Through our studies and commercial testing, we've built what we believe is the largest linked clinical and genomic data set in the field. We have already been able to use these data to drive test improvements, and we'll continue to do that over time.

Our teams have continued to present evidence demonstrating Galleri's performance at renowned medical conferences, including 2 new analyses at the American Association of Cancer Research Annual Meeting in April.

The first assessed the association between emergency department involvement in the diagnosis of cancer and overall survival across different cancer types in the Medicare population. Emergency department involvement was associated with a significant fraction of overall mortality in patients with cancer. Emergency department involvement in diagnosis remained a strong independent predictor of mortality after adjusting for sociodemographics, comorbidities and stage of diagnosis.

A second study evaluated adherence to mammography screening before and after MCED testing. Women who received a negative MCED result maintained their high adherence to guideline recommended mammography, with greater than 80% undergoing screening in the 24 months after MCED testing, similar rates in the 24 months before testing.

As a reminder, Galleri is intended to be used alongside existing standard of care single cancer screening tests, and these findings suggest that MCED testing will not negatively impact participation in guideline recommended cancer screening.

Earlier this year, we released top line data from the NHS-Galleri trial, which is the first randomized trial to demonstrate population scale stage shift for a multi-cancer early detection test. Working with the NHS, we agreed to a combined endpoint of Stage III and IV reduction over 3 rounds of screening.

What was observed in the trial was an increase in Stage III cancers detected and a decrease in Stage IV cancers detected, which ended up canceling one another out in this combined endpoint. While we did not achieve a statistically significant reduction in this combined primary endpoint, we did demonstrate a number of strong clinical utility findings.

We observed an increase in the detection of Stage I and II deadly cancers and a fourfold higher cancer detection rate compared to standard of care screening alone. These findings indicate we were able to find deadly cancers that we are not screening for and also find cancers that we've been missing with standard of care screening.

We also observed meaningful reductions in Stage IV cancer diagnosis and in the emergency presentation of cancer. These findings suggest that with multiple rounds of screening, we may be able to identify some of the most lethal cancers earlier. Reducing Stage IV diagnoses is incredibly meaningful because there is a large survival cliff between Stage III and Stage IV for many types of cancer.

Many Stage III cancers can now be treated with curative intent and finding these cancers at Stage III rather than Stage IV can make a meaningful difference in a patient's treatment experience and outcomes. The reduction in emergency presentation reflects a similar opportunity to improve the patient experience, their care and their outcomes.

Cancers presenting in the emergency room represent 20% of cancer diagnosis in the U.K. and similar numbers in the U.S., and these cases are among the costliest and those associated with some of the poorest outcomes. We believe that both the increase in overall and in early cancer detection and the decrease in metastatic and emergency presentation of cancer are important and relevant to providers and payers in evaluating the clinical and economic value of Galleri as a complement to standard of care screening. We are really looking forward to presenting these data plus the results from all 35,000 participants from our PATHFINDER 2 study at ASCO in just a few weeks.

I'll hand off now to Aaron for a review of our financials.

Thanks, Josh, and good afternoon, everyone. I'm pleased to present our results for the first quarter. First quarter results were strong with revenue of $40.8 million, up $8.9 million or 28% as compared to the first quarter of 2025. Total revenue for the quarter consisted of $39.8 million of screening revenue and $1 million of development service revenue.

Screening revenues was up 37% as compared with the first quarter of 2025 with test volumes of more than 56,000 tests, an increase of 50% over Q1 of last year. Net loss for the quarter was $93.2 million, an improvement of 12% as compared to the first quarter of 2025.

Non-GAAP adjusted gross profit for the first quarter of 2026 was $19.7 million, an increase of $5.4 million or 38% as compared with the first quarter of 2025. Primary drivers of the increased gross margin were improved fixed cost leverage due to the increase in volumes and a decrease in sample reprocessing costs, partially offset by a decrease in ASP.

Adjusted EBITDA for the first quarter of 2026 was negative $79.9 million, representing an improvement of $18.8 million or 19% as compared to the first quarter of 2025. We ended the quarter with a cash position of $823.1 million, providing us with the financial flexibility to navigate growth over the next several years as we pursue key milestones toward broad access to our multi-cancer early detection technology.

Back to you, Josh.

Thanks, Aaron. Bob, before your retirement at the end of this month, I want to take a moment to acknowledge the tremendous contributions you've made as CEO of GRAIL. All of us at GRAIL and everyone joining today's call who follows our story can appreciate the incredible progress you've led our teams through over the last 5 years, our spinout from Illumina, our commercial expansion and the scaling of our North Carolina laboratory operations.

As a result, GRAIL has a strong operational and financial foundation to advance multi-cancer early detection at scale and is well positioned for long-term growth. Bob, on behalf of all of our teams at GRAIL, thank you.

Thanks very much, Josh. Leading GRAIL and working alongside this extraordinary team has been the greatest honor of my 4 decades in healthcare. We are addressing one of the most urgent healthcare challenges of our time, and I am extremely proud of our pioneering work.

I'd also like to express my sincere thanks to each GRAIL employee. Every achievement we've made has been the result of the ideas and actions spurred by the great people across this company and driven by a commitment to a singular goal. Our vision is population scale, multi-cancer early detection, and we're making real advances each year.

I'm pleased to pass the reins shortly to Josh, who has played a central role in driving GRAIL's strategy and execution over the past 7 years.

Operator, we can go to Q&A.

[Operator Instructions] Our first question will come from Subbu Nambi with Guggenheim.

And great print. The FDA and CMS recently established a rapid pathway in which CMS will propose the NCD for Class 2, 3 breakthrough devices on the same day that the FDA provides market authorization. Given Galleri has the breakthrough device status and would be expected to be a Class 3 device, do you expect Galleri to be eligible for the rapid pathway? Or does the 2029 start date specified in the MCED bill negate this opportunity? Sorry for the long question.

Thanks, Subbu, for the question. We've looked at rapid right now, it's kind of just a framework without a lot of detail. But at a high level, it does look like the characteristics of our test, the breakthrough designation, the fact that we're driving for FDA approval does put us in what the act is intended for.

So we're hopeful that when the details come out, we will find ourselves being very much eligible for that. But we do have to wait and see how the details unfold for that particular piece of legislation. Josh, I don't know if any other comments on that?

No. I mean it's an important piece of regulation, and it's very encouraging. I mean, I think for years now, the government has been trying to shorten the gap between FDA approval and CMS coverage. This is something the administration has been prioritizing. It's great to see.

And I think to Bob's earlier point, everything that we've done from seeking FDA approval, having a breakthrough device designation, conducting an IDE that was reviewed by the FDA and CMS should comport with what this regulation is intending to do. So we're looking forward to seeing the details and the regulation itself.

Perfect. And how much growth from partnerships like Function Health and Hims & Hers are factored in your guidance for Galleri growth in 2026?

And then maybe I missed this, but given the beat, are you raising guidance? I'm hopping through multiple earnings, so pardon of my question here.

Aaron, do you want to take that one?

Yes. So on your first question, Subbu, nice to talk to you. So we've got our guidance, which we're reiterating still the same guidance, not updating it. You got a 10% range there. One of the reasons for that is to really learn and see how the uptake works in the digital health space.

Some of those partners like Function, we've got more experience with. But Hims & Hers and some of these other new agreements that we've signed, as they implement, we'll see what uptake is like. Depending on how they implement it, it can go quickly, sometimes it doesn't.

Your next question will come from Kyle Mikson with Canaccord Genuity.

Congrats on the quarter. First one is just a rough bigger picture question. It's been a few months since the NHS-Galleri reveal. Can you talk about the feedback from stakeholders since then? And then very exciting to have the ASCO presentations pretty soon here. Do you expect to have a material change in opinions following those abstracts and perhaps the call with the investors as well?

Sure. So first piece on the NHS. So we obviously -- we had a strong quarter. We were able to grow volumes by 50% and revenues by 37% in the screening part of the business. So we clearly saw current strength. Andy, maybe jump over to you to talk about customer response to NHS-Galleri.

Yes. Thanks, Bob. Thanks for the question. As Bob said, we've seen strong growth through Q1 kind of year-over-year, and that growth has been across brick-and-mortar providers, digital health and employers. Drilling specifically into healthcare providers, we've seen a significant expansion of new ordering healthcare providers in Q1 with about 1,300 new prescribers to Galleri that we saw in the quarter.

We've also added important new customers across our employer business, health systems, as Bob mentioned, Cleveland Clinic, Duke, OHSU, all kind of came on board to incorporate Galleri with agreements in Q1 and also added new digital health customers in Q1, all of this in the midst of the NHS-Galleri data being released.

I think specifically to the NHS-Galleri data, that media coverage and some of the negative media coverage that was generated has led to questions from customers, healthcare providers, employers and also from patients. As the data from the study has not yet been presented, it's been difficult for our teams to answer every single patient or provider question related to the study.

Therefore, once the data comes out at ASCO, there's definitely going to be interest from customers for us to walk them through that detailed data, and we've got plans to train all of our sales force immediately after ASCO on that data so they can follow up with customers.

As Aaron highlighted, we're confident in our growth prospects. And indeed, we're finalizing our sales force expansion efforts.

Yes. Wow, that was great. I guess my final question or second question is going to be about expansion opportunities kind of the near term here. So you've got the Epic EHR integration. I think planning for that began when that was basically announced in April or so. I know you have the Quest portal, you have athena, like based on your experience with those platforms in the last year or so, can you just talk about your enthusiasm of what Epic could do for you and then expansion plans to Oracle, Cerner or things like that? And then just on the sales force expansion as well, I mean, are you looking at like pretty healthy tailwinds in second half due to things like Epic and sales force expansion as well?

Yes. So if you think about maybe the first part, the Epic expansion, that's something we've been looking to do for a period of time. So we're really excited about announcing that. We know that, that is a huge part of the kind of easy button within health systems to be able to have the Galleri test within their normal workflow, both from the ordering side as well as the test results coming in. So it really just fits into the entire workflow of a physician. So it makes it much more likely to be able to be integrated into a health system.

So that implementation is starting now. And really in the second half of the year, we'll start to see some integrations into actual health systems there. So we look for that to build over the second half of the year.

Andy, maybe some discussion on the Quest side, what we're seeing there as well as the sales force expansion.

Sure. So with both Quest and Athena, we're seeing continued adoption of electronic ordering with Athena and Quest. Indeed, we've got about 2,000 healthcare providers now who have ordered through either the Quest or Athena integration, which has led to over 30,000 tests being deployed through either the Quest or Athena integration since we launched both of those integrations. So we're very excited about the continued use of Quest and Athena by our customers.

As Bob said, it really does provide that easy button for them. And with Epic now launching on top of that, it provides another kind of easy button for, as we announced in our press release, 450 health systems. And those are the big health systems across the U.S. And essentially, any health system that was on the Epic system in November 2020 or later is going to be eligible for our Epic or integration.

And then in terms of the sales force, we're going to have completed that expansion by the middle of the year. And then with the ASCO data coming out for both NHS-Galleri and PATHFINDER 2 and potentially an FDA approval at some point later this year or early next year, that's going to give the sales force a lot of wind at their back to continue the momentum that we've seen with Galleri that we're reporting today.

Your next question will come from Dan Brennan with TD Cowen.

Maybe just starting off, I know there's a question already about the feedback so far since the NHS-Galleri data are out. But maybe can you just share a little bit more on that? We'll learn obviously a lot more at ASCO, but I'm just wondering with that 20% plus Stage IV shift, kind of what the feedback has been from oncologists? And any particular cancers where oncologists or experts are feeling most optimistic about that shift?

So with respect to the reduction in Stage IV, the 20% plus reduction in Stage IV in particular, that is one of the things that's really resonating with both primary care physicians as well as with oncologists. And I would say over the last -- since that data has been released, we've seen more favorable things from oncologists who truly understand just how important that reduction is.

So we've -- I think over the last 5 years with Galleri being out in the market, we've seen good understanding from primary care physicians and -- but the oncologist community has probably lagged behind in their understanding because they're not frontline users of it. But I think that particular piece really caught their attention quite well. So I think that piece in particular, is resonating really nicely. Josh, any --

No. Yes.

No. Go ahead.

Okay. Great. And then maybe just in terms of the guidance range for the year, I know there's a couple of questions asked about like the buckets and the drivers there. But could you help like zoom out a little bit and just give a little bit more color about between health systems, concierge medicine direct to PCP, kind of where are you guys seeing like the most traction right now? And how you think about the rest of the year in terms of the guide? Does it remain in those buckets? Or has anything changed on that front?

Yes. Maybe I can give a little bit, and then I'll pass it over to Aaron and Andy to give some more color. So the self-pay piece remains the majority of Galleri's volume, accounting for kind of 2/3 plus of the volume.

In terms of volume growth, the brick-and-mortar physicians continue to be strong. Clearly, as we talked about our integrations with Quest and Athenahealth, that helped add new providers and reduce order friction. Going forward, we do see the sales force expansion continuing to drive extra volume. Digital health continues to provide a great opportunity in the self-pay market.

Here, we have access to people who are used to being in the self-pay market, and that's continued to do quite well with partners like Function Health and Everlywells. And then we have the new partnership coming on with Hims and then WHOOP that we just announced. So as Aaron mentioned, we'll have to see just how fast the uptake of those goes. But I think that gives you some sense. Aaron, anything to add on the color around the guide?

No. I mean I think it's -- Bob has covered it. We'll track to see how the quarters go and look at it again next quarter.

Your next question will come from Catherine Schulte with Baird.

Maybe first on guidance. I think ASPs stepped down sequentially. How should we expect those to trend for the rest of the year? Just curious on kind of volume versus ASP assumptions in your reiterated guide? And any color on how we should be thinking about second quarter revenue?

Yes. So maybe I'll hit the ASP piece. So if you recall, our vision all along has been to operate Galleri at population scale, and so we have plans for price reductions over time.

As we talked about, we made significant investments in our new scalable platform and have rolled that out throughout from late '24 all the way through '25 into this year. So with that, that gives us the ability to bring pricing down while maintaining strong margins. And so in 2025, we really began to lean into the price elasticity that we see in the market.

And so we're finding success by expanding some of our discounting programs. Much of that happened already in 2025. And so you're seeing kind of a decline as we set up new pricing structures within each of the channels.

So within 2026, we would only expect relatively modest decline to continue other than things driven purely by mix. So as the mix of the various channels changes throughout the quarters, you might see price increase or decrease on ASP based on that, but that's really going to be a mix issue with an overlay of maybe a slight decline in ASP per channel.

Okay. Anything on 2Q?

I mean again, we expect our growth for the year to be between 22% and 32% on the revenue side.

Okay. And last question for me. We've seen some competitors increasing their DTC advertising. We had one announced a celebrity spokesperson a couple of weeks ago. And you've talked about the sales force expansion, but any plans you have on the advertising side to make sure you're getting brand recognition with consumers?

So we have been doing a little bit more certainly in the social media channels and things to get the message out. One of the things we've actually found is the competitors by the competitors advertising the MCED space. That's actually brought a lot more awareness for MCED. So we're actually seeing -- while it's obviously a competitive -- potential competitive threat, we're actually seeing a fair amount of tailwinds from that as people get more and more acclimated to the whole MCED space to get more knowledge about the MCED space.

And when our sales team can go in and describe our product, someone is now aware and interested, we usually end up doing very well there. So, so far, largely a headwind, those we'll continue to and probably increase our marketing spend a little bit to be able to get more message out there through social media and things, but probably not to the level that some of the other competitors are putting out there.

Your next question will come from Doug Schenkel with Wolfe Research.

This is Colleen on for Doug. A bit of a follow-up from Kyle's question on sales force expansion. Can you provide any color on how many reps are currently in the field? Is it fair to assume you're back up to levels prior to the Illumina spin?

And then finally, on this one, how long do you expect it to take the newly hired reps to get to full productivity?

Andy, do you want to take that one?

Yes. So we're not going to get back to Illumina levels in terms of sales team in the field. The expansion of the sales force is in the provider channel. So we're expanding territories from about 90 territories up to 120 territories. And in terms of productivity of that team, we're going to have the majority of that team onboarded and trained around the middle of the year.

All right. And then just one on the FDA approval process for Galleri. Based on your conversations with the FDA post final PMA module submission, what's your read on whether the FDA will convene an AdCom? Our sense is that based on the timing, we should be hearing about that soon. And if an AdCom is called, what do you think the key areas of focus will be given the FDA already met at the end of 2023 to discuss MCED?

Josh, do you want to weigh on that?

Sure. As you mentioned -- good question. As you mentioned, we did submit the final module of our PMA earlier this year, and the FDA had accepted that file. We are in an ongoing iterative review process right now. And the FDA guidance on timing is typically 180 days from submission without an advisory committee and about 320 days with an advisory committee.

We'd be speculating right now about whether there will or won't be an advisory committee. So we can't really comment on that right now. But we've been very active in supporting the FDA's review. Discussions have been very constructive. But it's unknown right now whether the FDA will hold an advisory board. And if they do, what the focus of that advisory board will be.

As soon as we learn more, if we can share that, we will, but that's kind of where we are right now. We're in the middle of a very iterative review process.

Your next question will come from David Westenberg with Piper Sandler.

I just want to hit on the topic of the 22% to 32% guidance, but you obviously came in at 37%. So can you talk about -- I know you didn't want to answer the seasonality question, but can you give any additional color to why there might be some of the conservatism, whether it be like maybe you saw really good seasonality? Is there a channel mix? Is there ASPs that would make it come in below what you came in, in Q1?

I'll start and then have Aaron -- I think first part is it's just early in the year. Obviously, this is a pretty important year for us with our FDA filing. We have a number of factors out there. We have the sales force expansion. We have ASCO coming up at the end of this month. So there's a number of catalysts out there that we're looking to see how they go.

As we mentioned earlier, we have a number of digital health partners that we've signed, but now it's a matter of seeing how fast the uptake can go with them, how aggressive they are in the market as well as we also mentioned just some of the competitive pressures out there.

So in that whole mix, we kept guidance the same. And as Aaron mentioned, we would update again, look to see if there's anything new to report out at the end after Q2. Go Aaron.

Bob, nailed it again.

Right. Then maybe I'm just going to move on to the Epic integration. So you announced that the integration is going to be expected by the end of the year. How many health systems are you currently in active discussion with? And what's your expectation for winning testing in that other -- not DTC channel in the back half of the year? And then can that flow through for 2027? Can that start to be the bigger channel? Or am I too early on that?

Andy, do you want to give some color on that one?

Yes. In terms of Epic, there's about 450 health systems that we're targeting for the Epic integration. As I said earlier, it's essentially any health system that is on the November 2020 or later version of Epic that's going to be eligible for this integration.

And when I say 450 health systems, health system would be HCA. One health system would be Mayo. So these are big health systems.

We're currently in the process of the technical build and go-to-market readiness, building the tests and production environments in AWS. So all that kind of technical work is being done right now.

As Bob said earlier, we would actually get customers live on Epic in Q3. And the sales team currently are profiling customers to assess their excitement and conviction around when they want to go live on the Epic platform.

So we're currently assessing exactly what that list is going to look like. So I don't have a specific answer for you right now, but I can tell you there is a lot of excitement with our current health system adopters in terms of the Epic or integration. And could you repeat the last part of your question because I didn't quite catch it.

I was just thinking about how we should think about mix between hospital and DTC channels in 2027 and beyond.

I think that's too early for us to give any guidance. A lot of that's going to be driven by when we get the FDA approval. So I think it's a little early to comment on that.

Yes, I think Epic itself is going to give us a tailwind in terms of health system integrations, but the demand itself, we have to create. A health system needs to want to adopt Galleri. Epic then is the easy button for them that improves the provider experience by streamlining Galleri ordering, resulting and follow-up.

But as I said, health systems are very excited about Epic Aura integration with Galleri. That's going to sit alongside our Athena and Quest electronic order integrations as well.

Our last question will come from Bradley Bowers with Mizuho.

Just want to maybe get into something we've talked about a little differently. Just wanted to hear about, I assume it's kind of a pre-ASCO preview, but we're going to get NHS-Galleri and PATHFINDER full data. It might require some of the slices that we've seen before performance in deadly cancers or hard to detect or those without a paradigm. So is this group of the eventual customers, are they kind of conducive to these slices? Do they understand the superior sensitivity of Galleri or specificity? And also that kind of leads into how competitor dynamics have been we're about 6 months with other tests on the market.

Josh, do you want to?

Yes, that's a great question. I think that it's fair to say that our customers are fairly well versed in the performance of Galleri. Galleri performance has been demonstrated in multiple large studies now, from case control studies to interventional studies and intended use path, the PATHFINDER study, PATHFINDER 2. And now they're going to see the full data set from NHS-Galleri.

But as it relates to performance, we think the customers absolutely understand the very high specificity, the safety profile of Galleri, its ability to detect where in the body a cancer signal comes from with very high accuracy. It's very strong episode sensitivity in the deadly cancers and the dramatically improved cancer detection rate that we saw in PATHFINDER 2 relative to when added to standard of care screening and what we reported out in our press release around NHS-Galleri.

So we think that is very well understood by many customers, but there's still a lot of education yet to be done. And obviously, the primary care community is enormous in the United States. And ASCO will be a big opportunity for us to share a more -- a deeper look at the NHS-Galleri trial in all of its glory, and we're very much looking forward to that.

That's great. Very excited for that. Just maybe to touch on that, what does the business kind of look like post ASCO pre-FDA approval? We'll pretty much have the totality of the big data sets, but that kind of gets into uses of cash and timing of the sales force ramp. So how do you think about maybe managing the pedal? And maybe how does FDA approval impact the business? Is it like turning on a faucet or is it kind of a slower build?

One of the things we're going to have to see is the impact of FDA approval. Certainly, our early research would suggest it's going to -- providers and patients are both going to view that very favorably. And -- but it's early days to exactly predict what the impact of that is going to be.

Yes. I mean I'd just add, I mean, fortunately, the fundraising we did last year, we've got the opportunity to intercept that inflection point if and when it shows up. So I think we're well situated.

There are no further questions at this time. I will now turn the call back to GRAIL for closing remarks.

Well, thank you, everyone, for joining today's call. We appreciate the time and your questions, and we look forward to seeing many of you at the upcoming ASCO show.

Good day, ladies and gentlemen, and welcome to the GRAIL Fourth Quarter 2025 Earnings Call. [Operator Instructions] Please be advised that this conference call is being recorded. GRAIL Investor Relations, please begin.

Thank you, operator, and thank you all for joining us today. On the call are Bob Ragusa, our Chief Executive Officer; Aaron Frieden, our Chief Financial Officer; Josh Ofman, President; Sir Harpal Kumar, Chief Scientific Officer and President, International; and Andy Partridge, Chief Commercial Officer. Before we get underway, I'll remind you that we'll be making forward-looking statements based on current expectations.

It's our intent that all statements, other than statements of historical fact, including statements regarding our anticipated financial results and commercial activity will be covered by the safe harbor provisions for forward-looking statements under federal securities laws. Forward-looking statements are subject to risks and uncertainties and -- actual events or results may differ materially from those projected or discussed.

All forward-looking statements are based upon currently available information, and GRAIL assumes no obligation to update these statements. To better understand the risks and uncertainties that could cause actual results to differ, we refer you to the documents that GRAIL files with the SEC, including GRAIL's most recent quarterly report and upcoming annual report. This call will also include a discussion of GAAP results and certain non-GAAP financial measures, including adjusted gross profit and adjusted EBITDA, which excludes certain specified items.

Our non-GAAP financial measures are intended to supplement your understanding of GRAIL's financials. Reconciliations of the non-GAAP measures to most directly comparable GAAP financial measures are available in the press release issued today which is posted to our website. And with that, we turn to Bob.

Good afternoon, everyone, and thank you for joining us to review results for the fourth quarter and full year 2025 and discuss recent business updates. 2025 was a year of significant commercial growth for GRAIL, and we have shared a number of exciting developments so far in 2026. We issued a press release this afternoon with top line results from our NHS Gallery trial. We observed a substantial reduction in Stage I cancer diagnosis, increased Stage 1 in new detection of deadly cancers and a fourfold higher cancer detection rate outcomes that matter for patient care. While there was a trend towards reduction in combined Stage 3 and 4, the trial did not meet the primary endpoint of statistically significant reduction. These data show the benefit of multi-cancer screening with gallery and provide the strongest evidence for the recommended annual screening interval, or Paul will talk through the top line NHS calorie trial results shortly. In our earnings press release, we also noted full results from all 35,000 participants in PathFinder 2 and were consistent with data presented from the first 25,000 participants presented at ESMO last year.

We anticipate presenting full data from both NHS Gallery and Pathfinder 2 in mid-2026. Based on strong results from the NHS Gallery trial and the PATHFINDER 2 study, we also announced today that we are moving forward with a planned expansion of our field sales and medical team. We believe this expanded engagement will enable us to continue to drive commercial momentum.

To recap quickly, on the strong commercial performance for Gallery in 2025, which we shared in January. The U.S. Galleri test volume grew 36% to more than 185,000 gallery tests and U.S. Gallery revenue grew by 26%. Our prescriber base is now approximately 17,000 providers, up 30% from prior year. Galleri's growth in 2025 was driven by both breadth and depth of prescribing. We have been in the market with the Gallery test now for more than 4 years.

And from the launch of Gallery through December 31, we have sold almost 0.5 million gallery tests. We remain on track for continued commercial growth in 2026 with new and expanding partnerships, including digital health opportunities and further integration into health systems. We are focused on expanding awareness of multi-cancer early detection and Gallery's important performance and capability differentiation.

We anticipate growing patient, provider and employer conviction in gallery as other performance, safety and clinical utility data sets are read out. A few weeks ago, we announced that we completed our PMA submission with the FDA. The PMA marks a critical step forward making gallery available to more people and advancing early detection to provide a significant public health benefit. The submission represents years of focus, disciplined work to achieve design, development and validation of all large diverse screening populations. Josh will share more about our PMA later in this call.

Additionally, earlier this month, the Nancy Gardner sold Medicare multi-cancer early detection screening coverage Act became federal law. This establishes a Medicare coverage pathway for FDA-approved multi-cancer early detection tests. As a leading MSAD developer, it is our privilege to stand with legislators, patient advocates, clinicians and researchers who have championed the cause. I'll now hand it over to Harpal to discuss top line results from the NHS calorie study.

Thank you, Bob. We're very pleased to share top line results from the NHS Gallery trial. I want to begin with a huge thank you to the more than 142,000 participants who took part in this study as well as to NHS England, the Cancer Prevention Trials Unit at Queen Mary University of London, cancer alliances, investigators and the clinical teams whose dedication made this landmark trial possible. Detailed results from the NHS Gallery trial will be submitted for presentation at the upcoming ASCO meeting in Chicago in late May.

The design of the NHS Gallery trial was informed by a large body of evidence showing that across multiple cancer types, reductions in late-stage disease are strongly associated with reductions in cancer mortality. While we did not observe a statistically significant reduction in combined Stage III and IV cancers through the trial, which was the primary endpoint of the study, there was a favorable trend after the prevalent screening round, and we saw compelling evidence of Galleri's benefit.

Comparing the 2 arms of the study, Stage 4 diagnoses in the prespecified group of 12 deadly cancers decreased with each year of sequential gallery screening with a greater than 20% reduction in the second and third rounds. Similar reductions were observed across all cancers. The reduction in Stage IV cancer diagnosis is a critically important outcome, which we believe can lead to more effective intervention for patients particularly given the substantial and growing arsenal of effective treatments for many Stage I cancers.

In fact, there is a dramatic improvement in survival for many types of cancer at Stage 3 as compared with Stage 4. These results are the first time a multi-cancer early detection test has demonstrated population scale stage shift and reduction in metastatic disease in a randomized trial. Screening with Gallery increased the overall cancer detection rate fourfold compared to standard of care, and identified substantially more Stage 1 and 2 cancers in types that are typically detected at late stage.

Screening with the gallery test also resulted in a substantial reduction in the number of cancers detected clinically through emergency presentation, which are associated with significantly higher mortality and health care costs. And these benefits came with a strong safety profile. No serious safety concerns were reported in any of the approximately 70,000 participants who received the gallery test across three rounds of testing.

This is the first randomized multi-cancer early detection data set and is unprecedented in scale. Additional analysis are underway to better understand these rich data. As with any study, it's important to evaluate the results in the context of the design and execution. One observation is that we saw higher-than-anticipated incidents of Stage I cancers in this trial as compared with prior study experience.

The number and distribution of cancer stages across screening rounds suggests the potential for a stronger effect with longer follow-up as data matures. And so we're planning to extend data collection by 6 to 12 months, and we'll reevaluate the impact with more mature data. In both the U.S. and the NHS data, the time to diagnostic resolution appears to improve over time as physicians gain experience with the gallery test and diagnostic workup.

Our learnings from this trial enrich our understanding of cancer biology, multi-cancer screening and the importance of implementation, particularly in ensuring rapid and thorough diagnostic investigation after a positive test result. Our mission is to detect cancer early when it can be cured. And we're delighted that these results show the potential for more patients to receive treatment with curative intent and have more time with their family and friends.

We believe this is the best chance to bend the cancer mortality curve at population scale. As a reminder, the data we're sharing today is limited to our top line analysis. We plan to submit the detailed results for presentation at ASCO later in the year. I'll now pass it to Josh Ofman, to review more about our recently completed PMA application.

Thank you, Harpal. At the end of January, we completed the submission of the final module of our PMA application to the FDA for gallery. We're extremely proud of this pivotal milestone in advancing early cancer detected and addressing unmet needs in cancer screening. From the beginning, GRAIL has been completely committed to rigorous scientific and clinical evaluation to ensure that multi-cancer early detection testing is supported by strong data.

The PMA submission is focused on test performance and safety results from two large registrational studies, including the first 25,000 participants in the U.S.-based PathFinder II study with 1-year follow-up and data from the prevalent screening round were the first year of the NHS Gallery trial, the largest and only randomized controlled intended-use trial of any NSAID test.

The PMA submission is also supported by a bridging analysis, to compare performance of the version of gallery used in our registrational trials to the updated version that has been submitted to the FDA for premarket approval. The results from the first 25,000 participants enrolled in Pathfinder do were presented in October at the ESMO Congress. And we've now completed the analysis of the full 35,000 participants and the results are consistent.

The performance data from the prevalent screening round of the NHS Gallery study, including metrics focused on test performance, clinical validation and the clinical benefit of detection at Stages 1 through 3, including a reduction in Stage 4 were also included to further enhance the data set and provide additional data on more cancers to the FDA. As a reminder, the FDA designated the test as a breakthrough device in 2018. The PMA was submitted at the end of January, and we are anticipating about a 12-month review period. To discuss our fourth quarter financial results, I'll pass it off to Aaron.

Thanks, Josh, and good afternoon, everyone. I'm pleased to present our results for the fourth quarter and the full year of 2025. Fourth quarter results were strong with revenue of $43.6 million, up $5.3 million or 14% as compared to Q4 2024. Total revenue for the quarter is comprised of $42.3 million of screening revenue and $1.3 million of development services revenue. Development services revenue includes services we provide to biopharmaceutical and clinical customers, including support of clinical studies pilot testing, research therapy development.

Full year total revenue was $147.2 million, up 17% from full year revenue in 2024. Full year 2025 revenue was comprised of $138.6 million of screening revenue, up 28% over full year 2024. U.S. Gallery revenue in 2025 was $136.8 million, up 26% over 2024 and in line with our guidance of 20% to 30% growth. Revenue also included $8.6 million of development services revenue, a decrease of 49% from 2024. We are seeing continued demand for the gallery test, and we sold more than 57,000 tests in the fourth quarter and more than 185,000 tests for the year.

Screening revenue of $42.3 million in the fourth quarter was up 34% as compared with the fourth quarter of 2024, primarily based on an increase in sales volume. In 2025, we began leaning into the price elasticity we see in the market and are finding success in expanding access with our discounting programs. Development service revenue in the fourth quarter of 2025 was $1.3 million. Net loss for the fourth quarter of 2025 was $99.2 million, an increase of 2% as compared to Q4 2024.

Net loss for the full year was $408.4 million, an improvement of 80% as compared to the full year 2024. Net loss in 2024 included goodwill and intangible asset impairment of $1.4 billion. In addition, net loss for 2025 and 2024, included amortization of Illumina acquisition-related intangible assets of $138.3 million. Non-GAAP adjusted gross profit for the fourth quarter of 2020 was $23.1 million, an increase of $5.2 million or 29% as compared with Q4 2024.

Full year non-GAAP adjusted gross profit was $73.6 million, an increase of $15.8 million or 27% and as compared with the full year of 2024. Primary drivers of the increased margin were revenue mix and efficiencies of scale related to increased gallery volume. Adjusted EBITDA for the fourth quarter of 2025 was a negative $71.8 million representing an improvement of $12.2 million or 15% as compared to Q4 2024. Adjusted EBITDA for the full year 2025 was a negative $320.6 million, an improvement of $163 million or 34% as compared to the full year 2024.

We ended the quarter with a cash position of $904.4 million, this balance included $436 million in proceeds from both our private placement of equity in October as well as our ATM equity issuance program in November and December. As a reminder, we have shared in the past our long-term gross margin target of 50% to 60% at scale. We are making good progress on attaining these margin targets. And as we saw in the third quarter, volume efficiencies make a big difference.

In connection with our supply agreement with Illumina, we are obligated to pay them a royalty on revenues. Those royalty payments are suspended until December of 2026. When resumed, we expect to pay alumina a royalty in the high single digits, subject to certain terms and perpetuity on net sales generated by our products on revenues and oncology.

We expect that these payments will make an impact on our gross margins beginning in 2027. Given strong performance in the self-pay market and the momentum we are seeing with positive data readouts, we are reiterating the guidance we shared in January today of Galleri sales growth of 22% to 32% and cash burn for the full year of 2026 to be no more than $300 million. Our cash runway extends into 2030, and we are well positioned to navigate growth over the next several years as we pursue critical milestones toward broad access. Bob, back to you for concluding remarks.

Thanks, Aaron. To close, our teams at GRAIL continue to do great work advancing towards our vision of population scale multi-cancer early detection. We are approaching our tenth anniversary as a company this March, and we are energized by recent milestones and achievements, including the consistently strong performance we are seeing for Galleri across our studies. We presented positive registrational clinical study results for the first 25,000 participants in the Pathfinder II study in October and to today share top line results for the NHS Gallery trial and the full 35,000 participant PATHFINDER II study. We're looking forward to data presentations for both studies later in the year.

The business continues to grow and we are excited about expanding or partnerships with digital health companies and health systems to continue to expand access to gallery. We have now completed our PMA submission with the FDA and new federal law provides a pathway for Medicare to cover FDA-approved multi-cancer early detection test. We're in a strong financial position with more than $900 million in cash as of December 31. I'd like to thank each of our employees for their incredible commitment and dedication to our mission to detect cancer early when it could be cured. We'll now turn the call over to question and answer. Operator, please go ahead.

Thank you. [Operator Instructions] Our first question will come from Subbu Nambi with Guggenheim.

Can you confirm that you don't expect the FDA approval decision to be impacted by the miss of the state shift endpoint? We know the FDA PMA package only included the prevalent screening round of net but reasonably reviewers at the FDA will see this outcome, right?

Yes. Thanks for the question, Subbu. So as you know, the FDA will look at the effectiveness and safety of our submission. And so with the data that we have, both from Pathfinder 2 as well as the current -- the prevalent around of the NHS gallery we'll be looking at that data. So there's not an obvious correlation or obvious impact between the final results of the NHS calorie study and the FDA on the test.

Perfect. And 1 follow-up. Is there any read-through from missing the NHS Gallery state shift endpoint to the Medicare REACH study which has a primary endpoint of incidence rates of Stage 4 cancers, right? And does that have any impact as Medicare as you look to getting some college?

Yes. Thanks again. Josh, do you want to take that?

Sure. Yes. No, you're absolutely correct. So the primary endpoint of the REACH study is a Stage IV reduction. -- which is what was observed quite strongly in the NHS Gallery trial. So I think the only read through is that we believe that it's critically important and clinically important to reduce the incidence of metastatic disease in stage 4 cancer, and it's a really important clinical end point, and we're looking forward to assessing that in the REACH trial.

Josh, what if we don't reach the statistical significance there. Would that have any impact? Or you are saying because it's 50,000, the study is not powered enough?

Yes. No, we believe this study is properly powered. It will have a control group, and we believe it is properly powered for that type of study, given the effect size that we know in the cancer detection rate that we're seeing. So we're very optimistic about observing that effect, but we need to study, obviously, to read out. That's going to take some time.

Your next question will come from Kyle Mikson with Canaccord Genuity.

Hopefully, can hear me. I guess the first 1 would be how does the results here kind of impact your strategy to expand gallery to other countries in terms of data generation and rollout plans, how would that differ now? And then maybe you could just touch on what are next steps in the U.K.? Have you had any discussions with them so far is that later on?

Thanks, Kyle. So we do think as we outlined in the releases that the strong reduction that we saw in Stage I cancer, the fourfold improvement in cancer detection rate compared to standard of care the absolute number of stage 1 and 2 cancers increasing and the reduction in emergency presentation, we think all of those will be important as we go to other countries and the discussions with them. Obviously, other countries will -- each one will evaluate those elements independently, but we do think that's going to be a strong data set to go out there. So I think that's going to be very useful. Maybe I'll pass it over to Harpal to comment on the U.K. and the impact there.

Yes. Thanks, Bob. I mean, just adding to what said first. I mean we think this is a really strong dataset that demonstrates compelling clinical benefit. We know that there is now a growing arsenal of very effective treatments for many types of stage -- many types of cancer at Stage 3. And so the potential benefits that we're talking about here from the NHS Gallery study are going to be applicable worldwide. And so I don't think it has any -- certainly no negative bearing on our international approach. Indeed, I would hope it has a positive bearing on our international approach. So we feel we're really very pleased with the overall set of results.

With respect to the U.K. specifically and the NHS, yes, look, we've just got these data. We haven't started having those conversations yet. My anticipation would be that they would want to see the full results before engaging in meaningful conversations, and we expect to have those at ASCO.

And then I hate to nitpick, but if you're expanding the sales force if the results didn't meet the endpoint, I guess like what's the thought process there, you're pretty bullish on the future here. I'm just curious what's driving that.

Yes. So again, if you think about the things that we saw in terms of reduction in Stage 1 and 2, the -- I assume the increase Stage 1 cancers and the reduction in stage 4 cancer. Those are things that we've looked at within the U.S. that are very, very reliant to clinicians. Maybe to give a little more color, I pass it over to Andy, our Chief Commercial Officer.

Yes. Thanks, Bob. Based on the market research studies that we've done and also consistent customer feedback that we've received from early adopting customers, the NHS Gallery results that we've released today, we believe, based on everything we've heard and done will be both compelling and meaningful to our customers in terms of the magnitude of both the Stage 4 reduction that we've disclosed and also the increased cancer detection rates are fourfold. And we believe that's going to increase both the depth and breadth of prescribing. Hence, we're expanding the provider sales force territories in the U.S.

Your next question will come from Schenkel with Wolfe Research.

I'll try to get them all out there upfront. And then listen. So first, really a follow-up to the very first question, and I think it's the most important question tonight given the stock reaction in the aftermarket. So I want us to be air tight on this. is the probability of FDA approval unchanged as a result of the NHS gallery readout. Because if the answer is the probability is unchanged. It would mean the value associated with FDA approval and by extension CMS reimbursement is also unchanged. So that's the first question. Yes or no, it has the probability not changed.

The second question is on NHS coverage in the U.K. I know -- again, you just got a question on this, but I'm curious if there are any examples you can point to where a diagnostic has been reimbursed after missing a primary end point. And then my third question is, has your analysis of NHS Gallar results led you to any explanation regarding why you came up short of the primary endpoint? Are there potential design issues or population SKUs, anything like that?

Yes. Thanks, Doug. Maybe Josh, I'll hand over to a question to you.

Thanks for the question, Doug. Everything we've learned from the FDA, their history with us, our conversations has been their focus is going to be on clinical performance and safety. And the data set that we are -- that we have submitted includes the full PATHFINDER I study of the first 25,000 participants and the first year which is the performance period of the NHS Gallery trial. In their advisory board meetings and their public comments, they have been quite clear that their focus is on clinical validation and not clinical utility.

And what we've tried to demonstrate in the NHS trial is a population level effect well beyond clinical validation and clinical performance. And we were able to demonstrate a really important finding of a substantial reduction in Stage I cancers and a fourfold improvement in the cancer detection rate. But those are things that are not part of our submission right now to the FDA. And based on their own comments, they're going to be focused on clinical validation.

And maybe, Harpal, you want to.

Yes, so I think you -- Doug, I think your second question was around endpoints on diagnostic studies. I think it's just worth pointing out that it's extremely rare for any diagnostic to go through a randomized controlled trial, it's very common for drugs to go through randomized controlled trials, but you actually very rarely see a diagnostic test evaluated as rigorous way as we have done through the NHS Galleri trial. I just think it's really important to make that point. Not only have we rigorously assessed it through an RCT, but it's a nor large trial, 142,000 people.

So we have a data set, the likes of which I am not aware any other diagnostic has been through other than sort of really significant interventional diagnostic type products. So I think that's the first thing to say. The second thing to say is this is an enormously rich data set, and it has a large number of components to it, and we've shared those with you today. It's absolutely right to say we didn't hit the primary endpoint, but what we did see was a very compelling clinical benefit here. And I think that story stands in terms of generating excitement out there in the clinical community around what's possible with a test like this, being able to reduce Stage I cancers gives clinicians the opportunity to use curative treatments that they otherwise wouldn't have the opportunity to use. So I think that's really very compelling.

And then your third question, I think, was about what are we learning looking at the data? And just a couple of comments on that. First of all, it's -- we've not had this data for very long. We're looking into it. There's a lot of data to work through. One of the things we've seen is that -- if I break apart the primary endpoint, it's a combined Stage III and IV reduction. And so when you break that apart, we did see a Stage IV reduction, but as we've commented on, we saw an increase in Stage III cancers.

And one of the things that looks to be the case when we look at the data is that we expect to see a stronger effect if we were to continue to follow up this cohort for a longer period of time. And that's why we're saying we want to extend the follow-up for a further 6 to 12 months, and that's why we'll be doing that. So that's one of the things that we've seen when we're looking at the data, but there's a lot more to learn.

[Operator Instructions] Your next question will come from Catherine Schulte from Baird.

I guess, first, just on that last point of extending the trial follow-up by 6 to 12 months. Is that something that you NHS have already agreed on? And I guess what is the goal of what you will see in that 6 to 12 months? Is it to push more on the Stage 3 reduction? Or is there something else that NHS is hoping to see?

Andrew?

Yes. Thanks, Catherine. We haven't discussed it in any detail with the NHS yet, but I think it's -- I really can't see any obstacles in being able to do that. What it requires is not going back to participants or clinicians. It would be a continuation of passive data collection which is already being recorded. And so it's just about the passage of time and agreeing with the NHS team that we can get access to that data. I think that will I don't foresee any significant obstacles in that regard.

And in answer to your second question, yes, what we want to see is particularly the control data maturing more than we've been able to. And perhaps if I just elaborate a little bit on that, what you tend to see in a screening trial in any screening trial is that you're finding cancers that would have been detected later, and so if you think about what that means in practice, you're pulling forward to your intervention arm cancers from the future.

For a control arm of the study, those cancers may not yet have manifested. So when you're comparing 2 arms of the study, what you'd like to have is long enough follow-up that you can compare the 2 arms really well together. And what we've concluded looking at the data is, we probably need a longer follow-up time to be able to do that adequately.

And then for the NHS, I know they put out their national cancer plan earlier this month and still reiterated their commitment to and interest in multi-cancer early detection they've got OLS closed and application process for what sounds kind of kind of like a DAC related study using ultacancer tests and primary caratatriage patients with nonspecific abdominal symptoms. Is that something that you guys are involved in? And maybe just talk to the broader relationship with NHS.

Yes, happy to do so. So we've been having ongoing conversations with the NHS really over the last 5 or 6 years. Those conversations continue very actively and certainly we'll continue here on in. Of course, we were very pleased to see in the NHS cancer plan a couple of weeks ago, a number of references to multi-cancer early detection. And indeed, the excitement within the NHS and the Department of Health in England for the possibilities that this new technology offers for really transforming the landscape for cancer patients.

So the multiple references in the cancer plan, I don't think it's an exaggeration to say comes from the conversations and relationships we've been having with the NHS over the last 5 or 6 years. With respect to the second part of your question, yes, there is a process underway to further evaluate the role of multi-cancer detection in a symptomatic context. And this is a follow-up from our SIMPLIFY study that we reported a couple of years ago, necessarily, the Department of Health has to go through a competitive application process, it doesn't -- it can't just offer that opportunity to GRAIL.

So that application process is underway. And as you might expect, we applying to be part of that process and are hopeful that, that will move forward. Certainly, we believe our data from the SIMPLIFY study is very strong and very encouraging in that context.

Our next question will come from Dan Brennan with TD Cowen.

Maybe just 1 on Medicare. So assuming you're successful with FDA, I'm just wondering, I know Medicare, you have the favorable pathway obviously an FDA approval, assuming you get that, that would be terrific. But we're under the impression that Medicare does consider clinical utilities. So how do you think they would look the NHS trial, and how would that potentially impact the Medicare decision.

Josh, do you want to take that?

Great. Yes. Obviously, Medicare is going to -- upon FDA approval now has the statutory authority to provide coverage for multi-cancer early detection tests and we'll initiate a national coverage analysis and really looked very carefully at the data. And we believe we're going to have a very robust package of data to submit to CMS, including all of our registrational trials everything about NHS gallery, including the substantial stage IV reduction, the fourfold increase in the population cancer detection rate, the increase in detection of stage 1 and 2 cancers and also very strong clinical performance overall.

And so we think that, that, combined with our real-world evidence, our clinical surveillance program and the REACH study in Medicare patients at the time of NCD will be a very robust package for them to evaluate. Again, Medicare has never evaluated in multicancer early detected test before. There's no known bar that has been set, and so we feel like we're going to be able to provide them an incredibly robust package of evidence to consider coverage for Gallagher.

And then maybe just on I appreciate the Stage 4 is down, which is terrific, but the 3 given some of the anomalies you discussed was up, like collectively across the agent Stage 3 and Stage 4, can you say if there was a decrease and kind of what the level of that decrease was?

Yes. I can't really comment any further at the moment. There was not a statistically significant reduction. But what we did see was a trend towards a reduction over time, and that was a favorable trend. I think that's as much as I can say at the moment, but we are planning to present the full results at ASCO later in the year.

And then if I could sneak in 1 final one. So the trial was set up for 3 years. Obviously, it was going to be a surrogate for mortality because mortality would just take too long. So I think that was pretty well established. Was there a decision when you set it up for 3 years as opposed to maybe setting it up with a longer follow-up period kind of how that decision was made? Obviously, it sounds like now you're hoping, obviously, the longer follow-up will still prove out the study, but I'm just wondering when you went into it, how was that decision made?

Yes. I mean, look, as with any study, it's designed and sized and powered with the best information you have at the time. And at the time, we felt that 3 rounds of screening followed by a year of follow-up would be sufficient. I think with the benefit of hindsight, we probably should have allowed for a longer follow-up period. The interestingly been a number of publications over the last couple of years about screening studies in general, not just about NHS Gallery, which make this exact point, that the trial should be followed up for longer than 12 months post the last appointment. As I say, this trial was designed 6 years ago, and that was the best information we had at the time. But as I've already touched on, on this call, we have the ability to continue to flow up, so that's what we're going to be doing.

And it's probably just worth noting that most screening trials have going on for decades, at least 1 decade, if not 2. And so this was a very -- in the context of screening trials, this was actually a very short trial with a very ambitious end point, and that's part of the story here. But it is the first time that an MSA test has shown the ability to shift the stage at diagnosis for the population in a randomized clinical trial. And I don't think we should let that kind of go by.

For our next question, we'll return to Kyle Mikson with Canaccord Genuity.

So just given you you see these results now, at this point, can you go to the FDA kind of narrow or adjust looks say your label maybe to cancers that you performed the best in or maybe like an older patient, like an older subset perhaps? And just generally, like how does this impact your thoughts on the -- like a potential advisory committee based on there was a comeback in 2030 already.

Yes, sure. Again, we don't think that this finding is going to impact the approvability of gallery with the FDA. The FDA is clearly going to be focused on clinical performance, safety and the profile of data that was delivered to them, and in that context, we will work through labeling with the agency. Should they seek clarification on the intended use, a narrowing of the indication to the things that you suggest, we'll be negotiating that with them in due time. But we feel like we have a very strong and compelling evidence package for our current intended use, which is adults at elevated risk for cancer such as adults over the age of 50 and with additional risk factors, if they're younger than the age of 50. So we feel like we have a robust package and we'll see where the labeling ends up.

Yes. Maybe just to add to that. The -- it's also -- we really brought up is across the 3 rounds of the large participants in NHS calories well as the 35,000 and Pathfinder 2. There was no serious adverse events across the entire trials. So those are really large numbers. So from a safety perspective, it was really good showing.

And we think the benefit risk profile is quite compelling as a result of that.

And just to add something that Josh said. In relation to your point about the 12 cancers, the reason we specify this group of 12 cancers is because it represents 2/3 of all cancer mortality. So if you can make a difference in that group, you really are making a dramatic impact at population scale. But I would draw your attention to something that's in our press release, which is when we talk about this stage 4 reduction, and the fact that it's more than 20% in the second and third rounds of screening, yes, true for the 12 cancers, but it's also true for all cancers. And so I don't think there's any reason at this stage to think that we should be narrowing our claims only to the 12 cancer types.

It's a great point, Harpal. Thank you for making that. And just to your last question about the AdCom it's certainly possible that there can be an AdCom. The FDA has already held an AdCom. And so we are not sure whether that's going to happen, we will wait and see. But we've made the case to the FDA that based on their prior AdCom that they've already held and the fact that we've addressed all of those issues in our submission, which was just completed recently that there's likely no need for one, but we'll see what the FDA decides.

Just a quick follow-up. Obviously, the NHS Galleri results are pretty relevant to the FDA submission. But I don't believe there's much read-through to USPSTF inclusion. So in a worst-case scenario, you don't get at the April, which you get not the U.S. would expect that. You could get a USPSTF conclusion, get into -- or get Medicare coverage according to the legislation and so forth. Are your thoughts on guideline inclusion unchanged? Or is that -- you still don't think that's necessary milestone for you guys that FDA is most likely going to happen?

Well, I'm not sure I'm fully following your question, but let me try to take a stab at it. We think the first most important milestone is to get an FDA approval. And we think that, that is going to be an incredible moment for patients and provide amazing amounts of conviction in the clinical community and the payer community. Many of the payers have told us that, that would be the gating step for them. They would like to see an FDA approval before they would provide coverage or consider gallery for coverage.

And then obviously, there will be a CMS NCA, a National Coverage Analysis decision, as we've discussed already. So we think those are the most critical things. And a USPSTF valuation would then come after that. And obviously, that was that is important if you don't have a coverage pathway within CMS. And that's why the USPSTF pathway was put into place because the CMS had no statutory authority to provide coverage for preventive services. But the CS does have statutory authority now. So we see the USPSTF as being supplemental to that. But in terms of guidelines, we think the FDA approval is going to be 1 of the most critical parts and then the very strong and robust evidence base we have about all the clinical benefits that Harpal has described.

Yes. Just to clarify, I was just saying like if the USPSTF Committee, if they're going to take this data into account, but it's -- we're talking to years in the future probably. So maybe it's not relevant. But anyway, thanks for the time. Appreciate it.

Thank you. There are no further questions at this time. I will now turn the call back to GRAIL for closing remarks.

We look forward to presenting full data from our 2 registrational studies in mid-2026, a longitudinal randomized controlled NHS trial, including clinical utility and performance and the full 35,000 participant PATHFINDER 2 study. So we look forward to providing future updates. And thanks, everyone, for joining the call.

Ladies and gentlemen, this concludes the call. You may now disconnect.

Good morning. Thank you all for joining us today. My name is Henry Jiang. I'm with the banking team here at JPMorgan, and it's my pleasure to be introducing the GRAIL team today. Joining me on stage and presenting today will be Bob Ragusa, CEO; and Dr. Josh Ofman, President. Just a quick note, we'll have time for Q&A at the end. And just please wait and we'll get you a microphone if you have any questions. But with that, I'll pass it over to you, Bob.

Thanks, Henry. Appreciate it. So welcome, and thank you for attending this session. I'm Bob Ragusa, Chief Executive Officer at GRAIL. We're pleased to be here to talk today about the company, the progress we've made as a company and the exciting year ahead. So here are our disclaimers. So today, I will share with you a business review and then Dr. Josh Ofman, who joins me up on stage here, our President, will review Galleri's differentiation and future opportunities.

So we're immensely proud of the progress we've made as a company. We launched Galleri in 2021, enabling individuals and their physicians to identify cancers before symptoms appear, often at earlier stages. These cancers typically have no recommended screenings. We see ourselves as leaders in an expansive field. We were the first to launch a multi-cancer early detection test, a brand-new testing paradigm for cancer screening and have been on the market for more than 4 years. So we demonstrated the performance of the test through a number of studies, most recently in a readout of the first 25,000 participants in the PATHFINDER 2 study, where we showed strong performance.

We are still the only multi-cancer early detection test that has presented and published data in the intended use population, which we believe is critical to understand the performance of an MCED test. We have completed more than 800,000 Galleri commercial and clinical tests and sold more than 185 Galleri commercial tests in 2025. Our commercial experience and large clinical data sets put us in the position to continue to lead this space. We generated between $147 million and $148 million in revenue, comprised primarily of Galleri test sales as well as development services sales to our biopharma partners. This opportunity is about scale, and we have invested in building our laboratory infrastructure to support it.

At the end of 2024, we launched our new highly automated test process, which expanded capacity to about 1 million samples per year and allows for additional expansion with moderate capital expenditure. We are building the business with intention and are making significant progress towards adjusted gross margins in the 50% to 60% range at scale. Based on our strong performance, we completed financing in Q4 of 2025 and ended the year in a strong capital position with $904 million of cash on the balance sheet. There are a lot of exciting things coming up for GRAIL. We shared this fall that we expect to complete our filing of our PMA in the first quarter of 2026. We will present full data sets midyear 2026 on the 140,000-person NHS Galleri study and the 35,000-person (sic) [ 35-person ] PATHFINDER 2 study. From a commercial perspective, we expect to continue to expand Galleri in the United States as well as advance Galleri in international markets. We're at the very beginning of an exciting journey to fundamentally change the way he was screened for cancer.

In Q4 2025, we strengthened our balance sheet by raising approximately $435 million. We raised $325 million in a pipe investment and we raised an additional -- we were able to support additional demand, raising an additional $110 million through our ATM program. We also announced a $110 million equity investment by Samsung, which is expected to close this month. These transactions provide us with financial flexibility to navigate our growth ramp over the next several years as we pursue critical milestones to support regulatory approval and broad access. We are seeing strong commercial momentum. In 2025, we saw a strong Galleri growth volume of 35% with total commercial test volume for the year of over 185,000 tests. Much of the increase is driven by both breadth and depth of prescribing in 2025. The prescriber base grew approximately 30% to over 17,000 prescribers.

We also saw continued growth in our repeat test rate, achieving over 30%, which gives us confidence that both physicians and patients are seeing value in the annual testing cadence. In 2025, we began leaning into the price elasticity that we see in the market, and we're finding success in expanding access with our discounting programs. MCED is a new paradigm for screening, and we're working closely with a number of partners to drive market growth. This includes operational partners to support efficient ordering and test execution, health system partners to educate physicians, engage the community and deploy testing in appropriate populations. Our digital health partners to enable access to curated memberships, provide education and offer MCED testing and distributor partnerships to tap international markets.

Over the last year, our operational partners such as Quest and athena have effectively helped us develop an easy button to deploy for physician ordering, making a real impact to both prescribing depth and breadth. Our telemedicine provider, Recuro Health, helps us provide simple access to Galleri through galleri.com and supports workflow for a number of our employer customers. Our health system partners support implementation of screening populations and enabling real-world -- enabling workups for positive tests and capturing and publishing real-world evidence.

Our digital health partners support access to large self-pay populations who are focused on wellness and preventative health care. They also support connections with health systems to link patients and providers for any follow-up for positive tests. Our international distributors enable us to access patient populations outside the United States. Our distributor partners leverage their own local infrastructure and expertise to bring Galleri to their populations in a capital-efficient manner. So far, we've launched partnerships in Israel, Canada and announced a partnership with Samsung in South Korea. We have a strong financial profile. We're focused on growing revenue and controlling spend. Revenue for full year 2025 is expected to be between $147 million and $148 million, approximately 17% to 18% growth over 2024.

We guided U.S. Galleri revenue to be up 20% to 30% from 2024's revenue of $108.6 million. We expect full year 2025 U.S. Galleri revenue will come in between $136 million and $137 million, a 25% to 26% increase over 2024. For full year 2025 cash burn was approximately $274 million as compared to 2024 cash burn of $579 million. We achieved this reduction through significant reorganization we undertook in the second half of 2024, where we effectively cut burn substantially while we continue to invest in market development and work towards broad reimbursement and broad access.

Turning to 2026 guidance. We expect our total Galleri revenue to grow at 22% to 32% in 2026. We expect full year cash burn to be less than $300 million. Today's cash balance provides runway into 2030, and we are well positioned as we head into major milestones, including the readout of our registrational studies and a filing of our PMA.

I'll now pass it over to Josh, who will review our differentiation and opportunity with Galleri. Josh?

All right. Thank you, Bob. Really happy to be here today to join you and really talk through this amazing opportunity that sits right before us. As you know, cancer is the leading killer among adults over the age of 50 in the United States, soon to be the #1 killer worldwide. And why is that? You've all been touched by cancer. We've all had losses to cancer, and it's because we're finding most cancers too late.

Today, of the hundreds of deadly cancers that we know exist, we screen for 5 single cancers. And these tests detect only 14% of all the incident cancers that are out there. Yet 70% to 80% of all the cancer deaths are from the cancers we're not looking for at all that have no recommended screening. GRAIL is dedicated to solving that problem, to identify cancers earlier when they can be treated more effectively and potentially cured. We simply have to move away from the model of looking at 4 or 5 individual cancers and also begin to look at an individual for whatever cancer you may develop because guess what, we don't get to choose the cancer that we get. Adding Galleri to single cancer screenings has the potential to fundamentally transform and improve the performance of our overall national screening program.

Based on our study results, by adding Galleri to standard of care single cancer screening, we may be able to identify up to 60% of cancers through screening. That's a vast improvement over the 14% that we see today. Here are some of those statistics. And we envision a future where MCED testing is broadly available, provides an enormous public health impact and will be delivered with a very strong economic value proposition to society and to payers. Galleri is setting the bar in multi-cancer early detection. We have the highest positive predictive value at 62%. We have the lowest false positive rate at 0.4%. We have very accurate prediction of where in the body the cancer signal is coming from, what we call the cancer signal origin or CSO, which enables efficient targeted workups to get to diagnosis rapidly.

When we launched, we had evidence that Galleri detected over 50 different types of cancer, which is remarkable. But with our much larger clinical and commercial experience now, we've documented well over 100. Critically, Galleri is the only MCED test that has published validation data in the intended use screening population, something I view as a prerequisite to be able to launch a commercial product and is conducting the largest evidence program ever undertaken for an MCED. And we have developed 3 major pillars for our leadership in this whole space. The first is technology. We developed Galleri specifically to be a screening tool for cancer. In our discovery work, we looked at multiple genomic features, multiple technologies. We compared them head-to-head and in combination. And we selected methylation-based technology based on its superior performance and the ability to not only detect cancer, but also predict where in the body that cancer comes from or a cancer signal origin.

Now the Galleri test works by identifying a cancer signal in abnormally methylated DNA fragments circulating in blood. This is a signal that is identified by machine learning pattern recognition. It is a signal that is shared by many or most cancers. And importantly, it's a signal that is almost never seen in people without cancer. Because the test is based on circulating tumor DNA, it preferentially detects cancers that shed a lot of DNA into the blood. These are aggressive and invasive cancers, limiting the concerns related to the overdiagnosis of indolent forms of cancer that people are more likely to die with than to die from. And the vast data sets that we've accumulated through large-scale studies and our commercial experience provide a data flywheel effect for us that enables test improvements over time.

Now we've also focused on delivery. As Bob mentioned, we invested in a state-of-the-art, highly automated CAP CLIA lab in Research Triangle Park, North Carolina, with 1 million test capacity per year today and the ability to improve that substantially and expand it over time. We also have substantial fixed cost leverage, which will enable us to continue with price reductions over time.

Now we're pursuing FDA approval with our breakthrough device designation, and we have developed an evidence package to support our PMA that includes 2 large registrational trials. We've conducted extensive clinical validation in screening populations across numerous studies that have demonstrated consistent results study after study after study. We've now been in the market for over 4 years. We've sold more than 475,000 commercial tests. Our experience and our engagement with the clinical community around MCEDs is simply unparalleled.

Now when GRAIL was founded, we were focused on this big idea, how could we transform the entire paradigm about how we detect cancer. But there was also a focus on establishing a very high evidence bar for the field. After all, this is population-level screening, and we are in a very exciting time for data readouts. In October, we presented data from the first 25,000 participants in what is the largest U.S. MCED study, PATHFINDER 2 at ESMO. Now we demonstrated that when you add Galleri to USPSTF A and B rated cancer screenings, it yielded a more than seven-fold, let me repeat that, seven-fold increase in the cancer detection rate in the population. When you add prostate cancer to those USPSTF screenings, we detected more than three-fold the number of cancers with the addition of Galleri.

Now remarkably, more than half of the Galleri detected cancers were found in early stages 1 and 2. These cancers are localized when treatments are more effective and even curable. And nearly 3/4 of the cancers detected by Galleri have no recommended screening tests at all. The positive predictive value, one of the key clinical metrics was nearly 62%. Now remember, that's an order of magnitude higher than anything that is typically seen in single cancer screening tests, meaning positive test results are very trustworthy and highly actionable. The episode sensitivity for 12 deadly cancers that account for about 2/3 of deaths was almost 75%. Galleri's high signal of origin prediction accuracy helped physicians guide an efficient diagnostic workup. And importantly, there were no serious study-related adverse events.

These data from PATHFINDER 2, along with the prevalent round of the NHS Galleri trial will be submitted to the FDA in Q1. We have 2 additional study readouts coming out in '26, including the full data set from the NHS Galleri RCT and the complete 35,000 participant PATHFINDER 2 study. These large data sets are completely unique in the field. They provide GRAIL with the deepest insights about early cancer detection, and they can help us improve our test over time. Taken together, this all demonstrates GRAIL's groundbreaking leadership of this emerging field. But we also know that to really achieve our aspiration of population scale screening, we need to demonstrate clinical utility, and we're evaluating this in multiple trials.

First, we saw a really important clinical utility measure in the PATHFINDER 2 study that could have a major public health benefit, and I've mentioned this to you already. The ability to increase the cancer detection rate in the population through screening by seven-fold when Galleri was added to standard of care single cancer screening. That's an important clinical utility measure. And in the NHS Galleri trial and in the Medicare REACH study, we are also assessing as a clinical utility measure, the absolute reduction in the incidence of late-stage cancer. It's an incredibly exciting time for commercial growth at GRAIL. There's an enormous unmet need for cancer screening. There's a large addressable population, and we have best-in-class performance with Galleri.

We're detecting cancers every single day, and our data readouts are generating palpable excitement with customers, generating physician and consumer confidence and creating a lot of momentum for GRAIL. There are some strong near-term accelerants. We're continuing to expand the awareness of MCEDs. We have established significant differentiation. We are increasing our provider, patient and employer conviction with Galleri with the high-quality data readouts and the vast evidence program that we've undertaken. We anticipate an FDA approval. And if that's achieved, that will drive even greater clinical conviction and market adoption. We see continued integration into health systems. In fact, there are a number of high-profile health systems like Mayo Clinic and Dana-Farber that have recently published their own experience with Galleri and shown positive predictive values of 70% to 80%, and those have been presented at major medical conferences.

These systems are also incorporating Galleri into their workflows, and many of them are offering Galleri to their own employees, signaling their conviction in Galleri. Additionally, implementation of Galleri ordering and result delivery in electronic medical records or EMRs has a very positive impact on growth. It's not surprising when you make it easier for physicians to order, the breadth and depth of prescribing simply increases. And finally, as many of you are aware, there's a massive migration right now towards a more consumer-empowered health care market, and this is helping build a growing self-pay market. This is fueled in part by the growth of HSAs tied to high deductible health plans and FSAs tied to employer offerings, which allow individuals to select preventive health care services and pay for them through those means such as Galleri.

GRAIL continues to make meaningful progress towards broad coverage and reimbursement, which is our aspiration for population scale screening. We first set out to develop a world-leading evidence base to support a paradigm shift in cancer screening, operational capacity to support population scale testing. Achieving FDA approval will serve as a major trigger for evidence-based coverage decisions with U.S. payers, could enable Medicare coverage and additionally support expansion in select regulated international markets. We've built out our lab infrastructure to enable substantial capacity. And as discussed, we are progressing our clinical utility and cost-effectiveness evidence base to support coverage decisions among U.S. commercial payers and enable engagement with international single-payer systems.

We've made amazing progress over the last 9 years, and we're looking forward to '26 as a very exciting year. And these are the critical milestones. We're going to be completing our modular PMA submission in Q1. We'll be presenting our full data from the NHS randomized clinical trial in the middle of '26 with a top line announcement in advance. We're going to be presenting the full PATHFINDER 2 results of 35,000 participants in the middle of '26. So it's going to be a very exciting year. I want to thank you all for joining us today, and we're happy to take some questions.

You mentioned the price elasticity. So obviously, I've done GRAIL test, my wife has done it. It's $900. We paid it. We're not too happy about it. What's the thinking in that in terms of pricing and in terms of scaling up to get population scale?

Yes, it's a good question. So we're in the early innings right now. So we -- as we mentioned, we know there's price elasticity in the market. We've tested some of that in the various channels, and we do different volume discounting. Over the long term, though, like in the MCED bill, we know the pricing is down towards $500. What we've really geared the business towards is that scale. We know that winning in this space is in the millions of tests. And so high-volume testing, which means we need to get our COGS down. And that's part of the automated system that I talked about and Josh talked about was really to drive the scalability in the COGS structure so that we see at that -- at the MCED bill pricing to be able to get to that 50% to 60% margin at scale. So long term, we'll probably be driving towards that and also making sure our COGS structure is such that we can be in that range.

Is there a pharma strategy? You've obviously produced a massive amount of data. Is there a pharma strategy for either in R&D or clinical development using the testing in clinical trials or anything like that?

Yes. So right now, we do have biopharma partners who are using our test for various things, both the data that we've generated as well as our test results, primarily in clinical studies as a filter for who comes into the clinical study. So that's already happening.

Can you give examples of what specific cancers you're testing for?

Yes. So most of the common cancers that you think of, lung, liver, gallbladder, pancreatic, those are all. So we're not -- we're not looking for a specific cancer in the test. We're looking for a shared cancer signal. And so we expect to continue to find more cancers. As Josh mentioned, in the early days, we had seen 50 cancers. We've now seen over 100 different types of cancer, and we'll continue to see different types of cancer.

More on the NPV side, the negative predictive value. Is there any progress or design where you could show and become substituting regular cancer screening in the future?

I'm sorry, PPV or...

NPV, negative predictive value.

Yes. So is your question, talk more about the NPV?

Yes.

And could we replace single cancer screening?

Yes, yes.

So it's really important, 2 things. One, what Bob just said. Galleri was not designed to look for any particular cancer. We're not setting out to find these 12 or those 20 or those 5. We are looking for this shared signal that is shared by many cancers. So it's -- and that's very confusing for people about when we come to mammogram looking for breast cancer or colonoscopy looking for colon cancer, our negative predictive value is about 99%, okay? So none of these screening have perfect -- we're going to miss cancers. And you saw that even our sensitivity for the group of cancers that account for 2/3 of deaths was about 75%. So the negative predictive value is about 99%, which stacks up pretty well with many of the single cancer screenings, but none of them are perfect. So Galleri was designed to be a complement to the existing single cancer screenings, which have sensitivity that's very high for those single cancers, but they have very high false positive rates and very low positive predictive values. So we will not replace colonoscopy. Colonoscopy finds precancerous polyps, they find precancer. We will not replace mammography nor should we. And so we are a complement to those existing single cancer screening tests.

Anyone else?

Just a follow-up question to the precancer signals. I think Natera just reported on improving their value in finding polyps and other precancer signals. Would you be also expanding Galleri to be able to look for other signals other than DNA cancer?

I mean you're asking a very interesting question. So what have we learned about blood-based cancer detection? Typically, it's very difficult to find precancerous lesions. There's questions about whether the blood-based colorectal cancer screening tests are even detecting adenomas, for example. What we do know is that in the heme space, the blood compartment, we have a very strong signal, and we do identify pre-malignant hematologic conditions. But it's highly unlikely that a blood-based test looking at ctDNA is going to be able to detect premalignant cancers from solid tumors or premalignancy in solid tumors. That's highly unlikely. And I think the question is still out about whether the blood-based colorectal cancer tests are actually detecting adenoma beyond what their false positive rate is.

Well, thank you for everyone. Appreciate your attention.

Ladies and gentlemen, please welcome the President of GRAIL, Dr. Josh Ofman.

All right. Hello, everybody. Good to see everybody. Thank you all so much for coming. We have a great day for you today. And hopefully, many of you will also take our tour to the lab, which will be incredible. But again, it's a pleasure to be here. We're thrilled to host an Analyst Day. I think this is officially our first in-person, real effort here. So it's terrific to have you all.

So we're going to go to a set of disclosures, which you're all familiar with. I won't -- did I go too far. I won't read any of them. But just make sure if you have any questions about any of this, please come to us.

And now I'm going to introduce our CEO, Bob Ragusa, who's going to give some introductory remarks. Bob?

Thanks, Josh, and thanks, everyone, for joining -- yes. Thanks, everybody, for joining us. I'm sorry, I'm not able to make it there...

Bob we can't hear you yet. Any chance we can hear Bob? There we go. Bob, up to you. Go for it.

So thanks, everyone, for joining us today. I'm sorry, I'm not to be able to join you there in person, but that does not disminish my excitement for you to be with the GRAIL team at our centralized lab in Research Triangle Park, North Carolina. I'd encourage you to spend time with our leaders and various experts and attendance, and enjoy the guided tour of our lab.

The lab is an operational hallmark [indiscernible] in our endeavor for population scale multi-cancer early detection. Our goal today is to share with you key highlights of the business and the tremendous progress that we have made as a public company since June of last year. We will also provide access to some critical experts. These are the physicians who designed and ran our key studies and the physicians who are on the front lines today using the Galleri test with their patients.

We've had a very packed agenda. Aaron and Josh will go through a brief business review, followed by a review of PATHFINDER 2 results in the NHS study design, and anticipated milestones by Dr. [indiscernible]. and Professor Peter [ Casini ]. We will have a Q&A session at the end of the first section, take a very short break to provide lunch and then we'll come right into the reviews of our international opportunity and the commercial business. Finally, we will close the formal presentation with a customer panel.

At the end of the day, we'll also provide the opportunity for [indiscernible] for those of you on site. So we hope you find this an enriching day. And with that, I'll pass it over to Aaron and Josh for the business review.

Thank you, Bob.

Thank you, Bob. Okay, everybody. Thanks for -- as Josh and Bob said, thanks for coming out here. This is the first one of these that we've done. We'll be doing more of those in the future. And I hope you can see, I mean, in a short 10 years, you have seen the data, you've seen the financials and all that stuff going on, but now you get to see the lab. You get to see the space where we're actually changing outcomes of cancer diagnoses.

So I'll start here with looking at the financials and just kind of what we've done in this time period. We're focused on detecting cancer early when it can be cured. It's our mission. It's what we came up with the idea with 9 years ago, almost 10 years ago, and we're marching down that trail. We've built something special here. We're at the beginning of that, and we're really excited about where it's going.

We see ourselves as a leader in this expansive field. We're first to market with an [ MSA ] test launched in 2021. We've demonstrated performance through several studies, most recently, the PATHFINDER 2 study, which you'll hear more about later today. And we've built this large commercial experience, large clinical data set over that time period. And it really puts us in a position to continue to lead, and we're excited, excited to be here.

So through the research studies and our clinical experience, this data set has allowed us to improve the test. It's allowed us to really show where this can go. The data sets we've [ read out ] just phenomenal in our eyes. And this opportunity is enormous, right? It's a huge, huge space. We're at the beginning of that, and we're really excited to see where this can go.

As you can see here, we did $125 million revenue in '24, [indiscernible] 9 months of 2025. We're growing at a 25% rate compared to last year. And it's, again, early days. This is a pre-reimbursement space as you'll hear more about our path to get to broader access, broad reimbursement and sell on from the rest of the team once I finish talking.

So we've built this lab. We can run a million tests. You'll go see how automated that is. It's really impressive. It's one of my favorite things to do at GRAIL, just walk through the lab and get a tour and see how it all works. It's really great. And most recently, we've managed to finance ourselves. We announced a $325 million [ pipe ]. And that really gives us the capital to navigate with flexibility, this ramp over the next 3, 4, 5 years. And we're excited that with the investors that have come in, in this time period. The partnerships that we've built and sell on. It really set us up well.

Next slide. There's a little financial outlook. So I always like slides like this where you can see revenues going up into the right on one side and cost going down on the other side. So we did a restructuring back in 2024. And since then, we've really managed to grow the business and execute against our milestones as we get to broad access, while growing revenues. And it's not easy. And this is a developing field. So with the financing that we've received, we now have the flexibility to adapt as the space grows, as we learn more about what's going to -- get to massive -- large adoption and so on.

We've updated our guidance yesterday to be in the midpoint, the mid-range of the 20% to 30%. And we brought down our cash burn for the year to $290 million net of the financing fees for the year. So again, continue to improve and perform well compared to how we thought we would.

What we've been focused on in 2024 with this new platform is really driving COGS down. You'll see that on the next slide and give you a little more color on that. So you see margins increased to 55% compared to the prior year of 41%. It's really driven by the new platform, variable cost and fixed cost improvement.

The way to think about the fixed cost is, last quarter, we ran 66,000 tests, or an average run rate of 260,000 tests, somewhere in there, compared to the prior year it's about 160,000, 180,000 test run rate on the older platform. Last quarter, we ran 45,000 tests. So you can see just how much fixed cost leverage we have there. We don't expect the clinical samples that we ran last quarter to repeat this quarter in a subsequent quarter, but it's really an example to show how much fixed cost leverage we get once we put volume on this platform.

Again, I can run a million samples based off of the equipment that we have today and the space that we have, and then we can add to that modularly as the demand comes in, in a pretty capital-efficient way.

And so with that, I think I'm turning it over to Dr. Ofman.

All right. Thank you, Aaron. Everybody hear me okay? Great. So now we're going to do a little kick off into the real core of the meeting. And just to remind everybody why we're all here. We are here because cancer is soon to become the leading cause of death in men and women worldwide. Right now, it's cardiovascular disease. That is expected to be overtaken by cancer either at the end of next year or the following year. And it's one of the diseases that has touched all of us and our families. Is there anybody in the room who's not been touched personally by cancer?

It's almost every room I go into, nobody raises their hand. So it is one of those diseases that keeps people up at night. And the problem we're trying to solve at GRAIL is why is that? Why is cancer going to become the #1 cause of death worldwide? It's because we're finding most cancer too late. And we are here and dedicated to trying to solve that problem.

And we've begun this incredible journey with what I believe is one of the largest clinical genomics programs ever undertaken. It began with our observational case-controlled study, which most of you are familiar with, what we call the circulating cell-free genome Atlas. And that was how we began to discover that we had a shared cancer signal that could be identified using methylation. We've used it to validate analytically our assay and then clinically validate our assay. And we've adapted our assay and learned a lot about the very nature of cancer through a biological signal that is being shed from cancers, and that is DNA being shed into the blood.

And what we learned here is that a methylation signature, a pattern, apparently methylated DNA is very indicative of cancer. And that pattern is almost never observed in people known not to have cancer. And that is when the light bulbs went off at GRAIL that we had a multi-cancer early detection test. And in that methylation signature, we can also see a fingerprint of where in the body that cancer signal is coming from, and that is the magic and the power of this assay.

We've then studied it prospectively in interventional trials. The PATHFINDER study, PATHFINDER 1 and PATHFINDER 2 around clinical performance. We've put it into a randomized controlled study in the NHS, which you'll hear about, to define clinical utility. And we're putting it now into a large prospective interventional real-world study in Medicare beneficiaries called the REACH trial. And again, we only introduced Galleri clinically, into clinical practice, once we had validated the assay in an interventional study in patients actually being screened for cancer.

And you may know there are other test developers now introducing tests into clinical practice based on case controlled studies. We do not think that is appropriate. And it is probably not in the best interest of patients because you cannot define the effectiveness or safety profile of a product from a case-controlled study. It has to be used in a population -- a screening population prospectively in an interventional study. And we have done that. And I think we've set the right bar for evidence for the field.

This is a new field. And if we want to change the paradigm of cancer detection, this is what's needed. You have to do it the right way, you have to build the evidence properly, and you have to introduce it clinically at the right moment when you've got the right level of validation, and you understand both the effectiveness and safety profile of your product.

Now again, we have shown consistently strong performance across a variety of studies. As you may know from working in diagnostics, which many of you do, it is very unusual to see the results of a case-controlled study be translated faithfully in the interventional study. The case control studies, if any of you have read my blog post, can be designed in ways that can really determine the results that are observed. So when you see a case-controlled study being recapitulated in interventional studies, it's actually not that common to see that.

But what you've seen here with Galleri is across the PATHFINDER 1 study, the PATHFINDER 2 study, real-world studies, studies done at Mayo Clinic and [ Dana Farber ], our own commercial experience, you see a very consistent set of results related to what we think is one of the most important clinical measures of an MSA test, the positive predictive value. Just so that all of you are reminded, PPV positive [indiscernible] value means, if you have a positive test result what is the likelihood that you're sitting there with cancer, right then? And our PPV, you see began being modeled from our observational study at about 44%, being recapitulated in PATHFINDER at about 43%, PATHFINDER 2 now, a larger, more diverse population at 62% then, and you see the other experiences.

And what we've learned about our assay is that as providers have gained more experience as providers understand how important it is to look hard for those cancer signals, you see the PPV going up. Mayo Clinic and [ Dana Farber ] are good examples. There are slightly older populations, but what we know about these sites is they were looking hard for those cancers. When they got a predicted signal that's in pancreas, over, liver, stomach, they didn't stop looking, and they found the cancer, and that's why their PPVs were so high. So again, consistent strong results is the hallmark of a well-validated assay.

Now I want to share a little bit about the opportunity of what we're talking about here before I hand it over to go through PATHFINDER 2. So what we've done here on the left side of the slide is we modeled, what does the world look like today? So my belief is that if you want to really understand Galleri, you have to begin with an understanding of what is going on in the world today. So let's talk about that.

The top row in burgundy there is what is happening in the world today. You have 5 screening tests today, breast, cervical colon, lung, prostate. They are finding 184,000 cancers every year in the United States. Pretty good, right? That's only about 14% of the incident cancers. But in finding those 184,000 cancers, they are generating over 8 million false positives. Okay. Let me repeat that. To find 184,000 cancers, they are generating over 8 million false positives.

In this country today, we are spending almost $40 billion a year on cancer screening. Where do you suspect most of that money is being spent? Working up all those false positives. So not very efficient. That's about a signal-to-noise ratio of 1:44. Not particularly efficient. Now those single cancer screening tests are great tests, they are saving lives. But the deal we made with single cancer screening is that we have very high sensitivity and we accept very high false positive rates. That's the deal we've made with single cancer screening tests. That would never be acceptable for a multi-cancer early detection test.

So we designed Galleri to be a complement to those single cancer screening test. We cannot replace those. They are highly sensitive, they find early premalignant disease, and they're saving lives. So adding Galleri to standard of care screening is the right approach. And when you do that, you add an additional 482,000 cancers, additional 482,000 and you only generate another 380,000 false positives. And that's modeled based on our data from clinical trials.

If you look at this now, this new picture of what the screening system can look like, you can see that it's much more effective in cancer detection and much more efficient in cancer detection. In fact, the signal-to-noise ratio gets driven down from [ 1 to 44, to about 1 to 14 ]. And the cost to detect the cancer gets reduced by about 65%. So a much more effective and efficient system. This is the system that we are driving towards. This is the paradigm change we are proposing and are driving.

On the right side of the slide is the fact that most of the cancers Galleri finds are currently unscreened. There are no recommended screening tests for the majority of these cancers. Yes, we will find interval breast cancers. Yes, we have found, and do find, interval colorectal cancers. Yes, we will find aggressive prostate cancers. But standard of care screen are going to find the majority of those early cancers. And what are we finding? The majority of what we find are cancers that currently have no screening today.

And for those of you who may say, your overall sensitivity is not high enough. Let me remind you that the current sensitivity for asymptomatic cancers for cancers that have no screening test is effectively zero, unless it's found incidentally. In other words, the false negative rate is almost 100% for the standard of care today, okay? So that is now the picture that I want you to think about as you now hear the data coming from our PATHFINDER 2 study.

We are now in our final push to complete our submissions to the FDA by Q1 of 2026. That submission, we believe Galleri will be the first FDA-approved [ MSAD ] test. That is our goal. That's been our commitment. We are submitting PATHFINDER 2 data, which you're going to hear about in a moment. We will submit performance data from the first 25,000, which was a prespecified analysis with 1 year follow-up. We will then submit the remaining 10,000 once that's completed.

The NHS-Galleri test, we will be submitting the first year of the prevalence screening round and data from the intervention [ arm ] as part of our PMA. And then there is a bridging study, which bridges the validation from our version that was used in those studies to the version that you're going to see on your tour of the lab, which will be our PMA device. So we have a bridging study. That will comprise the FDA submission, and we are looking forward to completing that in the first quarter of next year.

Now with that in mind, I want to very proudly introduce [indiscernible] from [ OHSU ], who is one of our principal investigators in the PATHFINDER 2 study. [indiscernible], the stage is yours. Thank you.

All right. Well, hello, everybody. Thanks again for the invitation to be here. It really is my pleasure to be, and privileged to be, presenting the initial results of the PATHFINDER 2 study that we just presented at the European Society of Medical Oncology in Berlin about a month ago. The study really is a landmark study that is really changing the way we're thinking about cancer screening. And I'm a radiation oncologist at [indiscernible] I'm also a clinical researcher. And we've had the privilege of collaborating with GRAIL for quite some time now on their prospective interventional studies from the PATHFINDER 1 study to the PATHFINDER 2 study, and the currently accruing REACH study that we're also enrolling on.

And I'm going to say we probably have one of the most robust experiences in the world in regards to providing these tests to participants, and walking them through the diagnostic pathways for a signal positive. We've enrolled nearly 8,000 participants on a multitude of these studies. So again, it's a pleasure to be here, and I hope I have some insights to offer.

Disclosures. So just jumping right into the PATHFINDER 2 study is the largest interventional [ MCED ] study ever conducted in the United States, enrolling nearly 35,000 participants across 32 North American health care systems, [indiscernible] being one of them, over 32 months. All participants in the PATHFINDER 2 study were at least the age of 50 with no clinical suspicion of cancer, nor diagnosis of cancer or treatment of cancer within the last 3 years. All participants had their blood drawn. The MCED test was performed and they were provided with the results.

For the participants who had a cancer signal detected, further diagnostic evaluation issued by the study team. The investigators were provided with protocol recommended guidelines for diagnostic workup, targeted to the cancer signal origin that the Galleri test had predicted. The PATHFINDER 2 study will be following all of these patients for 3 years to assess their cancer status, as well as any patient-reported outcomes, such as adherence to recommended screening guidelines. And the primary objective of the PATHFINDER 2 study was to evaluate the safety and performance of the Galleri test in a large and diverse intended use population.

So with this prespecified initial analysis, we analyzed 25,000 participants on the PATHFINDER 2 study who had at least 1 year, 12 months of follow-up. And the table to the right shows the baseline demographics of the study and a large and representative population was enrolled on the study across age, sex, race and ethnicity. And this is largely due to outreach efforts and recruitment strategies, and we believe that this is really important to assess the utility of the test in an intended use population.

216 participants were found to have a cancer signal for a cancer signal detection rate of 0.93%. For those participants with positive signals, the positive predictive value was 62%, meaning 6 out of 10 participants with a cancer signal where ultimately identified to have cancer. This PPV is higher than what's been previously seen with the Galleri study [ and is ] orders of magnitude higher than the PPVs of our current single cancer screening methodologies, such as mammogram or [ FIT ] testing for colorectal cancer, which have PPVs of around 5%, meaning that for patients with positive results, only 1 in 20 are found to have a cancer, and Josh alluded to the high burden of false positive there.

The specificity of the Galleri test on the PATHFINDER 2 study was 99.6%, which is consistent with previous reports of the Galleri test. And this was intentional. This was intentional to minimize the number of false positives, thereby driving the high PPV that you're seeing there. And we -- I agree, and I know GRAIL agrees that this is important for safe population screening.

I'll pause. We don't want black on the screens, but I can keep talking on my screen here. All right, there we go. Can we go back one slide? There we go. So yes, specificity was high. For interventional studies like the PATHFINDER 2 study, it's not known at the time of testing whether or not a participant has cancer. Thus, we calculate the episode sensitivity, which is a measure of a test identify cancers within a prespecified time frame, and in this case, 12 months. And the episode sensitivity for all cancers across 18 broad cancer types was 40.4%. These sensitivity was even higher in clinically relevant subgroups.

For the 12 cancers responsible for 2/3 of U.S. cancer deaths, episode sensitivity was 74%. It was 72% for 6 cancers, 6 aggressive cancers, low 5-year survival, 56% for all cancers, except breast and prostate, and 55% for cancers with outcome and screening options. And again, I want to remind folks that comparing episode sensitivity, one should not compare episode sensitivity from interventional studies like the MCED study to test sensitivity from case-control studies as they're designed completely differently.

Within the 1-year time frame of this initial analysis, 329 participants were diagnosed with the cancer. 200 of them, or 61% were screen detected, far higher than the currently 14% of U.S. cancers that are screen detected. The MCED test detected 133 cancers, and the MCED test identified sevenfold more cancers when considering the cancers that were screened detected through single cancer screening methods of breast cancer, cervical cancer, colorectal lung cancer. When also considering the 47 screen detected prostate cancers, the MCED test increased the number of screen detected cancers by threefold.

Cancer is identified on the PATHFINDER 2 study were clinically relevant. 114 were new primaries, 18 were recurrent cancers and 1 participant had a cancer of unknown primary site. 2/3 of these MCED detected cancers do not have recommended screening. Furthermore, most cancers that were identified were in early stages. 69% were between stage 1 and 3, 54% between Stage 1 and 2. And of these early- Stage 1 and 2 cancers, 74% of them do not have recommended screening strategies.

One concern with MCED testing is the fear of a diagnostic odyssey, particularly when -- particularly if a test does not provide a cancer signal origin to help guide diagnose [indiscernible]. The PATHFINDER 2 study showed a prediction -- accuracy of prediction for the cancer signal origin, 92% for true positives. And this accurate cancer signal origin helped guide efficient and targeted diagnostic workup, with the median days to diagnose a resolution after a positive signal being 46 days for all participants, 36 days for true positives, and 75 days for false positives.

Another fear with MCED testing is a fear of too many invasive procedures. We found this fear unfounded as well of the 25,000 participants who received an MCED test, less than 1% -- 0.6% and had an invasive procedure due to a positive MCED test result. Participants that did not have cancer had far fewer invasive procedures. And at the time of initial analysis, there have been no serious study-related adverse events reported during the diagnostic workup.

So in summary, these initial PATHFINDER 2 results demonstrate robust performance and safety across a broad population. It's the largest interventional MCED study conducted in the U.S. to date, increased the number of cancers detected by screening by more than sevenfold when added to recommended screening, demonstrated robust performance with a 62% positive predictive value, substantially higher than observed in prior clinical studies. Majority of cancers that were identified were early stage. The majority of those cancers do not have recommended screening strategies. The test also enabled prompt efficient diagnostic resolution with a favorable safety profile. And I believe these results really illustrate Galleri's clinical utility and potential to improve outcomes in an intended use population.

And I think we have a Q&A session after this. I'm happy to answer questions. Thank you all. And I'll be -- yes, so I should introduce our next speaker. Professor [indiscernible], who is from the U.K., who is an instrumental lead in the NHS-Galleri study that we're anxiously waiting.

Thank you, [indiscernible]. Thanks, [indiscernible]. Thank you very much. It's a pleasure to be here. So my disclosures, I'm on the Scientific Advisory Board for GRAIL, and I should perhaps say that I'm not a physician.

So you've heard a little bit about the [indiscernible] the [ SIMPLIFY ] study you have heard about and PATHFINDER 2. So I just want to say a little bit about this before talking about NHS-Galleri. The [ CCGA ] really was a very large case control study, which provided data on the ability of the test to detect and locate multiple types of cancer. And then also to demonstrate that a positive test result was extremely rare in people without cancer. And that was done in taking a large number of people with cancers before they were treated, but after diagnosis and a large number of people without cancer.

The SIMPLIFY study, which was done in the U.K. was done in people who were referred for diagnostic workup because of symptoms that their doctor felt were likely to be due to cancer. Only about 7% of those people actually had cancer. But nevertheless, the test was done the results were not disclosed. So they actually were mostly -- the sample was taken, but the result -- the test wasn't analyzed for some time. And the results show that actually the if you have a positive result, indeed, the chance that you had cancer is extremely [indiscernible] for symptomatic people. It was much higher than you saw in PATHFINDER 2.

And the -- the other thing, which the new results from [ SIMPLIFY ] show that the people who had a positive test result, but no cancer was found initially over the next 2 years, 1/3 of them had a cancer diagnosed. And then PATHFINDER 2, as you've heard, shows that you can actually detect cancers before symptoms are found using this test. So these are people who are coming for screening, and it showed that you really do find cancers and that there were no safety concerns whatsoever.

But all these studies are, if you like, showing that the test does what it sets on the [ care ], there's nothing to say that there's really a good advantage of having the test done. And that's what we wanted to set out in NHS-Galleri. That not only can we detect and locate multiple types of cancer. But by doing that, there is some benefit to the individuals. And so if you like, the first 3 studies are all to do with clinical validity whereas the other one is really the utility. Is there an advantage to you of having your cancer found early by going for screening?

So NHS-Galleri is being done in England, possibly because we say that the lifetime risk of cancer in England is 1 in 2, not 1 in 3, but I think that's probably just because we calculate things a little bit differently. Cancer rates are very similar in the U.S. and in the U.K. with a few exceptions. It's a very large study, 140,000 people. I was a graduate student at [indiscernible], the [ Husky Stadium ] takes 70,000 people. That's the number we've got in each arm [indiscernible] NHS-Galleri. I think a lot of you are from New York, I think 140,000 is like 3x the capacity of the [indiscernible] Stadium.

We wanted to make sure that we could compare actually what happens if you add the test and if you don't have the test. So all 140,000 people had a blood sample collected and we only randomized them once we had that blood sample. And then they were randomized to analyzing the blood sample, or storing it for future work. So half the people, 70,000 have had their test screen. And if it was positive, our team called them up. So [indiscernible] were analyzed here in the states some of them here, some of them in California. And the results we got back mostly within 2 weeks. We phoned the people up to tell them about the positive result and made an appointment for them to go to an appropriate clinic straight away.

All individuals, so we didn't tell people which arm they were in, unless we phone them up to say you've had a positive test. So all individuals were then invited back for a second blood sample at 12 months, and a third blood sample at 24 months. And in that way, this study is going to be able to tell you a lot about the performance of the test, not only when you first do it, but also on a subsequent test as what we call an incident screening round. So if you saw in PATHFINDER 2, there were quite a lot of Stage I cancers found initially on screen. I really hope that there'll be far fewer found at 12 months and 24 months, and this will give you very large amounts of data to look at the performance of the test in that way.

But it also means that we can compare what's going on in the 2 arms. And is it true that the people who have screened are less likely to get an advanced stage cancer [ Stage III ] and Stage [ IV ] cancer than those that were not screened. And if we can do that, it's Stage [ 3 ] and Stage [ 4 ] cancers that mostly are what kill people of cancer. Most Stage 1 and Stage 2 can be cured. And so if we can shift that we will really be doing something very useful, and you can say, be sure that screening with this test annually is a good thing.

So I want to talk about the time lines of the trial for a moment. We promised GRAIL that we would start recruiting in August 2021. My team were not so happy. They thought there were all sorts of problems. So we recruited a few people on the 31st of August 2021. But then in September, we sorted out all the teething problems, and we recruited 140,000 people in 10.5 months. That's the fastest recruiting clinical trials since the [indiscernible] vaccine trial in 1954. I've said that a few times. No one has corrected me, so I think it's probably true.

We collected blood samples at 12 and 24 months. So the last of the blood samples was collected in July last year. The main analysis that we hope to publish next year is on [ Kansas diagnosed ] up to July of this year. It takes some extra months because cancer registration doesn't happen instantly. And in fact, it's incredible that we're going to get results within about 6 months. That is a quarter of the time that it would take typically -- the cancer registry has been trying to get to 2 years and often, it's been 3 years before they've been able to publish results we've got complete data on cancer. So it takes a long time for the data to get from the hospitals to the registry and to be clean.

And [indiscernible] then be to other waves of publication so that the individuals in the study will be followed up for mortality, did they die, what did they die off? 2 years beyond that time and then a further 3 years. So it will be 6 years from the last person having an appointment in the trial, or 8 years from the from when they were last randomized.

So the main endpoint is a reduction in advanced stage cancer. And this is a little bit controversial. So I want to talk about it a little bit. And the first is that I think it's really important to think about [indiscernible]. Much of my career, I worked on parcel cancer, HPV vaccination. So I want to talk about that for a minute. We now know that [indiscernible] cancer is caused by HPV infection. If you have a persistent infection, it can start to lead to a precancerous lesion [ soapeneoplasia ]. If that's not treated, it can go on and to become invasive [indiscernible] cancer. And if you had a [indiscernible] cancer and you didn't treat it, or even if you did, you can get death from [indiscernible] cancer.

If you can prevent the infection, you'll be able to prevent the death of [indiscernible] cancer. No one said that you had to wait and show a reduction in mortality from [ cervical ] cancer in order to introduce HPV vaccination. And in fact, it was only 17 -- no, slightly less, about 15 years after we introduced HPV vaccination that we were able to show a reduction in [indiscernible] cancer as a result of that vaccination.

Similar argument [indiscernible] cancer screening. Cancer progresses through stages. For most cancers, prognosis gets substantially worse for the more advanced stages. If you find a cancer earlier, screening will lead to fewer advanced-stage cancers then the -- because the advanced [indiscernible] had substantially worse prognosis, you're going to likely to reduce cancer-specific mortality.

What data that exists shows that this is true. So these are metro analysis, each dot on this graph corresponds to a different randomized controlled trial comparing screening to no screening, different types of cancer screening. On the vertical axis, it's the relative reduction in cancer mortality. And on the horizontal axis is a relative reduction in advanced stage cancers. And you can see that the results are highly correlated. Virtually everything is either in the top right, saying that screening worked on both measures, or the bottom left that it really didn't work. And there's a second paper, which had more studies in it showing there.

And so if you reduce late-stage cancer, it makes [indiscernible] sense, that is going to result in a reduction in advanced stage. And if you wanted to look at mortality, we're going to have to wait longer and we'd have to screen more people. The study would probably have had to be 50% larger to last twice as long, and we would have no results for a long time. In that period of time, you could be making a lot of progress in terms of rolling out screening if it works.

And this graph, which is from the same sorts of studies, but here, there's one dot for each type of screening. So each one is a meta-analysis of that type of screening. And this is the significance. And you can see that if the results were not significant for a reduction in late stage, they were not significant for a reduction in mortality. And if they were significant, they were significant for both with one exception, and that was in liver cancer, where at the time these studies were done, everyone who got liver cancer even if they were [indiscernible] stage 1, died from liver cancer. So how are we doing this?

So first of all, we're going to test for a reduction in Stage 3 and Stage 4 cancers from these 12 prespecified [indiscernible] that account for 2/3 of cancer mortality in the U.S. and the U.K. If that significant -- the result is significant, the trial has shown that it can reduce advanced-stage cancers from these 12 types. But if it is, we want to look further. Does it have an effect on other types than the other than [indiscernible] or does it have an effect overall. And so we can do additional testing, first looking at everything other than prostate cancer, then everything, including prostate cancer. And because we're doing the sequential testing, we're only going to do the test, if the test before is significant, there's no problem with multiple testing.

There are lots of secondary objectives and some of the key ones is to see if there's a reduction in Stage 4 cancers, which are the most deadly cancers. We also want to look at the test performance. There will be 10x as much data from this trial than there has been so far from PATHFINDER 2 in terms of test performance. It really is a massive study. We'll look at the overall cancer detection rate. It's not important, if you like, that the sensitivity is poor compared to other screening tests because it's screening for lots of cancers at once. What's important is how many cancers you're finding, how many cancer deaths you will be preventing for every 100,000 people you screen. We'll be looking at safety, important. We're not expecting any adverse safety signals, but it's really important to demonstrate that at scale, this is safe, health care utilization. What actually happens, how many tests are we having to do in all these people are going to be testing positive. And we'll be eventually comparing cancer-specific mortality between [indiscernible].

So in terms of kind of specific mortality, hopefully, towards the end of next year, we should be able to look at predicted mortality, which is sort to say, based on the cancers that we have diagnosed, the stage that they were at, what do we think about when those individuals might die from cancer. We'll then in 2 years' time -- 2 years later, look at the actual mortality on a nested analysis, which gives us far more precision in able to look at that. And then 3 years after that, we will look at the observed mortality in the whole cohort. Thank you very much.

Okay. Thanks very much, [ Peter ]. My name is Harpal Kumar, for those of you who haven't met, great to see you all here. So have time now about 15 minutes for any questions that anyone has. So straight over here.

There's a roving mic. So if you just wait until the mic gets to you for any of our 4 speakers so far. Someone get [indiscernible].

I'm Subbu Nambi from Guggenheim. This question is for Professor [indiscernible] You articulated the endpoints on the NHS trial on Slide 36, basically the primary endpoints. Is this how the FDA will also look at this study?

Just someone else want...

Let me take a stab at that. Yes. So the FDA has been pretty clear in their several advisory boards. They are not looking at mortality. So the FDA is going to be looking at what they call clinical validation, clinical performance. And that's why in our submission, we're just submitting the data that we have now, which is the prevalent screening round from NHS-Galleri.

They are on record saying mortality is not anything that they're looking at. And clinical utility typically is not something that the FDA looks at for approval. They're really looking at clinical validation.

Got it, Josh. And Josh, could the [ SIMPLIFY ] trial data, which was presented at [ EDCC ] be sufficient to be a supplemental to existing [ PMA ] so you get approved as a diagnostic test for symptomatic patients?

It's a terrific question. We talk about that often. Remember, and maybe Harpal you're better to answer this. It was an observational study. And so what our thinking is, is that should we decide to pursue that, which is a good idea, we would likely need to do an actual prospective study in that population. Because remember, we -- as Dr. [ Casini ] mentioned, we did not return results in that particular study, but the results are quite compelling.

Okay. I saw lots of other hands. So can you just put them up again? Right next, and then I'll come to you.

This is Doug Schenkel from Wolfe Research. Actually, let me build off of Subbu's question on [ SIMPLIFY ]. So I remember being part of the pre-IPO process and you guys actually having a product in the pipeline called [ DAC ]. And I should be able to off the top of my head, remember what that acronym was for. But essentially, that's essentially what I think SIMPLIFY is getting at.

So the follow-up question, to Subbu, is I think the -- we need to think of that assay, and just correct me if I'm wrong. But that's where you really want more of a rule out test rather than a rule in. So again, I want to make sure I'm thinking about it correctly. And if I am, from a negative predictive value standpoint, which I think would be the more important metric, I think there were studies that showed 97% and 99%, I think SIMPLIFY was in that range. Is that high enough for that population?

Should I take this one? Doug, thank you. So largely remembered very well. [indiscernible] for cancer. So what we did in SIMPLIFY was we looked at patients being referred to a number of different types of clinic based on what their primary care physician suspected was the type of cancer that they had. And your memory is extremely good. But just to boil it down, the best performance in terms of negative predictive value was in patients suspected of having upper GI cancer. So liver, pancreas, stomach esophagus and so on. And there, the negative predictive value was 99.1%. So that is probably good enough as a rollout test, given that the background incidence of cancer in that population is higher than that.

But that's exactly what we want to sort of test further in a prospective interventional study as Josh referred to just there. It was lower in some of the other types of clinics. But again, that was an observational study, and we would want to test that in an interventional way. What's really important is that a large number of patients who are suspected of having cancer have very nonspecific symptoms. So these might be things like kind of unexplained weight loss or abdominal pain. And it can be very difficult for primary care physicians to know which clinic to send them to because it could be several different types of cancer, or it could not be cancer at all. And often, that initial choice of clinic turns out to be wrong. And so that's how patients end up going through a diagnostic [indiscernible] and taking a long time to get diagnosed. So there is a real opportunity there that we want to explore.

Maybe just two more points on this. So the CSO predictive capability of Galleri in this setting is uniquely important because, as Harpal said, it's almost impossible to know to send them to the [ OB/GYN ] clinic or the GI clinic what to get worked up. And even those false positives that were then converted to true positives, the CSO was right almost every time. There was like one exception, I think.

And the other thing I'll point out to you about negative predictive value, it was very high in the SIMPLIFY trial. It was just as high in PATHFINDER 2, okay? Negative predictive value was 99%. And that's, I think, critically important to get the right balance of sensitivity and specificity, PPV and NPV.

So you'll indulge me a little bit more on this, and that was all super helpful. And I understand, I mean, ultimately, the vision for the company is getting through the FDA, getting CMS reimbursement and having this as a test that's available broadly amongst the population you talked about.

If at the same time, there's a limit to what you can [indiscernible] there, right? I mean you're doing all you can do from a study standpoint. You're going through the FDA. You're still waiting for a congressional action to actually put you in a position where you could get reimbursed broadly. With that in mind, when I think about SIMPLIFY, when I think about, Josh, what you just said about what you saw in PATHFINDER, when it came to symptomatic patients and how the study or how the assay performed there, when you looked at the detection rate of patients who want -- or individuals who once were patients in had cancer, there is a very good argument for this assay in a more symptomatic population, or a population that is at higher risk. Either they had cancer before or they had hepatitis. So they're at heightened risk for liver or dense breast women who really can't benefit for mammography.

If we think of -- I could go on, but I won't and I've talked a lot already. My question is, are there alternative paths to reimbursement? From CMS, I could see where this goes from being seen as a screen to more of a surveillance tool, which might allow you to get reimbursed [indiscernible] I've heard about some self-insured employers looking at this as an attractive way to earlier detect cancer in higher-risk self-identifying populations. I just might be wrong. But if not, am I thinking about this thinking about things that could give you alternative paths to getting paid?

Yes. So it's a great point. Let me take a stab at it and jump in. I think -- in the United States, you've correctly identified the challenges with current -- getting to broad reimbursement. But -- and there are alternatives. We've looked at the alternative around surveillance and it's not quite so certain. And we've explored that directly with [indiscernible] and others. And there's a lot of uncertainty around that as well. If it was so clear, I think we might have thought about it a little bit differently.

We do know as a diagnostic test, there are clear pathways through [indiscernible] that are not available for screening. And we've contemplated that. We definitely made a very conscious decision at the time of the spin to get very focused on Galleri. And that took all the company's resources to get where we are today. As we emerge from that effort, we are looking at these other opportunities very carefully and Harpal's leading our charge really and looking at that symptomatic population.

Just to clarify one thing you said, we didn't have symptomatic people in PATHFINDER 2. I was just pointing out to the high-end PVA symptomatic screening, which I think is -- we're making the same point that, that's really high even there. But there are opportunities in the symptomatic. We do know it is being used in that population by doctors today and these other high-risk populations, people with prior viral infections, people with prior cancers are elevated risk groups that should have access to Galleri's screening test. Whether we do surveillance or diagnostic in them, I think is yet to come. So stay tuned.

I want to make sure we get some more questions in because there are lots of other hands on. So yes, over here. Yes.

This is David Westenberg at Piper Sandler. So just on the positive predictive value, can you talk about the time that elapsed from a positive diagnosis on GRAIL to a, say, ground [indiscernible] positive? And is there a way if you found that maybe you are finding cancers a little bit later, is there a way to [ run ] a supplement, or submit a supplement to the FDA, if that one being the case?

So [indiscernible], do you want to take that first?

Yes. So I think you're speaking to the metric of the time to diagnostic resolution. We call it diagnostic resolution, a time point whenever the investigator feels that we've exhausted all of our methods of trying to find a cancer. And for all patients, it was 46 days. It was faster for true positive patients. An example is somebody with a hepatobiliary signal. You get a CT scan, you almost immediately see a cancer, and you call it pretty quickly, whereas false positives were longer than that because you're going down the next step pathways of trying to find a cancer.

And certainly, I think there's an element of us looking harder now because PATHFINDER 1, with a high PPV, kind of encouraged us to maybe not set aside some indeterminate imaging finding, but to kind of aggressively pursue it. Many times in my experience, uncovered novel cancers. And yes, I mean, it's I guess the second part of your question was...

It was related to the FDA. Can you repeat that part of your...

Wanted to ask if you found cancer, say later in some of the submission data, like 2 years later, they come up with the cancer or anything like that?

So that didn't happen. So what we're referring to in the SIMPLIFY study was in symptomatic individuals, which is not our PMA submission to the FDA. In symptomatic individuals when we looked at those false positives and followed them for 2 years more, I'll let Dr. [ Casini ]

But it is worth saying in PATHFINDER 2, we are going to be following up all of those patients for a further couple of years. So we will know if the same thing happens what we've seen in SIMPLIFY whether the same thing happens in PATHFINDER 2 patients. The suspicion is, yes, that is going to be the case, but we don't have that data yet.

So it won't be part of the PMA submission right now. But to Harpal's point, we're going to learn a lot about that over the next 2 years of follow-up.

I'd ask one little follow-up to that. I will not ask my second question given the time. Just in terms of -- I believe your policy is to run a second Galleri test when you do have a false positive. Can you talk about what results you -- the statistics that you found when you ran that second Galleri test? Whether you've seen positive revalue and negative it value improve on that second one or not?

So what we can say and jump in anybody who knows in commercial practice today in the United States. If a doctor, and we will ask our doctors on the next panel, if you get a positive Galleri test and you do a workup and it's unrevealing rather than suggest whole body imaging, or ask you to just give up, we actually offer a free repeat Galleri test. And in that setting, if those repeat gallery tests are negative, we have found almost very few instances where those individuals end up being diagnosed with cancer.

So it's got -- we don't have enough sample size to compute a valid negative predictive value yet, but it's very high. And similarly, when that second Galleri test comes back positive, again, they are most often found to have cancer. I'll just give you an anecdote to what [ Nima ] just said. We've gotten several phone calls, I get these phone calls from doctors who've had positive pancreatic signal, or the 2 that are the most common. And they have ill-defined imaging findings, subtle inflammatory changes in the pancreas, for example. And I get called saying, hey, should we give up? And my answer is usually no, do not give up. And they do an endoscopic culture sound and in the 2 cases that have just most recently happened, they found head of the pancreas tumors in both of them. So again, if you get another positive signal, it is very likely to have cancer.

Yes. The false positive rate gets cut. I can't give you the exact statistics. But that -- it almost eliminates if there's another positive signal, it takes the false positive rate way down.

Over here, yes.

Its Alex Vukasin on behalf of Canaccord Genuity. Aaron, just 2 on the business generally to start. What will the impact of discounting beyond ASP going forward?

Yes. So we've got a list price of [indiscernible], and we discount down from that based off of volumes. As we get more and more large physician practices or digital health platforms that are offering the test, they'll hit higher volume tiers and the test price will come down. We've -- we're prepared for the test price to come down.

If you look at the CMS legislation, it reimburses at around $500 a test. We built this platform to be able to accommodate that. And so we're prepared for that. But that -- how rapidly that changes will really drug be driven by how fast uptake is in -- with our current pricing scheme.

Got it. And one more quick one from me. So in a perfect world, the NHS study is successful and enables wide-set adoption across the geography. My question would be, provided the study is ultimately successful with a strategy of leveraging other national health organizations to run studies in a similar fashion, becoming such a part of the adoption strategy going forward, or something of that nature already in the works or front of mind?

Yes, why don't I take that one? We don't think we're going to need to replicate something like the NHS-Galleri study in other countries. This -- if you look at any new medical innovation, you tend to have one major pivotal registrational study. We've actually got a couple of registrational studies. You don't need to repeat them in other countries.

Some countries do want to have smaller local studies done really to test it in their population. Usually, that's for reimbursement purposes. Sometimes it's for regulatory purposes. But those are typically much smaller. They're not big randomized studies of the sort of nature that we've been talking about for NHS-Galleri.

Okay. We're going to have to cut it there. I'm afraid for time. We now have 10 minutes, I believe. I'm looking at Alex at the back. Yes, where you can grab your lunch, go to the restroom if you need to, and then we'll start again in 10 minutes. And the lunches are right back here, behind this well. Right here. Thank you, everyone.

[Break]

Ladies and gentlemen, please welcome back to the stage, sir, Harpal Kumar.

Okay. Thank you, everyone, for coming back promptly. I hope everyone has managed to get some lunch. Please do carry on eating while we're talking. So we're going to move into more of a commercial section now. So I'm very briefly going to cover some comments on the international opportunity, and then Andy Partridge will talk about some of our experience in the U.S. so far.

So on the international opportunity, many of you will have seen this slide before, and Josh alluded to it earlier, cancer is a huge global problem. And we talked about the fact that it's the #2 cause of death currently around the world with the latest statistics, more than 10 million people are diagnosed every year. But to give you some context about what's coming in the next 15 years, that's projected to grow to nearly 29 million incident cases every year -- sorry, 19 million currently, projected to grow to 29 million in 15 years. So about a 50% increase in the next 15 years, and it's going to continue growing thereafter.

These are World Health Organization projections. For those of you who are more interested in the U.S., the projection is that by 2040, cancer cases are going to grow by more than 1/3 from where they are today. So the numbers are growing really very, very rapidly, and we are, as I just touched on, we see this as a huge global opportunity and one where we want to bring this technology to bear on participants, individuals right across the world, not just in the U.S. or U.K.

The numbers are staggering. So we see, as you'll have seen before, the opportunity in the U.S. is a TAM of about 100 million people. If you add in the EU, U.K. and Japan to that, it takes it up to about 300 million people. But of course, there are many, many other countries besides that. There's all of Asia, there's all of Africa and so on. So this is really an extraordinary -- both opportunity but also challenge given the [indiscernible] of cancer cases we have coming our way. So what have we been doing?

We've really been focused in the short term on identifying partners we can work with in specific countries where we can rely on their local expertise and infrastructure to bring Galleri to their populations. And at the moment, while we're in this largely pre-reimbursement phase in the U.S., we're looking for ways in which we can do that in a very resource and capital-efficient way. In other words, not having to embark on building a lot of sales and marketing infrastructure in those countries, but as I say, identifying partners that we can work with. And so where are we today?

Well, we've launched in a few countries around the world. We launched in Israel just about 10 months ago, 10 or 11 months ago. We announced just a few weeks ago that we've launched in Canada -- sorry, Israel is with a partner called [ Oncotest ], Canada is with a partner called [ Medcan ]. And obviously, in the U.K., we also have our partnership with the NHS, where pending results from an NHS-Galleri next year, we hope to have conversations about moving that forward. And as you know, a few weeks ago, we also announced a collaboration with Samsung to bring Galleri to Asia, starting in South Korea, and hopefully expanding thereafter to Japan and Singapore. These are all very substantial market opportunities. But as I say, where we're relying on our partner to be able to bring Galleri to them -- to those individuals in those countries for now.

Of course, there's a big wide open space in terms of countries we have not yet launched in. But I will just tell you, perhaps this is no surprise, I'm getting calls from pretty much every country around the world. On a pretty regular basis about how we can bring Galleri to those countries. The challenge at the moment is finding the right partner to work with in those countries. So but we are having many very interesting and encouraging conversations. So continue to watch this space.

And so just a couple of more words on the Samsung collaboration, which we announced a few weeks ago. So this will be Samsung developing an infrastructure to bring the Galleri test to individuals in South Korea, as I say, possibly extending thereafter to Japan and Singapore. At the outset, those tests will be performed here in [indiscernible] We're also going to be exploring some potential opportunities to collaborate with Samsung Electronics, which has a very wide array of interests in health care and medical technologies more generally. And those conversations haven't started yet, but there are some potentially interesting avenues that we want to explore with them.

And then also, as you know, between the Samsung Holding Company and Samsung Electronics, they will be investing $110 million into GRAIL, subject to us finalizing the closing conditions that we've told you about. So a really exciting collaboration that we are moving forward. And again, just to give you a quick insight into some of what we're doing internationally.

And with that, I'm going to hand over to Andy Partridge, our Chief Commercial Officer, who's going to tell you about our U.S. experience.

Thanks so much, Harpal. It's an incredibly exciting time to be in the commercial organization at GRAIL. I really do believe we've got a tiger by the tail with the Galleri test. We have a huge unmet need for cancer screening, a large addressable population worldwide, and best-in-class product performance with Galleri. We're detecting cancers every single day. Many of them early stage. Those of us -- those of you who are here with us in [indiscernible], can see all of the posters throughout our laboratory here of patients that we picked up with early-stage cancer due to the Galleri test.

We're also years ahead of other companies in terms of the expansive clinical evidence generation program that we've embarked upon, which is now reading out, generating excitement with our customers and building palpable momentum for us. We're also a long way ahead in terms of the partnerships that we've developed over the last 3 years, and we have [ 2 ] upcoming milestones that are going to generate additional customer confidence and excitement with the PMA submission and ultimate FDA approval, and the readout of our NHS-Galleri study.

We're continuing to drive volume, 26% growth year-over-year that we reported yesterday for Q3. That's driven by growth in our provider channel, which was 37%. That growth is due to increases in both breadth and depth of prescribing. So, so far this year, we've added almost 3,000 new prescribers for Galleri. And we've also increased the depth of prescribing for those prescribers by 20%. The drivers of the increases in depth have been repeat testing, contracting and discounting targeted media and new customers that we've added.

And in terms of repeat testing, we're now seeing 29% of our volume is from repeat tests. And it's exciting because some of these repeat tests with patients who are on the second or third year now of Galleri testing after they had no cancer signal detected in the first or second year, are now seeing cancer signal detected in those subsequent years that end up with earlier stage cancer detection, increasing physician confidence even more about the Galleri test. And in terms of volume, we've done about 40,000 tests over the last 12 months, which were repeat tests.

Also, our electronic order integrations have increased the depth of prescribing as well with partners such as Quest and Athena Health. So year-to-date, since we moved forward with a number of these integrations, we've had about 13,000 tests go through these new electronic integrations, which is essentially an easy button for physicians. As we've now incorporated Galleri into the workflow that they have every single day, making it much easier to prescribe Galleri. And we've seen a number of benefits from that.

We have about 1,000 providers now that are prescribed through either the Quest or [ Athena ] integration. These integrations have led to new providers coming on board. So over 300 of those 1,000 providers were new prescribers for Galleri. Those were physicians that did not want to prescribe until we actually built Galleri into their regular work order flow. We've also seen an increase in prescribing. So for those prescribers that were already using Galleri after the electronic order integrations, we've seen an increase in the depth of prescribing from these prescribers. Initially, a big bump which then plateaued down, which is a meaningful increase post electronic order integration.

And we've also seen improvements in efficiency. Improvements in efficiency as you see from Quest with things like kitless, shipping, bulk order that's improving our efficiency and also the electronic order integration has reduced accessioning issues. So with paper orders, we see a higher accessioning issue rate, which takes our customer service team time to resolve those. With these integrations now, that significantly reduced those accessioning issues. And with [indiscernible] Health, that's our telemedicine partner. They support orders coming through on [ galleri.com ], and they also support many of our enterprise clients as well and [indiscernible] Health has proven to be a very reliable partner for us.

We're also the leader in digital health. This is part of our overall market access strategy. Longer term, we're focused on securing broad public and commercial reimbursement focused on Medicare through the legislation. But shorter term, digital health with access to large patient populations who are health focused and cash pay through partners like [ function health ] and [indiscernible], give us an opportunity to increase the market access to Galleri immediately in the short term.

These are also scalable and also digital health partnerships are driving health system engagement. As we work with the digital health partners on that post positive follow-up for cancer signals that they detect, as those are referred to health systems, either they are already partnering with GRAIL and have already incorporated Galleri, or those health systems have them, that's a catalyst for those health systems to engage with us so that we can integrate Galleri into those health systems going forward. It also gives us an opportunity in terms of our international expansion, as many of these digital health partners, even though they're U.S.-based, have global operations. That's also an opportunity for us to expand Galleri with these digital health partners ex U.S.

We're also growing in the self-insured employer space. We have now over 150 self-insured employers that have incorporated the Galleri test across multiple different industries. The key driver for many of these self-insured employers is that cancer is the top condition now for 4 years in a row, driving increases in costs for employers, for their health plans. So there's a big focus for the employers to get those costs down. We're working with 14 national and regional payers now that are supporting these employers, and those 14 national and regional payers are processing claims giving them access to Galleri data for their beneficiaries, which is helping us engage with those national and regional payers going forward.

And this ecosystem also means that health systems get involved for for positive Galleri tests, again, driving this ecosystem, connecting employers, health systems and payers. In terms of these health system partnerships, we have the Mayo Clinic and [ Dana Farber ] publications, which are real world evidence, which have shown performance in the real world has actually exceeded our clinical trial data with -- you saw for earlier PPVs in excess of 70% published by both Mayo Clinic and [ Dana Farber ]. We have multiple additional health systems who have partnered with us who are working on their own publications of their own real-world evidence.

We have a number of health systems that have incorporated Galleri into their primary care and specialist workflows, such as [ Rush, Community and Mercy ]. Many health systems have taken the next step and incorporated it into their own employee populations. So Intermountain, HCA, Community and Children's Health offer now the Galleri test to their own employees of the health system. And again, this is driving more payer engagement as health systems come on board.

So with that, enough hearing from me. I think it's now time to hear from our customers. If we can bring up Anil Saldanha. He's led the integration at [ Rush ] in Chicago, where they, this year, integrated Gallery into their primary care and specialist organizations. Dr. Andrea [ Clemes ], Chief Medical Officer of MDVIP is going to join us. They were one of the first, if not the first partner for GRAIL back in 2021. They've done tens of thousands of Galleri tests throughout their network.

Dr. [ J. Friedman ], internal medicine physician from Scottsdale, Arizona. Incorporated Galleri in 2021. Done, I think, over 2,000 tests in Scottsdale for his patients and Dr. Eric [indiscernible], I think, incorporated Galleri in 2022 and now done over 1,000 tests in his practice in Century City in Los Angeles. So please come up and Josh is going to moderate a panel.

Okay. We're back on. Please. And do we have [indiscernible] on video?

I'm here.

[ Andrea ], thank you so much for joining us. Can you hear us okay?

Yes, all good.

Oh, there she is. Great. All right. Well, it's a pleasure to have you. I guess we've done introduction, so we might as well jump right into it. But before we do that, is there anything you'd like to say about your background? Is anything else, Erik, Anil, Dr. Friedman? No? Okay.

So let's jump right into it. So let's start kind of big picture. Let's talk about what drove each of you in your own ways to adopt multi-cancer early detection testing, and how you do that within your practice or your organization? So Eric, maybe we'll start with you.

Sure. So I only became aware of GRAIL and Galleri cancer screening in September of 2022, a little over 3 years ago, and I only became aware of it because one of my patients asked me about it and I never heard about it before. So we reached out the GRAIL and they presented us a lot of the information that you're hearing today, and it sounds really incredible. My first thought was, is this going to be the next [indiscernible] where it's a lot of smoke, but is the technology actually there? But here I am 3 years later, 1,034 Galleri screenings with [ 62 ] positive Galleri tests. I think it's incredible stuff, and I think it's only going to get better.

And Eric, maybe just to follow up. How do you communicate the value of early detection to your patients?

Well, we all know the toll that cancer can take not only on patients but on families and loved ones. And if heart disease and cancer are the top 2 killers in the country, and most of our patients are hopefully not dying from cardiovascular disease because we're proactive from that standpoint. How can we be more proactive from a cancer screening standpoint?

And so with the 5 current cancer screening guidelines that we have available, we're not really doing that great in terms of being able to detect cancers that people are dying from. So by offering Galleri [indiscernible], we're doing is offering ourselves an opportunity to take a huge step from a proactive screening standpoint when we know the early detection matters.

That's great. Anil, tell me a little bit about how -- what led [ Rush ] and your push at the Rush Health System to include gallery and how does it kind of align with what Rush is trying to do as a leader in health care?

So I just want to take like a historical break in terms of what Rush is. So Rush kind of started with the medical college and it was incorporated in 1837, a few days before the City of Chicago was incorporated basically. So we are pretty old like 170 years plus. And Rush was named after Dr. Benjamin Rush, if you remember, who signed the declaration of independence. So we have a long history of being in Chicago, a major city and catering to our communities.

And Rush is focused on a mission, which is around something called Chicago's [indiscernible] gap. And it's very interesting. We have -- depending on where you are born and work. So if you are in what you call the magnificent mile in Chicago downtown and you take like 4 subway stops west, you live 16 years less. So an interesting [indiscernible] a discrepancy that we -- our research has found a few years, and we have called this the Chicagos [indiscernible] gap. And if you go south, it's 30 years and beyond. So Chicago has a life expectancy issue.

And when we looked at some of the contributing factors and cancer was one of them. Fast forward in different directions, I work for a health system. That's really complicated just for me to say health system. It's -- we have 3 major hospitals, multiple outpatient centers. And when you have a complicated system, there's a lot of problems, right? And one of our mandates is to improve cancer screening as part of our quality efforts. And if you look at the challenges that you see in cancer screening you will appreciate a test like [ Galleri ], right?

The screening, we do really well. Not just Rush, but as an industry, we do really well on breast cancer screening. Lung cancer, we suck. Absolutely suck. And we only looked at like 5 cancer types for which you have like designated, like screening or diagnostic tests. When GRAIL was basically talking to Rush in the early days. Of course, I had a history with GRAIL. I was on the founding leadership team of the company called Tempus 10 years ago. And I used to talk to researchers from abroad who used to tell me, there's this new fascinating area called liquid [ bioxy ]. And I was like, wow, this is going to revolutionize cancer detection. This was 10 years ago.

So when GRAIL started talking to us, our Director of Iris Screening, Dr. Lisa [indiscernible] at Rush, she's screening patients, leading programs, this mammography, vans and stuff, we really find it very, very hard to screen patients. Of course, there's quality numbers to meet but it's not easy as a system to do this recommended screening. So when you have all these challenges with screening, where you looked at this test, it was very attractive.

There was one more reason which our [indiscernible] risk screening Director, Dr. [indiscernible], She's an oncologist. She was very fascinated by the prospect of using GRAIL for aggressive cancers, right, for which there's no other biomarkers, no recommended test. So all of this put together, it was very attractive for Rush to embrace. Not only to offer it to our patients, but also to look at this mission we have, which is to reduce the [indiscernible] discrepancy or Chicago's [indiscernible]. So we did it for our mission for our patients. Some of the other systems may have done it for other reasons. But for Rush, we want to offer the best outcomes for our patients, basically.

Well, thank you for that fascinating answer. Andrea, over to you. And how do you think -- or how has Galleri really fit in to the preventive care model that you've implemented at [indiscernible]?

Sure. Thanks, Josh. And sorry, I'm not with everybody today. They had a really bad travel thing over the weekend, and I decided to stay put this week. But [indiscernible], just a little bit of background also. We're not as old as Rush. But we have been around for 25 years, and we're a national network of primary care physicians, like over 1,300 over the United States, taking care of about 400,000 patients.

Patients pay a membership fee for an executive style physical. But unlike getting one at Cleveland Clinic, or Mayo Clinic, you get a doctor all year long to work with you on your health span and action plan for wellness and prevention. Our mission is making healthier lives happen for doctors and patients. We'd like to take care of them both. We have [ 11 pure review ] studies showing that -- we identify more patients at cardiovascular risk, better control of chronic disease, more preventative care services done. We have less heart attacks and strokes and our patients live longer if they're at risk. And we save the health care system millions of dollars a year.

So you can see we've been focused for years wellness prevention, early detection but mainly cardiovascular diabetes metabolic health. And my doctors would always ask me, what can we do about cancer and brain health? And so when GRAIL came to me before they launched, and my doctors, I know like to be at the forefront of medicine, we did a pilot with them just to see how would we work in our network? If our doctors would enjoy? I don't know [indiscernible] enjoy using it.

We have relationships with cancer genetic testing companies. There wasn't a lot of uptake with that. Once we finished our GRAIL pilot, we rolled it out. And over the last few years, we've done 55,000 tests. Almost every one of my doctors has ordered at least one. This has been the greatest innovation I've ever seen uptake in my network. And so it gives my physicians that extra piece to focus on cancer prevention and really identifying it early because that's what we're all about.

Thank you, Andrea. James, for you, maybe you can share a little bit about why you've been adopting Galleri, but also maybe starting another threat about what you found as the most compelling and relevant performance metrics that made you kind of want to adopt this technology?

Well, my background is a busy practicing internist in Scottsdale, Phoenix area. So very heavy hospital work for 30 years. I am one of the early adopters of [ CT coronary ] calcium score back in 1987. I probably ordered more than anybody else in the Phoenix Valley. That has changed the trajectory of how we have managed [indiscernible] disease, and it has been proven to be a great way of risk stratifying and now it is just now standard after maybe 35 years.

So I'm an early adopter, the physicians need to obviously manage complex patients, but we need to diagnose patients early. It's just the earlier, the better. And so I read about this multi-cancer detection serologic test. And I knew it was going to be probably early when I adopted it, but I have followed it really going back to my days in molecular biology study at UCLA. I knew that the answers are going to be in the DNA. And so I started using this test in '21, and it has made a huge difference.

One thing that's not emphasized, but I sat on our tumor board for 30 years on our campus at our hospital, I'm part of the Honor health system. And at any stage that we diagnose cancer earlier than the later stage, we make a difference. The interventions, the targeted therapies that we have today, the pathway inhibitors, our cancer patients are doing so much better. I don't think that's baked into the data here. But in a real world where I see and deal with patients, these patients who are diagnosed in Stage 2 rather than 3, or Stage 3 rather than 4, I do see the outcomes, and it's far better than just patients showing up with symptoms.

So we can catch these patients early. It makes the difference. It's worked out great in my office. I have a discussion on top of all the other cancer screenings are all emphasize, it would be a disservice to patients to focus on this Galleri test without them understanding that this is in addition to everything else that they need to screen for. Really important because year after year, they go, I had it last year, and I go, well, this is not a genomic test of your DNA looking for mutations. This is looking for circulating cancer.

So now the patients understand that most of my patients want a year after year, and the uptake has been excellent, and I'm very excited about the data. The data just proves what we're seeing, but obviously, anecdotal to my patients, now we get to see supportive data that just makes it even more exciting.

Was there any particular area of performance like the false positive rate or the false negative rate or the PPV that was most impactful to you?

I think all of that, the PPV is excellent, getting better. I also know that through machine learning and through the AI that's still evolving, it's just going to get better. Like all the DNA tests, we know this is going to get better. We know it. And so I'm very excited for the future.

That's great. Thank you so much. All right. So we can see that across very different health care settings, different health care systems, there's this belief in the power of early detection, and how it can translate directly into improved outcomes for patients. But let's talk about what implementation really looks like on the ground.

So Anil, how did Rush actually operationalize this? Or how do they go about doing it? And then we'll get to everybody on the panel.

Yes. I think I did mention I work for a health system, right? I want to say it again. I work for a health system, right? So I mean, until you work in a health system, you don't really appreciate the complexity of health care. So we started talking to GRAIL about a couple of years ago. So just going through the, I would say, the legal regulatory side of the house, it took some time, but we also -- I think when we look back, it was a great decision from Rush where we required GRAIL to integrate into our [ EMR Epic ]. So that took some time -- and this, of course, challenges with integrating with a major EMR, such as [ EPC ].

So -- but when I look back, that was a great decision or a requirement from Rush, mandating that we want this, right? So we wanted our primary care physicians to offer this to our patients, right? It took some time. There were integration challenges and [indiscernible] mentioned about some of the changes GRAIL had to do last year. So it was difficult from an integration perspective. But for -- but that was just more on the ordering side of things.

But inside Rush, we had to change a lot of things. So we had to update or whatever standard operating procedures, SOPs, the clinical workflows, train or employ basically clinical staff. So it took a long time. And of course, you have to get people excited about a screening test, right? I mean not everyone is focused on cancer. And here, we were just primarily focused on the primary care side of the house, not even cancer right, and at the system level.

So just to give you insights into the complexity, we today offer GRAIL, at 4 sites, or 4 centers in the Chicago land area. 3 major hospitals, but also a brand-new cancer center that we built, I think it was $70 million last year. It's a brand-new standalone because for [ Ruche ], access to care is one of our primary strategies. And when you say access to care, it means health systems start building new buildings new hospitals all over the place. So we offer GRAIL at 4 places. And -- so we had the [indiscernible] integration, which allowed us to order. But also we had to put together a clinical team, including a nurse [indiscernible] across all sites who are available whenever like we offer like these tests to patients.

And I want to say this is a work in progress. We started offering GRAIL, I think, in September. Right around like maybe a week after that, we had a feature in Chicago Tribune highlighting [ Rush's ] choice of GRAIL and this blew up the entire region. We have not seen the kind of interest among our patients, among our executives, the family members of executives and of course, it makes me look really good.

Well, thank you for that. Eric, maybe over to you. As you've introduced Galleri to patients, two things. One, what kind of language is resonating best with the patients about this? And then you've actually, secondly, managed to have a very high retesting rate, annual retesting rate. You've achieved upwards of 70%. What do you think is driving that level of patient engagement?

For me, I think it's primarily about starting a conversation. And -- so I'll have a conversation with a healthy 25-year-old. And I'll preface it by saying I'm going to present some information to you, not because I think you need it, or [indiscernible] I think you need to consider it. But just because I think it's something people should be aware of. Might this be something that you would want your parents to consider.

So you asked, have you heard about Galleri cancer screening? And barely the answer is no. Well, it's a newer blood testing that's looking for tiny DNA changes when normal cell tissue becomes cancer, self tissue and it can screen for 50 different kinds of cancer. It's being described as a liquid, [ biopsy ], it's a snapshot in time. Where if it's negative, you've got a 99% certainty of not having any of those [indiscernible] of cancer at that moment in time. There's no predictive value for a negative test, but it's technically being recommended to consider for anyone over the age of 50 because that's when everyone's risk of cancer increases.

But particularly, if you have an own family [indiscernible] has kind of cancer and then to consider doing it on an annual basis not as a replacement for any current cancer screening guidelines like annual [ MAMR ] [indiscernible] females starting at age 40, or periodic colonoscopy starting at age 45. But it's meant to be as an adjunct to try to give ourselves the best chance to identifying any one of these cancers, most of which we don't have any ways to screen for.

And we mentioned that the overall risk of a false positive Galleri test is 0.5%, which is unheard of in the cancer screening world. If you did get a positive Galleri test, the positive predictive value historically based on PATHFINDER 1, and actually meaning you have cancer was 43.1%. Oftentimes, people will hear that and say, so I do this test, I get a positive test. I have less than 1 in 2 chance of actually having cancer. That's not great. Do I really want to do this test and subject myself to that potential in going down that rabbit hole, not being found to have cancer.

But what's the positive predictive value of an admirable mammogram and actually meaning someone has breast cancer? 4.4%. What's the positive predictive value of a positive cologuard stool test and actually meaning someone has calling cancer? 3.7%. So 43.1% positive predictive value of a positive Galleri test and actually meaning you have cancer is an order of magnitude better than what we're doing as standard of care. And based on this PATHFINDER 2 trial data from just released a few weeks ago, now that positive predictive value has improved to 61.6%. Fascinating stuff. And so when you present that information, it's really compelling.

And then you'll oftentimes get the question of, okay, so if I do this test, do I need to do it every year? Can I do it every other year? Can I do it every 2 years? And my response is, well, if you find merit in this enough to start doing it. And you get that negative test with that 99% [indiscernible] any of those state kinds of cancer at that moment in time. There is some data to support GRAIL's recommendation to do it on an annual basis. There is an American Cancer Society study from several years ago, completely seperated from GRAIL. They looked at 300,000 patients who are at relatively low risk of cancer, ages 30 to 65 mostly female, nonsmokers. They [indiscernible] their blood and they've banked it. And they [indiscernible] over the course of 3 years for any incident development of cancers. When GRAIL became aware of this study, they asked to access some of that bank blood for the people that were diagnosed with cancer. And what they found was a Galleri campus signal might have been detectable on average of 323 days before the cancer was diagnosed, essentially a year.

So there are some data to support the recommendation to do it on an annual basis. And if you think about starting to do it, getting that negative test with that 99% certainty and not having any of those in kinds of cancer at that moment in time, and you get into a cadence of doing it every year. If [indiscernible], you as my patient is going to get cancer, we're presumably giving ourselves the best chance of identifying it as early as humanly possible. So it's as treatable as possible with the least amount of toxicity from a treatment standpoint. [indiscernible] I want that for my patients? Why wouldn't I want that for my family and loved ones? And that's the conversation.

That's terrific. Thank you. And Dr. Friedman, you've ordered over 2,000 Galleri test since 2021. Love for you to share with the audience here what your workflow is like? And from the early education to how you follow up? And then also talk about patients who have initially tested negative and then how you have found cancer in annual testing?

So I have a large practice. So I'm coming from a zone of a busy primary care basically I'm [indiscernible]. So I have a very busy practice, lots of sick people, complicated [indiscernible]. But I do about 8 physicals a day, and I do a real physical. I mean, I am thorough. There is no shortcut to doing the right thing and taking care of patients. So I normally do address all their cancer screenings.

It was a hassle. In my office staff bucked a little bit in '21, we have to have this kit, but the company has been great. This has made it so easy. So my patients know about it and some they're highly educated people. So they often actually ask me about it, even if I -- they're new patients, and I've never talked to them about it. But it's just another 20 seconds of explaining. I usually tell them that we've done a great job with breast, colon, prostate. People aren't dying like they were. 75% of the [indiscernible] now are really from head and neck, lymphatic gastric esophagy, liver, gallbladder pancreas and other aggressive cancers, and we're not doing anything for those cancers. And I think the people understand that. And so if they can afford it, they do it.

And eventually, this is going to be a test that's going to be a lot less costly. I know it will be, and then we're going to do it for everybody. And I think that's going to be a [indiscernible] changing for the field of early detection.

And how about people who've had a negative test 1 year? And then what's been your experience with annual testing?

Again, I would say I have probably over 50% of my patients are getting annual testing now.

And have you found cancers and people who were initially negative?

I'm working up a lady now who had a positive endometrial signal, I did a [indiscernible] ultrasound. They didn't see something, but maybe they did. And so she's now going to get her MRI. I'll center one of my [ GYN ] oncologist getting her MRI at Mayo, I think, maybe tomorrow. But I'm working her up. I think we found it early because she -- this was her third test. So I think we probably found it early enough, hopefully.

That's great. Andrea, we've -- we've talked about how Galleri is able to flex in different systems. We can integrate with EHRs. We can be delivered in clinical practice settings and keeping that focus on prevention, you and your team have done over 55,000 tests. What's the most striking thing that you've learned about early detection, about the real-world performance and patient outcomes by looking at this vast experience within [ MDVIP ]?

Yes. I mean it's been exciting to see my physicians adopt this technology. And I think they have the same conversations as the physicians here have said. When you know about the false positive rates of other screening tests, you can have that really good conversation with patients.

I know it's made a huge difference. I know of a [ doc ] in Alabama, who screened 55-year-old male with no symptoms and got stage one esophageal cancer. And those stories penetrate my network to say that this really is something. I have one of the leaders in the network, not only lectures my docs on Galleri, but also prospective MDVIP physicians. And you'll always say, we have 4 screening tests. And for everything else, we just cross our fingers and hope and this is much better than that.

I was excited when you showed me the PATHFINDER 2 data to say that my cohort of 55,000 tests has the same positive predictive value, the same false positive rates, everything as the bigger studies so that my doctors are comfortable knowing that what's happened in clinical trials is really happening also in our real-world cohort.

That's great. I'll just share an anecdote with the audience here. There was a congressional hearing in D.C. about MCED legislation. And one of the patients, Roger, who had diagnosed with an early pancreatic cancer was on the stage and in the hearing. And he was getting grilled about the lower sensitivity than single cancer screening, the false negative rate. And his response to the congressional panel was current clinical care in this country has a 100% false negative rate for asymptomatic cancer. So what are you talking about?

And that's what he gave back to the panel. And I think it was a fascinating way to present that data. That our ability to detect unscreened cancers before symptoms present in current health care today is effectively zero, unless something was found incidentally. I thought that was fascinating

So time to just wrap up these stories and these lessons from you all are so valuable. But just in the last few minutes, in one line for each of you in your mind, and maybe start with Eric, what's next for Galleri in your practice?

Standard of care. My hope is that something like this can become standard of care. One piece of information that I share with patients that I think is quite compelling is that there are now over 10 life insurance companies that are offering Galleri cancer screening for free to their clients. because they see the data and they understand it's in their best interest to keep their clients alive as long as possible. It's an interesting dichotomy between the end game of a health insurance company, an end game of a life insurance company. But absolutely, I think my hope is that something like this can become standard of care.

And at Rush, what's next?

The key word I wanted to mention with our strategy with GRAIL is we have systemized the GRAIL test. That's a very important keyword. And we are the only system in the region to offer the systemized workflows for GRAIL. Which means we not only offer follow-ups to the patients we screen at Rush, but for everybody in the region with a positive signal, and we are already seeing those patients from conscious practices, from rival systems, who haven't systemized. So we are getting those patients into Rush for follow-up care, like diagnostics, whatever. So we -- that's why we took a long time in systemizing the GRAIL test. And this is part of our system strategy going forward already.

James, what's next for you?

I would just echo what Eric said. I really think that this -- I've been in practice 39 years, and I have not, I think, led my patients astray ever. And we have enough evidence, I have enough evidence that I know this is going to be standard of care [indiscernible] in the next few years. And so I will continue to be using this test in the future, of course.

And Andrea, let's close with you. What do you see as the next step for Galleri in your organization?

Thanks, Josh. Yes, we're looking at the differences in adoption across my network because we do have 55,000 tests, but that's out of 425,000 patients. And so we know we need more adoption across the network, how can we increase utilization? We've done some fun things like events in the doctor's offices where you guys are so nice in bringing a [indiscernible] and we do the test on all the patients who show up at the event.

What other things can we do like that and what other ways can we make GRAIL available to our patients so that my doctors can say the same thing that the gentlemen in the state can say that this is the standard of care.

Well, thank you so much. So just in closing, I want to thank our amazing panelists for your contributions. Obviously, this is the type of technology that can transform the way you deliver care to your patients. And gives you a new tool to address the burden of cancer in ways that we've not had before. And I want to thank you for your efforts, for the insights that you've shared with us today. And this is just the beginning. So hopefully, we'll all come back in a couple of years and share even more. So thank you very much.

And what's next? I think -- Yes, Andy, come on up. We're going to do a Q&A now to the team. Yes, Andy, we're going to join us up here for Q&A. And I'm sure there are some great questions. Andrea is still on the line as well. Where do you want to start?

Anybody, any questions from the audience? Doug?

Two quick ones. Dr. [ Saldana ], and first off, thanks to all of you for taking the time with us today to all of you. My guess, and I could be wrong is that Rush has a much more diverse mix of patients than the other panelists when it comes to reimbursement profile and economic status. Again, just correct me if I'm wrong, but if that is the case and given at least in my experience talking to physicians, there tends to be a bit of concern about accessibility and making certain tests available to some patients and not others based on insurance or economic status. How do you manage that?

So great question. So when we started offering this test, it was a serious consideration. So in our case -- so we are offering this test to the patient. So we have like 3 tiered approach. Anybody about the age of 50, we send out e-mails and we tell them, hey, this test is available. And of course, in the EMR, anybody about the age of 22 with certain conditions like smoking history, cancer, history, first level of relationship and in certain conditions, anybody above the age of 22. And the third tier, what we call is anybody wants it. So these are all the patients we offered Galleri tests.

And we are highlighting that, look, this is not FDA approved and then it's not covered by commercial insurance, and it's out of pocket. But also there's certain -- if you look on the Rush website where we talk about the test, there is FAQ. And like, we have a section which you can review which says, is this covered by insurance? There's certain like, I would say, like [ TRICARE ], I think they cover for certain conditions. And that's the extent to which we have gone in terms of reimbursement.

Like I said, we have a diverse population with disparities. We are looking at philanthropy and other -- we are also talking to GRAIL to see how we can offer these tests. Again, don't quote me as this like the [indiscernible] like -- but this is something we are looking at offering to our diverse populations. We've only started offering about 2 months. And already, the demand is so much just from the patient side. For the diverse, we are looking at innovative solutions through like philanthropy and others, yes.

And then just very quick, this can be kind of yes, no. The way the company -- and I think, Josh, you talked about Galleri, I mean this is truly supposed to be a [ complement ] to other tests for screening that are in guidelines. It doesn't sound like you have had any concerns, or anything in your practices that would suggest a patient getting a negative Galleri test that emboldens them to not use other tests that are in guidelines. Is that the case?

It's my concern. And I think [indiscernible], that's why you have to talk to the patient. I worry that the word will be out that this is just the holy grail, and that I don't need to do anything else. Quite the opposite. Every patient needs to know that this complements what we already do and it has to be done annually. And it is not a genetic map of your DNA that might give us clues that you have a risk.

And if we don't educate the patients correctly, there are going to be patients who fail to seek out care when they have symptoms, or will declare themselves cancer-free. So this test has to always be done in conjunction with the screenings that are required.

And I'll just add one thing from our studies. We -- that's a huge safety concern for us and for the FDA, by the way. And so we've been measuring in our studies, PATHFINDER and PATHFINDER 2, by survey, by patient self-report. Are they more or less likely to continue with their standard of care screening? And what we're finding is that when you're taking Galleri as a screening because you're actually more likely to continue with your current cancer screening because it emphasizes the importance of screening as long as the education is there correctly that in no ways this ever replacement.

Yes. Thank you, Josh. How important is the gallery data more to you guys? Would you ever consider switching to other vendors, given there are other NCD tests coming online?

Maybe start with Eric?

The data is super important in having that information to present to patients and to standby. I oftentimes will talk about the comparison with [ Guardant Health ], which last year came out with Shield as a blood test that's looking for cell-free DNA that's specifically looking for colon cancer. And -- it's -- if colon cancer is present, Shield has shown to be 83% sensitive and being able to detect it, which is not as good as Cologuard at 92%. And Shield has also carried a 10% risk of a false positive. But Shield was FDA approved last year. And because it's FDA approved, it's fully covered by Medicare.

But you contrast that with the overall risk of a false positive Galleri test, again, 0.5%. And if something like colon cancer is present with Galleri, Galleri offers an 82% sensitivity of being able to detect colon cancer, which is very similar to what Shield is offering. And the [ Garden ] information, I think, is based on preliminary case control data, where they don't necessarily have interventional real-world trials that validate what they've seen preliminarily.

And so I hope that answers your question, that I do think that data is hugely important. And I feel like GRAIL has been accumulating a massive amount of information over the course of the last 4 or 5 years, and they're only going to accumulate more.

[ James ]?

Yes. Just to follow along on that, I mean we get a cell signal of origin as well with GRAIL. It reminds me of the patient who was working up in anemia. And yes, the next month, I saw him he didn't send in the stool cards. And then finally, the following month he did, and I called him to tell him, they were normal, and he told me he would let his dog know. He wasn't about to do it from his own toilet. He went out to the front lawn and took a sample of his dog's poop.

But what I'm trying to say is the patient comes in every way, and they don't understand the importance of why we're working anything up. And sometimes they want the least path of resistance. But I think this Galleri test is after the -- in addition to the screen, I keep emphasizing that. But this test is far better then Cologuard. How many patients did I call it -- and these Cologuards were done because they didn't want to have endoscopy, and they were low-risk people. But basically, 95% of those phone calls ended up with an endoscopy and we didn't find cancer. This is a far better test.

How about compared to the other MCED tests that are out there?

Again, the Cancer Guard has no cell site of origin, and I don't think it has the data. So I'm not going to use it.

Please, [ Nima ]?

Just as an anecdote, I mean the CSO, I think, is incredibly important for my comfort level of ordering this test and feeling confident with the work up. An example is last week, I was in our liver tumor board. And hepatocellular cancers are usually not worked up with a PET/CT. This patient was worked up in the outside. Somebody ordered a PET/CT, we reviewed it. They had a very large hepatocellular carcinoma that had absolutely no FDG avidity within the tumor. It was completely unapparent on the PET/CT. But if you got a contrast enhanced, multiphase CT scan, it was right there in your face.

And that concerned me because I think other tests when they don't provide a CSO recommend a PET/CT and you could just be complying completely blind. And there's no impetus for somebody to be like, well, maybe let's order a CT multiphase that delivered to [indiscernible] cancer, you really wouldn't do that.

I'll also just make one other comment. We've looked because we get asked this question all the time, there are no data available today worldwide, supporting the use of whole body imaging for cancer screen. The only studies that have ever been done are in -- are outside the United States and the conclusions of those small studies were that it is not appropriate for early cancer screening. So again, I think I would recommend there are lots of approaches to multi-cancer early detection. Some have CSO capabilities. Others do not.

I think I'd ask for the data to support the use of their whatever approach may be, whether it's ours with the CSO or theirs with whole body imaging. And then there are other tests, again, that just are relying on case-control data and everybody needs to know the questions to ask. When you get presented with that, you need to ask them. Is this really -- do you have any interventional data to support this? Because too often, we've seen case-control data -- I guess the best example is the THRIVE study, the DETECT-A study. [ Bird Vogelstein ], one of the world's leading oncologists did a case-controlled study that showed amazing results. It was put into a healthy 65-year-old women, the blood test barely worked. The PPV was 5.9%. They had to do whole body PET/CTs to find any cancers. So again, ask the right questions. it's really important.

Andrea, how about for you? How do you feel about the [indiscernible] data?

[indiscernible] data, sorry. Yes. And we recently had this discussion you and I. And as the Chief Medical Officer of a bigger company, I have all the companies coming after me to talk to me and try and pitch their [ wares ], if I want to say it that way. And so I am sitting through listening to data, looking at how do we analyze it. I lean on external advisers to say what's the right type of data. And for now, we're still working with GRAIL for continuing above our 55,000 tests because you have the most data and interventional not case control.

Great. Thanks, Andrea. Other questions? Yes, sir?

How do you think demand for GRAIL test will change if it gets FDA approved? And do you expect Medicare to cover it? And how many other payers will cover it too?

So maybe start with Andy. And then ask the panelists.

Yes. So as you know, we're working with Congress to get MCED legislation passed into law. Medicare cannot pay for screening unless there's an act of Congress. So that's what we're working on right now, Josh can share more about the status of that legislation. But it is our anticipation that our longer-term reimbursement plan will include Medicare once that Act of Congress is passed. So we will be able to offer all Medicare patients. So at some point in the future, the Galleri tests.

We're also working with other payers right now, but we're early on in our payer engagement. The NHS-Galleri study results are going to be a key component of our payer engagement. PATHFINDER 2 is also a key component. Obviously, FDA approval as well as we know from payers the clinical data, having the clinical data published, and having an FDA approval will dramatically increase their willingness to provide coverage for Galleri. And that is our long-term plan to ensure that patients get access to the Galleri tests.

And do -- if any of our panelists want to jump in, how do you feel that an FDA approval will change the demand that you're seeing from your patients? Do you think it will measurably affect that? Or will reimbursement itself be the biggest issue?

I want to say from a Rush perspective, we'll remove the disclaimer. We have it at every place. That's the only big change we're going to do because we're already seeing the patient demand basically. So just as an example, to keep up with the demand for screening at Rush, we are holding, I think, like GRAIL camps at our 4 sites in December. So we only started 2 months ago, and we already have like really big demand for screening. So from our side, we're going to remove the disclaimer. So that only -- I think it's going to -- it's just better for patients to get covered either through commercial or Medicare or any of these. But from a system perspective, I think more, I would say, patients and the community members will have access to screening.

And I'll just remind you something Andy said in his talk, the self-insured employers are effectively payers, and they are reimbursing the test for their employed population. So there is, in that regard, reimbursement already.

And then the second question is just from your real-life experience, doing this -- do you do the second test if you get a positive test and doing two tests? How much do you lower the false-positive rate?

Well, we do a second test if the first is positive, and we've done a workup. And we have not found a cancer. We either will do more of a workup, then we'll repeat the test, I like to repeat it at 3 months. And if it's positive, then it's likely there is a malignancy. And if it's negative, then it's unlikely that there is a malignancy after we've done a good work up.

Right. But out of the -- when you get a positive test the first time, how often do you get a second test that's positive?

Well, we don't because we've worked the patient up and we found a malignancy, and then we're not going to do the test again.

I think you're asking if -- let me see if we've got your question right. You get a positive Galleri test. They do a workup, right? And are you saying the second test being like the imaging test? Or another Galleri test?

I thought a lot of doctors would -- if you just give a straight blood test [indiscernible] you just follow up with a right to a blood test.

That's not at all what happens, yes. Let's clarify that. So a positive blood test gets followed up by a directed workup. So Galleri will say, cancer signal detected, predicted origin liver. The next test is not another blood test, it's an image of the liver, hopefully, not a PET/CT. But the appropriate type of imaging test in the liver to find the cancer. If nothing is seen, and the doctors convinced it's been an effective work up, then you would do another Galleri test to try to reach resolution. And if it's negative, you can pretty confidently assume that, that first test was a false positive.

I don't have a number for you that you're looking for about how it lowers the false positive rate just because we haven't done that in a large enough population yet.

If I can help answer that question. So I think GRAIL has some data on retests. Following an initial positive test, you take that diagnostic evaluation, you don't find cancer. So GRAIL offers a free retest at whatever time interval. And I think the data that GRAIL has is involving 145 patients that were retested. And 30% of them, again, tested positive, and we're persistently positive and then reevaluated for cancer and perhaps, in fact, identified to have cancer.

But the other 70% had a negative test that was repeat, and they were followed for 18 months and not identified to have cancer. So I think that's where they're getting the information to say that if you repeat a test, and it's negative, that you can be fairly certain that, that first positive test was, in fact, a false positive. And that you just resume your annual gallery cancer screening as you ordinarily would.

That's right. There was only one example I'm aware of where a test, a blood test was done twice in a row, and that was in the THRIVE study. And that was again because the blood test wasn't working.

I think there's a question.

Yes, I just have a really quick one, and I guess it's for both the physicians and GRAIL. Just can you remind us if it's done on a fasting basis? And if it's not, do you get some interference and that's could contribute to some of the false positives that you see and need to tell the patient maybe did you, in fact, fast? So just a quick one, hopefully.

My understanding is that it doesn't require a patient that needs to be fasting. Oftentimes, when we have patients come in for their physicals, they're fasting anyways. And then we introduce Galleri cancer screening and by starting the conversation. And if it was something they want to start doing that may be doing at the time of their annual physical would make a lot of sense because then each time they come in for their physical, they'd be able to repeat the Galleri cancer screening. But to my knowledge, I don't think that if you've eaten that it's going to affect the -- the Galleri test result in any way.

Or we offset the test by 6 months after they've been in for a thorough physical, and we've done comprehensive blood work. So they come in every year for physical. They come in every year for a Galleri, but the Galleri 6 months from their last physical. And we've done that on many of our patients. We think there probably is some theoretical advantage to that.

There's no data we're aware of that suggest that food introduction has any effect on methylation patterns. There are hypothetical things like [indiscernible] blunt trauma, other things that have happened could affect your methylation being on a methylating chemotherapy agent, for example, which is why we don't do Galleri and people who are actively being treated for cancer. But nothing we're aware of as it relates to food.

Okay. Well, if there are no other questions, I think that will wrap up our program today, if I'm not mistaken, Alexis, am I correct? All right. So I want to thank our panelists. First of all, thank you so much. I want to thank our esteemed audience. Everybody who made it here despite the difficult travel schedules and the uncertainty, it's highly appreciated. I want to thank Dr. [ Clemes ] for continuing to hang in there by video. It was terrific having you to be part of this. And again, I want to thank everybody for being here and the staff at GRAIL. Hopefully, you'll be getting tours or have done tours and I want to thank all the [ GRAILERS ] for all their hospitality. So thanks, everyone -- and the other speakers. Thanks.

Good day, ladies and gentlemen, and welcome to the GRAIL Third Quarter 2025 Earnings Call.

[Operator Instructions]

Please be advised that this conference call is being recorded. GRAIL Investor Relations, please begin.

Thanks, operator, and thanks, everyone, for joining us today. On the call are Bob Ragusa, our Chief Executive Officer; Aaron Freidin, Chief Financial Officer; Josh Ofman, President; Sir Harpal Kumar, Chief Scientific Officer and President, International; and Andy Partridge, Chief Commercial Officer.

We'll be making forward-looking statements on this call based on current expectations. It's our intent that all statements other than statements of historical fact, including statements regarding our anticipated financial results and commercial activity will be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act of 1933 as amended and Section 21 of the Securities Exchange Act of 1934 as amended.

Forward-looking statements are subject to risks and uncertainties. Actual events or results may differ materially from those projected or discussed. All forward-looking statements are based upon currently available information, and GRAIL assumes no obligation to update these statements. To better understand the risks and uncertainties that could cause actual results to differ, we refer you to the documents that GRAIL files with the SEC, including the Risk Factors section in GRAIL's most recent quarterly report on Form 10-Q.

This call will also include a discussion of GAAP results and certain non-GAAP financial measures, including adjusted gross profit or loss, which are adjusted to exclude certain specified items. Our non-GAAP financial measures are intended to supplement your understanding of GRAIL's financials. Reconciliations of the non-GAAP measures to most directly comparable GAAP financial measures are available in the press release issued today, which is posted to our website.

And with that, we can turn to Bob.

Good afternoon, everyone, and thank you for joining us. On today's call, we will review third quarter results and discuss recent updates. These include PATHFINDER 2 results shared at ESMO, updated SIMPLIFY data shared at EDCC and recent strategic and financing activities. We remain very pleased with our commercial progress. Growth in Galleri volumes and revenue in the third quarter of 2025 were 39% and 29%, respectively, as uptake continues to grow. From the launch of Galleri through September 30, approximately 420,000 Galleri commercial tests have been sold by more than 16,000 healthcare providers. We are continuing to progress our activities beyond the United States as well, recently announcing a strategic collaboration with Samsung to bring the Galleri test to key Asian markets.

Subject to execution of definitive agreements, we and Samsung will work as exclusive partners to commercialize Galleri in South Korea and potentially other Asian markets, including Japan and Singapore. In addition, we plan to explore other strategic and operational collaborations. Samsung has also agreed to make an equity investment of $110 million in GRAIL, subject to closing conditions.

In October, we also introduced Galleri commercially in Canada in partnership with Medcan, a global leader in proactive health and wellness services. Eligible adults in Canada may now access the Galleri test at Medcan's clinics. In addition to these operational updates, we recently completed a $325 million private placement. This transaction strengthens our balance sheet as we progress through additional milestones. Galleri is the only MCED available, which has demonstrated performance in people being screened in the intended use population. This includes data from our registrational PATHFINDER 2 study, where a prespecified analysis was presented at ESMO last month.

I'll ask Josh then Harpal to discuss recent results from Galleri's clinical program.

Thank you, Bob, and hi, everybody. We were really pleased last month to share very positive performance and safety results from the prespecified analysis of the first 25,000 participants in our registrational PATHFINDER 2 study. This study started in 2021, and PATHFINDER 2 is a large prospective trial in a very broad and diverse enrolled group representative of Galleri's screening eligible intended use population. Releasing the first results of this study at ESMO was so exciting and a big milestone for our company and all of our partners and investigators, and it was a meaningful contribution to the evidence base for the effectiveness of multi-cancer early detection. As you'll recall, we found that adding Galleri to recommended screening for breast, cervical, colorectal and lung cancer yielded a more than sevenfold increase in the overall cancer detection rate.

Approximately 3/4 of the cancers detected by Galleri have no recommended screening options. And more than half of the new cancers detected by Galleri were in Stage 1 or 2 and more than 2/3 were detected at Stages 1, 2 or 3. One of the most important clinical metrics, the positive predictive value, or PPV, which is the likelihood of receiving a cancer diagnosis following a positive test result, Galleri's PPV was 61.6%. Specificity was 99.6%, translating to a false positive rate of 0.4%, a critical safety metric. Galleri's ability to accurately identify where in the body the cancer is located also helped guide an efficient and effective diagnostic evaluation. Importantly, there were no serious study-related adverse events reported thus far.

Diagnostic resolution, an important economic and patient-centered outcome measure took a median of 46 days. and only 0.6% of all participants had an invasive procedure. And again, no serious study-related adverse events were reported. Invasive procedures were 2x more common in participants ultimately diagnosed with cancer than in those who are ultimately not diagnosed with cancer. PATHFINDER 2 and NHS Galleri make up our registrational clinical program for Galleri. Our PMA submission will include these data from the first 25,000 enrolled in PATHFINDER 2 to complete 12 months of follow-up, plus findings from the prevalent round of screening from the NHS Galleri randomized clinical trial as well as the results of a bridging study between the version of Galleri used in the 2 registrational trials to the updated version that we plan to submit to the FDA for premarket approval.

As a reminder, we announced positive top line results from the prevalent round of screening in the NHS Galleri trial in May of this year, namely that data from the prevalent screening round showed a substantially higher positive predictive value than that was observed in the first PATHFINDER study.

Now to review important new findings from our SIMPLIFY study, I'll hand it off to Harpal.

Thanks, Josh, and good afternoon, everyone. Working with the University of Oxford, we recently shared positive long-term results for an extended follow-up of the SIMPLIFY study at the Early Detection of Cancer Conference, or EDCC in October. As a reminder, we conducted the observational SIMPLIFY study in symptomatic participants in the U.K. to understand whether our technology could play a role helping clinicians guide investigation and accelerate time to diagnosis when patients present with concerning but nonspecific symptoms. Examples of these symptoms could include unexplained weight loss, fatigue, persistent abdominal pain and others. The previous primary analysis from SIMPLIFY published in the Lancet Oncology in 2023, followed participants until diagnostic resolution or up to 9 months and demonstrated Galleri's PPV in this population was approximately 75%.

Patients determined to have a false positive Galleri result were followed for an additional 15 months in the National Cancer Registry for England and Wales. The updated analysis presented at EDCC includes the subsequent registry follow-up period for all 79 of the patients who were originally classified as false positives, and the data contained a number of important learnings. First, approximately 1/3 of the participants initially believed to be false positives were diagnosed with cancer during the full follow-up period. Second, of that group, a cancer signal of origin or CSO prediction from the Galleri test was correct in all but 1 patient. And finally, with the reduction in false positives in SIMPLIFY from 79 to 51, the updated PPV for Galleri in this symptomatic population increased to 84.2%.

These findings reinforce the importance of proactive follow-up after a positive MCED test result and the value of the Galleri test's accurate CSO capability. Now to Aaron for a review of our financials.

Thanks, Harpal, and good afternoon, everyone. I'm pleased to present our results for the third quarter. Revenue for the quarter was $36.2 million, up $7.5 million or 26% as compared to the third quarter of 2024. Total revenue for the quarter is composed of $32.8 million of screening revenue and $3.4 million of development service revenue. Development services revenue includes services we provide to biopharmaceutical and clinical customers, including support of our clinical studies, pilot testing, research and therapy development. We continue to see demand for our Galleri test and sold more than 45,000 tests in the third quarter. We have historically observed seasonal fluctuations over the course of the year, in particular, relatively high volume in the second and fourth quarters and lower in the first and third. And we would expect these seasonal trends to continue. Screening revenue of $32.8 million in the third quarter was up 29% as compared with the third quarter of 2024. U.S. Galleri revenue was $32.6 million, up 28% compared to the third quarter last year.

At the beginning of the year, we guided full year 2025 U.S. Galleri revenue growth between 20% to 30%. We are refining this growth guidance today to the middle of that range. Cost of screening revenue, exclusive of amortization of intangible assets as a percent of screening revenue decreased mainly due to lower variable costs of Galleri testing performed on our automated platform, partially offset by a decrease in ASP and higher sample reprocessing costs. Net loss for the quarter was $89 million, an improvement of 29% as compared to the third quarter of 2024. Gross loss for the third quarter 2025 and 2024 were $13.7 million and $22.2 million, respectively. Non-GAAP adjusted gross profit for the third quarter of 2025 was $20 million, an increase of $8.2 million or 69% as compared with the third quarter of 2024.

In Q3, we achieved a non-GAAP adjusted gross margin of 55% compared to 41% in the third quarter of 2024. This change was largely driven by improvements in variable costs on our updated Galleri platform that launched last year and by an increase in sample volume for the quarter as we ran a onetime batch of research and development samples for clinical validation, resulting in reduced fixed cost per sample related to higher lab efficiency at higher volumes. We do not expect similar clinical validation sample volume in future quarters, but the higher number of samples processed demonstrates the benefits we expect to see in lab efficiency as the sample volume grows.

We ended the quarter with cash and investment position of $547.1 million. Including net proceeds from the $325 million private placement in October, we have approximately $850 million of cash and investments. This does not include the recently agreed upon investment in GRAIL by Samsung, which is subject to closing conditions. In August, we drew down our cash burn guidance for the full year 2025 to be no more than $310 million from no more than $320 million. Today, we are updating our cash burn guidance further to no more than $290 million for the full year of 2025, net of $13 million in placement fees from our recently completed financing.

Expected full year burn represents a significant decrease of approximately 50% compared to 2024 as we remain focused on cost management. We believe our cash runway extends into 2030, enabling us to achieve major planned clinical and regulatory milestones.

I'll hand it back to Bob for concluding remarks.

Thanks, Aaron. Our strategic priorities are seeking FDA approval of Galleri and pursuing broad reimbursement. We are advancing Galleri in the near and midterm towards key clinical and regulatory catalysts to achieve broad access while maintaining our disciplined cost management. As we move into 2026, our key milestones are the completion of our modular PMA submission to the FDA and full clinical utility results from our 140,000-participant NHS Galleri study, which we expect to read out midyear. This longitudinal data set will be reviewed by the NHS to determine Galleri's potential deployment within the U.K. population. Lastly, we look forward to welcoming many of you on site tomorrow at our centralized labs in Research Triangle Park, North Carolina. A live webcast of our Analyst Day will begin at 11:00 a.m. Eastern Time and will also be available at the Investor Relations section of our website.

Let's now go to Q&A. Operator, please go ahead.

[Operator Instructions]

Our first question will come from Subbu Nambi with Guggenheim.

The FDA time line is moved to Q1 instead of first half of 2026. What changed?

Yes, Subbu, thanks for the question. So I think the main thing is just as we move forward in time, we've gotten more certainty in the range of when we'd be able to deliver that. So we've been saying first half for a fair amount of time, and it looks like things are on track well enough where we're more confident to be able to put out for the first quarter. So it's really just kind of tightening the confidence intervals around the time frame.

Perfect. And you're currently running a promotion on your website offering $150 off of Galleri for patients getting tested from October to year-end. What incentivized you to offer this promotion? How has the demand elasticity in response to this promotion been? And is this -- are you piloting a reduction to $800 moving forward? And could this impact ASPs moving forward?

Yes. Maybe a couple of comments, and I'll turn it over to Andy Partridge, our CCO. So we've done a fair amount of work looking at the price elasticity on the test. And this is kind of a reflection of some of that work. We do know that there's significant price elasticity and going into the end of the year is a good time to exercise some of that. But maybe to answer some of the other pieces. Andy, do you want to take that?

Yes. Thanks, Bob. So as you saw, we have reduced the price on the website. The growth that we've seen in Q3 year-over-year has been predominantly driven by the provider channel, where we've seen improvements in both breadth of prescribing, bringing new prescribers onto using Galleri and also depth of prescribing. So discounting has been a component of increasing that depth and breadth of prescribing. Also the integrations we've done with companies like Quest and Athena have also driven a lot of that breadth and depth. And then finally, repeat testing, which price is also a component of that has also driven that depth of prescribing as well. So we're very pleased with what we've seen in the market.

Your next question will come from Kyle Mikson with Canaccord.

Congrats on the progress. So you've obviously bolstered the balance sheet nicely. You should have over an additional $400 million by early '26 with the Samsung investment. I was just curious how you plan to use the additional capital? And specifically, how does the commercial strategy change, especially in light of recent or upcoming competition? And I appreciate to hear Andy's thoughts on that as well.

Yes. So I think you hit some of it. Obviously, it gives us a lot more flexibility on the balance sheet. With competition emerging, it does give us more flexibility in how we think about flexing our commercial investments. So we're looking at those things as well as any of the other areas that we need to really fortify as we continue to scale and expand our test footprint in the marketplace. But I guess, Andy, do you want to also comment on that?

Yes. I think, Bob and I really covered it. I think the thing that I would emphasize is we feel like we've got a lot of momentum right now with customers for all of the reasons that I described and definitely coming now off the back of the PATHFINDER 2 data that we presented at ESMO, there's a palpable momentum that we have in our business.

Got it. That's helpful, guys. And also, Hims & Hers has made an investment in the company recently. Consequently, there's been some speculation that means GRAIL is going to take a direct-to-consumer approach to Galleri at some point. So could you just comment on those plans or the potential to take that route over time in light of the increasing focus on longevity among consumers?

Yes. No, it's a good question. We're -- as we just reiterated our time line for our PMA, we're very committed to the PMA pathway. And so there's kind of no change in that. In fact, you saw a slight acceleration in the actual time frame. But beyond that, we do also recognize that the digital health channel is an important channel out there more broadly in this sector as well as many others. And so we want to make sure that we're able to utilize all the channels that are available to bring. We've talked from the very beginning about how do we get broad access for Galleri, and that will be one other element to enable broad access. But that also would not diminish our -- again, our push towards a PMA and broad access through that.

Your next question will come from Doug Schenkel with Wolfe Research.

So I want to actually talk about NHS England a little bit more, and then I have a COGS-specific question. So starting on NHS England, looking back to May 2024, when the statement was issued saying that early results were not compelling enough to justify a large-scale pilot, were they referring to any clinical utility data from year 1 or to test level performance metrics such as PPV, sensitivity and/or specificity? Can you share a little bit more on what prompted that decision?

And then on the same topic, has anyone besides GRAIL and the NHS evaluation team seen the year 1 NHS Galleri data. I'm just curious if anyone else has seen it? And then if not, at what venue do you anticipate releasing that data more broadly, keeping in mind that you've said the FDA module submission is expected to be, I think, completed in Q1. So it would seem like that data would need to be released soon.

Yes. Harpal, do you want to take that one up?

Sure. Thank you, Doug. So on NHS England's decision last year, important to reiterate that what they would have wanted to see in order to initiate a pilot at that stage was very exceptional data. And they looked at a few specific metrics, of which PPV was definitely one. To remind everyone, it isn't possible to look at the sort of broad utility measure of Stage 3 and 4 reduction with only 1 year of data. That has to come with 3 years of data. But PPV was certainly one. And you'll have seen our announcement earlier this year that the PPV in that first round was substantially greater than we saw in our first PATHFINDER study, which to remind everyone was 43%.

So it gives you a sense of some of the information that was seen at the time. But again, to reiterate what the NHS would have wanted to see was truly exceptional data in order to accelerate -- and the point is they were looking about an acceleration of an implementation rather than waiting until the final study results. And what they said at the time was, it wasn't exceptional enough to accelerate that implementation and so that they wanted to wait for the final study results.

In answer to your second question, no, only the NHS evaluation team have seen that data so far.

To the third question, yes, it will be the data from the prevalent round only from the intervention arm will be part of our FDA PMA submission package in Q1 next year, but that does not mean it will be in the public domain at that point. There won't be any data in the public domain from NHS Galleri until we have the final study results.

Yes. And we're expecting that full readout in the midpart of 2026.

Your next question is your final question and will come from Bradley Bowers with Mizuho.

Just one on volumes and then maybe one a little high level. But just on volumes, pretty acceleration here outgrew some seasonality. Just wanted to hear what's kind of driving volumes here, what cohorts? And then how that -- how we should think about that into next year and if international will have a tangible contribution next year?

Yes. Aaron, you maybe want to take the volume question and maybe pass this off to Andy as well.

Yes. I mean I think Andy, I can tag team that. So yes, you're right. I think volumes were up 39% for the quarter year-over-year. Andy has kind of touched on already where we're seeing more provider pull-through and so on for the reasons that you stated. As far as international goes, there's very minimal international volumes today. It's an area that we're focusing on. And as you see through the Samsung engagement and so on that we're being opportunistic there, and we're excited about what could be. It's probably a little too early right now to say what volumes will be next year. But we're getting, as Andy said earlier, momentum internationally and lots of momentum domestically.

So Andy, anything you want to add?

Nothing else to add. I think we covered it.

And then if I could just double-click on the SIMPLIFY study. I think that's actually an interesting data point that going back and following up patients who were previously identified as false positives. I mean, does this -- were these patients, I guess, that went under typical protocols? Why were these cancers, I guess, kind of missed in follow-up? And then also, there's, I guess, some serious implications about the possibility to detect cancers even earlier than the current paradigm or what follow-up testing would be. So I just wanted to hear your thoughts on that.

Yes. Harpal, why don't you go through that?

Yes. I mean, look, first of all, it is, as you say, a really interesting set of data, and it's relatively recent. So we're still examining some of the detailed information. I think one of the most significant points is that many of these patients are presenting with very nonspecific symptoms. And these are the types of symptoms that could be indicative of cancer and often they are, but they could also be indicative of many other conditions. And so primary care physicians, when they see patients like this and they suspect cancer, will typically refer them to where they think that cancer is likely to be in the body. But given these nonspecific symptoms, many of them could be several different sites. And so then what happens is a patient gets referred to a particular type of clinic and they get worked up in that clinic for that type of cancer. But if nothing is found at that point, they may not be worked up any further.

And because this was an observational study, we didn't provide the CSO prediction to the clinician at the time. But what we've subsequently determined from this further follow-up is, had we done so, it would have provided a directional investigation in all but one of the patients, which we think is a really encouraging development in terms of that CSO prediction capability.

Yes. And I would just add to Harpal's point, the value of the CSO because what we've also seen in centers that have adopted Galleri in the U.S. is physician confidence growing in the value of that CSO. We've seen real-world publications from both Mayo and Dana-Farber where their PPVs have been in excess of 70%. So that physician confidence in the value of the CSO really means they really work that diagnostic workup to a final resolution. And what we've seen there, therefore, there is more cancers being diagnosed due to that guided diagnostic follow-up from the CSO.

We have time for one more question. So we'll return to Doug Schenkel with Wolfe Research.

So I think it's an Aaron question. Cost of screening revenue, I think in dollar terms, it was down $3 million relative to Q2. That's kind of a mid-teens decline sequentially on a per test basis. I think it was down 28% on a per test basis year-over-year. So I just want to make sure, at least I'm in the right ballpark in doing the math. And if so, that's pretty impressive and remarkable. Can you just share how you're getting there and the durability and the trajectory from here?

Sorry, jump up.

Yes, I was say Aaron talked a little bit about that in the prepared remarks. But yes, Aaron, why don't you go into a little more detail on that?

Yes. Doug, I think it's really an example of what we've been saying for a year now about the platform that we've built for high throughput, the capacity that we have to run 1 million samples a year and just what higher volumes will show from a fixed cost leverage perspective. Comparing year-over-year, you've also got the variable cost impact that we've been talking about. We've kind of talked about that as a 4 to 5x more samples per flow cell compared to the older version. So it's really a demonstration of what more volume will do to our fixed cost leverage and why we're really focused on driving more volume, getting more access out there because we've got the infrastructure to handle it and the margins are there for the day.

And there are no further questions at this time. I will now turn the call back to GRAIL for closing remarks.

So thank you, everyone, for joining today's call.

Ladies and gentlemen, this concludes the call, and you may now disconnect.

Good day, ladies and gentlemen, and welcome to today's GRAIL analyst call. [Operator Instructions] Please be advised that this conference call is being recorded.

GRAIL Investor Relations. Please begin.

Thanks, operator, and thanks, everyone, for joining us today to discuss detailed PATHFINDER 2 study results presented over the weekend at ESMO.

On this morning's call are Bob Ragusa, our Chief Executive Officer; Aaron Freidin, our Chief Financial Officer; Josh Ofman, President; Sir Harpal Kumar, President, International Business and Biopharma.

We'll be making forward-looking statements on this call based on current expectations. It's our intent that all statements other than statements of historical fact, including statements regarding our anticipated financial results and commercial activity, will be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act of 1933, as amended, and Section 21 of the Securities Exchange Act of 1934 as amended.

Forward-looking statements are subject to risks and uncertainties. Actual events or results may differ materially from those projected or discussed. All forward-looking statements are based upon currently available information, and GRAIL assumes no obligation to update these statements. To better understand the risks and uncertainties that could cause actual results to differ, we refer you to the documents that GRAIL files with the SEC, including the Risk Factors section on GRAIL's most recent annual report on Form 10-K and quarterly report on Form 10-Q. Bob, please go ahead.

Thank you. Good afternoon, everyone, and thank you for joining us. We were very pleased to share results from the first 25,000 participants enrolled in our PATHFINDER 2 study at the ESMO Congress this past weekend. This analysis is a registrational data set, which will be included in our PMA submission to the FDA in the first half of next year.

Our first interventional study named PATHFINDER was completed in 2021, and results were later published in the Lancet. We subsequently undertook the 35,000 participant PATHFINDER 2 study, a much larger, similarly designed prospective multi-center interventional study. PATHFINDER 2 is intended to assess the performance and safety of Galleri in a large population representative of Galleri intended use group. PATHFINDER 2 and NHS Galleri make up our registrational clinical program for Galleri. At 35,000 and 140,000 participants, respectively, these are two of the largest screening studies completed to date and the two largest studies in the multi-cancer early detection field.

From the beginning, GRAIL has focused on producing high-quality clinical evidence. Our evidence space includes clinical validation in large case controlled and interventional studies as well as real-world evidence studies, REACH and other observational data sets. The ongoing clinical program supporting Galleri totals nearly 400,000 participants. Importantly, Galleri is the only MCED available, which has reported results from people being screened in the intended use population.

Thanks, Bob. I'll now briefly walk through recent announcements that have strengthened our balance sheet via two transactions, totaling $435 million. First, we announced last week a strategic partnership with Samsung, which includes an equity investment of $110 million by Samsung into GRAIL, subject to closing conditions. GRAIL and Samsung C&T will work as exclusive partners to commercialize the Galleri test in South Korea with a possible extension into other Asian geographies, including Japan and Singapore. Samsung C&T will undertake key activities to drive adoption of Galleri, while GRAIL will initially perform the Galleri tests at our Central Labs and Research Triangle Park, North Carolina.

In addition, we and Samsung Electronics plan to explore additional potential strategic and operational collaborations. Samsung has considerable expertise, operating businesses in South Korea and more broadly, in Asia, and we are -- look forward to working with Samsung to bring our multi-cancer early detection technology to these new key markets.

Second, we announced this morning a private placement of $325 million of equity. This financing includes participation by new and existing institutional investors, including Deep Track Capital, Farallon Capital Management, Hims & Hers, Braidwell Limited Partners, three life science investment firms, and a tech and life-science-focused family office investment firm. We are very pleased to partner with these quality investors to help realize our mission to detect cancer early when it can be cured. Net proceeds from these transactions are intended to support commercial activities and reimbursement efforts as well as for working capital and other general corporate purposes.

As a result of today's pipe financing, we believe, we are very well capitalized with an expected runway now into 2030. That runway does not include the agreement by Samsung to invest $110 million in the GRAIL, which is subject to closing conditions. Now let's move to Josh and the PATHFINDER 2 data set.

Thank you, and hello, everybody. Great to join you today to walk through the data that was presented this weekend at the European Society or Medical Oncology Congress in Berlin. As Bob mentioned, PATHFINDER 2 is a registrational study for Galleri, which enrolled more than 35,000 adults over the age of 50 at multiple centers across the U.S. Blood draws were taken once at enrollment and the Galleri test result was returned. If a cancer signal was identified, participants received a workup based on a signal of origin guided recommendation, what we call a CSO guided recommendation, but it remained at the physician's discretion.

PATHFINDER 2 is intended to evaluate the performance and safety of Galleri in a large, diverse patient population. Enrollment demographics and characteristics were intentionally diverse as any successful population scale MSET innovation needs to demonstrate performance in a large intended use representative screening population.

The data set we just shared at ESMO this weekend was from the first 25,000 participants of the 35,000 enrolled that completed 1 year of follow-up. 25,000 was a prespecified cutoff for results to be included in our Galleri PMA submission to the FDA. Now let's turn to the findings.

The most important metrics for an MCED test, we believe, are the cancer detection rate. How many cancers does Galleri detect in a population being screened when added to standard of care screening and the positive predictive value, or PPV, which means if you have a positive test result, what is the likelihood you actually have cancer. The higher the PPV, the more trustworthy and actionable the test result is. In PATHFINDER 2, Galleri's observed PPV was 62%. And just as a reminder, the observed PPV in the first PATHFINDER study was 43%. So this represents a meaningful step up now in a large more representative population.

Specificity for the test was 99.6%, which means the inverse of specificity or the false positive rate was 0.4%. That's less than 0.5%. We also report the negative predictive value or NPV and episode sensitivity, which is a different metric than test sensitivity, which would be normally reported in a case-controlled study. The NPV, or the negative predictive value, was 99.1%. In interventional studies like PATHFINDER 2, we measure episode sensitivity based on how many cancers are detected within a predefined period of time. In the case of PATHFINDER 2, we set this time period to 12 months. We're very proud that our episode sensitivity for all cancers including cancers with low DNA shedding, where we expected lower sensitivity, was overall 40.4%. This represents a significant improvement over the current state where screening sensitivity for detecting asymptomatic cancer is effectively 0 for every cancer where there is no screening option available today. And if you look at certain subsets of cancers, the episode sensitivity is much higher.

Here, we look at Galleri's episode sensitivity in some of these different predefined subgroups. Starting at the bottom, in cancer types without recommended screening options, Galleri's episode sensitivity was 55%. That is 55% of cancers, where today there is no available screening. In all cancers, excluding breast and prostate, Galleri's episode sensitivity was 56%. And moving up to the most aggressive cancers, in a group of six of those aggressive cancers that have the highest 5-year mortality, Galleri's episode sensitivity was 72%. Finally, in the 12 aggressive cancers that are responsible for 2/3 of cancer deaths in this country, Galleri's episode sensitivity was 74%. Now remember, Galleri's episode sensitivity performance is coupled with a very high specificity, or a very low false positive rate of 0.4%. We feel very good about the balance that our technology has struck between episode sensitivity and specificity.

Critically, these episode sensitivity numbers should not be compared with test sensitivity numbers from case-controlled studies, where diagnosed cancer cases are used and controls are selected. As described in my recent blog post on the grail.com website, those case controlled studies can be subject to many biases, if not very carefully conducted.

Now another way to evaluate a cancer detection test is to look at the cancer detection rate, or how many cancers are found in the population when deploying the test. In PATHFINDER 1, we found that when you added Galleri to standard of care screening, it more than doubled the number of cancers detected. In PATHFINDER 2, adding Galleri to USPSTF grade AB recommended screening tests, we detected 7x more cancer. So how did we measure this? Of the 329 participants diagnosed with cancer in PATHFINDER 2, 133 of them were MCED detected. 20 were detected by breast, cervical, colorectal and lung cancer screening.

If we compare the 153 detected by MCED, plus the AB screenings to those detected just by AB screenings that is 153 versus 20, or a 7x difference. If we add in USPSTF Grade C recommended prostate cancer screening, then we see a 3x increase in the number of cancers detected or a threefold benefit. This is a significant benefit. And this is only possible because Galleri can detect so many cancers that do not have screening options today.

You can see here that the cancer types detected by Galleri and PATHFINDER 2 represent a broad range, including cancer types with existing recommended screening. We know that Galleri can find interval cancers where recommended screening tests exist today. So even when participants are compliant with other screening, Galleri may still find a cancer, but most importantly, 73% of Galleri detected cancers in PATHFINDER 2 do not have recommended screening options. This test is truly a breakthrough and is enabling patients and providers to find cancers that would rarely be diagnosed until after symptoms arise.

Now you see here the stage distribution of the Galleri detected cancers. And remarkably, more than half of the cancers identified were in Stages 1 and 2. These include head and neck, liver, pancreas, kidney, lymphoid, anal, colorectal, lung, breast, plasma cell bladder and testicular cancers. And as you may know, with the advent of new therapeutic and treatment approaches, Stage 3 cancers have become more treatable with better outcomes, and almost 70% of Galleri detected cancers were in Stages 1 through 3.

We believe an accurate built-in cancer signal of origin capability is critical to guide rapid and appropriate diagnostic workups after a positive test result. Feedback we received from the physicians and regulators is also very consistent here. In PATHFINDER 2, the Galleri test's first CSO prediction correctly identified the cancer signal of origin 92% of the time, leading to very efficient diagnostic workups. This is in line with what we saw in the first PATHFINDER study.

We also look at the time to diagnostic resolution. Following a positive Galleri test report, it's important that we and physicians make maximal efforts to achieve full resolution as quickly as possible to avoid any prolonged diagnostic journey. The median time to diagnostic resolution among true positives was just over 1 month, 36 days. Among all MCED positive participants, full resolution occurred at a median of 46 days, and patients that received a positive MCED test and where cancer was not found, these cases were resolved at a median of 75 days. We are very pleased with these results, and we note these are much shorter time lines than was observed in the first PATHFINDER study.

Now, let's turn to the safety findings. Galleri was safely implemented in the intended use population in PATHFINDER 2. Of the 25,000 participants analyzed, 0.6% and had an invasive procedure done as part of their diagnostic workup. We defined invasive procedures broadly to include endoscopy as well as biopsies and surgery. Invasive procedures were 2x more common in participants with cancer than in those not found to have cancer, and there were no serious study-related adverse events reported as of the date of this analysis.

So now let me summarize these results from the PATHFINDER 2 study. Adding Galleri to standard of care screening for breast, cervical, colorectal and lung cancers, yielded a more than sevenfold increase in the cancer detection rate. More than half of the Galleri detected cancers were found in early stages 1 and 2 when cancers are more treatable and potentially even curable. Nearly 3/4 of the cancers detected by Galleri do not have recommended screening tests today. Galleri's ability to accurately identify where in the body the cancer signal is located help guide an efficient diagnostic workup, and importantly, there were no serious study-related adverse events.

So these results from PATHFINDER 2 mark Galleri's ability to provide asymptomatic adults and their loved ones with a way to detect cancer early when cancers are more treatable and potentially curable. And this represents a really exciting next step in the evolving evidence space to bend the cancer mortality curve through multi-cancer early detection. Now back to you, Bob.

Thanks, Josh. Operator, let's open the lines for questions.

[Operator Instructions] Our first question will come from Subbu Nambi with Guggenheim.

18 of the 133 MCED detected cancers were recurrent. I thought that was a bit high. Could you tell us if it was in line with your expectations? And if not, why? And I know how many years out from the cancer were these patients. Do we have information on that. They have to be 3 years out to be included in the trial, right?

Harpal, do you want to discuss?

Yes, you want me to take that rather than Josh?

Josh, you could, yes.

Yes, thank you. Good question. We don't have the detailed information on each of those recurrent cancers, but the criteria for this study was they had to be at least 3 years post treatment. So they are not actively treated cancers. So these were cancers that were in remission or had been cured. The number of recurrent cancers in the population did meet our expectations, that will be variable in any given study, but we do expect and have found throughout all of our clinical studies and our real-world experience that we are finding recurrent disease in people who have been long cured or posttreatment for their active cancer. So this did sit with our expectations and also with what we saw in the original PATHFINDER study.

Thank you for that, Josh. Just safety is an important metric, at least in the NHS trial and then even in this trial, 0.6% of your patients had an invasive procedure. Are there any prespecified endpoints for the safety metric with the FDA? Or did 0.6% make the cut?

No, there were no prespecified metrics. And we know that for a given CSO directed workup that the endoscopy is a very appropriate first test. So if you get a CSO that says esophagus, stomach, colon or larynx, they often go right to endoscopy, which is categorized as an invasive procedure in this study. So the fact that only 0.6% of all subjects had an invasive procedure is very positive from a benefit risk profile perspective. And of course, of the 0.6% participants that were more than twice as many of the invasive procedures occurred in people ultimately diagnosed with cancer, as opposed to the false positive. So very -- that's a very low number of invasive procedures, particularly given that endoscopy is often the right first test.

Your next question will come from Kyle Mikson with Canaccord.

So I wanted to just focus on the addition of a PET imaging because I don't think you've done that in previous studies. So I was -- first, I was wondering if that helped PPV or any other of the detection metrics? And also does the addition of the imaging kind of reduce the importance of your CSO prediction accuracy?

That's a great question. The -- let me go back as to the reason why we even introduced that part of the study. So in commercial practice today, Galleri CSOs are actually reported, 1 CSO is reported, and the workup is very effective at resulting in diagnostic resolution. However, there are cases where the initial workup does not reveal the cancer. And in those cases, commercially, we offer a free repeat Galleri test to bring that to rapid resolution. We do not recommend whole body imaging. And it was for that reason that we introduced the PET CT into that step of the study.

So if in the study, people got a positive Galleri result in a CSO and the initial workup was unrevealing, they got both a PET CT and a blood draw. The purpose of that was to show that the blood draw is the best way to achieve diagnostic resolution. And in fact, that analysis is still ongoing and will be reported out shortly. But the initial preliminary results are that the PET CT revealed very few cancers and did not meaningfully impact our PPV.

Good. Appreciate that. On the topic of cost, just using the PATHFINDER 2 data here, we estimate that you would need to price Galleri at like $200 to meet the quality cost threshold for NHS. So clearly, much, much lower pricing right there. Do you think that the economic benefit analysis that's going to be done by the NHS right now is going to be a bottleneck and cause some friction when they roll that out -- roll Galleri out even if all the data is positive.

Well, let me comment on your math first, and then I'll turn it over to Harpal. Something's not adding up with your math. We've published robust cost effectiveness analyses already looking at cost per qualities. And there is -- it's based on modeled stage shift and interceptions and we've shown that it's highly cost-effective, even at the list price. So I'm not sure you're doing the economics quite right. So you might want -- we can talk to you about that off-line. And then I'll turn it over to Harpal to comment on the NHS.

Thanks, Josh. I mean, look, we are waiting, as you know, for the results from the NHS Galleri trial. That will give us updated information on what proportion of participants do end up with a cancer diagnosis, and that will -- and we'll be able to look at that by different subgroups and so on, and that will determine how the NHS chooses to move forward in terms of deployment. And that then would also, if you like, trigger the conversation that we will need to have with the NHS about how much the test is priced in order for it to be cost effective. So those are discussions to come. We haven't had them to date, but we will absolutely be following up and initiating those once we have results from the NHS Galleri trial.

Your next question will come from Yuko Oku with Morgan Stanley.

PATHFINDER 2 demonstrate a shorter median time to diagnostic resolution than the original study, particularly for the false positives, what factors would you attribute to this improvement?

It's a great question. I think there are two main factors. The first factor was going back to the original PATHFINDER study. That was the first real interventional study done of an MCED. And I think physicians were less aggressive in working up the CSO than they are today. And second, PATHFINDER, the original PATHFINDER study was conducted during COVID, where lots of endoscopy suites, clinics, mammography suites were not open regularly, and patients were not visiting the clinical sites nearly as frequently. So I think between the COVID effect and just the experience that the clinical community now has in working up CSO directed signals, I think that those two things combined with the short -- much shorter median duration to diagnostic resolution. .

Great. That was pretty helpful.

Yes. I mean, I'm actually speaking to you from Berlin, where I've been at the ESMO conference. And it's really notable that many of the clinicians we talked to Josh's first point, with such a high PPV, there's now such a high degree, the confidence that this is more likely than not to be a real cancer and so there is a real effort now on the part of clinicians to say, if I get a positive test, I really want to look to make sure that this patient does indeed have cancer. And so that process of investigation is more intensive and more comprehensive and thorough now than perhaps would have been the case with the first PATHFINDER study.

And Harpal, do you want to just mention this what we saw in SYMPLIFY that kind of compounds this issue?

Sure. Happy to do that. So the SYMPLIFY study, for those of you who don't recall, was a study that we conducted in the U.K. in symptomatic patients to understand if this test could play a role, helping clinicians guide investigation when participants -- when patients are presenting with symptoms that might be nonspecific. And originally, what we saw was that there was a PPV of around 75%. What we've done, and indeed, the data has just been presented today or published today, is that we have followed up all of the patients who were originally designated as false positives. And what we found is two really important pieces of information.

First of all, over 1/3 of those patients initially designated as a false positive, 35% have subsequently been diagnosed with cancer within 2 years of that blood draw. And so more than 1/3 of the false positives have turned into true positives. But secondly, of those, all but one patient, the CSO prediction was correct. And so that really offers the opportunity for a very effective and efficient diagnosis. And it takes the PPV in that symptomatic population up to 84%.

Your next question will come from Doug Schenkel with Wolfe Research.

A few topics, on clinical utility, as we've seen in the past, FDA approval does not always translate to CMS reimbursement. Ultimately, the key dynamic will be likely stage shift, as you acknowledged in your prepared remarks as a proxy for survival benefit. Is there anything in PATHFINDER 2 that makes you more comfortable about a positive outcome on this metric when we head to NHS Galleri? Or ultimately, do we just need to wait for the readout?

And building off of that, given FDA requirements outlined at the FDA panel on MCED in 2023, what boxes have you checked with the FDA and what remains to be done? So essentially trying to get at the clinical utility question, which would be key to reimbursement and then separately, the regulatory question in the U.S. with the FDA.

No. Doug, really good questions. Let's take the clinical utility one first. There's nothing directly that can be inferred from the PATHFINDER 2 study to the stage shift or the reduction in late-stage detection. That is the primary endpoint of the NHS Galleri, but there are many aspects of PATHFINDER 2 that give us more confidence in the overall performance of Galleri. And those specifically are the dramatically increased cancer detection rate when added to standard of care screening, and secondly, the much higher PPV that we've been observing as well as the episode sensitivity, which is quite high.

For those of you who may not have been following this, when case-controlled studies report high sensitivity, they very rarely translate into that level of performance in actual interventional studies, and we've seen that even in the MCED field with the one interventional study that was done in 65-year-old women, where the performance of the assay from the case-control study simply did not come close to replicating. So we're very pleased with that episode sensitivity, those numbers coming out of PATHFINDER 2 relative to what we had seen in prior studies.

So I think those three things together, Doug, give us a lot of confidence in the performance, but they don't directly speak to stage shift or the reduction in late-stage cancer because that will much more be related to the case mix of cancers in that individual study and the stage distribution in that individual study.

I'll turn it over to Harpal in a minute to comment more on the NHSCU. But on the FDA, based on the 2023 panel, it became -- it was quite clear what the FDA said in respect to the meaningful necessity of having the CSO directed workup. And given what we've seen now with Galleri and PATHFINDER 2 with very high CSO accuracy and very rapid diagnostic resolution, we feel really confident about that finding.

The other thing the FDA emphasized was the false positives being one of the biggest harms related to screening. And with our 0.4% false positive rate, we feel very good about that. And the other thing they mentioned, of course, as it relates to safety, was the over-diagnosis. And we've published now multiple times that low shedding tumors that are indolent are not typically detected well by Galleri. So Galleri is very unlikely to contribute to the problem of overdiagnosis of indolent cancer. So on those three dimensions, we feel very good. And then I'll ask Harpal to comment more on the clinical utility question.

Yes. I mean I think you've largely covered it, Josh. But you're right, Doug, that your primary endpoint in NHS Galleri will be looking at that reduction of late-stage cancers. And in order to find a reduction, you have to have a randomized controlled trial. And that's, of course, what an NHS Galleri is.

I think just to add one point to what Josh said, one of the things that encourages me greatly from PATHFINDER 2 is that more than half of the cancers were found at stages 1 and 2. And that's in a cohort of cancers where 3/4 are currently unscreened. And so I think to the extent that you can take any guidance from a study that doesn't have a comparator arm, I think those points really do encourage me as well.

Okay. And I guess I will admit a completely unrelated follow-up. And I think it's more for the finance team, so unrelated to the studies. I am curious where investors in the private placement provided access to any data as part of their investment evaluation that is not currently available in the public domain.

Doug, good question. No. I mean all the information that they've seen is not public.

Your next question will come from Kyle Mikson with Canaccord.

Yes. Thanks for follow-up. On the topic of follow-up actually on the study design. Do you guys -- do you think that the 1-year follow-up is enough for this type of a test given, obviously some cancer spread or appear more slowly than others. And then have you talked to the FDA about follow-up and just kind of longer-term data and if that's necessary?

Great question. On the 1 year, we have to find a period of time to represent ground truth because there is no effective ground truth. I mean one thing we've learned through Galleri implementation is how imaging is not really the right ground truth. So time is the best source that we have. And so we think 1 year is enough. It -- we did a large study with the American Cancer Society that's been published that looked at kind of the dwell times of cancer across stages. And it came out to be very consistent with about a 1-year time period on average across tumor types that they are advancing from stage to stage.

So we do think 1 year is about the right time frame. Both for defining ground truth, but also for the frequency of testing that will be required to detect early cancers. So that's the most important finding as it relates to the finding of ground truth. The FDA has reviewed all of our studies, all of our protocols under IDE and approved them, and they've all had that 1-year time frame. So I think most, at least in my experience, agree that, that's a very reasonable way to define the episode.

Yes, again, perhaps. I'll just add -- sorry, I was just going to add a comment. Just -- we do think that, that 12-month period is the right period to be looking at this sort of episode sensitivity metric, but just to be really clear, PATHFINDER 2 is going to be following all the patients for 3 years. So we will see if later cancers emerge following those. That initial 12-month period. And as you know, in NHS Galleri is three rounds of screening and we'll be following up those patients over longer periods as well.

So we will see the extent to which cancers later emerge, and indeed, if you were listening to my comments on SYMPLIFY earlier, you will see that we do indeed see that. And so there is that possibility, but it doesn't detract from the point that in order to report on this episode sensitivity metric, 12 months is the right period.

And we have not shared any of that long-term data with the FDA yet, because we haven't completed its collection. So that will all be shared with the FDA in time.

All right. Great. And I believe that 14% of the cancer is detected here in the study were recurrences of 19 cancers. If you take those out, you get a high 30% episode sensitivity in the high 50% PPV. So the question is like do you think these cancers would be found using an MRD test in the real world? Or are they appropriate for screening test like this?

Well, remember, these are not people with active cancer. So whether they should have MRD tests is really when they're actively being managed for cancer. So these are people who are completed -- have completed all their treatment, are out of their cancer active status, they are not being treated for cancer. So they're just normal people, who are cancer survivors, who are at elevated risk for cancer, who are being screened. So let's not confuse that with getting MRD testing. That's not what was happening in this study.

So I don't know why you would want to remove those people from this study because that is a very important population to be doing cancer screening in people who have completed their cancer therapy or have been cured or are in remission for cancer. So very different setting than MRD testing or anything like that. That's not what this was going on in this study. These were people being screened for cancer.

There are no further questions at this time. I will now turn the call back to GRAIL for closing remarks.

Just like to thank everybody for attending the conference call today.

Ladies and gentlemen, this concludes the call. You may now disconnect.

Hi, everyone. I'm Yuko Oku, and I'm on the life science tools and diagnostics team at Morgan Stanley. Before we kick it off for important disclosures, please see Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

If you have any questions, please reach out to your Morgan Stanley sales rep.

With that, it's my pleasure to host GRAIL today. And from the company, we have CEO, Bob Ragusa; and CFO, Aaron Freidin. Thank you.

Okay. To start, could you provide a quick overview of GRAIL's mission for folks that are not as familiar with the story? And what are you focused on over the next 12 months?

Sure. And first of all, thank you for -- thank you, Yuko, for having us as well as the Morgan Stanley team. GRAIL's mission is to detect cancer early when it can be cured. And 70% of the cancers that are out there are not [ going to look for ]. So standard of care screening looks for about 30% of the cancers that are the -- cancers that cause 30% of the death. Galleri is really looking at -- looking for those other 70% of the cancers. And so for example, in the PATHFINDER study, when we added Galleri to standard of care screening, we found we more than doubled the number of cancers found. We did a very high positive predictive value of 43%, very low false positive rate of 0.5%.

And we also provided a cancer signal of origin with a high accuracy of around 90%. And so right from the beginning, Galleri has been designed as a population scale screening test. And part of the reason for that is we recognize the numbers here are enormous. So if you look at the TAM in the U.S., there's about 100 million individuals who are screening eligible for a multi-cancer early detection test. If you go to the U.K., where we're running the NHS Galleri study, there's another 19 million. Across the EU, there's another 160 million. And even, for example, in Japan, there's almost 50 million. So really large numbers. So a lot of -- all the things we've done for this are really geared towards population scale screening.

And so what we're looking forward to the next 12 months. So we've just read out over the summer, our NHS Galleri study, where we found substantially higher positive predictive value than PATHFINDER. So PATHFINDER s already at 43%. In our PATHFINDER-2 study, we gave the top line results, again, substantially higher positive predictive value and higher cancer detection rate. And in both studies, the specificity or false positive rate was consistent as well as the cancer signal of origin accuracy was very consistent and no adverse events in those studies.

So we're really looking forward to it. We submitted and are hopeful we'll be able to present at ESMO in October with our PATHFINDER-2 full data readout. And then in the middle of next year, the full readout on the NHS Galleri study. So again, PATHFINDER-2 was 35,000 people and NHS Galleri 140,000 people. So large studies. And then the other big thing next year is we're looking in the first half of 2026 to submit our final module for our PMA to the FDA.

Great. A lot to dig in there. So maybe starting off with the competitive landscape. You're first to market in the multi-cancer screening space. Could you elaborate on the competitive landscape today and how you see Galleri positioned? And sort of related to that, one of your competitors launched an MCD at a lower list price versus Galleri. Does that pressure your ASP at all?

Yes. So a couple of things there. So first of all, kind of our first-mover advantage. We look again, the test was designed and built for population scale. So we believe from a performance standpoint, we're in really good shape. We also have the largest clinical study. So we studied nearly 400,000 people across all our studies. And then in the more recent studies, PATHFINDER 6,600 people, PATHFINDER-2 35,000 and NHS Galleri 140,000.

So really large studies. So we have a lot of data in interventional studies prospectively in the intended use population. And then the third piece from a competitive standpoint is just our commercial experience. So we've been out there for more than 4 years. We understand what works and doesn't work. We understand how to integrate it into a clinical practice, what are the important elements. And so some of the things to think about there is the low false positive rate, the high positive predictive value. So high positive predictive value gets you to very actionable results.

So when providers see a positive on Galleri, they know that there's something that you really have to go look at, as opposed to some of the other screens, which are low single-digit positive predictive values. So that's an important aspect. And then the other thing is just the cancer signal of origin to have a cancer signal of origin is really a differentiator. It's what helps guide an efficient diagnostic workup for it. Then you mentioned ASP pressure and new entries in the market. So if you look at the tests coming out, one in particular with Cancerguard, we feel really comfortable about our -- again, it's the suite of metrics that make it for a population scale screen.

So the fact that we have high sensitivity and good cancer detection rate. So again, doubling the number of cancers found compared to standard of care, the very low false positive rate, the high positive predictive value and the cancer signal of origin capability. And so when you look at just the specifications and compare one to another, if you take 97.4% published specificity for the other tests and you look at 99.5% of Galleri, on the surface it doesn't seem like that big a difference. When you dig into the details, that's a more than 5x degradation in false positive rate as you go from 99.5% to 97.4%.

And again, since we were designed for population scale, we're looking at big numbers. So if you look at 1 million people, that means with the Galleri test, you're looking at 5,000 false positives. With the other tests, you're looking at more than 25,000 false positives. And then if you couple in the cancer signal of origin guides, the directed workup. So you have an efficient workup on the Galleri side. On the other side, there is no cancer signal of origin. So you have more than 25,000 with a non-guided workup.

So we feel good about the competitive landscape. And we think our performance, coupled with our -- all the studies. So we're the -- Galleri is the only NSAID with demonstrated performance in individuals being screened for cancer in the intended use population. So coupling performance in our studies, we feel really good about our competitive position and our ability to be priced to where we are.

Great. So you mentioned a lot of the pros of being a first-mover advantage. But one of the cons you can say is that you have to pave your way for reimbursement, right? So when you were thinking about potentially developing multi-cancer tests versus a single cancer test and then taking a multi-cancer approach after that, like what are the criteria? Or what are you thinking around that?

Yes. So again, we've looked at through GRAIL's history, looked at kind of all combinations to get in there. And we really focused on multi-cancer because that's ultimately is where the need was. Again, if you look at -- you have -- it's always meant to be a complement to standard of care screening and standard of care does a good job of looking at the 30% of the -- cancers that cause 30% of the deaths. So really comprehensively look at the other 70%, we found it impractical to go cancer by cancer because there are so many cancers that make up that huge long tail. And the reality is in the early discoveries, we found a shared cancer signal across those. And so that really points us towards the NSAID. There have been some forays to try to use a single cancer test to get reimbursed for a multi-cancer test.

And we think that raises a lot of questions. We're hearing at this conference, we heard in the previous conference to some of the questions around that strategy. So not for me to go into detail on that. That's another company's strategy, but we'll be looking to see what happens there. But I think when you're evaluating any -- whether it's single cancer, multi-cancer, you really have to look at the data, how much data is there in the intended use population. And again, here's where we've spent a lot of effort across really large studies to really understand how the test performs in intended use.

And we've been really pleased that our case control data translated into PATHFINDER very well, and it's also translated into very large NHS Galleri studies and PATHFINDER-2 of 35,000, 140,000 people. It's unusual for the performance to actually get better in those studies. A lot of times, you see when it goes from case control to the intended use population that degrades. We've been very happy with the fact that it's at least replicated in the latter 2 cases gotten better.

Okay. Great. Well, let's dig into those results. You recently announced the top line results for PATHFINDER-2, which demonstrated substantially higher PPD and cancer detection than PATHFINDER. So ahead of the detailed results at ESMO. Could you provide a high-level overview of the trial design and key aims of the trial? Given this is one of the key data that will be part of your PMA submission in first half '26, what are the regulators focused on in the study?

Yuko, as you said, the study was designed and is part of our registrational clinical package to go to the FDA. PATHFINDER-2 is designed as a safety and performance study in the U.S., it's 35,000 folks in the total, one time point, one test and then followed for a year. That period expired. We're now going to present that data next -- at ESMO, and we're excited about that. We enrolled that study to be very -- to look like the intended use population, right, to specific -- the right demographics, the right ethnic mix, socioeconomic mix and so on. And I think that's why you're actually seeing the performance in PPV, as we said, improve. It looks more like the intended use population.

And so we'll be submitting that as we said at ESMO. We'll -- as we said earlier, the PPV is substantially greater. Specificity is in line with what we had previously said in PATHFINDER, so the cancer signal origin. The other really important part is that we've improved the number of cancers found when compared to the standard of care, when compared to PATHFINDER. So PATHFINDER was more than 2x. We're now -- we're greater than that, which is really important as you think about cancer yield. And so we think the FDA -- what we know what the FDA is going to look at is benefits and harms. They look at the performance. As they've looked at our performance in our prior studies, they were done under IDE. So the FDA has been on this journey with us since 2019 when we were in breakthrough with them. And we're excited to get this data in their hands.

What are some of the reasons that PATHFINDER-2 may have shown a higher cancer detection rate in PPD than the prior PATHFINDER trial? Are there any key differences between trial design or population enrolled in the study?

Yes. that's exactly where it's at. And PATHFINDER-1 was enrolled. It was enrolled during the pandemic, and it was a highly screened population. There's very well known that certain populations like to get screened more than others. With PATHFINDER-2, we really took the time to make sure that we weren't focused on a highly screened population that we're looking at what the world looks like, who's not getting screened that should, but still asymptomatic, no symptoms for cancer and so on.

So that test performance, I think, is really more representative of what the world actually looks like when it comes to cancer versus what folks who enroll in these studies can sometimes look like.

Okay. Given that physicians should have had more time to gain clinical experience with Galleri versus when the original PATHFINDER study was run, is there a potential for a diagnostic resolution to be shorter than the 57 days for those with positive signal, 162 days median diagnostic resolution for false positive results seen in the prior study? And then will we see these metrics with the detailed results at ESMO?

Yes. So it is one of the endpoints that we presented at ESMO. And again, if you recall, that follow-up was all done during the pandemic. So we'll see what it looks like when it comes out and we present it. We do these qualitative releases, not because we don't want to get the data out there, but if we put the data out there, we're not going to be able to go present it at one of these large conferences, which we think is really important. It's a great -- it's where you want to present this type of data. So we'll see it all then.

Okay. All right. Looking forward to it. All right. So I want to jump into NHS Galleri. You shared top line results from NHS Galleri trial as well, which also showed substantially higher PPV in the first round of blood draws than observed in PATHFINDER, though PPV may decline in the subsequent blood draws. Similar to the question on PATHFINDER-2, are there any key differences in the population enrolled in NHS Galleri, or is -- or its design that may have driven PPV higher than in the PATHFINDER?

Yes, it's a good question. So in NHS Galleri, similar to PATHFINDER-2, we went to extraordinary lengths to make sure that we had a population that was representative of the U.K. So we looked across ethnicity to make sure we had the match ethnicity mix as well as socioeconomic scale. So in the U.K., they actually have scales for in quadrants. And so we made sure those all match. So we're very comfortable that the population is very representative, likely one of the things that changed the incidents that would have impacted the PPV.

Anytime you have that culling effect in the first round, you could have an impact on PPV as you go into future rounds. That's definitely a possibility. But the important element within the NHS Galleri that sets us aside is an interventional longitudinal 3-year study with a year of follow-up. So it's actually looking for clinical utility. So we're looking for stage shifts, so reduction in late-stage cancers in the intervention arm compared to the control arm. So look at Stage 3 and 4 reduction versus the control arm as well as the Stage 4 reduction versus the control arm. So we should be able to get a measure of clinical utility out of that. And that will all come out in the middle of next year.

Great. And I know you said previously that regulators aren't focused on the clinical utility aspect of NHS Galleri, but it is important for payer conversation and physician buy-in, right? So outside of NHS Galleri, what other clinical utility studies are underway that you believe are important from a reimbursement perspective?

Sure. So the REACH study in the U.S. in the Medicare population. So this is 50,000 people, again, over 3 years, similar to the NHS. It will be compared against a synthetic comparator arm. So -- but the intervention arm is 50,000 people. So that will generate, again, the clinical utility data in the U.S. Medicare population that should be able to be used for payer discussions. So we're looking forward to that data as well in the future.

Great. And do you have an estimated time line for when that would complete?

That one -- so we'll probably be through a lot of the milestones before that study is actually completed. So we'll probably look at using partial data out of that for actual payer discussions.

Great. Okay. So one of the things that KOLs are concerned about with NSAIDs in general is the potential that it would lead to lower adherence to existing screening products. Have there been any studies conducted to date to address that concern?

Yes. So it's kind of again from the beginning realm when we recognize you want to have a population scale screened, and we recognize the goodness that are in standard of care screen. So we've never really been targeting to try to replace those, that's really been as a complement to those. And so in PATHFINDER, one of the things we measured is the people who are participating in it and got a Galleri screen, what was their likelihood of continuing on with their standard of care screening. And we're happy to see that the standard of care screening continued on quite well with that group. And so in PATHFINDER-2, that's also one of the readout elements we'll look at is what's been the inherent standard of care screening with people taking Galleri.

Great. And then the repeat order rate has been steadily increasing with 25% reorder rate in 2Q despite being ahead of any meaningful reimbursement. What are key drivers of the uptick in reorder rate in your view?

Yes. So we're really happy with the reorder rate being where it is at 25% for a non-reimbursed non-guideline test. People are really seeing the value on an annual basis of taking the test. And so the improvement in that is, I think, through more physician interaction, more physician understanding how to follow up on guidelines, doing more work, as Bob has said, in our studies we've shown, a PPV of over 40% is something that you need to follow up on as a clinician. When you compare it to mammography, which is around 5%. People who get -- I'm sure you've had mammograms and they say, you have a positive but don't worry about it, you're going to go get a follow-up. That's not what physicians tell people who have positive Galleri tests. So I think the more data we have, the more FDA approval we have, the more clinical utility have, I just see that number continuing to grow. But we're very happy with where it's at for it being an out-of-pocket test.

Another potential driver of volume for you is the 7% of orders coming in 2Q from the Quest platform. What's driving that growth? And how much volume do you think you will eventually see coming from the platform? And how could the platform also help you with further improving the repeat ordering rate?

Yes. The Quest partnership has been really, really great for us, and we're excited about it. We're still early days as far as some of the longer-term impact of it. But what we do know is where physicians have onboarded the Quest, we've seen those physicians ordering more tests. There's this theme I'm sure you guys are all aware of that barriers to getting testing, whether it's in any sort of health care, when you remove those barriers, make things easier for somebody to get a blood draw or order a test generally shows an improvement in the number of people ordering the test are compliant. So we're excited about where that's at. We're also now starting to see new physicians come on to the platform that are using Quest, but we're still in the early days of some of those integrations, but we're excited with what we've seen so far.

Does it also have additional features on the platform that sometimes it has alerts for ordering again when you're due for a next test. Is that some of the features that are available on that?

So we've seen those in some of the integrations that we've done with different EMRs. I don't know if Quest specifically has that or not. But we've seen different health systems where they have a flag for you should offer Galleri to this person or it's their turn to take it again. It helps the physician remember that they should offer it or ask.

Okay. I know one of the things that is required for the PMA filing also is the bridging studies. So could you talk a little bit about the bridging studies that will be needed to support PMA approval, Galleri 2.0?

Sure. So we've talked about our new version of the test. The studies were run on the previous version. And so in the discussions with the FDA, we know we'll have to show a bridge between older version and the current version of the test that we're running. And so that's being integrated into the PMA process. So in the first half submission next year, we'll have that bridging information in there.

How large is the study required to be for bridging?

Yes. So that we're still working out with them. It will be substantial, but it will also be samples that we already have as opposed to going and getting new samples from the studies.

Great. So legislation is working its way through Congress and if passed grants the ability for CMS to cover Galleri test upon FDA approval. Can you provide an update on where that bill is in review and the next steps? And then also, could you provide an example of other screening paradigms that might have undergone the same process in establishing Medicare reimbursement?

Sure. Maybe starting with the second one, first. The colorectal screening, so quite a while back, colorectal screening law was passed to be able to enable CMS to be able to reimburse for that. And one of the key things you see in that field is just the level of innovation that's occurred in the ensuing decade after that to be able to really drive innovation in that field.

And so that's part of the hope of the NSAID bill as well is not only -- it's not a GRAIL test, it's an NSAID legislation. And so really driving innovation and providing more certainty about reimbursement at the end of the game so that people can invest in innovation. But at the end of last year, we had -- it was in the package that was ultimately shot down by the 1,600 going to 160-page bill. But -- in that process, it came out of the House Ways and Means Committee at 38 to 0, so a unanimous vote in favor of it. As we look at it going again this year, we have more than half of the House, more than half of the Senate, and nearly 2/3, not only as supporters, but as cosponsors.

So it's the third most cosponsored bill in Congress, and it's the #1 most cosponsored bill in health care. It also has about 700 advocacy groups that are pushing for its passage. And so we think it's positioned as well as it can be and now it's really looking for the right funding vehicle. So we're hopeful that it will occur this year, but obviously, a lot of it's outside of any of our control.

Should the efforts to establish CMS statute fail to pass, you have another shot on goal. You can work through the USPSTF pathway following FDA approval to establish reimbursement. So how quickly following FDA approval could USPSTF review Galleri? And how do the recent headlines around potential dismissal of all members of USPSTF effect time lines?

Yes. So since USPSTF is a really important pathway for us, we obviously are pretty cognizant of change -- potential changes there. I don't think we have any more insight than what's been in the media in terms of what's actually going to happen there. But upon FDA approval, we would go pretty immediately to USPSTF to give the data and really show the impact on kind of the battle of cancer that a test like Galleri could provide and hopefully secure a strong recommendation of USPSTF.

Since there isn't an established time line for USPSTF review for an NSAID in particular, when a new emerging technology comes to market, like how long does it typically take? Or do you have any prior examples of how we can think about those time lines?

Yes, I'm not sure we have any clear time line on that. NSAID is, as you say, a novel space. But the flip side of that is when you look at the impact that NSAIDs had and by the time they take it up, if you look at the level of impact in terms of Galleri test will be out there, the number of cancers we will have detected, the fact that it's FDA approved, we'll have all the studies behind us really showing both the benefit/harm ratio as well as the clinical utility benefit. So we think that will put a fair amount of pressure on being speedy in the process, just given the goodness and the impact on cancer it could have.

Okay. There have also been some noise from KOL community that methylation-based early detection tests have limited ability to detect early-stage cancers. Remind us of the demonstrated Stage 1 sensitivity for Galleri. And is that sensitivity sufficient to justify benefit versus cost and risk in your view, why or why not?

Yes, happy to talk. So we've talked about PATHFINDER-2 or PATHFINDER. In PATHFINDER, we more than doubled the number of cancers found by the standard of care and more than half of those that we found were early-stage cancers, Stage I and II cancers. That's an intended use population study, not case controlled. We have case controlled data from CCGA that shows Stage 2 sensitivity of 70%, which are all cancers you can treat with curative intent. So I think we've got data that shows that we can find these early-stage cancers.

And I think it's really important to focus on the fact that you don't know what cancers you're screening for, right? We're screening for cancer in your body. We're not going after a single cancer and then another cancer and so on. And you don't know what that incidence is, you don't know when you're going to find. So if you're -- so just looking at sensitivity by cancer by cancer, does that actually make sense? Or should you be looking at how many cancers are you finding with this test that currently aren't being found. And we're finding more than double the number of cancers found in PATHFINDER, and we've improved that ratio in PATHFINDER-2. And we've shown that those cancers are early stages. So I think we've got data that shows that we're finding early-stage cancers that you can treat with curative intent.

Okay. Given the very large potential opportunity for Galleri, pricing could come under scrutiny or should it be ruled out broadly. What is -- what price point are you comfortable with where you can still achieve an attractive margin profile?

Yes. We built the version of the test that's on the market now and the PMA version to be a population scale test, as Bob has said, we built that with it -- will it have a low COGS and a fair margin at a lower price point than we're at today. If you think about the NSAID legislation that would peg the reimbursement for NSAID at $508 a test. We're comfortable with being in the 50% to 60% margin range at those prices. And with the platform we have today, we're currently able to run about -- the system is capable of running about 1 million tests a year. We're running at a fraction of that. So we've got significant fixed cost leverage to grow into.

And we could -- if a bunch of demand showed up tomorrow, we'd be ready to handle it. So we expect the price to come down, and we're prepared for that.

Okay. And through first half '25, more than 370,000 commercial Galleri tests have been ordered by more than 15,000 health care providers. Despite Galleri being essentially ahead of any reimbursement, you're guiding to 20% to 30% year-over-year screening revenue growth this year. What are the key drivers that will swing revenues to the high end versus the low end?

Yes. This year, we said we've guided 20% to 30%. Last year, we grew -- revenue grew in the Galleri for about 21%. Volume grew at just under 30%. And what we're seeing...

Last quarter.

This past quarter. The -- what we're seeing drive that are a couple of different things. The telemedicine health wellness platforms are becoming more popular. We've got self-insured employers that we sell through, and that base is building. And also our PCPs through things like Quest and Athena Health are ordering more tests. We've got a TRICARE program, and we'll see how that goes. It's still too early to really say what that will contribute. And then there are some headwinds. We've got our first responders like firefighters and so on, they take the test, but that's usually connected to grant NIH-type money, we know what's happening in that world. But overall, we're confident that we're going to be in that 20% to 30% range for the year.

Great. And then where are you seeing the greatest volume growth to date in terms of channel, health care networks, self-insured employers, life insurance, self-pay.

Yes. I'd say it's the depth of our ordering base, our PCPs, again, through things like Quest and so on, getting it into their protocol because you've got to remember that the cancer incidence is about 1%. So if a physician orders 99 tests, they might not find a cancer. If they order 150, they might not find a cancer. But when they're finding them, then they're seeing that it works. They're seeing how it changes their patient's life and so on. We've got different programs put together to connect physicians who have lots of experience with new ones, and that's been successful as well. And I think I've already mentioned the wellness platforms as function health grows, we expect to grow.

Great. And outside Galleri, how should we think about development services business?

Yes, development services business is great, it represents our biopharma partnerships with folks like AZ, where we're working with them on their trials and their drug designs and so on. It's not a revenue line that we guide because it's quite lumpy and out of our control at times. But it is important work that we're doing with those partners. But I would expect it to be pretty -- our investment in that is pretty static, and I would expect the revenues to be pretty static.

Great. And then you also talked about doing more with less after the August 2024 restructuring. What efficiencies have you identified or learned? And what changes, if any, are expected in '26?

Yes. So in '25 -- '24, we effected that restructuring. And in '25, we've been working through our PMA module submission. And we've found that we've been able to stick to our time lines, targeting '26 for the final submission with 40% fewer resources. So the organization and our people, we've got some core values here, solve problems together, embrace change and so on. Our teams are doing a really great job of coming together to really change cancer outcomes for patients in the world.

So from an execution standpoint, we're doing what we thought we would. And then financially, those I would expect in '25, when we're submitting the PMA submission. We've got -- as Bob said, we've got concordance bridging studies, clinical validation, analytical validation and so on. Those things will not repeat in 2026. So there'll be some R&D dollars that will free up. And then it will really be thinking about how we spend sales and marketing dollars. We've really been focusing on growing revenue efficiently. We're not chasing every gallery sale across the United States. We're really focusing on where we've seen success. And so if we're seeing more success there, we'll invest more dollars. But we really want those dollars to be capital efficient.

Great. With your Investor Day set for November, could you give us a little preview of what we might hear there?

Yes. So we're -- we scheduled an Investor Day for November 13. We're going to run that at our RTP site, Research Triangle Park site. That's where our main laboratory is, and so people will be able to see that. And throughout the day, we'll be able to talk about our studies that we've already done as well as the top line readouts. We'll also be able to, at that point, on PATHFINDER-2 go into more of the detail of the actual readout and for NHS Galleri, be able to frame up how the data -- how we're going to look at the data and so people get a better understanding of that.

And then importantly, we'll be able to have investors hear directly from people who are current Galleri users, so they can hear firsthand experiences of Galleri users. So we think it will be a great day for people to get a much better feel of just the kind of size and scale of our operation as well as the clinical studies coming out and firsthand experience.

Great. And then just in the last couple of minutes here, I want to wrap up with a bigger picture question. What about GRAIL's story do you feel is underappreciated by investors?

Yes. So I think -- I'm not sure about underappreciated, but if we look -- if we kind of just look to the future, one of the big things we have coming out is what we've already done in terms of GRAIL being the only NSAID with demonstrated capability in the intended-to-us population of people being screened for cancer. We have -- mid next year, we have the readout on clinical utility. So it will be great to see out of the NHS Galleri study, the clinical utility. We'll be in process of FDA approval. So we submit in the first half of next year. We expect about a 1-year process for that to get the FDA approval.

And then that really starts to unlock broader reimbursement, especially if it gets coupled with the NSAID bill. So we think those elements give a lot of great inflections. Even earlier on, we have the PATHFINDER-2 readout, which we'll have hopefully next month at ESMO. So a lot of good things there. And then I think maybe the underappreciated thing not through by investors, but in general is in all these things, we typically talk about the future, what's going to happen. And if you just look at what's happening now today, literally every week, every day, we're detecting cancer in asymptomatic people. So it's not a future thing. In the future, we'll detect a way more. But right now, we're detecting a substantial number of people every week. And it's changing patients' lives. It's changing the way providers practice medicine in cancer, and they're seeing things that they've never seen before. I mean, we've had physicians who are older than I am that have see of early-stage pancreatic cancer that say, I've never seen one of those. And so that change in patients' lives today is really impactful. I think that piece might be underappreciated.

Well, that was great. Thank you so much.

Well, thank you.

Thank you.

Good day, ladies and gentlemen, and welcome to the GRAIL Second Quarter 2025 Earnings Call. [Operator Instructions] Please be advised that this conference call is being recorded. GRAIL Investor Relations, please begin.

Thanks, operator, and thanks, everyone, for joining us today. On the call are Bob Ragusa, our Chief Executive Officer; Aaron Freidin, our Chief Financial Officer; Dr. Joshua Ofman, our President; Sir Harpal Kumar, our President, International Business and Biopharma; and Andy Partridge, our Chief Commercial Officer.

We'll be making forward-looking statements on this call based on current expectations. It's our intent that all statements other than statements of historical fact made during today's call, including statements regarding our anticipated financial results and commercial activity will be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act of 1933 as amended, and Section 21 of the Securities Exchange Act of 1934, as amended.

Forward-looking statements are subject to risks and uncertainties. Actual events or results may differ materially from those projected or discussed. All forward-looking statements are based upon currently available information and GRAIL assumes no obligation to update these statements. To better understand the risks and uncertainties that could cause actual results to differ. We refer you to the documents that GRAIL files with the SEC, including the Risk Factors section in GRAIL's most recent quarterly report on Form 10-Q.

This call will also include a discussion of GAAP results and certain non-GAAP financial measures, including adjusted gross profit or loss, which are adjusted to exclude certain specified items. Our non-GAAP financial measures are intended to supplement your understanding of GRAIL's financials. Reconciliations of the non-GAAP measures to the most directly comparable GAAP financial measures are available in the press release issued today, which is posted to our website.

And with that, we turn to Bob.

Thank you. Good afternoon, everyone, and thank you for joining us to review second quarter results. For nearly a decade, GRAIL has made key investments to advance our vision for population scale, multi-cancer early detection and establish a durable advantage in a growing field. The time frame to establish evidence in this space is long, and we are setting the evidence bar high. We started population scale clinical studies years ago and now have several years of follow-up data. Our pivotal implementation and clinical utility studies in the intended use population are beginning to read out, and we are delighted to see results not only confirm earlier studies, but actually improve certain performance measures as we evaluate Galleri in larger populations. We plan to submit detailed results from the prespecified analysis of the first 25,000 patients in our registrational PATHFINDER 2 study for presentation at the ESMO Congress 2025 in October.

As a reminder, we announced positive top line performance and safety results from this data set in June, namely that we observed substantially greater additional cancer detection and a substantially higher positive predictive value in PATHFINDER 2 compared to the first PATHFINDER study, and Josh will describe these results further shortly.

We've been working with advocates and stakeholders to deploy MCED, and we are finding aggressive cancers in real-world commercial setting, many of which are in early stages. Galleri test orders continue to grow at a strong clip with more than 45,000 Galleri commercial tests sold in the second quarter. As of June 30, more than 370,000 Galleri tests have been prescribed by more than 15,000 health care providers since we launched Galleri commercially in 2021. We continue to drive provider and patient awareness of the MCED opportunity and Galleri's ability to detect cancer earlier when it is more amenable to treatment. GRAIL has established several partnerships with health care systems to make Galleri available to patients, and we were very pleased to add Rush University System for Health in July. Rush is 1 of the largest health systems in the U.S. and the first in the Chicago area market to offer the Galleri test.

Additionally, we recently entered into a new collaboration with Everlywell, a digital health company pioneering and next generation of biomarker intelligence, and Galleri is now available for requests directly on EverlyWell's website via prescription.

We remain on track for continued commercial growth in 2025. We are also encouraged by increasing Galleri volume via the Quest Diagnostics test ordering platform at midyear which follows Galleri integration into the platform earlier in 2025. In late 2024, we began the use of a new version of Galleri for which we are submitting our PMA in commercial channels. This new version incorporates an industrial scale platform with significant automation intended to enable us to scale more efficiently with future demand. As a result of the scale and complexity of the system, there are certain new processes to sort through with a large-scale rollout. For example, for a small proportion of samples, we've experienced increased turnaround times with higher reprocessing costs. We are now working to implement the fix to this issue.

Before I hand it over to Josh, I'd like to notify the group that we will host our 2025 Analyst Day in November. Feature speakers will detail key study results in clinical surveillance findings. Frame our upcoming longitudinal clinical utility data and describe firsthand customer experience with Galleri. Event details will be announced at a later date. Josh, please go ahead.

Thanks, Bob, and hello, everyone. We've spoken in the past about key performance metrics, features and capabilities for multi-cancer early detection tests, which are quite different from those for single cancer screenings. Most critically, any test developer must confirm clinical validation in the intended use population of asymptomatic adults eligible for screening before they introduce those tests into clinical practice. This critical criteria was the reason that GRAIL did not introduce Galleri into clinical practice until we saw the results from the PATHFINDER trial in these screening population. Even test with strong results in observational case-controlled studies, may fail to confirm those results in the actual screening population. Full clinical validation requires demonstration of compelling performance in the intended-use population. It is simply not possible to know the benefits and potential harms of any test before being adequately studied in the intended use population. It is also important to note that any multi-cancer test seeking FDA approval will need to demonstrate this as well. So in terms of performance metrics, we've discussed what we consider to be most clinically important for MCEDs, positive predictive value, or PPV, which tells us among positive test results, how many cancers are found or how many are actually true positives. And the specificity, critically important, which defines the false positive rate, as well as the cancer detection yield when added to standard of care screening and the ability to localize where in the body a cancer signal is coming from. After hundreds of thousands of commercial tests performed, we've now confirmed how essential it is for any MCED test to report a predicted CSO or cancer signal origin to guide an efficient and effective clinical workup. We believe that any other approach, such as relying on whole-body imaging with its radiation exposure, costs and lack of any performance or safety data is simply not practicable.