Compass Therapeutics Aktie

All right. Good morning. Let's kick off our next session. I am -- it's my pleasure to be hosting Compass Therapeutics. And with me is Tom, CEO of the company. Tom, welcome. It's the first time for me to host you at the GS Conference. So welcome and look forward to a very exciting discussion.

Before we -- okay. Before we begin, I'm going to kick it off to you for opening remarks.

Sure. Thank you very much. Thank you for inviting us to the conference. I'm really excited to be here. So Compass Therapeutics is located in Boston. We're a monoclonal antibody discovery and development company in oncology. We currently have 4 drugs in the clinic, which hopefully we'll talk about today.

So our lead asset is a drug called tovecimig. That's a DLL4, VEGF-A bispecific antibody, and we just read out secondary endpoint results from a randomized trial, and we're going to approach the FDA with those results later this summer. Our next most advanced program is a next-generation CD137 agonist antibody called 471. That drug has shown responses in the post-checkpoint inhibitor patient population. Our third drug, and we presented data last weekend at ASCO, is a novel PD-1, PD-L1 bispecific antibody, which sounds counterintuitive, but that drug came out of a screen using a technology that we developed. It came out of a screen for synergy with PD-1 blockade. And fascinatingly, PD-L1 turned out to be the best combination partner for PD-1 blockade. At ASCO last weekend, we presented data from a Phase I dose escalation study in which we have responses in, again, the post-checkpoint patient population. And finally, we also have a PD-1, VEGF-A bispecific antibody, which obviously is a new class of drugs, and that drug is now in Phase I testing, moving through the first dosing cohort.

So happy to talk about those. And again, thanks for inviting us. Happy to be here.

Great. Yes, very exciting and a lot to talk about. Can you go into -- give us a quick view on what's the catalyst for the next 12 months? What's that path look like?

Sure. I think we're very excited about the next 12 months because we've got multiple catalysts for each of our 4 drugs. So beginning with tovecimig, we'll have a conversation with the FDA later this summer. If that conversation goes well, we would then plan on submitting a biologics license application. And about a year from now, we would potentially be in label negotiations. So that would be incredibly exciting. We've got a fast track designation for that drug. So we almost certainly would get a priority review, which would put our PDUFA date in the second half of '27. So at this conference next year, it'd be super cool to be talking about our PDUFA date. So those are the big things for tovecimig.

Also interestingly, we believe that we've uncovered some rather unique combinatorial synergy between tovecimig and the chemotherapy drug, paclitaxel. So we've been thinking about which indications we might combine tovecimig with, and we're looking at potentially ovarian cancer and gastric cancer, among others. So that will also be some interesting information coming up for tovecimig.

For 471, fascinatingly, we identified a potential biomarker of activity, which was based on analysis of biopsy specimens from a Phase I study. And we discovered that NCAM, neural cell adhesion molecule, also known as CD56, is correlated with responses to 471 in a Phase I study. So in the second half of this year, we're going to be initiating an NCAM-positive Phase II basket study.

8371, our PD-1, PD-L1 bispecific, in the Phase I dose escalation study, we identified responses in patients with triple-negative breast cancer, Hodgkin lymphoma and non-small cell lung cancer, again, all post checkpoint inhibition. And those were monotherapy responses in the post-checkpoint population. And based on that earlier this year, we initiated cohort expansions in the Phase I study in patients with those 3 diseases, triple-negative breast, Hodgkin lymphoma, non-small cell lung cancer, and later this year, that the -- by the way, the cohort expansion portion of that study has been enrolling extremely well. And I think later this year, we'd be in a position to report some data from the cohort expansion, which could inform pathways to further development for that drug.

And then finally, for our PD-1 VEGF-A bispecific, that drug we call 10726, by the end of this year, we should get dose escalation data from the Phase I study. So in the next 12 months, I think we have really meaningful catalysts for all of our 4 drugs.

Again, very exciting. What does your cash runway look like? And also what does...

So ended Q1 with $195 million, which is cash runway into 2028, covering all of those clinical trials that I have just described. We have begun some commercial preparation for launch, but our cash runway probably doesn't fully fund us to profitability. So it probably doesn't cover all of the launch.

I see. Okay. Let's now move our discussion into tove. That's a very exciting product. I think you mentioned that potential BLA filing soon in the future. So with respect to this mechanism, for the DLL4, can you walk us through this mechanism in terms of how it could be used broadly across patients post IO frontline therapy?

Yes. So tovecimig, as you mentioned, is a DLL4, VEGF-A bispecific antibody, DLL4, delta-like ligand 4, is the cell surface ligand for Notch1. VEGF-A, of course, is the well-known soluble ligand for the VEGF family of receptors. So VEGF-A, VEGF receptor signaling and DLL4 Notch1 signaling have different phenotypic effects on angiogenesis in the tumor microenvironment. So this drug really is a next-generation angiogenesis inhibitor.

And a couple of fascinating things. Dual blockade of those 2 pathways has been shown to be synergistic in preclinical models. And what could turn out to be even more important potentially is that DLL4 upregulation in the tumor microenvironment has been shown to mediate resistance to VEGF targeted therapies such as Avastin. So we believe that this can be a next-gen angiogenesis inhibitor, which would mean just like bevacizumab or VEGF kinase inhibitors. These could be used in patients with multiple different malignancies and combined with multiple different chemotherapy regimens. So we could be on a pathway to, in our dreams, replacing Avastin in all of the Avastin labeled indications, including renal, gastric, colorectal, et cetera. So that's where we would ultimately imagine going with that drug.

I see. Okay. Very ambitious. How do you -- I think recently, you guys presented some survival data with the tove and paclitaxel combination, the Phase II/III COMPANION-002 study in the second-line BTC. What were the key highlights there?

Sure. So let's -- maybe briefly on the study design. So the study design was a 2:1 randomization of tovecimig plus paclitaxel versus paclitaxel alone in patients with advanced biliary tract cancer who have received 1 prior line of therapy. So it's a pure second-line study.

So crossover was allowed from the control arm, paclitaxel, to the combination arm after a centrally confirmed progression event. So this is very, very important because about 54% of patients in the study crossed over to receive active drug. Now because it's a 2:1 randomization that means about 85% of patients in the study received tovecimig at one point in time, either at randomization or at crossover.

So let's go through the efficacy endpoints. The primary endpoint was overall response rate. We hit the primary endpoint. We more than tripled the response rate with paclitaxel and that was statistically significant. And all responses were assessed by blinded independent central review. So a very, very rigorous process.

The next -- the key secondary endpoint was progression-free survival, and we hit that endpoint, and that was highly significant. The difference between tovecimig and paclitaxel had a hazard ratio of 0.44 with a p-value less than 0.0001. So a highly significant effect on PFS, which, frankly, is very clinically meaningful in this disease because patients with biliary tract cancer suffer from anatomic complications, obstruction of the biliary tract, for example. And any delay in progression has a very clinically meaningful impact in this disease.

The next endpoint was overall survival, as you mentioned. So the -- because of the crossover, the intent-to-treat analysis, which, of course, make -- the intent-to-treat analysis makes no sense, right? Because we're comparing chemotherapy plus tovecimig versus chemotherapy plus tovecimig. It's like, what are we talking about here, right? So the statistical word there is confounded. So the ITT analysis was confounded by the crossover. But we did some subset analyses, which showed that patients who crossed over to receive tovecimig versus patients who had paclitaxel alone, more than doubled their overall survival.

We also had a very key secondary endpoint, which is something we call PFS2, which was an analysis of the crossover patients before crossover and after. And we saw a significant improvement in PFS after patients crossed over to drug. I think the most important analysis is if you look at all the patients in the study who got tovecimig at any time, their median overall survival was 9.9 months. Patients who got paclitaxel alone, their median overall survival was 6.05 months. So I think a clear effect on overall survival.

And we also have to put those data into some historical context. So in second-line biliary tract cancer, believe it or not, there are no labeled therapies in the United States. The only second-line therapies are available are for patients with actionable mutations. FGFR2, IDH1, HER2, et cetera. But that's a relatively small component of the patient population. Maybe 20% total for all of those actionable mutations. The other 80% of patients get a mix of chemotherapy regimens, the 3-drug combinations, FOLFOX and FOLFIRI and in multiple randomized studies, the median overall survival with those regimens is in the 5.7 to 6.3 month range. So spot on from what we saw with paclitaxel, 6.05, and 50% longer if you got tovecimig in the study. So we're very excited about the overall survival results.

I see. Okay. And can you walk me back a little bit, maybe was that an oversight, when you guys first designed the study, allow the crossover and then did the analysis -- like what was the rationale behind that design initially and which became very much apparent that...

Yes, yes. So the study was simply undoable without a crossover. So the patient advocacy groups would not support the study. And I think even more importantly, scientific review committees at a couple of academic centers in the U.S. declined the study because it didn't have a crossover. So the study was simply undoable without a crossover.

And I think -- look, I think it was -- it's absolutely the right thing to do. for patients. I think, obviously, you know this full well. The RAS inhibitor data that was presented at ASCO last weekend, a p-value on overall survival of something like 10 to minus 11 power, right? Do we really need a p-value that low? I think it's better to offer patients crossover for drugs that clearly have signals of efficacy.

So basically, the design -- I guess, the complication related to the design, something that you guys already foresee.

Yes.

Right, from the beginning. The results were something that you were expecting. When you looked at the OS and it did not meet stat sig.

Yes. Yes, it's almost impossible for it to have met stat sig.

Yes. Okay. Got it. And what about the combination safety compared to paclitaxel, have you heard any concerns about from doctors regarding the grade 3 AEs?

Yes. So we have not. The AEs in the study were generally manageable. I think the most common on-mechanism adverse events, so for tovecimig is hypertension. So hypertension is on mechanism for VEGF blockade. There are now published algorithms for managing the hypertension associated with VEGF blockade. We have -- GI oncologists have more than 20 years of experience with Avastin, so managing Avastin-induced hypertension is just not an issue for docs. And on the paclitaxel side, neutropenia, anemia, these are the expected AEs associated with chemotherapy.

I see. Okay, got it. How large is that second-line setting? And also, when you look at this data, how translatable is it to other solid tumor indications?

Those -- thanks. Yes, those are 2 very important questions. So last month, at the beginning of May, the Cholangiocarcinoma Foundation, which is the main patient advocacy group, the Cholangiocarcinoma Foundation commissioned a new epidemiology study of biliary tract cancer in this country. And they discovered that there are more than 25,000 new patients annually in the United States. So that's an enormous market.

And from our work that we've done, we believe approximately 2/3 of those patients will move on to receive second-line therapy. So that's about 15,000 patients annually in second-line BTC in the United States alone. So it is clearly a multibillion-dollar annual commercial opportunity.

The second half of your question is also incredibly important. So we believe that the data that we've reported in patients with biliary tract cancer, really suggest that this drug could be broadly used in patients with other solid tumors. And I think we're going to start with indications where paclitaxel is part of the standard of care. So the 2 I mentioned, gastric and ovarian. So post-platinum, patients with ovarian commonly get some form of paclitaxel, paclitaxel-Avastin; with gastric cancer, second-line standard of care is paclitaxel plus the VEGF receptor-targeted antibody, ramucirumab. So those are 2 very straightforward places for us to go.

I think we're also considering -- and we'll come to this, I hope. But we're also considering adding our own PD-1, PD-L1 blocker to that regimen. So tovecimig-paclitaxel-8371 as really a next-gen IO angiogenesis combination regimen.

I see. Okay. Got it. And you mentioned that you're expecting the BLA filing in the second half of this year. So given the complication with the OS, is it something that -- I know you guys are meeting with the FDA, I think, in early August. Is there -- do you anticipate any complications with the FDA? Or do you believe that this is something that the FDA has also been expecting and...

Yes. Yes. And look, we have -- we hit the primary endpoint of overall response rate. We have a massive effect on PFS with a hazard ratio of 0.44. We've got the lowest hazard ratio in this indication, I think, that's ever been reported outside of targeted therapies. So we have an overwhelming treatment effect. And hitting ORR, hitting PFS, I mean, I just described 80% approximately of oncology drug approvals in this country. So FDA -- among all of our constituencies, I think FDA and KOLs are the most familiar with the confounding effects of crossover.

I see. Okay. That makes sense. You guys also have a 1L study going. Can you walk us through the design for that study? And then how long do you expect that study to enroll and run for?

Sure. So that's a great question. The investigators at MD Anderson in Houston were the third-largest enroller in our second-line study. And after treating some patients in the second-line study, they approached us with a proposal to add tovecimig to the frontline regimen of gemcitabine, cisplatin and durvalumab.

Now when we got that proposal at the time, we were still blinded to all of the data in the study. So we thought it was a really nice symbol, and hopefully, the folks at MD Anderson had seen something. But now having talked to the folks at MD Anderson, after the study read out, we now know that the folks at MD Anderson had seen some dramatic antitumor responses in the second-line setting.

So that study is a single-arm study, adding tovecimig to the frontline regimen of gemcitabine, cisplatin, and durvalumab. That study is enrolling. We did -- because this was a new chemotherapy regimen, we had a small safety run-in, which we're -- I think we're through that now. And we just met with the lead investigator at ASCO, and we're going to expand that study out to add some additional sites to speed up enrollment a little bit.

Your question about how long it would take, I'm not sure. I think it's probably maybe another year of enrollment. And then maybe late next year, we could sort of get a read on the efficacy signal there. But we're excited about some of the things that we're seeing so far from that study.

And what is your bar for success in terms of both efficacy and safety in that first-line setting?

Sure. So I think it has to be -- the combination needs to be well tolerated, which I think we now -- we have evidence that that's the case. So gem, cis, durvalumab in the TOPAZ-1 study had about approximately 26% overall response rate. Median progression-free survival in the 6.5 month range. Median overall survival of 12.8 months. So those are the bars for gem, cis, durvalumab -- for the gem, cis, durvalumab regimen. So I think we need to see something better than that. The investigators are looking at 6-month PFS as a marker for how we think about moving this drug forward.

I see. Okay. So for the rest of the conversation, I want to start moving into the other exciting assets that you guys have. So let's kick it off with CTX-471. So you guys are expected to enter a Phase II basket study using a biomarker like the NCAM and CD56 positive tumors by midyear. What is the status for the study and how many patients are relevant with this biomarker?

So in the Phase I study of 471, we collected pre- and on-study biopsies. And in that study in -- again, as a monotherapy in the post-checkpoint patient population, we had responses in patients with small cell lung cancer, melanoma and mesothelioma. And we did an analysis of biopsy specimens and we discovered that the patients who had clinical benefit from the drug had tumors who were -- that were NCAM positive.

Our most dramatic responder in that study was a patient with metastatic small cell lung cancer who received frontline chemotherapy plus atezo, then second-line therapy with nivo and was treated in the third line setting where realistically that patient's expected median overall survival would unfortunately be measured in single-digit weeks. So maybe 9, 10 weeks maximum. That patient had a deep response, was on drug for more than 3 years when the patient had a PET negative CR. We looked at that patient's tumor, and it was very highly positive for NCAM.

That made us look at other patients' tumors, and we presented this data at SITC about 18 months ago, and we showed that there's a correlation between response and NCAM positivity. So that has sent us down this road. So we are -- the study design is finalized, submitted to FDA. We should be beginning that study in the coming quarter.

And in terms of your question about how many patients are out there, there's a significant patient population. If you add up neuroendocrine tumors, neuroendocrine carcinomas, melanoma and small cell lung cancer, it's probably in the range of 60,000 patients annually in the United States. So it's an enormous potential market. So that basket study is going to enroll NCAM-positive patients.

I see. And what's the -- what drove the selection of the tumor types in this basket trial? And of all these different indications that you're studying, which one do you think that you're more -- you have the most conviction on?

Sure. So the tumor types came out of some validation work that we did looking at staining tumors for NCAM. So that's how we selected the indications and also selecting indications where we saw efficacy signals in the Phase I study.

I think that's a very interesting question, the way you phrased it, for sure that obviously, we're super excited about small cell lung cancer just based on what we saw in the Phase I study. But if we could show in neuroendocrine tumors and neuroendocrine carcinomas that we had an efficacy signal there. That is a massive unmet need. And I'm really excited about sort of going into a novel tumor type there.

I see. Okay. Got it. Any guidance on when data would be available for...

Sure. So study is going to get up and running in the next quarter. I think probably mid- to late next year, I would think.

I see. Okay. And then will you go straight into a registration trial at that point?

Well, if the data supported it, yes, for sure.

I see. Okay. So you would pick a lead tumor to go into? Or is it one of those that -- a registrational program with -- basically, be a tumor, a biomarker...

I would love it to be biomarker led. I would love it, right? And then that way, we could get a very broad tumor-agnostic label, which I think would be very, very interesting if we could do that.

I see. Okay. Great. So let's move on to the next asset, which I think is very interesting, the CTX-8371, which is the dual PD-1, PD-L1. So let's talk about the mechanism, what -- how does it work? Why does -- dual PD-1, PD-L1?

So again, this drug came out of some very comprehensive work that we did in our -- in research. And asking the question, what is the best combination partner for PD-1 blockade. And honestly, I think we were a little surprised that PD-L1 emerged as the best combination partner for PD-1. And we spent a long time investigating the mechanism of action. And we actually published all that data a couple of years ago. But clearly, the drug does block both the ligand and the receptor. There's no question about that. But it does more than that. It's definitely a cell engager. So it connects PD-1-positive cells to PD-L1-positive cells.

I think the most fascinating thing we discovered is that the bispecific exposes a metalloproteinase cleavage site on PD-1, leading to the cleavage of PD-1 off the surface of effector T cells. So this drug actually converts PD-1-positive T cells in the PD-1-negative T cells. It's an incredibly unique mechanism of action, and it's why we had confidence going into the post-checkpoint patient population.

Right. So which leads to my second question. In the post-checkpoint setting, right, so patients already seen checkpoint inhibitors and then you basically administer the drug, which is another checkpoint inhibitor, and you saw activity there. How reliable is that data? I think you guys talked about -- I think you guys presented some data at ASCO, some imaging data as well. Maybe just walk us through the data.

Sure. Sure. I think how reliable are the data? I mean, we had confirmed responses in patients with triple-negative breast cancer, Hodgkin lymphoma and non-small cell lung cancer.

And I think the scans that we showed in the ASCO poster, which is available on our website, those scans really speak for themselves, I think, right? The patient with triple-negative breast cancer who relapsed while getting adjuvant KEYTRUDA, then got TRODELVY plus 2 other chemotherapy regimens. That patient had almost 9 centimeters of linear tumor burden, including a 5-centimeter metastasis to her pericardium, lining the heart. And all of that tumor burden has disappeared. The patient is now in a durable response for over a year in the post-TRODELVY setting.

Similarly, the patient with Hodgkin lymphoma who happened also to be post-transplant. We showed PET scans for the first time at ASCO last week. And that patient had a deep metabolic PR post-checkpoint and the non-small cell lung cancer patient similarly had dramatic decline in their linear tumor burden.

So you didn't ask this, but you asked me how reliable the data are. But the real question is why are we seeing this, right? And we believe the answer to that is incredibly simple. 8371 is a better checkpoint inhibitor, period. We have -- I know this sounds like I'm trash talking, so stay with me. But we have the best Phase I checkpoint inhibitor data ever. There's no other checkpoint inhibitor, which, by the way, includes KEYTRUDA that has better Phase I data than we do. We have more responses in fewer patients, and our data are in the post-checkpoint population. All of the early checkpoint inhibitor Phase I data were in checkpoint naive patients. So we simply believe we have a better checkpoint inhibitor.

I see. Okay. Makes sense. And what is the potential of 8371 in combination with your other 2 agents that you just talked about? I think you mentioned that -- exploring development with these different combinations. Maybe just walk us through like what are you guys thinking there?

Sure. I love it. So I think in the past, maybe 5 years, I think one of the more important advances in oncology is the combination of checkpoint inhibitors with angiogenesis inhibitors. So from my point of view, the real -- the first study that showed this was the Roche study IMbrave150, which was bev-atezo versus sorafenib in frontline hepatocellular cancer. And that showed that the combination of VEGF targeting and checkpoint inhibition was synergistic. And that now spawned a whole set of studies, combination of checkpoint inhibitors with VEGF kinase inhibitors.

And really, from my point of view, is -- probably, people aren't going to love this. But from my point of view, the bev-atezo study is what got the PD-1 VEGF bispecific field going. So we would love to have a sort of super combination, which would be tovecimig, a dual angiogenesis inhibitor and 8371, a dual checkpoint inhibitor. Put those 2 together, and that could be the next generation of angiogenesis-checkpoint inhibition combination.

So we're going to test that in -- we've got some designs on the table right now in gastric cancer and biliary tract cancer and just thinking about sort of where we could go with that. That would be a very, very sort of wide field for us to go after.

Fantastic. So we only have about a minute left, so I want to talk about the last asset, the fourth one, which is your PD-1, VEGF bispecific. How do you -- I mean this is a very crowded field. We saw data at ASCO from Summit, and then there are some -- many other companies developing something similar. How do you think about your asset and how do you position it among the others...

Sure. So we developed that drug ourselves. We know that, that drug has better PD-1 blockade than ivonescimab. We did head-to-head preclinical studies, and our drug, 10726, is superior to ivonescimab in some preclinical studies. So we believe we have a novel better drug.

So we're going to test that. We selected our Phase I indications carefully. We wanted to go into indications where both checkpoint inhibition and angiogenesis inhibition have already had demonstrable efficacy signals. So we're going to go into patients with hepatocellular, renal cell, gastric and endometrial cell cancer. Each of those 4 indications has either PD-1 or PD-L1 blockade or VEGF-targeting or VEGF receptor targeting as approved therapies. Hepatocellular, bev-atezo; renal cell, cabo-nivo, frontline regimens of the combination.

So those are our 4 Phase I indications, and that's how we think we can differentiate development. Phase I is underway, first dosing cohort fully enrolled, should be moving to the next -- second dosing cohort shortly.

Fantastic. Very exciting time for Compass Therapeutics indeed. It's been a pleasure hosting you. And I'll pass it back to you for any final remarks.

Well, thank you very much. Again, thank you for inviting us, and I'll go back to the very first question you asked, which is I think the next 12 months are going to be incredibly exciting for us with multiple catalysts for each of our 4 drugs in the clinic. So looking forward to talking to you next year.

Great. Thank you.

Thank you.

Greetings. Welcome to Compass Therapeutics Top-line Secondary Endpoints Call. [Operator Instructions] Please note, this conference is being recorded. At this time, I'll turn the conference over to Anna Gifford, Chief of Staff. Thank you, Anna. You may now begin.

Good morning, and thank you for joining us. My name is Anna Gifford. I'm Chief of Staff at Compass Therapeutics. With me today is Dr. Thomas Schuetz, CEO and Vice Chair of the Compass Board. Earlier this morning, we released positive secondary endpoint data from the Phase II/III COMPANION-002 study, which we look forward to discussing on this call.

The slide presentation accompanying this webcast and a copy of the press release are available on our website. Please note, we'll be making forward-looking statements on today's webcast. These forward-looking statements are described in our press release issued today and the company's SEC filings. With that, I'd like to turn the call over to Dr. Thomas Schuetz. Tom?

Thanks so much, Anna. And I just want to echo Anna's greeting. Happy to be with you all today, and we're very excited today to discuss with you the initial data from our COMPANION-002 randomized trial. Today, we're going to be discussing select analysis of the secondary endpoint efficacy data as well as demographic data and some top-line safety data. The rest of the analysis from the study, we look forward to presenting at a major medical meeting later this year.

I would also like to echo Anna's forward-looking statement comment. I will be making forward-looking statements today. Okay. So on Slide 3 is an executive summary of the data analysis so far in our COMPANION-002 study. So just to reiterate, we hit the primary endpoint in the study of overall response rate, more than tripling the response rate in the control arm, and we presented those data last year. The key secondary endpoint was progression-free survival.

And today, we're reporting what can only be described as an absolutely stunning result. We have a 4.7-month versus 2.6-month median BICR-assessed progression-free survival with a hazard ratio of 0.44 and a p-value less than 0.0001. I'll talk more about that data in a minute. In terms of overall survival, the overall survival analyses were compounded by crossover from the paclitaxel arm to the combination arm, 54% of patients crossed over and 85% of patients in the study ultimately received tovecimig in combination with paclitaxel.

I'll talk more about that, of course, in detail. Fascinatingly, those 54% of patients who crossed over from the control arm lived an incredibly long time. The crossover patients had a median overall survival of 12.8 months which is consistent with what you would see in the frontline setting with gemcitabine, cisplatin and IMFINZI, the patients who did not cross over had a median overall survival of 6.1 months. I'll show all of those data in this presentation. The safety profile was consistent with our previous studies.

I'll talk more about that, of course. Importantly, we're now preparing for an FDA meeting in advance of a planned BLA submission. It is our intention to seek full approval. However, having hit on overall response rate and really dramatically hitting on progression-free survival, we feel at absolute minimum, this data set supports accelerated approval, and I'll talk more about that in a couple of minutes as well.

So let's just quickly review the design of the study. COMPANION-002 was a randomized trial in patients with advanced biliary tract cancer who had received 1 prior line of therapy. So this is a pure second-line study. It was a 2:1 randomization of tovecimig plus paclitaxel versus paclitaxel alone. 111 patients were randomized to the combination arm, 57% were randomized to the control arm.

In the control arm, after centrally confirmed progression, patients were allowed to cross over and receive tovecimig plus paclitaxel. And as I mentioned, 31 patients from the paclitaxel-only arm crossed over to the control arm to the combination arm to receive tovecimig. So therefore, 31 plus 111, 142 patients in the study received tovecimig at one point during the study. I'll talk more about that in a couple of minutes. On the bottom of this slide is the statistical hierarchy.

Overall response rate was to be analyzed first, progression-free survival second, overall survival third. In terms of duration of response, we don't have that analysis today, and we look forward to presenting that at the medical meeting presentation later this year. Okay. Let's dive into the data from the study. So let's start with the baseline demographics that are shown here, men, women and race.

You can see the bottom 3 rows are the most important. These were the prognostic variables that were the 3 stratification factors for the randomization. The first was anatomic location of the primary tumor, intrahepatic cholangiocarcinoma versus other, very well balanced. ECOG performance status, 0 versus 1. You can see those are within single-digit percentages of each other.

And then finally, disease status, disease outside the liver or locally advanced disease. The majority of the patients in this study had metastatic disease outside the liver. And all of these 3 important prognostic variables were well balanced between the 2 treatment arms. Just again, an important reminder here that we hit the primary endpoint in the study. All of these analyses were done via blinded independent central review, so-called BICR. So the BICR assessed response rate was 17.1% in the combination arm with tovecimig, 5.3% in the control arm with paclitaxel.

We had a centrally adjudicated complete response in the tovecimig combination arm. Okay. In terms of BICR-assessed progression-free survival, here are the PFS curves, the red line is the tovecimig plus paclitaxel group, a median progression-free survival of 4.7 months, a median progression-free survival in the paclitaxel control arm of 2.6 months. That revealed a hazard ratio of 0.44, again, with an extraordinarily significant p-value of less than 1x 10 to the minus 4.

Just a reminder also that we powered this endpoint for a hazard ratio of approximately 0.6. So a hazard ratio of 0.6 represents a 40% reduction in the risk of progression, so 100 minus 60 and what we saw was a 56% reduction in the risk of progression, about 50% better than we powered the study for. Let's move to overall survival. This is the intent-to-treat analysis for overall survival.

The overall survival analysis was confounded by crossover, and I'm going to talk a lot more about that in 1 minute, but this is the intent-to-treat analysis. Now what is most important to understand here is that the "control arm" includes 2 different sets of patients. The 54% of patients who crossed over and received tovecimig in combination with paclitaxel and the 26 patients who did not cross over and receive paclitaxel alone.

But this is the intent-to-treat analysis where the patients are allocated to these 2 curves based on the treatment to which they were randomized. But again, it's very important to keep in mind here that the "control arm" is really 2 different sets of patients, and we're going to talk a lot more about that in a minute. One of the things that we have discussed in the past with all of you is the crossover adjustment statistical methodology.

That methodology is called the RPSFT, or the rank preserving structural failure time. So the rank preserving structural failure time statistical assumptions were not met. So you can see that the RPSFT and the intent-to-treat analysis are virtually identical. So one of the prespecified secondary endpoints is an endpoint that we called PFS2. And when we saw the intent-to-treat OS curve, we wanted to look specifically at the PFS2 analysis. So PFS2 is an analysis of progression-free survival in the crossover patients.

So you can see on the bottom left, where you see number at risk, 31 and 31, those are the same individual patients. So pre-crossover in red, post-crossover in blue. And you can see that there is a significant difference in progression-free survival post crossover. The patients who crossed over actually had a very rapid initial progression with a median PFS of 1.9 months. Then after crossing over to receive tovecimig, their PFS improved to 3.5 months. Now time 0 on these 2 curves is different.

Time 0 for the red line is randomization, time 0 for the blue line is time of crossover. So once these patients who had progressed very rapidly on paclitaxel crossed over to receive tovecimig, their progression-free survival improved significantly. And those 2 curves are different with a p-value of 0.0016 and a hazard ratio of 0.36. Another kind of subtle aspect in this curve perhaps is you can see that there's a rather long tail on this progression-free survival curve. So there are many patients here.

And by the way, this blue curve, of course, is now patients treated in the third-line setting. So many patients here who have not progressed 6, 9 and 12 months out after crossing over to receive tovecimig. That observation led us to do this analysis. So this is an analysis of overall survival in the control arm. What we did is we looked back and we split the patients into the crossover patients and the patients who did not cross over.

The patients who crossed over and equals 31 had a remarkable median overall survival of 12.8 months compared to 6.1 months median overall survival with paclitaxel alone in the patients who did not cross over. Now obviously, you all know this and we know full well that when you do an analysis like this, you might have simply selected the patients who were going to do better anyways. And maybe the patients who happened to cross over to tovecimig were the patients who might have done better anyways.

So what we did is we did this analysis for progression-free survival. So as I go to the next slide, just keep an eye on the red and blue curves. For progression-free survival, they are reversed. So the patients who actually crossed over in red actually did worse on paclitaxel than the patients who did not cross over. Despite progressing much more rapidly, actually significantly more rapidly with a p-value of 0.007. Despite those patients progressing more rapidly, I'm just going to go back one slide, they ended up living significantly longer once they cross over and receive tovecimig.

So we believe this analysis suggests strongly that the addition of tovecimig to paclitaxel is associated with an improvement in overall survival. These slides, by the way, are available on our website this morning. This is top line safety data. Lots of numbers on this slide. Just want to highlight one number here. The main difference between the 2 treatment arms is hypertension. Of course, hypertension is on mechanism for VEGF blockade.

There are now published algorithms for managing the hypertension associated with angiogenesis inhibitors. So here's a summary and a brief discussion of our next steps. So the study obviously is positive by definition with a significant improvement in overall response rate, more than tripling that what you saw in -- what we saw in the control arm.

For progression-free survival before crossover, there was an incredibly significant treatment effect with a 56% reduction in the risk of progression outside of targeted therapies, to my knowledge, this is the lowest hazard ratio on progression-free survival that's ever been reported in this disease. The OS analyses were confounded by crossover and the patients who crossed over despite initial very rapid progression, lived an incredibly long time at 12.8 months median.

As I said earlier, 12.8 months is the exact median overall survival in the experimental arm of the study TOPAZ-1. So in the frontline setting, gemcitabine, cisplatin plus IMFINZI has a median overall survival of 12.8 months and those crossover patients now treated in the second and third-line setting had a median overall survival of 12.8 months.

Our safety profile was consistent with our prior studies, and the drug was well tolerated. And as I mentioned earlier, our next steps will be to meet with the FDA to discuss this data in advance of a BLA submission. As I mentioned earlier, it is our intention to seek full approval based on this data.

But after a discussion with FDA, we certainly believe that the combination of ORR and PFS supports accelerated approval as it has for many, many dozens of other oncology drugs. We feel quite strongly about our data because when our data are put in context, compared to several different chemotherapy regimens that are used in the second-line setting, such as FOLFOX or FOLFIRI, where one randomized trial was done.

You can see that FOLFOX had a 2.8-month median progression-free survival compared to 2.1 months with FOLFIRI, median overall survival is 5.7 and 6.2 months with our study. The pooled median overall survival is approximately 9 months, 50% longer than you see with any chemotherapy regimen in this setting. significant improvement in overall response rate, very significant improvement in progression-free survival.

Overall survival ITT analysis confounded by crossover and the crossover patients lived an unbelievably long time and just a very, very satisfying observation for us to see how long those patients lived. So next steps for us, put all the data together, meet with FDA and discuss the pathway to a biologics license application submission. Thanks for your time this morning. Happy to take questions.

[Operator Instructions] And the first question is from the line of Jonathan Chang with Leerink Partners.

First, how do you view the efficacy and safety profile of tovecimig plus paclitaxel compared to chemotherapies used in this treatment setting? And just as a follow-up, can you provide more color on the crossover adjusted OS analysis based on RPSFT? How should we interpret those data given that the statistical assumptions for the analysis weren't met?

Okay. Thanks, Jonathan. So in terms of the first question, of course, we didn't -- when you look at paclitaxel in comparison to FOLFOX or FOLFIRI, fairly similar safety profiles there. The real difference here is, again, hypertension, which again is on mechanism for angiogenesis disruption. There are now published algorithms for managing the hypertension associated with drugs like Avastin.

And in the Avastin label, there's language about treating hypertension rather than discontinuing Avastin, and that's the approach that we took in this study. Your second question is paradoxically very complex and very simple. So the statistical assumptions for the RPSFT analysis were not meant. So the RPSFT numbers that we're reporting here, we're reporting for full disclosure -- just for full disclosure, but the RPSFT analysis is meaningless, which is why we presented the RPSFT analysis -- why we presented the ITT analysis on Slide 8.

Our next questions are from the line of Maury Raycroft with Jefferies.

This is Amin on for Maury. A couple of questions from us. First on -- just to make sure we're interpreting the data correctly and using the right comparisons. If we look at the pure tovecimig-treated patients versus patients who received paclitaxel without crossover, it looks like the OS figures are like 8.9 months versus 6.1 months. Is that the right way to think about the underlying treatment effect here? And I have a follow-up on FDA interactions.

Yes. That is completely correct. So the combination arm, 8.9 months, the paclitaxel-only arm, 6.1 months, correct?

Okay. That's clear. And have you had any regulatory discussions with the FDA in the past few months to see how they view the bar for a successful study? And if not, when do you expect to have your next discussion with the FDA?

Okay. Two-part question. The answer to the first part of your question is no. We have not had any discussions with the FDA in the past few months. The second part of your question, we expect to complete the analysis of all of the other endpoints in the study within the coming approximately 1 month.

And then we would put everything together into a meeting request and package and send all of that into the FDA, which should put us in position to have a meaningful conversation with the FDA in approximately the middle of the summer. If that conversation goes well, then that would put us in a position to submit a BLA application before the end of this year. And because we have a Fast Track designation, of course, that could potentially put our PDUFA date sort of inside the second half of next year.

Our next question is from the line of Biren Amin with Piper.

Can you maybe talk about the influence of drug discontinuations or dose reductions with the tovecimig arm versus pac alone? And then maybe another question. I know, Tom, you're not talking about duration of response today, and that's going to be at a medical presentation. But what was the data there, and read-through on PFS? If you could just maybe tell us, I guess, from like a high-level perspective.

Okay. A 2-part question. In terms of all of the data for dose reductions and treatment discontinuations, I don't have the totality of that data set today. I did -- because hypertension was most common, I looked at that specifically and there were 4 patients, 3.7% who had drug discontinuation from hypertension. The rest of that data is in process for analyzing.

In terms of your second part of your question, in terms of DOR, we did not prioritize that analysis for this presentation. The only thing I'll maybe add to that is one of the things that was very, very interesting to us is in the PFS2 analysis. So again, patients who very rapidly progressed on paclitaxel only then crossed over, there are additional responses in those patients after crossover. So that's also a very interesting piece of data that we're scouring through now.

And maybe if I could have one follow-up. On the patients that crossed over, were they [indiscernible] or were there any baseline characteristics? Because if I look at on PFS2, I think you reported 3.5 months on the patients that crossed over on PFS2. And if I calculate and add the 1.9 months that they had on PFS1, that gets you about 5.4 months.

And so where I'm going with this is your OS was significantly higher at 12.8 months compared to the tovecimig arm at 8.9. And I think the difference is on those patients that crossed over. I mean, they seem to have been doing slightly better. So was there anything from like a baseline characteristic of those crossover patients?

So I don't know the specific answer to the question as you phrased it. We are examining all of the information for those 31 patients incredibly carefully. And we're going to be in a position to talk more about that. I very much, Biren, I think that the caveat that you made here is quite important, right? We need to make sure that these patients who crossed over that we're not biased here by selecting a patient population that was going to do better anyways.

And that's why we did the PFS analysis on paclitaxel that we show on Slide 12. And as -- if PFS is a marker here, not only did the crossover patients not do better, they did much, much worse on paclitaxel only. So as measured by PFS, the crossover patients were actually a worse subset. And despite that fact, they lived significantly longer once they crossed over to receive tovecimig.

[Technical Difficulty] your question.

Tom, can you hear me?

Yes, yes. Sorry.

Sorry, everything went silent there for about a minute or so.

Yes. Sorry about that.

Maybe to follow up on Biren's question, do you have much, if any, patient biopsy data? And are you going to be looking at retrospective DLL4 expression in these patients, I guess, specifically in those 31 patients who crossed over and did better on tovecimig with the intention of trying to see again if you can tease out anything that's specific about this patient subset?

Yes. So we collected archived biopsy specimens in the study. And we're now -- we're going to embark on sort of a comprehensive biomarker analysis now with the real -- I think the real onus on us is to do as much work as we can to try to tease out why those patients who crossed over did so amazingly well. So yes, to your question, we collected biopsy specimens, and we're going to embark on a comprehensive biomarker analysis of those specimens and in addition, blood samples, of course.

Okay. And then to the extent that this potentially becomes a conversation with FDA about an accelerated approval pathway, any additional or just initial thoughts right now as to where you would look to conduct a confirmatory Phase III trial, whether that would be in the second line? Or would you look to do this in the front line? And just how quickly you think you might be able to get this up and running?

Sure. So again, just to repeat, it is our intention to seek full approval based on this study. These data are only single-digit days old here for us. But just some high-level thoughts on your question. Adding tovecimig to the frontline regimen of gemcitabine, cisplatin and durvalumab is something that we're doing right now. I don't want to go too far into a rabbit hole here with you, Steve, but something else that we could do is we could swap our own PD-1, PD-L1 blocking antibody, 8371 for durvalumab in that study, which would be something that we'd be incredibly excited to do.

Our frontline study adding tovecimig to gem/cis/durvalumab ongoing at MD Anderson, and we're continually reviewing data from that study with the investigators, again, to help us think about future studies. Another study that we could think about would be tovecimig-paclitaxel versus FOLFOX in the second-line study. Maybe that's a study that we do in Europe, where FOLFOX is probably used a little bit more commonly in the second line setting than it is in the U.S.

Okay. That's helpful. And then just lastly, I understand you're going to have kind of a more comprehensive update of safety data at a future medical meeting. But is there just anything that you can say about DLL4 specific toxicity? And I guess I'm specifically referring to something like pulmonary hypertension.

Sure. I never -- you and I have talked about this before. It's as a bispecific antibody, it's hard to ascribe anything to either end of the molecule, right, either safety or efficacy. But since you asked specifically about pulmonary hypertension, you -- as you all review this slide deck, you'll see that on Slide 13, pulmonary hypertension is not on that slide.

So in the study, there were 3 AEs of pulmonary hypertension, 2.8%, so something substantially lower than we saw in our Phase I and Phase II studies in Korea. I don't have an explanation for that. I do know that we looked much more thoroughly for that in this study with serial BNP measurements and serial echos, and we saw it at an incidence of 2.8%.

Our next question comes from the line of Michael Schmidt with Guggenheim Securities.

I'm still trying to wrap my head around the OS data, I suppose. And I guess, Tom, any additional hypothesis why the crossover patients did so much better than patients who received tovecimig plus paclitaxel in the treatment arm? And I'm just curious if there's anything maybe you could comment on post-progression treatment in the tovecimig treatment arm where patients perhaps had less opportunity to receive third-line therapies than the crossover patients, for example? And also curious if you saw any imbalances in prior PD-1 use in the various treatment arms.

Okay. Multiple different questions there. I'm going to take those in reverse order. More than 90% of patients in the study had a prior PD-1 blocking regimen. So the vast majority of patients had either durvalumab or pembrolizumab. We don't have all of the post-study therapy data analyzed so far. But the one thing I did look at the end of last week only because it was so topical, I think there was only one patient in the study who got a RAS inhibitor.

So I don't think post-progression therapies are an explanation for that. But again, that's very preliminary. Michael, the first part of your question is, of course, fascinating, which is the first part of your question is why do we see this? So one obvious hypothesis is maybe 2 months, 1.9 months, 2 cycles of paclitaxel does that condition the tumor microenvironment to be more receptive to angiogenesis inhibition with tovecimig.

That's sort of a fairly straightforward hypothesis. I think we're thinking about that. We're going to do some preclinical work on that. That might be an interesting thing to test in maybe some other indications as we move forward in the future. Now that we have this unequivocal demonstration of efficacy here. As we think about moving into other indications, maybe that's a question we think about in gastric cancer, where paclitaxel is part of the standard of care, maybe a couple of cycles of pac and then add tovecimig into that. Obviously, incredibly early days in our thinking about that observation.

Okay. And maybe just a follow-up. Just curious if you've had any additional regulatory interactions with the FDA since the study started originally. And I'm just wondering how you feel about approvability with the 1.05 hazard ratio in ITT. I mean, generally, I believe FDA is looking for an HR that's less than 1 in OS for these types of studies. But obviously, in BTC and cholangiocarcinoma, there is a lot of history of accelerated approvals. The drug clearly works on PFS and ORR. And I'm just curious if you've had any other interactions with the agency throughout the trial.

So no is the specific answer to your question. But I think, again, it's very, very important, I think, to think about this hazard ratio, right? When you see a hazard ratio of 1.05, right, the knee-jerk reaction is that somehow there is toxicity in the experimental arm. But that's not the case here.

The reason that the hazard ratio was 1.05 is because the control arm patients who crossed over did so amazingly well. In terms of the very broad general question you asked, Michael, there are a number of examples of approvals with either ORR or PFS where the hazard ratio on OS is above 1. So I'm not worried about that, especially because it's so clear that the patients who crossed over really drove the hazard ratio. So I think because of that, this analysis of the crossover patients, I think, is a demonstration of efficacy of the drug.

Our next questions are from the line of Li Watsek with Cantor Fitzgerald.

Maybe just a follow-up for crossover versus non-crossover patients. Just curious any difference in the subsequent treatments or other factors could have also contributed to the OS difference that you observed. And what other crossover analysis that you guys may be able to conduct to show there is OS benefit to the FDA?

Sure. That's a fantastic question. So in terms of the first half of your question, Li, I don't have all of that analysis done yet, but our very early review of that data suggests that it's not post-study therapy. The second part of your question is absolutely fascinating because as many of you know, in the CLARITY study, which was ivosidenib versus placebo, the crossover adjustment RPSFT analysis was done post-hoc [indiscernible] study.

So while the RPSFT was prespecified here, the statistical assumptions were not met, but there are multiple other statistical methodologies that can be used to look at adjusting OS curves for crossover, and we're exploring those other methodologies now.

The next question is from the line of Charles Zhu with LifeSci Capital.

I believe these may have been somewhat addressed from different angles. But how do you think the FDA might be looking at some of your OS data here in light of hitting ORR as well as PFS and particularly since the FDA seems to place a bit of an emphasis on no detriment on overall survival relative to a hazard ratio that is at least numerically above 1.

And related to that somewhat, maybe just circling back to the RPSFT, what exactly were those certain statistical assumptions that were not met in this particular study? And could you provide some color as to perhaps why it looks like when you ran that analysis, the OS hazard ratio seems to have gone up to 1.13?

Yes. Okay. very, very important questions. So let me take the second part first, which is a 2-part question. So when the ITT hazard ratio is above 1, the RPSFT cannot work. So it's that simple. We're providing the RPSFT numbers here today solely for full disclosure. Those numbers are completely irrelevant because the assumptions for the statistical method were not met.

Now the first part of your question, I want to just take head on, right, which is -- and specifically, I'm going to use your word harm, right? So again, the assumption is with a hazard ratio of 1.05 that that's evidence of harm. That is fundamentally not the case here. And that is the single most important take-home message of these data because the hazard ratio of 1.05, I would strongly argue is prima facie evidence of benefit because the crossover patients that did so well are the patients who drove the hazard ratio on the ITT analysis above 1.

Those patients that live 12.8 months took the ITT hazard ratio above 1 because those patients were included in the control arm. because of where they were randomized. So the ITT analysis is not evidence of harm. It's evidence that the crossover patients did incredibly well. This is a super, super important point.

Our next question is from the line of Matt Phipps with William Blair.

Can you remind us for patients who did cross over, what inclusion criteria needs to be met for them to be allowed to cross over? And I guess, were there patients who didn't cross over who wanted to but didn't meet any of those criteria? And then I guess, just confirming you have not yet done something like a 2-stage adjustment or inverse probability of censoring as other sensitivity analysis around this crossover OS?

Okay. The second part of your question, very straightforward. No, we have not done a 2-stage analysis on the crossover. There are a couple of other statistical analyses that we're doing on the crossover as well that are in progress. In terms of the first part of your question, I went back to the schema. The main criterion for a crossover was a centrally confirmed progression event.

So the patient was required to have a BICR confirmed progression event and then meet some of the selection criteria for the study. Matt, I'm sorry, this very specific question you asked, I don't know the answer to. How many patients wanted to cross over but didn't for whatever reason. I'm sorry, I don't know the exact answer to that. I can look that up as we continue our evaluation of the data.

Our next question is from the line of Sean McCutcheon with Raymond James.

Just one from us. Can you speak to the PFS results in the context of what would be expected for FOLFOX in second-line BTC. Obviously, you received this question a lot, but given the median PFS below 5, I think some context necessary for how you're thinking about the competitive profile relative to standard chemo in this setting.

Sure, sure. So I just put up the PFS slide again, 4.7 months in the combination arm versus 2.6 months in the paclitaxel only arm. I think the CHOICE study, which was a randomized trial of FOLFOX versus FOLFIRI, is the best benchmark here for what to expect, 2.1-month median PFS for FOLFIRI, 2.8 months median PFS for FOLFOX. That's what people see with this chemotherapy with each of these 3-drug chemotherapy regimen out there.

In ABC-06, which was FOLFOX versus best supportive care, there was a very long scan frequency there. And more importantly, in ABC-06, the control arm was not scanned. So we don't know whether or not FOLFOX and ABC-06 was better than supportive care. Also, very importantly, our study is blinded independent central review. So all of our PFS data are blinded -- our BICR-assessed progression. ABC-06 was all investigator-assessed. So I don't think there's any KOL who believes that the PFS with FOLFOX is greater than 3 months.

The next question is from the line of John Newman...

By the way -- sorry, that's why we used 3.0 months as the powering assumption for median PFS in the control arm in our power calculations. Sorry, John, go ahead.

Just kind of going back to a couple of questions, I think as a follow-up on Biren's original question. Do you have any sense as to the discontinuation rate for the combination arm versus the patients who crossed over from the control? I'm just curious if you've been able to look at that to tell whether or not perhaps for whatever reason, that discontinuation rate was different, either one way or the other?

We have not looked at that, I'm sorry, something that we'll be looking at in the coming weeks.

Next question is from the line of Reni Benjamin with Citizens.

What was the -- can you just remind us what was the study powered to detect in terms of OS delta between the 2 arms? And if you look at the OS of tovecimig treated patients, crossed over and the original treated patients versus those not, what do those 2 numbers look like? And just have you done any sensitivity analysis regarding prior therapies and how that might have impacted PFS or OS?

Okay. So a multipart question there. Let's start with the power calculations. The original power calculations were for OS were 6.2 months in the control arm and that was based on multiple different FOLFOX studies. Both CHOI and ABC-06 had a median OS of 6.2 months in the FOLFOX arm. The assumption on OS in the combination arm was 10.9 months.

The pooled median there was right around 9 months based on a 2:1 randomization. So those were the power calculations. Okay. The second part of your question is partly here. The median OS in the paclitaxel-only arm was 6.1 months, very consistent with what you see with FOLFOX and the median OS in the original combination arm patients was 8.9 months. So that's probably the correct comparison, 8.9 versus 6.1. Ballpark, 40-ish percent improvement.

Got it. And then any other just subset analyses that you looked at regarding maybe prior therapies or anything else we should be looking at that might further support the OS benefit?

So no, we have not done that specific analysis, Ren. Just as I mentioned earlier, so many patients, greater than 90% had gem/cis plus a checkpoint inhibitor. Perhaps we could check durvalumab versus pembrolizumab, but we have not done that.

Our next question is from the line of Stephen Willey with Stifel.

My follow-up was answered.

The next question is from the line of Joe Pantginis with H.C. Wainwright.

This is Sara on for Joe. I just wanted to kind of hone in a little deeper on the PFS numbers as you discussed potentially going or seeking accelerated approval. Looking at PFS, are you thinking the numbers you got -- that you presented today represent an approvable now metric? And kind of curious how you're weighing that against your data for OS and even the ORR as well, maybe as you look to move ahead with your FDA meeting?

Sure. I think the most -- in addition, obviously, to the extraordinarily low p-value, the hazard ratio here of 0.44 is without any question, an approvable number. That is a 56% reduction in the risk of progression.

Our final question is from the line of Albert Lowe with Craig-Hallum.

The portion of patients that cross over differs from your expectations in the design of the trial. And did this aspect affect the feasibility of the RPSFT analysis?

So that's an interesting question. We didn't -- it was very, very hard to estimate ahead of time the fraction of patients that would cross over. I think 54% is maybe a little higher than we had initially thought of. And in addition, I think something that was also affected the RPSFT a little bit was the timing of those crossovers. It's a very good question, a very, very complicated question also.

But I think it's maybe a little higher than we had originally thought when we were designing the study because, again, crossover patients would be treated in the third-line setting, where the number of patients that make it out of a second-line therapy into third-line setting is -- that's not a huge number. So it's a little higher, I think. But good question, tough to answer.

At this time, this will conclude our question-and-answer session. I'd like to turn the floor back over to Dr. Thomas Schuetz for closing comments.

Great. Thanks so much. Just wanted to thank everyone for joining the call today. I really appreciate your time this morning. I think I'll probably just close by sort of going back to the next steps slide. We're super excited about the data we have. We have an unequivocal demonstration of efficacy, multiple different ways here.

So we're going to put everything together, meet with the FDA to discuss these data in advance of a planned BLA submission. If that discussion goes well, we should be in a position to initiate the BLA submission toward the end of this calendar year. Look forward then to BLA review and potential U.S. approval of tovecimig in 2027. Thanks again.

Thank you. This will conclude today's teleconference. Ladies and gentlemen, thank you for your participation. You may now disconnect your lines at this time and have a wonderful day.

Good morning, everyone. Welcome to day 3 of the JPM Healthcare Conference. My name is Sherry Yang, an associate in the Healthcare Investment Banking Group. And it's my pleasure to be introducing Compass Therapeutics today. We have Tom Schuetz here, the CEO, with me on stage. Let's give a warm welcome to Tom to the podium.

Thanks, Sherry, and thanks to JPMorgan for inviting us to present at the meeting this year. Just very briefly, I will be making forward-looking statements today, and I would refer you to our regulatory filings if you have any questions about those. Compass Therapeutics, we're based in Boston, Mass. We're a monoclonal antibody discovery and development company in oncology. We have 3 drugs in the clinic, and I'm going to talk about each of these drugs today because we've developed very important efficacy signals for each one of our drugs that's in the clinic. And this quarter, our fourth drug is going to enter the clinic, and I'll talk briefly about that drug as well.

This slide is a snapshot of our pipeline. Our most advanced program is Tovecimig. Tovecimig is a DLL4 VEGF-A bispecific antibody. That drug is a next-generation angiogenesis inhibitor. And recently, we announced that we hit the primary endpoint in a randomized study of Tovecimig in patients with advanced biliary tract cancer, and I'll talk more about that study in detail.

Last week at ASCO GI, we presented data from a Phase II study in patients with very advanced colorectal cancer, and we have unequivocal monotherapy in patients with colorectal cancer treated in the third- and fourth-line setting.

Our next most advanced program is the drug we call CTX-471. That's a next-generation CD137 agonist antibody, and I'll talk about the efficacy data for that drug as well. In the past 6 months or so, one of the most important developments at the company is with our third program, CTX-8371. That is a novel PD-1, PD-L1 bispecific antibody. I'll go through the discovery and development of that drug, but most importantly, we now have responses in the post checkpoint inhibitor patient population. And that's extremely important. I'm going to spend some time discussing that program in detail. Finally, our fourth program, a PD-1, VEGF-A bispecific antibody, that drug will go into the clinic later this quarter.

Our management team, some folks in the room here with me and others. Importantly, last week, we announced some additions to our management team. Cyndi Sirard, our Chief Medical Officer; and Arjun Prasad, our Chief Commercial Officer. Arjun comes to us from Servier and Agios, where he participated in the launch of a drug in patients with biliary tract cancer treated in the second-line setting. So obviously, very on-point experience, and I'll talk more about that in a couple of minutes.

Okay. Let's talk about Tovecimig. So VEGF-A, of course, the well-known soluble ligand for the VEGF family of receptors, DLL4 is delta-like ligand 4. That is the cell surface ligand for Notch-1. These 2 signaling pathways have different phenotypic effects on angiogenesis in the tumor microenvironment and dual blockade has been shown to be synergistic. Interestingly and what could turn out to be ultimately quite important is that DLL4 up-regulation in the tumor microenvironment has been shown to mediate resistance to VEGF targeted therapies such as bevacizumab.

And the reason that's important is because we have shown monotherapy activity with this drug in patients with colorectal cancer and gastric cancer who were previously treated with VEGF targeted agents such as Avastin or [ Cyramza ] in colorectal cancer and gastric cancer, respectively. Our Phase I program was completed and then a small Phase Ib study was done in which Tovecimig was combined with either irinotecan or paclitaxel. Those true drugs were chosen because paclitaxel is part of the standard of care in patients with gastric cancer second-line therapy for patients with gastric cancer is SYMRAZA plus paclitaxel. Irinotecan, of course, is part of the well-known FOLFIRI regimen that is used to treat patients with colorectal cancer.

And in this study, there was quite an unusual observation. This is the waterfall plot for all patients treated in the study. On the far right-hand side of this slide, there are 2 bars and those are 2 patients with advanced biliary tract cancer, who had very deep and very durable responses to therapy. And those 2 patients happen to receive Tovecimig in combination with paclitaxel. That empiric observation was then confirmed in a small Phase II study that was disease-specific for patients with advanced biliary tract cancer. This is the waterfall from the Phase II study. And you can see there is a clear treatment effect here with multiple responses in patients with advanced biliary tract cancer treated in the second- and third-line setting.

When we shared these data with the FDA, discussions with FDA led to the design of this study, which is currently ongoing in the United States. This study is called COMPANION-002. This is a randomized trial in a 2:1 fashion of Tovecimig plus paclitaxel versus paclitaxel alone in patients with advanced biliary tract cancer who have received 1 prior line of therapy. So this is a pure second-line study. As I mentioned earlier, we have read out the primary endpoint of this study. Tovecimig significantly improved overall response rate in this study as compared with Tovecimig. I'll go through those data in some detail. The key secondary endpoints of progression-free survival, overall survival are expected to read out later this quarter. I'll talk more about that timing in a minute.

So on this slide is a summary of the overall response rate data. So on the top line here, Tovecimig more than tripled the overall response rate compared with control, and that was statistically significant. We had a centrally adjudicated complete response in this disease, which is extraordinarily unusual. I should mention that all of these data are responses as assessed by blinded independent central review. So this is an extremely rigorous assessment of response.

I'm just going to go forward 1 slide and then come back to this slide. Here is the waterfall plot from the randomized trial. And you can see clearly that there are a difference between the 2 treatment arms. Patients in the control arm on top, the majority of these patients have increases in their linear tumor burden as evidenced by bars above the line, below the line is good. On the bottom, you can see the vast majority of patients treated with Tovecimig have decreases in their linear tumor burden. Let's go back to the previous slide for 1 minute. There's also something extremely important that came out of the best overall response rate data. In the red box on the bottom -- second from the bottom in the progressive disease line, there's a very significant difference in the incidence of progressive disease in the -- between the 2 arms.

Now because this is best overall response rate, this could occur at any time during the time that a patient is treated on study, except for progressive disease. If progressive disease is your best overall response by definition, that means it occurred at the first scan time point, which was week 8. So already at week 8, we see a separation potentially of the progression-free survival curves with 42.1% progression in the control arm, but only 16.2% progression in the combination arm.

So we believe that there is a high likelihood of the study being positive on progression-free survival, which is the next endpoint to be analyzed, and that will be followed by an analysis of overall survival. So where are we with the study? So in August, we made, what I believe, is an extremely important announcement and that is in the red box on the top here. In August, we announced that we have fewer deaths in the study than originally projected, said the exact opposite way, more patients are alive and living longer than we had projected. Now importantly, these are pooled blinded data. However, given what we saw in the overall response rate data, we believe that this is suggesting that we're seeing an effect of Tovecimig on overall survival.

For reference here, one 3-drug regimen that is used in patients with this disease is the 3-drug combination FOLFOX. In one randomized trial with FOLFOX at month 18, there was less than 10% of patients remaining alive. When we made this disclosure in the fall, at 18 months follow-up in our study, there was more than 20% of patients alive, of course, because we had not hit the 80% mortality threshold to trigger the analyses of the secondary endpoints.

So an extremely important update that we made to the study in August and September. We disclosed last week that we believe we're on track to report the analyses of progression-free survival and overall survival later this quarter. Should those studies be positive -- should those analyses be positive, we believe that Tovecimig has the potential to become second-line standard of care in patients with advanced biliary tract cancer. First line standard of care is chemotherapy plus a checkpoint inhibitor, gemcitabine and cisplatin plus either durvalumab or pembrolizumab. In the United States, there is no second-line standard of care. FOLFOX has a 6.2-month median overall survival, which is 0.9 months better than best supportive care.

That is not a standard of care. So should our PFS and OS analyses be positive, we would prepare to commercialize this drug in the United States. How many patients are out there? So in 2025, we completed some market research, and we've identified approximately 25,000 new patients annually. So this is a very significant commercial opportunity. Unfortunately, only about 15% of patients have an actionable mutation in their tumor, making them eligible for a targeted therapy. Such as FGFR2 or IDH1. So unfortunately, the other 85% of patients literally in the U.S. have no labeled standard of care. So we would target those patients, making some adjustments for how many patients might be well enough to make it to second line therapy.

We believe that the treatable patient population is approximately 15,000 patients annually, assuming perhaps 6-plus months on drug and making any modern reasonable assumption about drug pricing. This is well over a $1 billion market annually in the United States alone in second-line biliary tract cancer only.

However, there are many other opportunities to expand the indications for this drug. And we're preparing to initiate a basket study in patients who have tumors that are known to be DLL4 positive, and there are many other such indications, including, as I mentioned earlier, colorectal cancer, where we have unequivocal monotherapy activity for this drug in the third- and fourth-line setting as well as gastric cancer, hepatocellular, ovarian cancer and others.

So following the approval of Tovecimig in the United States, we would move rapidly to expand the label into many of these other indications. Ultimately, of course, our goal would be to replace Avastin in all of the Avastin indications, which would make this an enormously commercially successful drug. So with Tovecimig, our lead program, here's where we are today, our randomized study, by definition, is positive because we achieved the primary endpoint in that randomized trial. We expect to analyze the secondary endpoints of progression-free survival and overall survival later this quarter.

Interestingly, MD Anderson in Houston was the second largest enroller in our randomized trial. And after they had treated 6 or 7 patients or so, they came to us with a proposal to do an investigator-sponsored study where Tovecimig is being added to the frontline regimen of gemcitabine/cisplatin and durvalumab. That study is now ongoing at MD Anderson will be very interesting to read out data from that study potentially later this year. And as I mentioned, the potential to expand the label, following the readout from our randomized trial, we would expect to have an interaction with the FDA.

If that goes well, we could potentially submit a license application later this year because we have fast-track designation in the U.S., we would certainly get a priority review, which would put our PDUFA date inside the first half of 2027, and we're now preparing to commercialize this drug in the United States.

Let's spend a few minutes on a couple of our other drugs, starting with CTX-471. 471 is an agonist antibody of CD137. It binds to a unique epitope with a unique affinity in a Phase I dose escalation study followed by cohort expansions. We had responses in the post-PD-1 patient population in patients with melanoma. We had just under a 30% response rate there. We had 1 out of 4 patients with mesothelioma who responded. And fascinatingly, on the top of this slide, we had a patient with metastatic small cell lung cancer who received frontline therapy with chemotherapy and the PD-L1 blocker atezolizumab, was on that regimen for about 4 months and then progressed, then got second line nivolumab, was on that for about 2 months and then progressed. So this is a third line metastatic small cell lung cancer patient, the median overall survival of that patient population is approximately 9 weeks.

Think about that number. This patient started monotherapy with 471, quickly responded. That was confirmed. This patient had a PET-negative complete response and was on therapy for more than 3.5 years when he came off therapy with a complete response. Interestingly, we collected biopsy specimens from this study and this patient's biopsy, which is shown on this slide, turned out to be very positive for neural cell adhesion molecule, NCAM, also known as CD56. That made us look at other patients' biopsies in this study. And I think we might have made an important discovery here. NCAM might be a biomarker of response to CTX-471 because it could mediate NK cell activation in the tumor microenvironment.

So we're now planning to do an NCAM-positive basket study. NCAM is expressed on neuroendocrine tumors, small-cell lung cancer, of course, melanoma and many others. That study should begin in the first half of this year.

Let's now spend a couple of the last minute talking about CTX-8371. So at Compass, we developed the technology that we call StitchMabs. StitchMabs is a tool that allows us to screen for biological synergy in bispecific drug candidates. We used that to ask an important question, which is what is the best combination partner for PD-1 blockade in a bispecific antibody. StitchMabs also allows us to create small libraries. We did that. We screened that library and fascinatingly, the best combination partner for PD-1 blockade turns out to be PD-L1 blockade, a very unexpected discovery.

On the top right-hand side of the slide, the combination of dual ligand receptor blockade in a bispecific antibody is between 100 and 1,000 fold more potent than either antibody alone. But it turns out not to be just dual ligand receptor blockade, which it is, but on the right-hand side of this slide, 8371 is unequivocally a T-cell engager. In addition, in the middle right-hand side of this slide, 8371 exposes a cleavage site on PD-1, leading to the cleavage of PD-1 off the surface of effector T cells.

This drug actually converts PD-1 positive T-cells into PD-1-negative T-cells that subsequently cannot be suppressed. So this is a very novel next-generation checkpoint inhibitor. We recently completed the dose escalation portion of a Phase I trial. We enrolled patients with melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin's lymphoma and triple-negative breast cancer, all who have previously received checkpoint inhibitors. That is an extremely important take-home point.

All of these patients are treated in the post checkpoint setting. We have no dose-limiting toxicities in the study, which is fascinating in and of itself because we believe this drug could be anchored in the tumor microenvironment via PD-L1 where it could provide local high-concentration blockade of PD-1. So because this is a 3+3 design, no DLTs, 5 dose levels, we've treated 15 patients, right? 5 x 3, and we already have 3 responses.

We have a response in a patient with non-small cell lung cancer. This is a patient post ipi-nivo in the blue circle here, you can see complete disappearance of a metastatic tumor. Our most important patient in this study is shown on this slide. This is a patient with triple-negative breast cancer who relapsed while receiving adjuvant KEYTRUDA then got Trodelvy followed by 2 different chemotherapy regimens. This patient had 9 centimeters of tumor burden at baseline. And in the 2 blue circles here, a lung metastasis on the top and a pericardial heart metastasis on the bottom, that was 5.2 centimeters large.

Those have completely disappeared. This patient is a near complete response in the post Trodelvy setting now durable at month 8, we recently announced. Finally, we announced last week that we have another response in a patient with Hodgkin's lymphoma. We now have solid tumor responses and our first hematologic malignancy response, the triple-negative breast cancer patient is 1 of 2 patients in the study with triple-negative breast cancer who were evaluable.

The Hodgkin's lymphoma patient is the only patient in the study with Hodgkin's lymphoma. And that patient has had a confirmed metabolic partial response. We've now opened cohort expansions in patients with non-small cell lung cancer and triple-negative breast cancer, and we're currently evaluating the next steps for patients with Hodgkin's lymphoma.

Finally, in the last minute, our fourth drug CTX-10726 is a novel PD-1 VEGF-A bispecific, 2x2 valency and terminal anti-VEGF, C-terminal PD-1 blockade. We showed some preclinical data at SITC in the fall, demonstrating that this drug has superior PD-1 blockade to other drugs in the class. And interestingly, it has better tumor control in mice than other drugs in the class.

I'm sure you all well know, this is a new class of drugs, PD-1 VEGF-A bi-specific antibodies and our drug is superior to other drugs in the class, in both syngeneic mouse models and in xenografts where we're testing this against human tumors. That drug is going to go into the clinic this quarter in patients with renal cell cancer, endometrial cell cancer, gastric cancer and hepatocellular cancer.

So this is my last slide. 2026 is going to be a very busy year for us at the company, starting with the PFS and OS readout from our Tovecimig clinical trial in patients with biliary tract cancer. As I mentioned, if those data are positive, we would then have an interaction with the FDA. If that goes well, that would be followed by a biologics license application, which again could put us in a position to launch this drug in the United States in the first half of 2027.

Our DLL4 positive basket study to begin following that readout, our NCAM-positive basket study for 471. And again, for 8371, our cohort expansions are now open in patients with non-small cell lung cancer and triple-negative breast cancer. Just to speculate here, should we see additional responses in patients with triple-negative breast cancer, I think we would have an accelerated conversation with the FDA about moving that drug directly into an approval trial in the post-Trodelvy patient population. Stay tuned for that. That's going to be one of the more important developments at the company in the coming year.

And then finally, our fourth drug in the clinic 10726. We look to report data in the second half of the year from that Phase I study. Thank you very much. Happy to take some questions, and Sherry and I are maybe going to have a conversation as well. Thank you.

I can start here. So starting off with your Tovecimig assets, you're currently waiting for secondary endpoints, and this could be transformational for your company. In April, you achieved statistical significance results in your primary endpoints of ORR, what gives you confidence in the upcoming PFS and OS readouts?

Sure. Thanks for that question. I think that's an extremely important question and I went back to Slide 11 in the presentation to help address this question. So in the red box on the bottom, you can see the difference in progressive disease in the study. So with 42% radiographic progression already at week 8 and unfortunately, this disease has tremendous early mortality. Unfortunately, some of these patients in the control arm may have already died by week 8 in -- with FOLFOX, think about this number, by the way, the 2-month mortality with FOLFOX is about 10% to 15%. So 10% to 15% of patients with this disease don't live 2 months. So we believe that the median progression-free survival in this study is going to be approximately 2 months. That's what these data would suggest with only 16.2% progression in the combination arm. There's a suggestion here that the progression-free survival curves are already separating and potentially separating in a very meaningful way.

This study is powered to detect a hazard ratio of approximately 0.6. A hazard ratio of 0.6, of course, would be clinically meaningful by any definition and would actually be an extraordinary result in this indication. In terms of the OS readout, simply the amount of time that has gone by gives us confidence that we're seeing an effect on overall survival.

Because the study enrolled 168 patients, as you can see on this slide, in a 2:1 randomization, 111 in the combination arm, 57 in the control arm, 168. The 84th patient was enrolled the first week of March in 2024. So we are coming up on 2 years out. Every patient in the study is more than 16 months out from joining the study because the study was fully enrolled in August of 2024. So simply, the amount of time that has passed suggests to us that we're seeing something very, very important and meaningful here.

Can I ask the indication selection for Tovecimig versus you have a PD-1 VEGF going into clinic as well? Can you talk about selection.

Sure, sure. That is a fantastic question. Thank you. So with Tovecimig, we're mostly focused on DLL4 positive malignancies so there's a whole set of malignancies there that I mentioned. So ovarian cancer, for example, is well known to be DLL4 positive in addition to hepatocellular gastric and colorectal cancer. But you're correct. There is some overlap between our development program with 10726, our VEGF-A PD-1 bispecific antibody. The overlap would be patients with renal cell and gastric cancer.

So I think we have very good mechanistic rationale to go into both of those indications. Ultimately, I think where we'd like to end up is with combination therapy. And I think for our PD-1 VEGF bispecific, I think -- ideally, it would be great to see something in -- to see a signal in patients with hepatocellular cancer, for example where frontline therapy is the combination of VEGF blockade and PD-L1 blockade. So second-line hepatocellular would be a very interesting place to go into.

In terms of Tovecimig. I think ultimately, we'd like to move in a direction where we're combining Tovecimig with 8371. And I think there, we would probably focus on patients with gastric cancer and probably renal cell cancer with Tovecimig. So it's a very interesting question. Honestly, that will be a very good problem to have, right, if we see efficacy with both drugs in those indications.

Now, I guess, still focusing on Tovecimig. You mentioned your most recent thoughts on like your -- in terms of commercial readiness within the context of your new commercial officer, Will you be commercializing this on your own? Or are you speaking to potential partners?

So we are preparing to commercialize this drug in the United States on our own. I think interestingly, I'm just going to go back one slide here. On the far left-hand side of this slide is a diagram of the liver and the biliary tree. And the reason that I'm focusing on that is to make a very simple point, patients with biliary tract cancer have anatomic complications of their disease, so they end up with obstruction in their biliary tree, which requires endoscopic stent insertion and replacement, and that type of procedure is not generally done at community hospitals. So the vast majority of these patients are seen at referral -- academic referral centers.

So we believe with a focused commercial team, we can commercialize this drug ourselves in the United States, and we are preparing to do so. We have said publicly that we're entertaining conversations with strategics. But I don't know where those conversations will go. Certainly, the rest of the world, Japan and the European Union, we would need to address commercially in the future, but we are going to launch this drug ourselves in the United States.

Thank you. Now turning to your 8371 asset, your PD-1 and PD-L1 bispecific, you've shown responses in 3 separate tumor types within the first 15 patients that were dosed, all of them are post checkpoint inhibitors. What about this asset is driving this efficacy?

Sure. So I'm just going to go back to the mechanism of action slide here because this drug is clearly different from a mechanism of action point of view than any known checkpoint inhibitor. So either PD-1 blockers or PD-L1 blockers do something relatively simple, which is on the far left-hand side of this slide. Those drugs will either block the interaction of PD-1 with its ligands or block PD-L1's interaction with PD-1. That's what they do. 8371 does some -- not only does it do those things, it does some other things as well. And I think the activity of this drug as a T-cell engager is quite fascinating. And then the fact that it converts PD-1 positive T-cells in the PD-1-negative T-cells is an extraordinarily unique mechanism of action. So this observation has now been confirmed in the clinic with responses in the post-checkpoint patient population.

So these are extremely difficult patients to treat. In the post-checkpoint patient population, there's really very, very few options for these patients. And for us to have monotherapy activity in this patient population is an extremely important signal for us. And the diseases where we've seen activity triple-negative breast cancer, my God, post Trodelvy in the triple-negative breast cancer patient population, there's absolutely no therapy for these patients. So this would be a wide open field for us to not only develop this drug, but ultimately to get this drug approved in that indication. And the most recent update that we gave, Hodgkin's lymphoma is a very important observation because as you may know, Hodgkin's lymphoma is a PD-L1-driven malignancy.

So seeing a response in a patient with Hodgkin's lymphoma is directly on mechanism for this drug. And this patient with Hodgkin's lymphoma, I can tell you, had prior brentuximab, prior nivolumab and a transplant and we're seeing a monotherapy response with 8371.

So this is a drug we're extremely excited about and something I don't commonly talk about on the bottom of this slide in the gray bar, the potential for proprietary combination regimens. I think one of the most important advances in oncology in the past 10 years has been the combination of angiogenesis inhibitors with checkpoint inhibitors. The very first observation there was the study IMbrave150, that was done by Roche, where the combination of bevacizumab and atezolizumab in front-line hepatocellular cancer was superior to standard of care sorafenib.

That was the very first observation that was published in the New England Journal of Medicine in 2020. And that study has opened the floodgates for testing these hypotheses. And the PD-1 VEGF-A bispecific field is a completely new class of drugs targeting both angiogenesis and checkpoint ambition. So where we really want to go with this drug is to combine Tovecimig with 8371 as a super next-generation angiogenesis plus checkpoint inhibitor regimen.

I have a question on commercialization. Do you have the infrastructure in place today to do that? Or what do you -- how do you plan to support that?

Sure. Very important question. So we announced last week that we hired Arjun, our Chief Commercial Officer, and we're now building that infrastructure, and we'll do so over the coming 12 to 18 months as we prepare for the launch of this drug.

Thank you. Now moving to your last asset that you talked about or didn't have a chance to mention, your 10726, your PD-1 VEGF bispecific. You presented your preclinical data, yes, against the most leading asset in this space, which is ivonescimab. Can you share us about what stands out specifically in the terms of differentiation?

Sure. So when we were developing this drug, we spent some time investigating whether or not we should block PD-1, block PD-L1. Ultimately, we landed on a very similar construct to ivonescimab that you mentioned. But very quickly, we realized that our PD-1 end of this molecule is a better binder of PD-1, and it is a more potent inhibitor of PD-1 signaling. So that was the first little hint that we got that this drug could be different. We then did head-to-head testing in preclinical models and in selected preclinical models, we have shown that 10726 is actually superior to ivonescimab.

Now take that for what it is. I just want to be fair here. We're comparing these drugs in mice. So we have to be fair about that. But we clearly see a differentiating signal and I think recently -- I apologize because this is going to be a little bit of a tease, so stay with me here.

But recently, scientists at Compass have made what I believe is potentially an extremely important observation about the mechanism of action of this drug that suggests it could well be a very differentiated asset. Stay tuned for that. We would love to potentially discuss that later this year. But we believe that we have some clear differentiation of this drug. Ultimately, of course, we'll need to differentiate this drug in the clinic.

And then just after that tease, when do we first expect the clinical data? And are you expecting to go this on your own or a partner in this very increasingly competitive space?

Sure. So Phase I initiation this quarter, which would put us in a position to have some clinical data in the second half of this year. The second half of your question, of course, is fascinating as you obviously know full well, there are now multiple drugs in this class. It is going to become a competitive area and strategic partners are quite interested in this class of drugs. And specifically, we have a strategic interest in this asset. Of course, we will do the best thing for our shareholders. We're currently going to initiate the Phase I study this quarter, but we'll see where that goes in our conversations with potential strategic partners.

Awesome. Thank you so much, Tom. That concludes our presentation, and please give another round of applause for Tom.

Thank you.

All right. Thank you, everybody, for joining us. I'm here with Thomas from Compass Therapeutics. Thank you so much for joining me this afternoon or this -- I don't know what day is it?

Thanks so much for inviting us. Happy to be here.

Great. Let's start things off with a minute or 2 from you, introducing yourself, the company. What are you looking forward to going into '26?

Sure. Compass, we're based in Boston. We're a monoclonal antibody discovery and development company in oncology. We currently have 3 drugs in the clinic and a fourth drug about to enter the clinic. So 2026, to answer your question specifically, is going to be an incredibly eventful year for us. We -- for our lead program, Tovecimig, a DLL4xVEGF-A bispecific antibody. We have a readout on the secondary endpoints of progression-free survival and overall survival that will be coming up in the end of Q1. So that will be a very big important update for us. In the second half of this year, 2025, something very, very important was observed in our Phase I clinical trial of our PD-1, PD-L1 bispecific antibody. We have 3 responses in the first 15 patients treated in the dose escalation study, including the first-in-human de minimis dose.

So we have some incredible observations of efficacy there, and we're moving toward cohort expansions in patients with triple-negative breast cancer and non-small cell lung cancer based on what we've seen so far, and we should have a readout from that in the second half of the coming year with a presentation at a scientific meeting in the first half of the coming year. Then our fourth drug, a novel PD-1xVEGF-A bispecific antibody is going to enter the clinic at the beginning of the coming year. Obviously, a class of drugs.

Everybody is feeling good.

That you're well familiar with. But we've got a differentiated molecule, we believe, of course, so looking forward to getting that drug into the clinic. And our CD137 agonist antibody, where we've discovered a biomarker of response, we're going to do a biomarker-driven basket study with that drug to begin in the first half of next year. So '26 is going to be an incredibly exciting and eventful year for us.

A lot going on. Excellent. Let's start with that DLL4xVEGF bispecific that you mentioned. Obviously, we had BTC data earlier this year, very nice delta in ORR. Based on the latest look, as we head into PFS data, as you mentioned next year, I think confidence is reasonably high. Can you talk about what's driving that differential response, how you think about the evolution into longer follow-up data?

Sure. So again, Tovecimig, a DLL4xVEGF-A bispecific antibody, DLL4, delta-like ligand 4, the cell surface ligand for Notch-1. So this is a next-generation angiogenesis disruptor. And as you mentioned, earlier this year, we announced the results of the primary endpoint analysis in a randomized study, and we more than tripled the response rate in the control arm compared with the combination arm, including Tovecimig. As part of that analysis, which was best overall response rate as assessed by blinded independent central review, we noticed that there was a substantial difference in the incidence of progressive disease. And that, I think, is quite important. 42% progressive disease at week 8 in the control arm, only 16% in the combination arm. So...

That's going to be a major driver for PFS.

Exactly. So suggesting that the PFS curves are already separating early. So we're enthusiastic to get the PFS readout. The second half of your question, so both the PFS and the OS analyses are driven by 80% OS events. So initially, we did that because in every second-line biliary tract cancer study ever, PFS and OS are basically right on top of each other or they're 2 months apart, some number like that. So we said let's just do the 2 analyses together. But we announced in August that what we are observing, and this is quite a simple disclosure because it's a simple statement of fact. We observed that there are simply fewer deaths in the study than we had projected and which means patients are living longer and more patients are alive than we had projected. So what's driving that, right? So...

On the controlled trial where we would expect at least the control arm to have a reasonably predictable event.

That's right. That's right. So it's -- we -- what we see on a weekly basis are pooled OS events. So I just need to be clear about that. That's what we're -- that's the data that we're receiving. But it's very hard not to conclude that we're seeing some effect on overall survival. And based on our overall response rate data, the progressive disease incidents in the 2 arms, what we believe we're seeing is the formation of a tail on the Kaplan-Meier curve in real time. That's what we believe we're seeing.

Maybe important to note that this is a 2:1 randomized study. So if you're waiting for 80% OS events and they're just not happening in 65% of patients.

That's right. So that's a great summary. I think that with a 2:1 randomization and if the drug is having an effect on overall survival, that certainly could explain what we're seeing, but wouldn't that be great?

It might be great.

Right.

Well, then let's talk about the opportunity in second line. This biliary tract cancer in general, not an enormous indication, second line, obviously, a subset. Can you talk about what the market opportunity is in second-line BTC and where you might go from there?

Sure. Sure. So Biliary tract cancer, I think, is a bit of an underappreciated opportunity. About 25,000 patients annually are diagnosed in the United States. The claims aggregator, Komodo Health, did an analysis that they presented publicly at the Cholangiocarcinoma Foundation meeting a couple of years ago. And in -- we did some third-party market research earlier this year where we updated that analysis. But in 2023, scientists from Komodo reported that there were 23,000 patients annually in the United States, making it a very, very important indication. Our analysis that we did this year suggests that number is closer to 25,000. And there was a JAMA oncology paper published, which suggested that the incidence of biliary tract cancer is increasing.

But what's duration of therapy for second line currently?

Okay. So interesting. So the duration of therapy for second-line chemotherapy is certainly low single-digit months. So in our Phase II study, which was a single-arm study, just to be fair about that, our median PFS in that study was 9.4 months. So we clearly were seeing something different. Whenever I'm asked this question, I'm always quite conservative, and I use the lower bound of the 95% confidence interval from that study, which was 5.4 months. So if we're seeing that...

It's still reasonable to expect that maybe in the randomized study, you could see mid- to high single digits treatment that would indicate a pretty substantial market relative to where we're currently sit.

Exactly. And we believe that something like 15,000 patients annually -- and again, this is in the U.S. alone, in second-line BTC alone, about 15,000 patients will make it to second-line therapy. Make the math easy, 6 months on drug. As you know way better than I, recent oncology drug approvals are priced significantly high. So this is a multibillion-dollar commercial opportunity.

Bet you, in rare indications. Absolutely. So let's talk about the expansions beyond that. There's an IST going on in first line currently. You're looking at a basket that includes a number of tumor types, where do you think this mechanism, this dual anti-angiogenic mechanism makes the most sense going forward?

Sure. So a couple of different thoughts there in that question. So yes, we have a frontline study ongoing at MD Anderson right now. And that's quite interesting because MD Anderson was the second largest enroller in the second-line randomized study, which is open label at the sites. So it's tempting to conclude that they must have seen something in order to send us a proposal for an investigator-sponsored study. So they're adding Tovecimig to the TOPAZ1 regimen, which is gemcitabine/cisplatin and durvalumab. That study initiated earlier this year and is ongoing now. Should get a -- I'm going to get an update from the investigators in the early next year and might be able to talk about some of that next year. And obviously, moving to the frontline setting, which would be 50% more patients, potentially...

Presumably more duration.

Potentially 50% more time on drug. Now suddenly, you're talking about a multibillion-dollar opportunity in BTC alone. But the second part of your question, I think, is fascinating because there are many different malignancies that are enriched for DLL4 expression. So among those, hepatocellular, gastric, ovarian, renal cell, colorectal. So several different malignancies are enriched for tumors that express DLL4. The way you asked the question, I think, is you had a sort of subtle way that you asked the question, which is how might targeting angiogenesis in these various indications...

In that list that you just mentioned, hepatocellular, colorectal especially feel like really fruitful areas...

Exactly. Right. Because colorectal, the global standard of care in colorectal first line, second line, third line, if you're KRAS mutated is chemotherapy plus Avastin. FOLFOX Avastin, FOLFIRI Avastin, LONSURF Avastin, right? So colorectal would be very fruitful indication to potentially combine Tovecimig with chemotherapy. We're looking at some second-line designs right now, thinking about combining Tovecimig with FOLFIRI.

Better Avastin, better in IDH1 in a molecular regimen.

Exactly. That is exactly right. Better version of Avastin, next-gen version of Avastin. Ultimately, commercially, we would want to think about replacing Avastin in all of the Avastin labeled indications, which then this would be an incredibly successful drug.

That would be -- well, that would be quite a product. Let's talk about the commercial readiness. You've made comments about manufacturing capability in the past. But where are you from a prescriber awareness perspective, especially in second-line BTC. How aware are the docs about this and how ready are they to adopt it?

Sure. So maybe a 2-part question there. So first of all, on the manufacturing side, something that I think is super important, but just always sort of gets swept under the rug. We've developed, I think, some extremely important internal expertise on bispecific manufacturing. So we've got a commercial-ready manufacturing process for Tovecimig, which is very robust and something I'm very, very happy with. In terms of prescriber awareness, so we have begun our prelaunch preparations with some initial pre-commercial work. We'll have more to say about that early in the coming year on the leadership side. So that's something also I'm very, very excited about. One of the things that I'm super happy about in our randomized trial, we've had -- we are very, very fortunate to sort of have a who's who of academic medical centers. And...

You mentioned MD Anderson, obviously.

Yes, MD Anderson, Johns Hopkins, Mass General, Stanford, UCSF, Mayo, Chicago, WashU, it's just a tremendous -- Columbia, a tremendous list of academic medical centers. And I think that will put us, I think, in a good position for expanding prescriber awareness and in 2026, really want to begin our full-on commercial preparations for the potential '27 launch of this drug.

Excellent. Well, I want to make sure we have time to discuss those other assets you mentioned in your opening remarks. There's quite a list of them. But one thing that I wanted to make sure we touch on is that PD-1, PD-L1 bispecific 8371. That's a very interesting molecule, very different from other approaches we've seen in this space. Can you tell us a little bit about the design of the molecule and how you're positioning it in those lead indications you mentioned?

Sure. I think a couple of years ago, scientists at Compass decided to tackle a very challenging problem, which is the design of a next-gen angiogenesis disruptor as a bispecific antibody. And our scientists developed a technology that we call StitchMabs. That technology allows us to covalently link any 2 monoclonal antibody fragments together in a 15-minute room temperature incubation. And what we did with that is we made a small library, okay, which is not something that is commonly done. You don't commonly hear about libraries of biologics because it's so difficult from a molecular biology point of view. But we made a small library, did a screen and what came out of that screen was absolutely fascinating that the best combination partner for PD-1 blockade was actually PD-L1 blockade. Really interesting. I, frankly, was quite surprised...

Very surprising, yes.

To see that. And because it was so unexpected, frankly, we spent probably a solid year investigating the mechanism of action, and that drug is extremely unique. In addition to being a standard ligand and receptor blocker, it is unequivocally a T cell engager. In addition, it does something incredibly interesting, which is the bispecific exposes a cleavage site on PD-1, leading to the cleavage of PD-1 off of effector T cells. So this drug converts PD-1 positive T cells into PD-1 negative T cells. It's an incredibly unique mechanism of action.

Three things going on at once really.

Yes. So we took it into a Phase I study last year, a standard '3+3' design, 5 different dose levels ranging from 0.1 mg per kg to 10 mgs per kg. And we had no dose-limiting toxicities observed at any dose level. suggesting that we could actually have a differentiated safety profile because this drug might be anchored in the tumor microenvironment via PD-L1 to provide local high concentration blockade of PD-1.

But you're not -- so this is a 1x1...

No, it's a 2x2 valency. That's very important.

And even so, even at 10 mgs per kg, I would expect you to be well below doses where you were saturating these receptor systems.

Most PD-L1 -- so most PD-1-based drugs are dosed in the 1 to 3 mgs per kg range. Most PD-L1 drugs are in the 10 mgs per kg range. So we believe at 10 mgs per kg based on that we are saturating. So fascinatingly -- and again, I count everybody when I report the data. So 15 patients because we had no DLTs, it's only 3 patients at each of the 5 dose levels. So 15 total, including the low doses. Among those 15 patients, we already have 3 confirmed responses. So we've got a near CR in a patient with metastatic non-small cell lung cancer treated in the fourth-line setting.

And these are all PD-1 exposed post-checkpoints...

These patients are all post-checkpoint patients, a super important point. That patient, by the way, had squamous histology with low tumor mutational burden, just a fascinating observation. Our most important development at the company, in my opinion, in the past 6 months is a patient at the 3 mg per kg dosing level with triple-negative breast cancer. This patient relapsed while receiving adjuvant KEYTRUDA. So technically, this patient is refractory, exactly, then got Trodelvy and 2 salvage chemotherapy regimens, 9 centimeters approximately of linear tumor burden at baseline, which has completely disappeared, now durable through week 16.

This patient could convert into a CR, started out with 87 millimeters of tumor burden, now down to about 5 millimeters. So it's just an incredible observation. Based on that, we're going to do cohort expansions in patients with non-small cell lung and triple-negative breast. And at the last -- at the final dosing level, we have another response in a third indication. That was just confirmed last week, and we'll probably announce that indication early in the coming year and potentially move directly to a Phase II study there. So we're incredibly excited about that drug. And if we have discovered a next-generation checkpoint inhibitor, obviously, that would be transformational for the company.

Yes, those are really very interesting results and obviously, a very unique molecule there. In our last minute or 2, I would -- well, I do want to ask you a follow-up question about that PD-1xVEGF that you mentioned, you said you expect this to be differentiated. Obviously, we've seen a ton of these come out of the woodwork in the past year or 2. What makes yours different?

Definitely, I -- the premise of your question, I think, is unassailable. We've got a ton of these out there now. So one of the things that makes ours different is we have better PD-1 blockade than other molecules that are in development. And I -- this is my own opinion, I don't believe these drugs are going to be able to be differentiated based on the VEGF end of the molecule. It's possible for sure. But I think VEGF capture is quite -- is not is not really that challenging in a therapeutic. So I think these drugs are going to be differentiated on the PD-1 end.

Are you using a similar epitope to the PD-1, PD-L1 bispecific or something?

Yes, yes, that's important. So the PD-1 end of our PD-1xVEGF came from the PD-1, PD-L1 bispecific.

Do you observe the same PD-1 cleavage activity in the VEGF bispecific?

Don't know yet. I don't know yet. So that is a fascinating question. I don't know the answer to that yet. So we are fivefold more potent than other drugs in the class. We presented data at SITC a couple of weeks ago that in head-to-head preclinical studies, take those for what they are. In head-to-head preclinical studies, we're superior to drugs like ivonescimab. So we're going to go into our Phase I indications are going to be gastric cancer, hepatocellular, renal cell and endometrial cancer, 4 indications where both PD-1 blockade and VEGF signaling disruption are effective either as monotherapies or in combination. So those are going to be our 4 Phase I indications, which I think should also provide a way for us to differentiate the development of that drug.

Fabulous. Very active '26 coming up for you guys. We didn't even get a chance to talk about the CD137.

Next time.

Next time. Thank you so much for joining us, Thomas.

Sure. Thanks, [ John ].

I'd like to welcome everyone to day one company one of the Piper Sandler Healthcare Conference. I'd like to welcome Compass Therapeutics, their CEO, Tom Schuetz. Welcome, Tom.

Thanks, Biren. Thanks for having us at the conference. Really appreciate it.

And I was looking at your stock price year-to-date, up 290%. I mean that's quite impressive compared to XBI of 30%. So the company is clearly doing something right. Can you tell us -- maybe we start off with the two clinical stage programs. And if you could maybe provide us an overview of both programs, target indications and then we can dig in a little bit more.

Sure. Yes, I think to your first point, I think it might be related to our high-quality analyst coverage. Compass Therapeutics, we're located in Boston. We're a monoclonal antibody discovery and development company in oncology. We actually have three drugs in the clinic, two bispecific antibodies and one monoclonal antibody and a third bispecific antibody going to enter the clinic early in the coming year.

So our most advanced program is a DLL4 VEGF-A bispecific antibody and that drug is called tovecimig that is currently in a randomized trial in patients with advanced biliary tract cancer. Earlier this year, we announced that we hit the primary endpoint in a randomized trial of overall response rate, more than tripling the response rate seen in the control arm. To my knowledge, we have one of the highest response rates ever seen in patients with advanced biliary tract cancer treated in the second-line setting.

In addition, which -- and we'll get into this, I'm sure, there was a substantial difference in the disease control rate as well, suggesting that we are -- could see an important difference in progression-free survival as well. We'll come back to that point in a minute.

Our second program that is currently in a clinical trial is a drug called 8371, that is a novel, potentially first-in-class PD-1, PD-L1 bispecific antibody. That came out of a screen for synergy with PD-1 blockade using a technology that our scientists at Compass developed, and our scientists did a screen for synergy with PD-1 blockade and discovered made an important discovery that PD-L1 blockade is the best combination partner for PD-1 blockade in a bispecific antibody.

That drug has recently completed a dose escalation Phase I study fascinatingly. Now we saw no dose-limiting toxicities in that study. But more importantly, 15 patients treated in the post checkpoint setting, we already have 3 responses. We have 3 confirmed responses now including a patient with non-small cell lung cancer, triple negative breast cancer.

And the third indication we've not yet disclosed but the patient with triple-negative breast cancer is extremely important. So this patient relapsed while receiving adjuvant KEYTRUDA. So technically speaking, this patient is actually refractory, then received TRODELVY followed by two additional chemotherapy regimens, started the study with approximately 9 centimeters of tumor burden, and that is now down to approximately 5 millimeters. So greater than a 90% decline. The patient is now durable continuing on therapy, potentially this patient could convert to a complete response, which would be absolutely amazing.

And I just want to make one final point about 8371 and I know I'm repeating myself, but all of the patients were treated in the post checkpoint inhibitor setting. And we already have 3 responses in the first 15 patients treated. So I believe, of course, I'm biased, we have the best Phase I data of any checkpoint inhibitor because drugs like KEYTRUDA, Opdivo, Tecentriq, those were all tested in the checkpoint-naive patient population. This is a little bit of a subtle point but I believe this is extremely important that we're seeing monotherapy responses in the post checkpoint patient population.

That's great. So I mean, both are -- seem like a very exciting programs with a lot of potential. And then I guess maybe if we could start with Tovecimig. COMPANION-002 trial, the Phase II/III pivotal study as you mentioned, you've reported the primary endpoint and achieve that on overall response rate versus paclitaxel alone. PFS, OS end points are expected by the end of Q1. Can you tell us how we should look at the readthrough from overall response rates to PFS and OS and the confidence in the PFS and OS endpoint?

And then I think also you had disclosed that the 8 weeks, there were a significantly greater number of patients that progress in the PAC arm versus the tovecimig arm. So maybe can you talk about the rate-throughs from that data point as well?

Sure. So we reported the best overall response rate data in April of this year. And of course, best overall response rate can include many different things. It can, of course, include complete responses, and we had a complete response as adjudicated by blinded independent central review, an extremely unusual finding in advanced biliary tract cancer.

Partial response, stable disease, but progressive disease can also be your "best overall response". But if PD is your best overall response. What that means is, by definition, it had to occur at the first scan time point, which was at week 8. So if you had stable disease at week 8, you'd be in the SD category. So if PD was your best overall response, what that means is it had to occur at week 8. And in the combination arm, we only had 16% PD, in the combination arm, as you mentioned, we had 42%. So 100 minus those numbers is a maximum of 58% progression-free survival maximum at week 8, 84% in the combination arm. So the progression-free survival curves are probably already significantly diverging. So we are quite confident that we'll hit the PFS endpoint.

And I think one of the things you asked an important question about read-through, right? And I think one of the things to keep in mind with the read-through from the response rate to the PFS and OS endpoints is the waterfall plots. So the waterfall plots from the study are fundamentally different.

So in the combination arm, the majority of patients had decreases in their linear tumor burden which I alluded to earlier with the disease control rate. The disease control rate was close to double in the combination arm as compared with the control arm. So we believe that will read through directly to PFS. And then as you mentioned, both PFS and OS analyses are triggered by OS events and we reported in August, and then we reiterated in November with our Q2 and Q3 earnings releases, respectively, that we're seeing fewer deaths in the study than we initially projected.

So because of that, we've recently updated at 18 months median follow-up when we still had not hit the number of total events, we were well above where you'd be expected based on historical data in this disease. So we're enthusiastic about the OS endpoint. And as you mentioned, looking forward to reporting those data toward the end of Q1 of the coming year.

And you mentioned that the OS event rate has been slower to accrue. This is a 2:1 randomized design. So clearly, with 80% events that are required for the study to unblind, you would need patients in an active arm to have an event. Is that a fair characterization? And I guess, in your view, what do you think are the reasons why the events have been slow to accrue?

Sure. So a 2-part question there. The first part of your question is yes, we need to see 80% pooled OS event in order to trigger the analysis of PFS and OS. So second part of your question, of course, is very important but also, of course, very complicated. So whenever you see something like this, you wonder whether or not the control arm is doing something that you didn't anticipate. We have any evidence to support that? Probably not because in our best overall response rate analysis, the response rate in the control arm was only 5.3%. So paclitaxel is not doing something that we didn't expect. The 3-drug combination of FOLFOX in a randomized trial had a response rate of 4.9% to [indiscernible] so we're not seeing it there.

And in terms of the incidence of progressive disease with 42% progression at week 8 and the median PFS in the control arm is probably going to be something like 2 to 2.5 months. It's going to be in that range. I don't know what it's going to be. But based on our overall response rate data, it suggests that it's in that range.

So the control arm is not doing something unanticipated. I know for sure that we are not missing data. We've had extremely low numbers of patients lost to follow up in this study. And I think our clinical operations group at the company is just doing a phenomenal job here. We've only lost something like 5% of patients to follow up, which is just staggering low number for the study. So -- and I know today that every patient, except for one single patient that is known to be alive today was known to be alive in either October or November. So we're very up to date on data collection, which then leaves the third possibility that we're seeing a drug effect which is, of course, what we believe.

We believe that what we're seeing is fewer patients have died, more patients are alive for a longer period of time because tovecimig is affecting overall survival. That's what we believe.

And in the paclitaxel control arm, there is an option for those patients to cross over to receive to tovecimig. Can you talk a little bit about the percentage of patients that have crossed over and have received tovecimig in the trial? So that's the first question.

And the second question is, how are you going to account for those patients that cross over onto tovecimig in your OS analysis?

Okay. So the first part of your question, we know that about half the patients approximately half the patients in the control arm crossed over to receive active drug, which also could be contributing perhaps not to the fewer number of OS events that we're seeing. We are accounting for crossover using a statistical technique called the rank-preserving structural failure time, RPSFT. This is a statistical analysis that adjusts the Kaplan-Meier overall survival curves for crossover. And this statistical technique was actually used in biliary tract cancer in a randomized trial that led to FDA approval in the study called ClarIDHy, C-L-A-R-I-D-H-Y, ClarIDHy which was a study of the IDH1 inhibitor, TIBSOVO versus placebo. That also allowed a crossover in that study a little bit more than half, maybe closer to 2/3 of patients actually crossed over and they use the RPSFT to analyze their overall survival data.

And it is my understanding, by the way, I don't -- I can't -- I don't know if this is true or not. But it is my understanding from talking to folks who are at Agios at the time that the RPSFT was recommended to Agios by the FDA. So that's what I was told. I assume that's true. So with the RPSFT, the adjusted hazard ratio for OS in the ClarIDHy study was 0.49, and that got that drug labeled in second-line BTC. You could not have a more perfect regulatory precedent for us.

And so this is going to be your primary OS analysis, it's going to be the -- on the rank-preserving structural failure time...

Yes.

And so can you talk a little bit about the stats hierarchy after ORR? What's the next endpoint that you're going to look at? Is it PFS? Or is it OS?

PFS. So the stat hierarchy is important because we're using a technique called hierarchical testing to control for alpha spend. So there are a couple of ways to do that, one commonly used way is to "split" the alpha, but hierarchical testing has been shown to control alpha spending better than alpha splitting.

So the way that hierarchical testing works is you do the primary endpoint analysis, if that's positive, which it was with a p-value of 0.031, all of the alpha era then rolls over to the next analysis, which is PFS. If PFS is positive, a full 0.05 alpha rolls over to the OS analysis, then to the DOR analysis.

Got it. And then -- how do you think -- you talked about ClarIDHy and how FDA looked at the rank-preserving structural failure model. Have you had discussions with FDA or other regulatory experts on the acceptance of this model, given the draft guidance on the OS endpoint that was issued by FDA earlier this year?

So in that draft guidance, I think it's fairly clear in that guidance that in indications of tremendous unmet need that crossover is acceptable on to FDA and second-line biliary tract cancer in the United States outside of patients who have tumors with actionable mutations, which unfortunately is a small fraction of the patient population, there is literally no labeled therapy in the United States. So there's -- it's the large -- it's an unimaginable unmet need with no labeled therapy. So in no scenarios, crossover designs are acceptable.

And so the RPSFT was in the protocol from the beginning and our statistical analysis plan was submitted well over a year ago, just after the study was fully enrolled, so way, way ahead of time. And FDA had no comments on that.

Great. And so the study is on track for completion in Q1 in terms of the PFS, OS readout. After that readout, what are the next steps on filing the BLA? Should we expect that to occur, I guess, in the second half of the year?

So I think the next step after the PFS and OS readouts would be to complete the full analysis of every endpoint in the study and then have a meaningful interaction with the FDA. So presumably, that interaction would occur in Q2 and which would put us in a position if that interaction went well to submit a license application in the second half of the year. We have fast track designation, so we would certainly get a priority review, which should put our PDUFA date inside the first half of 2027. So we could be -- today, we could potentially be within call it, 18 months of launching this drug in the United States.

That's great. And what's the market potential in second-line biliary tract cancer in the U.S.?

Sure. So biliary tract cancer is much more common than you might think. So about 25,000 patients annually are diagnosed with biliary tract cancer, and there was a recent JAMA oncology article indicating that the incidence of biliary tract cancer is increasing. It is by -- over the next decade, it's projected to become one of the most common malignancies in the country. So 25,000 patients annually, some of those patients are eligible for surgery, unfortunately, only about 10% of patients get surgery. About half of those patients relapse.

So we did some third-party market research earlier this year that was commissioned by -- we commissioned a well-known firm to do that market research. 70 physician payer interviews and surveys. And based on all of that work, which is a very large project, we believe, about 15,000 patients annually in the United States alone would be eligible for this therapy. So it's about 3x larger than the platinum-resistant ovarian cancer market.

And then if you think about the rest of the world, Japan, which has a smaller population, of course, than the U.S., but the incidence of BTC in Japan is higher. And the total number of patients in Japan is probably close to the total number of patients in the U.S. and the EU, of course, just about twice the size of the United States. So there are probably well over 100,000 patients diagnosed annually just between EU, Japan and U.S. So it's a very, very large market.

And how does the company think about the ex U.S. opportunity? Would you commercialize it yourself? Or would you potentially seek a partner?

So I think in the United States, we're preparing to commercialize this drug ourselves. I think biliary tract cancer is an indication where patients are mostly seen at academic centers. so a small targeted sales and marketing force, I think we can launch this drug ourselves and we are preparing to do so. I will have more to say about that in terms of our commercial infrastructure in the beginning of the coming year.

I think one of our corporate goals for 2026 will be to initiate regulatory interactions in Japan and the EU. Specific question, we have said publicly that we're having some conversations with potential strategic partners about ex U.S. geographies. Of course, we'll do what's in the best interest of our shareholders. So we'll see.

And we've got a few minutes, I do want to touch on 8371. So there are 5 dose cohorts that you value in the dose escalation. In the next phase of the study, I believe you're going to evaluate two of those cohorts. Have you decided which two cohorts, which two doses you're going to evaluate for the next phase of the study?

Yes. Because we've seen this truly, again, in my view, a remarkable efficacy signal in Phase I dose escalation. We now are going to move to cohort expansions. So we're going to enroll patients with non-small cell lung cancer and triple-negative breast cancer into two cohorts of 28 patients each, so a total of 56 patients. Within those 28 patients within each indication will be randomized to one of two doses, 3 mg per kg or 10 mg per kg. So we've decided on the two doses just based on what we've seen early on and enrolling those patients to do some small project [ optimus ] work in terms of dose finding, identify a Phase II dose, confirm the efficacy signal we've seen in dose escalation.

And I think non-small cell lung cancer, of course, is a more complicated indication for sure. But triple-negative breast cancer is not. So post TRODELVY, if we're seeing responses in that patient population, I'm quite confident that, that would be a single arm response rate study to approval. And in the first half of next year, if we confirm the efficacy signal in patients with triple-negative breast cancer, we're going to move directly to a potential approval study next year.

The third indication, and by the way, we enrolled patients with 1 of 5 tumor types into the study. In addition to non-small cell lung cancer and triple-negative breast cancer, we enrolled patients with melanoma, head and neck cancer and Hodgkin's lymphoma. So we've had a third response at the highest dose level in one of those other three indications which we have not yet disclosed waiting for some more data from that patient. But that indication is very, very interesting, and we're now working with some KOLs on potentially going straight to a Phase II study that also, again, in the post ADC, post-PD-1 patient population would be a potential approval study.

So I think 2026 is going to be an incredibly exciting year for 8371 with moving to two potential approval trials with that drug next year. So that's a drug we're incredibly excited about. And I think if we have discovered the first next-generation checkpoint inhibitor, we'll be off to the races.

That's great. I mean so a lot of exciting updates over the next 12 months. But you also have a third program that you're potentially moving into the clinic with the PD-1 VEGF. And I think the IND is expected to be filed soon. How does that fit in given the excitement of the first two programs? Do you plan to carry that on yourselves? Or would you potentially partner it at some point?

Sure. So our fourth program, as you mentioned, a drug we call 10726, a PD-1 VEGF bispecific antibody. This is now a new class of drug. Many companies are now working on this class of drugs, and we have a very novel drug candidate, and we presented some data last month at SITC, suggesting that in certain preclinical models, our drug is superior to ivonescimab. So you're correct, IND filing followed by Phase I initiation in the first half of next year. Our Phase I population, we've defined as patients with hepatocellular cancer, gastric cancer, renal cell cancer and endometrial cell cancer, four different indications where both PD-1 blockade and VEGF blockade are effective. So our plan is to initiate that Phase I study and get clinical data next year. But we have stated publicly that there's tremendous interest not only in this field, but in this asset. And again, what we do with this drug moving forward, we'll do what's best for our shareholders.

Perfect. I think we're about out of time. Really appreciate you coming to Piper Sandler Healthcare conference and sharing insights on the story.

Thanks, Biren, and thanks so much for having us.