Curis, Inc. Aktie

Good morning, and welcome to Curis' Emavusertib Update Call. [Operator Instructions] Please note this event is being recorded. And I would now like to turn the conference over to Diantha Duvall, Curis' Chief Financial Officer. Diantha, please go ahead.

Thank you, and welcome to Curis' Emavusertib Update Call. Before we begin, I would like to encourage everyone to go to the Investors section of our website at www.curis.com to find the Curis announces positive emavusertib update press release. I would also like to remind everyone that during our call, we will be making forward-looking statements, which are based on our current expectations and beliefs.

These statements are subject to certain risks and uncertainties, and actual results may differ materially. For additional details, please see our SEC filings. Joining me on today's call are Jim Dentzer, President and Chief Executive Officer; Dr. Ahmed Hamdy, Chief Medical Officer; and Dr. Jonathan Zung, Chief Development Officer. We will also be available for a question-and-answer period at the end of the call. I'd now like to turn the call over to Jim.

Thank you, Diantha. Good morning, everyone, and welcome to Curis' Emavusertib Update Call. We're excited to report updated data from the TakeAim lymphoma study in primary CNS lymphoma, one of the most rare and most difficult to treat of the NHL subtypes. As a reminder, the TakeAim lymphoma study is a 3-part study of emavusertib in combination with ibrutinib in patients with relapsed/refractory PCNSL. Part A, the dose escalation part of the study is complete. Part B is the single-arm study in BTKi-experienced patients and Part C is the randomized study in BTKi-naive patients.

As you may recall, we reported data for patients treated in Parts A and B of the study last year with a May 1, 2025 data cutoff. At that time, we reported a 71% overall response rate in BTKi-naive patients with 5 of 7 patients achieving a response. We're pleased to report that as of the July 1, 2026 data cutoff, the ORR is now 86% with 6 of 7 BTKi-naive patients achieving a response. When we focus on evaluable patients, those patients who were able to complete at least 1 cycle of treatment, the response rate increases to 100% or 5 of 5 BTKi-naive patients.

For context, it is important to note that published studies of BTK inhibitors in PCNSL have generally shown response rates of 40% to 70%. Clearly, the combination of emavusertib plus a BTK inhibitor appears to be better than BTKi alone. For BTK-experienced patients, those patients whose disease has progressed while taking a BTK inhibitor, the results look arguably even more impressive. Last May, we reported a 27% response rate with 7 of 26 patients responding.

A year later, we have increased the patient data set by 50%. We now have 39 patients, and the response rate has remained consistent with a 26% ORR and 10 of 39 patients responding. When we focus on evaluable patients, again, those patients who were able to complete at least 1 cycle of treatment, the response rate increases to 33% or 10 of 30 BTKi-experienced patients. For context on this population, patients who have failed both frontline therapy and BTKi have a very poor prognosis with many patients proceeding directly to hospice or best supportive care.

That emavusertib is helping patients change that story and reverse their disease is very encouraging. In short, the updated data in both BTKi-naive and BTKi-experienced patients continue to show strong activity and continue to support the potential for accelerated approval submissions in both the U.S. and Europe. As the study continues to advance with strong support from clinical investigators and key opinion leaders in the PCNSL community, we look forward to completing full enrollment in the registrational data set on schedule in 2027.

Now let's turn to CLL. As you recall, last year, we engaged with a number of KOLs who are excited about expanding our emavusertib studies into additional NHL subtypes. They were especially interested in exploring emavusertib's potential to fundamentally change the treatment paradigm for CLL patients, where the current standard of care is BTK inhibitors. Over the last decade, BTK inhibitors have become standard of care in CLL and NHL because of their ability to block the BCR pathway and help patients achieve objective responses.

However, these responses are typically partial responses, not complete remission. The result is that patients treated with a BTK inhibitor end up having to stay on it in chronic treatment for the rest of their lives. Additionally, because they never achieve complete remission, many of these patients develop BTKi-resistant mutations and ultimately, their disease progresses. We are looking to improve upon the current standard of care by adding emavusertib to a patient's BTKi regimen, applying a dual blockade to the 2 biologic pathways driving CLL.

This dual blockade with BTKi blocking the BCR pathway and emavusertib blocking the TLR pathway and enable patients whose NHL subtype partially responds to a BTK inhibitor to achieve deeper responses with the combination, including the ability to achieve complete remission or undetectable disease and the potential for time-limited treatment. If we are successful, adding emavusertib to BTKi could change the treatment paradigm in CLL, reducing the risk of developing a treatment-resistant mutation and improving a patient's overall quality of life.

The first step in testing this hypothesis in CLL is our proof-of-concept study in patients currently on BTKi monotherapy who have achieved partial remission but have been unable to achieve complete remission or undetectable MRD. Enrollment in the CLL study continues to gain momentum. Just a few weeks ago, we announced that we had 11 clinical sites activated and that we had consented our first 6 patients. Since then, we have consented 4 more patients, bringing the total to 10 patients consented.

With that strong momentum, we are pleased to reiterate our guidance that we expect to dose the first 5 patients by the end of this month, and we are raising our guidance for clinical data from 5 patients to 5 to 10 patients by year-end. It's been a terrific year so far with updated PCNSL data, reinforcing the regulatory strategy for our first NHL submission and demand for CLL enrollment exceeding our expectations, reflecting both the clear unmet need in CLL and the support from the clinical community that emavusertib has the potential to address that need.

We look forward to providing additional updates as the year progresses. With that, I'd like to open the call for questions. Operator?

[Operator Instructions] And your first question comes from the line of Kripa Devarakonda from Truist.

Congratulations on the progress. I was wondering if you can remind me what the specific number of BTKi-experienced patients required for the registrational data set is? And is there a floor ORR the FDA expects to see for this patient population? And I know you didn't -- I don't think you mentioned it, but just was wondering if there is -- if you have any sense of median duration of response for these responders that you talked about today?

Yes. Thank you, Kripa. I appreciate the questions, and thank you for joining. So just as a reminder, when we went back and had our discussions with FDA, one of the reasons we selected PCNSL in this salvage-line setting is because the alternatives are so grim. So patients post BTK, once they failed not just chemo and methotrexate in frontline, but then they've gone on a BTK inhibitor and their disease has progressed after that, they have no options.

There's nothing approved. There is no consistent guideline. And many of those patients are frankly too frail to even take another round of chemo. So oftentimes, these patients end up going to best supportive care or hospice. So the ORR in that population is really zero. Nobody publishes results for that population because nothing works. When we had the discussions with the regulatory authorities, what we said is, look, we all understand that the real-world response rate is zero.

Let's just suggest a statistical lower bound of 10%. And if we can get more than 10% responses statistically p-value less than 0.05, would that be sufficient? And then the answer from both the EMA and FDA says, yes, there's nothing for these patients. If you can show that you can exceed that lower bound, that would work. So now we had a discussion about the stats. And if we see a response rate of 20% or higher, in order to achieve a p-value of 0.05, we would need somewhere in the range of 45 to 60 patients.

So then the question to EMA and FDA was, would that size of data set be sufficient, knowing that we need to address safety as well as efficacy. And our conversations were very successful. Both agencies thought that was reasonable. And so that's where we're headed. And that's why we expect to have that data set fully enrolled by next year. And then the follow-on question that you asked about duration was, well, what sort of duration do we expect to see? Well, in this population, as I said, nothing works.

So any duration would be terrific. The largest study ever done in this population was the iLOC study by Carole Soussain in Paris. And that study, as a reminder, showed the progression-free survival in BTKi patients is 2 months. So we've shown so far that we can get to 4 to 6 months. In fact, some of our patients have been on drug now for over 2 years, approaching 3 years. I suspect we're going to have a very strong story to tell, assuming that the data hold between now and full enrollment. Our response rate and our duration are better than we were expecting. So thank you for those questions.

And your next question comes from the line of Yale Jen from Laidlaw & Company.

Congrats on the great data. My first question is that given for the PCNSL that the both patient -- BTK naive and BTK experienced patients show very compelling data, would you also consider filing for the first line as well as for second line? And what might be the additional work needed for potentially achieve both -- sort of both paths? And then I have a follow-up.

Yes. So thank you, Yale, first and foremost, for the questions and also for dialing in today. We appreciate it. Yes, I mean you raised a very exciting prospect. So we are looking at an oral-oral combination of patients that in the evaluable population has a response rate of 100%. And those are patients that are second line. They've already been through chemo and methotrexate, right?

Chemo and methotrexate is frontline therapy. But the published reports for chemo and methotrexate are that the response rate is 80%. We're looking at a response rate in second line with an oral-oral, so a far easier regimen to tolerate than frontline with chemo and methotrexate. Now I'm not prepared to suggest that with our small data set, we only have 5 evaluable patients, 7 ITT, right? It's a very small data set.

I don't know that I want to take that next step and say that we think we can leapfrog into frontline therapy in these patients. I think that's premature. But I would say we feel very confident that the drug is active. It's clearly adding efficacy to a BTKi regimen. And we think that the prospects for gaining our first label, first in the salvage line and then with full approval in combination with BTKi.

Our overall thesis is, there's a $12 billion market for patients with NHL who take a BTK inhibitor. Our view would be we are going to go into all 5 of those indications, PCNSL first, but then CLL, Waldenstrom's, mantle cell, marginal zone, wherever a patient takes a BTKi inhibitor today, those patients tomorrow if these data hold suggest they should be taking BTKi plus ema. And that's a really exciting place for us to be. Thank you that...

Okay. Great. And maybe just a follow-up. With this data at this moment, would you thinking of schedule a meeting with the FDA or you will wait until, for example, end of the year to have this data -- to have a meeting with FDA, maybe even accelerate the process further instead of waiting for the completion of the enrollment in next year for the salvage line. And at the time also in terms of the BTK naive, if you have more data there, again, the same question, whether you will have a conversation with the agency to discuss all the possibilities.

Thank you again, great question. So on the regulatory strategy, I'd say we've got a really good dialogue going with FDA. They greatly appreciate. And we should remind everyone, when we went to the FDA, we brought with us 2 key opinion leaders, right? The Head of Primary CNS lymphoma for Sloan Kettering and the Deputy Chair of Lymphoma for Mayo Clinic in Rochester, and the support from the community and then the support that we gained from FDA and the EMA was really encouraging.

At this point, the dialogue is terrific. They're glad that companies like Curis are pioneering novel molecules in areas of clear unmet need where patients really do need access to a therapy that can extend the quality of their life. And so far, the data seem to support that enthusiasm. I'd say right now, we plan as the data come in to reach out to the FDA and EMA where appropriate to take advantage of any opportunity we can for accelerated treatment or favorable regulatory action that could be beneficial to getting this drug to patients as fast as possible.

So as I said, right now, we are continuing to look at a drug that is performing really well in this first indication. And the second one, CLL, the much larger indication, the enthusiasm from the community is really exciting for us. And I look forward to both better data as we move forward in CLL as well as PCNSL, but also an ongoing discussion with regulatory authorities. So I'd say stay tuned.

And your next question comes from the line of Sara Nik from H.C. Wainwright.

Congrats on the progress. Happy to hear it. And I just had one question regarding the PCNSL. If I heard correctly, the BTKi-naive cohort, enrollment has been, I think, still at 7 patients since the May '25 cut. I just wanted to understand if Part C is still actively enrolling. And if it's not, maybe some -- if you can provide some color on any potential impediment? Is it just the competing frontline options, site prioritization or something else?

Yes. No. So thank you, Sara. So again, just as a reminder, we started enrolling in the early days in Part A, which was dose escalation. We enrolled patients as low as 40 -- 50 milligrams all the way up to 400 milligrams. And we did it in multiple indications, and we did monotherapy, we did combo. We did naive patients. We did experienced patients. So in those early days, we dosed several naive patients in PCNSL.

And it's those patients that we continue to follow. And in fact, one of those patients who wasn't a responder last year in May has now become a responder. And in fact, we have another CR in that population, which is very encouraging. The next step strategically for us is to gain our approval. So once we had our dose and we're following those patients, we moved into relapsed/refractory patients in the experienced setting because those are the patients that are going to support what we hope is an accelerated approval.

We know that once you get accelerated approval, you have to follow on with full approval, and that has to be a randomized study. It will be a BTK in one arm, BTK plus ema in another arm. And we're going to need to be able to show as part of our submission that we've got a contribution of components that, in fact, what appears to be true now, it continues to hold that emavusertib plus BTKi is better than BTKi alone.

So we've made really good progress on our approval data set. I expect the full approval data set is one that's typically with most companies that comes several years later. So yes, we are getting started in that study, and we're beginning to enroll patients. We need to have that study ongoing by the time we file for our BTKi-experienced label, and we will. And as those data mature, we look forward to obviously reporting out on those as well. But the lead and clearly, the emphasis is on the registrational data set, which is the BTKi-experienced patients. I hope that's helpful.

And your next question comes from the line of Boris Peaker from JonesTrading.

I'd like to add my congratulations on the progress. Maybe my first question on PCNSL. If we look at BTKi resistance, at least from what I could find on PCNSL, it's either typically with BTK C481S mutation or just a bypass of activation of MYD88 TLR pathway altogether, which obviously what IRAK4 targets. I'm just curious if you've sequenced the baseline tissue or liquid biopsy of these BTKi-experienced patients to get a better understanding what their actual mutation was and how your drug kind of fits in within that mechanistic pathway.

Sure. Thank you, Boris. I appreciate the question, and thanks for joining. I'm actually going to ask Ahmed Hamdy to chime in on that. Ahmed, if you wouldn't mind.

So Cys481 mutation will happen in the subpopulation of patients who are currently on a BTK, yet some part of the population is responding. On the other hand, our emavusertib works on the TLR, IRAK4 pathway. So adding ema to BTK in that population, although may help in some of the patients or the population that has the Cys481 but it should augment the BTK inhibition. So the dual inhibition of the TLR and the BCR should inhibit NF kappa B which is the driver of the disease regardless of the presence of a subpopulation that is mutated.

Yes. And let me answer that as well, Boris. So again, I'm going to take you back to the mechanism of the drug. So on our website in our corporate deck, I think we elucidated this, I hope, fairly clearly. The problem of disease for patients with non-Hodgkin's lymphoma, for B-cell lymphoma, is NF kappa B is in overdrive. What's driving NF kappa B is the BCR pathway and the TLR pathway separately. BTK inhibitors are blocking the BCR pathway. We block the TLR blocking both pathways off to allow better downregulation of NF kappa B and better control of this dysregulated process that governs survival and proliferation of cells of the malignant cells.

Cys481 is going to prevent covalent BTK inhibitors from binding at the binding pocket. And that's clearly going to impact the ability to knock down the BCR pathway. By blocking the TLR pathway, again, we're in a completely independent pathway, we should be able to help those patients. For patients with MYD88 mutation, MYD88 mutation typically, as you know, the myddosome complex where MYD88 lives is in the toll-like receptor pathway.

When patients have a MYD88 mutation and the majority of PCNSL patients do, for example, that's going to cause constitutive activation of the toll-like receptor signaling, which all things being equal, will cause extra overactivity, if that's the right way to think about it of NF kappa B. So whether it's a Cys481 mutation or a MYD88 mutation, knocking down toll-like receptor activity ought to be helpful, and that's exactly what emavusertib does. So I think you're right, those are 2 key mutations that we would look for.

As you know, there are a lot -- there are probably 15 to 20 different mutations depending upon the patient and the type of B-cell lymphoma that matter. And we expect to gain more information on that, especially as we add different NHL subtypes into our studies. But at this point in time, I think it's very clear based on the PCNSL data that we've seen to date, based on the mechanism, preclinical data and enthusiasm in CLL, emavusertib in knocking down TLR signaling seems to be making a difference. That was a really long explanation. I hope that's helpful.

No, absolutely. That was very helpful. I guess I just had a quick follow-up question. Just in the PR definition of PCNSL, I know you look at brain MRI, eye examination, CSF cytology. Is there any way to kind of report how close these patients were to kind of the threshold of PR? Or were they far away from the threshold so if the FDA reanalyzes to be confident that they'll come back with a PR as well versus a patient maybe right on the threshold could be reclassified potentially as progressive disease.

Yes. So this is one of the reasons why we went for primary CNS lymphoma because it is such an aggressive lymphoma. It's part of the DLBCL disease space, right? DLBCL that's in the brain. So in these patients, 80% of them are going to come under control with chemo and methotrexate. Once they fail, they're going to go on a BTK inhibitor. Some lower percentage, 40%, 70%, depending upon the study you look at, can gain a response. Once they fail BTK inhibitors, they unfortunately progress very quickly.

Those are the patients that are coming into our study. So it's not that they're close to PR and they're stable. They're, in fact, progressing. Their brain tumors are physically growing. And if they do nothing, which is unfortunately what happens to many of these patients, their prognosis is very grim. So there isn't an expectation that some sort of magic will happen. And had they stayed on a BTK inhibitor while their tumors are growing that it would magically start not just stabilizing, but reduce.

That's why it was so powerful. It's why the FDA and EMA were so supportive of us. That we've got a data set that shows clearly when patients who are on a BTK inhibitor have started to progress and their brain tumors are no longer impacted by that BTK and their brain tumors are physically growing, we can do more than stabilize them.

We reverse them. That's really unusual. There are no other published data sets I'm aware of in PCNSL where that's ever happened. I think that's why FDA and EMA were excited. It's certainly why we're excited. And I'm hopeful that with our full registrational data set next year, we have the ability to see this have an impact in patients much more broadly as we commercialize. I hope that's helpful.

And this concludes our question-and-answer session. I would now like to turn the conference back over to the company's President and CEO, James Dentzer, for any closing remarks.

Thank you, operator, and thank you, everyone, for joining today's call. And as always, thank you to the patients and families participating in our clinical trials, to our team at Curis for their hard work and commitment and to our partners at Aurigene and the investigators and academic community for their ongoing collaboration and support. We look forward to updating you again soon. Operator?

The conference has now concluded. Thank you again for your participation. You may now disconnect.

Good afternoon, ladies and gentlemen, and welcome to the Curis First Quarter 2026 Business Update Conference Call. [Operator Instructions] This call is being recorded on Tuesday, May 12, 2026.

I would now like to turn the conference over to Diantha Duvall, Chief Financial Officer. Please go ahead.

Thank you, and welcome to the Curis First Quarter 2026 Business Update Call. Before we begin, I'd like to encourage everyone to go to the Investors section of our website at www.curis.com to find our first quarter 2026 business update press release and related financial tables. I would also like to remind everyone that during the call, we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. For additional details, please see our SEC filings.

Joining me today on today's call are Jim Dentzer, President and Chief Executive Officer; Dr. Jonathan Zung, Chief Development Officer; and Dr. Ahmed Hamdy, Chief Medical Officer. We will also be available for a question-and-answer period at the end of the call.

I'd now like to turn the call over to Jim.

Thank you, Diantha. Good afternoon, everyone, and welcome to our first quarter business update call. We continue to make steady progress in our TakeAim Lymphoma study in primary CNS lymphoma, one of the most rare and most difficult to treat of the NHL subtypes. As a reminder, the TakeAim Lymphoma study is a single-arm registrational study with an ORR endpoint that is evaluating emavusertib in combination with ibrutinib after a patient has progressed on BTKi therapy. And after collaborative discussions with both FDA and EMA, we expect the study to support accelerated submissions in both the U.S. and Europe.

We anticipate providing updated emavusertib clinical data from the TakeAim Lymphoma combination study with ibrutinib in patients with relapsed/refractory PCNSL in the first half of 2027. We continue to make good progress on enrollment on this registrational study and appreciate the ongoing support of our clinical investigators, key opinion leaders and regulatory authorities.

As you recall, last year, we engaged with a number of key opinion leaders who were excited and highly supportive about expanding our emavusertib studies into additional NHL subtypes. They were especially interested in exploring emavusertib's potential to fundamentally change the treatment paradigm for CLL patients, where the current standard of care is BTK inhibitors. Over the last decade, BTK inhibitors have become standard of care in CLL and NHL because of their ability to help patients achieve objective responses.

However, these responses are typically partial responses, not complete remission. The result is that patients treated with a BTK inhibitor end up having to stay on it in chronic treatment for the rest of their lives. Additionally, because they never achieve complete remission, many of these patients develop BTKI resistant mutations and ultimately, their disease progresses. We're looking to improve upon the current standard of care by adding emavusertib to a patient's BTKi regimen, applying a dual blockade to the 2 biologic pathways driving CLL. This dual blockade can enable patients whose NHL subtype partially responds to a BTK inhibitor to achieve deeper responses with the combination, including the ability to achieve complete remission or undetectable disease and the potential for time-limited treatment.

If we are successful, adding emavusertib to BTKi could change the treatment paradigm in CLL, reducing the risk of developing a treatment-resistant mutation and improving a patient's overall quality of life. The first step in testing this hypothesis in CLL is our proof-of-concept study in patients currently on BTKi monotherapy, who have achieved partial remission but have been unable to achieve complete remission or undetectable MRD. We anticipate the dosing of the initial 5 patients in the TakeAim CLL combination study with zanubrutinib by mid-2026, and we expect to have initial data in December.

In January, one of our collaborators, Dr. Patrick Grierson of the Siteman Cancer Center at Washington University in St. Louis, presented a poster with initial clinical data in gastric and esophageal cancer at the ASCO GI Cancer Symposium. In this study, patients are treated with emavusertib in combination with FOLFOX and anti-PD-1 plus or minus Herceptin as first-line therapy for metastatic or unresectable gastroesophageal cancers. The initial data showed results for 16 evaluable patients, demonstrating both a manageable toxicity profile and encouraging preliminary results.

As you can see, we had a very productive quarter and look forward to an exciting 2026 as we advance our registrational study in PCNSL and our proof-of-concept study in CLL. With that, I'll turn the call back over to Diantha for the financial update. Diantha?

Thank you, Jim. Curis reported a net loss of $24.2 million or $1.25 per share for the first quarter of 2026 as compared to a net loss of $10.6 million or $1.25 per share for the same period in 2025. The increase in net loss was primarily due to a change in fair value of warrant liabilities associated with the January 2026 PIPE financing. Research and development expenses were $6.4 million for the first quarter of 2026 as compared to $8.5 million for the same period in 2025. The decrease was primarily attributable to lower employee-related and manufacturing costs.

General and administrative expenses were $5.1 million for the first quarter of 2026 as compared to $4.0 million for the same period in 2025. The increase was primarily attributable to expenses associated with the January 2026 PIPE financing, partially offset by lower employee-related costs. Curis' cash and cash equivalents as of March 31, 2026, of $15 million, together with anticipated gross proceeds of up to an additional $20.2 million from the exercise of the January 2026 PIPE financing Series B warrants upon the public announcement of dosing of the fifth CLL patient in our TakeAim CLL study expected later this year should enable the company's planned operations into the second half of '27.

With that, I'd like to open the call for questions. Operator?

[Operator Instructions] Your first question comes from Sara Nik with H.C. Wainwright.

Regarding the CLL study, you guided to announcing dosing of the first 5 patients by midyear. I was wondering if you could provide as of today, how many patients have been dosed so far? And maybe any color on the current pace of site activation and enrollment?

Sure. Thank you, Sara. I appreciate the question, and thanks for calling in. So we're trying and getting out of the realm as it is 5 is already a pretty small number. We're going to try and get out of the patient-by-patient update. But as I would say, we're obviously very, very confident that we are hitting our target on track and the process of both getting our sites up and running and our patients consented into the study is on track, and we look forward to providing an update mid-summer.

Your next question comes from Yale Jen with Laidlaw & Co.

In terms of PCNSL, you mentioned you're going to have an update in the first half of '27. I wonder that will related to the data or simply just the enrollment status or any other color?

Sure. Again, thanks for calling in and appreciate the question. So on PCNSL, yes, I mean, you're exactly right. What we have said is we expect that we're going to be in a position or at least we're hoping to be in a position where we could be fully enrolled in that study in 2027. So our expectation would be we could have a substantial update on enrollment in the first half of 2027.

Right now, of course, we're a long way from that. We'll continue to provide updates as we know more going through the year. But right now, I'd say we're cautiously optimistic. We are on track, and we look forward to having that discussion at that time.

Maybe just to follow up on that. In terms of the current sort of enrollment situations, I know it's very lumpy. But overall, are they within your expectation or either better or worse, at least at this moment?

No, it's on track. You're exactly right. This is one of the issues, of course, when you're developing a drug in an ultra-orphan space, there are just frankly not a lot of those patients around. So we will go, as we have in the past, some months where we don't have any patients, then some months where we get 2 or 3 on any given month, your description is lumpy is spot on. But as we take a step back and we say not on any given month, but are we on track to hit our enrollment targets for -- in time for a disclosure in the first half of 2027. And I'd say, yes, we continue to see the same kind of performance over time that we have been. Excitement continues to be very strong. And as I say, we look forward to providing that update with the full data set in 2027. So -- but stay tuned. We'll provide updated guidance as we go along through the year. Great question.

And again, congrats on the progress.

The next question comes from Kripa Devarakonda with Truist.

This is Anna on for Kripa. Just two questions on CLL. I think you mentioned you're evaluating 2 doses kind of to satisfy the Project Optimus. And I know it's a small sample size, but are there any expectations for any meaningful differences in the safety profile when you're kind of adding emavusertib to these combinations? And in terms of the CLL standard of care, I was just wondering how -- if you could remind us kind of how you're differentiating there?

Yes. So let me talk to the first part, and then I'll ask Ahmed to chime in on CLL. So the first question is, yes, as part of the discussions that we had with FDA and EMA, they were very clear that we need to make sure to include data on 100 and 200 in our submissions, which, of course, we will do. I don't anticipate that there is a whole lot of there's a whole lot of question about safety between 100 and 200. I think as you may remember, we have dosed emavusertib as high as 500 milligrams.

So I think the safety profile should be manageable at both. It's really a question of we know that the dose is active at both 100 and 200. And we just need to satisfy ourselves that 200 is the best dose as a starting dose for patients and that they have the ability to dose up or down from a safety perspective as needed. Maybe diving into CLL in particular, I'll ask Dr. Hamdy to comment.

Sure. thanks for the question. I think CLL, although BTKs and BCL-2s have done quite a difference for patients, yet the problem is patients have to continue dosing chronically for extended periods of time, leading to potential resistance and mutations, along with toxicities like cardiovascular and bleeding and bone marrow suppression, which is really one of the hardest things for CLL patients. The treatment goal or the unmet medical need currently in CLL is getting patients to a treatment-free remission period. And when we look at the current state of affairs in CLL, most patients do not achieve a CR or MRD negative, allowing them to stop treatment in a monotherapy setting.

And basically, BTKs work by inhibiting the BCR signaling pathway, which would also inhibit the NF-kappaB, which is the driver of the disease. But because those patients are not getting to a CR or MRD negative, there's quite a bit of preclinical work that has been done by renowned key opinion leaders stating that there is a constituent activation of the NF-kappaB through the TLR pathway, which emavusertib inhibits. The concept of combining emavusertib with a BTK inhibitor can potentially lead to a more profound inhibition of the NF-kappaB and therefore, hopefully, we can see more CRs than the monotherapy or with BTK alone. So we think the combo can really make a difference for those patients.

On the other hand, as you know, the space has also been trying to combine BTKs with BCL-2s and anti-CD20s, although some of these combinations have a higher CR rate and MRD rate. yet it comes with a high toxicity profile, specifically on the bone marrow with infections and so forth. So I hope we are quite differentiated from what we see right now. And as you've seen with our programs, we've combined with ibrutinib in a lot of patients, and we have not seen any additive toxicities or bone marrow suppression. So we feel that this can really be a paradigm shift in the treatment of CLL in a combination setting when we inhibit 2 nodes in the main pathway that is activating the disease. I hope that helps.

[Operator Instructions] we have a question from Boris Peaker with Jones.

This is Danya for Boris. My first question is about a follow-up for the CLL trial. What specific signs of activity are you looking for in the initial patients to validate this dual blockade you've been discussing?

Yes. Again, I think that's probably a best question for Dr. Hamdy. Ahmed, if you want...

I'm sorry, I didn't hear clearly the last part of the question, if you mind repeating it?

Sure. Just what initial or specific signs of activity are you looking for in the initial patients that you'll be enrolling?

Well, currently we're combining with zanubrutinib in patients who are currently in a PR or a PRL, which is basically all zanu patients. And the idea is to see deepening of responses where we can see patients inching towards a CR and getting to an undetectable MRD status where we can get patients to a treatment-free remission by stopping those drugs.

Yes. And let me add to that as well. So in these early days, so I'll differentiate a little bit the goal where Ahmed was headed from the early days. So just as a reminder, a patient coming into the study, as Dr. Hamdy said, is currently on zanu and they're in partial remission, meaning their CLL counts, right? They've dropped 50% or more and then they've plateaued. So they can get their cancer level down by 50%, but no lower than that or wherever they've plateaued.

At that point, we enroll them in the study and add a second pill, we add ema. So what we really want to see, frankly, is that we can take them from plateauing to decreasing their disease burden. And at that point, from a patient's perspective, of course, any decrease is good. But we want to see the disease trending down.

Now from a regulatory perspective, our goal, of course, we expect to see patients with significant reductions, and we're hoping to see patients that are able to do what they can't do on monotherapy, meaning get all the way down to complete remission or MRD and maybe even time-limited treatment. But in these early days, what we're really hoping to see is a patient comes in having plateaued on zanu and if they add a second pill, if they add emavusertib, we can see them reduce their cancer burden. That's what we're hoping. Does that make sense?

Yes. And just the last question. Are you speaking of commercial partnership for the AML program?

No, not yet. I would say at this point in time, we have addressed the financing of the company with the January financing, and we appreciate that, that gave us the ability to not just continue executing against PCNSL, but add the PCNSL program. And right now, we're focused on generating data in those indications. And of course, what we'd love to be able to do with additional resources is add AML into that same mix and take the next step because the next step in AML would be a registrational study.

At some point in time, could a partnership make sense? Absolutely, we have discussions just as every biotech company does. But right now, our goal is to use the resources from the financing that we've gained to continue to push forward both on the registrational study and on the new study in CLL and hopefully be able to continue the success with data that we've seen so far.

There are no further questions at this time. I will now turn the call over to Jim Dentzer for closing remarks. Please continue.

Thank you, operator, and thank you, everyone, for joining today's call. And as always, thank you to the patients and families participating in our clinical trials, to our team at Curis for their hard work and commitment and to our partners at Aurigene, the NCI and the academic community for their ongoing collaboration and support. We look forward to updating you again soon. Operator?

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon, ladies and gentlemen, and welcome to the Curis Fourth Quarter 2025 Business Update Conference Call. [Operator Instructions] This call is being recorded today, Thursday, March 19, 2026.

I would now like to turn the conference over to Diantha Duvall, Curis' Chief Financial Officer. Please go ahead.

Thank you, and welcome to Curis' Fourth Quarter 2025 Business Update Call. Before we begin, I'd like to encourage everyone to go to the Investors section of our website at www.curis.com to find our fourth quarter 2025 business update press release and related financial tables.

I would also like to remind everyone that during the call, we will be making forward-looking statements which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. For additional details, please see our SEC filings.

Joining me today on today's call are Jim Dentzer, President and Chief Executive Officer; Dr. Jonathan Zung, Chief Development Officer; and Dr. Ahmed Hamdy, Chief Medical Officer. We will also be available for a question-and-answer period at the end of the call.

I'd like to now turn it over to Jim.

Thank you, Diantha. Good afternoon, everyone, and welcome to Curis' Fourth Quarter Business Update Call. We continue to make steady progress in our TakeAim Lymphoma study in primary CNS lymphoma, one of the most rare and most difficult to treat of the NHL subtypes. As a reminder, the TakeAim Lymphoma study is a single-arm registrational study with an ORR endpoint that is evaluating emavusertib in combination with ibrutinib after a patient has progressed on BTKi therapy. And after collaborative discussions with the FDA and EMA, we expect this study to support accelerated submissions in both the U.S. and Europe. We continue to make good progress on enrollment in this registrational study and appreciate the ongoing support of our clinical investigators, key opinion leaders and regulatory authorities.

As you recall, last quarter, we engaged with a number of KOLs who are excited and highly supportive about expanding our emavusertib studies into additional NHL subtypes. They were especially interested in exploring emavusertib's potential to fundamentally change the treatment paradigm for CLL patients, where the current standard of care is BTKi. Over the last decade, BTK inhibitors have become the standard of care in CLL and NHL because of their ability to help patients achieve objective responses. However, these responses are typically partial responses, not complete remission. The result is that patients treated with a BTK inhibitor end up having to stay on it, in chronic treatment for the rest of their lives. Additionally, because they never achieved complete remission, many of these patients develop BTKi-resistant mutations, and ultimately, their disease progresses.

We are looking to improve upon the current standard of care by adding emavusertib to a patient's BTKi regimen, applying a dual blockade to the 2 biologic pathways driving CLL. This dual blockade can enable patients whose NHL subtype partially responds to a BTK inhibitor to achieve deeper responses with the combination, including the ability to achieve complete remission or undetectable disease and the potential for time-limited treatment. If we are successful, adding emavusertib to BTKi could change the treatment paradigm in CLL, reducing the risk of developing a treatment-resistant mutation and improving a patient's overall quality of life.

The first step in testing this hypothesis in CLL is our proof-of-concept study in patients currently on BTKi monotherapy who have achieved partial remission, but have been unable to achieve complete remission or undetectable MRD. We have begun activating clinical sites in the U.S. and Europe and expect to have initial data at the ASH Annual Meeting in December.

With that, let's turn to AML. At the ASH meeting in December, we presented data for our ongoing AML triplet study, which is evaluating the triple combination of emavusertib with azacitidine and venetoclax in AML patients who have achieved complete remission on aza-ven but remain MRD-positive. These data were for the first 2 cohorts, where patients received emavusertib for either 7 or 14 days in a 28-day cycle, in addition to their azacitidine and venetoclax treatment. In this study, 5 of 8 evaluable patients were able to achieve MRD conversion. That is, they were able to convert from MRD-positive to undetectable disease. We're very encouraged by these initial data and the exciting potential of combining emavusertib with azacitidine and venetoclax.

As you can see, we had a very productive quarter. And then we look forward, of course, to a very exciting 2026 as we're advancing our registrational study in PCNSL and initiating our proof-of-concept study in CLL.

With that, I'll turn the call over to Diantha for the financial update.

Thank you, Jim. Curis reported net income of $19.4 million or $1.23 per share for the fourth quarter of 2025 as compared to a net loss of $9.6 million or $1.25 per share for the same period in 2024. The net income in the fourth quarter of 2025 is due to a $27.2 million onetime noncash gain attributable to our sale of Erivedge to Oberland.

Curis reported a net loss of $7.6 million or $0.58 per share for the year ended December 31, 2025, as compared to a net loss of $43.4 million or $6.88 per share for the same period in 2024. Research and development expenses were $5.8 million for the fourth quarter of '25 as compared to $9 million for the same period in '24. The decrease was primarily attributable to lower manufacturing, employee-related and clinical costs. Research and development expenses were $28.3 million for the year ended December 31, 2025 as compared to $38.6 million for the same period in 2024.

General and administrative expenses were $2.9 million for the fourth quarter of '25 as compared to $3.4 million for the same period in 2024. The decrease was primarily attributable to lower employee-related costs. General and administrative expenses were $14 million for the year ended December 31, 2025 as compared to $16.8 million for the same period in 2024.

Curis' cash and cash equivalents as of December 31, 2025, together with initial gross proceeds of $20.2 million received in January 2026 and expected gross proceeds of an additional -- of up to an additional $20.2 million from the exercise of the January 2026 PIPE financing Series B warrants upon the public announcement of dosing of the fifth CLL patient in our TakeAim CLL study expected later this year, should enable our planned operations into the second half of 2027.

With that, I'd like to open up the call for questions. Operator?

[Operator Instructions] Our first question comes from the line of Kripa Devarakonda from Truist Securities.

Just one quick question in terms of how you guys are thinking about prioritizing kind of the trial progress between the pivotal PCNSL versus CLL and AML?

Sure. Thanks for the question, and thanks for calling in. So as you can imagine, we're very thoughtful about how we're prioritizing our resources. Thankfully, the January financing puts us on a very solid course, but we're still prioritizing our resources to be as efficient as we can in our spend.

So with that said, we are definitely prioritizing NHL ahead of AML. Right now, of course, we've got a dual-pronged strategy where we're pushing forward very aggressively in PCNSL. That's one of the smallest and most rare of the subtypes of NHL. As well as CLL, which is inarguably the largest. PCNSL, of course, is going to be for registrational approval, and we're moving ahead, really right on track on that one.

With CLL, we just started that study. So in terms of spend, I'd say the bulk of our spend is going towards PCNSL. And in these early days, CLL is, of course, much smaller. But I imagine that over time, that will get larger. My hope is that by the time we get to the end of the year, we will have made significant progress towards a registrational data set in PCNSL and hopefully have some initial data, our first view at CLL. So those two are clearly our first priorities.

As we are able to raise more cash and we can get more work started, I think that's when we start to look at AML. But right now, I think the bulk of the work in AML is more analyzing what steps we want to take as we have more resources and what makes the most sense. And making sure that operationally, our focus is on PCNSL and CLL.

Our next question comes from the line of Yale Jen from Laidlaw & Company.

Just two up here. The first one is in terms of the PCNSL, you mentioned the enrollment is on track. Could you give us any update at this moment? Then I have a follow-up.

Sure. We're trying not to give enrollment on PCNSL, other than we're on track for what we've suggested. And as we all know, it's very hard to find these patients. We get a patient or 2 a month. But it's pretty choppy. You might go 1 month where you don't get any patients, and then the next month, you get 3. So I'd say right now, we are enrolling patients.

And on margins, I think everything is going according to plan. And if we are correct, I have said in the past that we're somewhere in that 12- to 18-month range from full enrollment. So that would place us at full enrollment with the potential to -- after 6 months of following patients filing, that will be somewhere in the 2027 range. But we could well be in a position by the end of the year that we are really close to that full enrollment number and we've got some nice data to talk about. But I don't expect we're going to have a whole lot to say ahead of that.

Okay. Great. Yes, that makes a lot of sense. And then maybe just a quick question for -- in terms of the modeling for next year, given that you have this $27 million noncash items as well as reduced revenue in the fourth quarter of last year. Should we model that there will be no meaningful revenue for 2026 and maybe before your product approval and other stuff?

Thank you, Yale. Actually, I'm going to ask Diantha to chime in on that one.

Sure. So Yale, that's correct. We'll have no meaningful revenue. The revenue effectively ended in November of 2025. But from a cash flow perspective, remember that we had sold the royalty, the right to about 85% of those royalties to Oberland prior to giving them the remaining 15%. So from a cash flow perspective, the remaining 15% of those cash flows are now going to Oberland. We'll have no revenue and the remaining 15% of cash flows, but it's not a meaningful impact to cash flows.

Yes. What you saw in the release is really the noncash wind-down of that arrangement. It was a very small revenue stream associated with Erivedge in the last couple of years, and we just sold what was remaining to Oberland to complete it all up. But we are now completely independent of the Erivedge stream.

Okay. Great. That's very helpful. And congrats with the good balance sheet and advance the programs forward.

Our next question comes from the line of Li Watsek from Cantor.

This is Daniel Bronder on for Li. Congrats on progress. Just a question from us on the expected or potential update at ASH '26 on CLL. Just curious, what kind of data we should be expecting? How many patients you expect to be able to share at that point? And how would you determine success at that early stage?

Sure. So I'm going to start answering that one, and then I'll ask Dr. Hamdy to chime in as well. So I mean, first and foremost, let's not get too far ahead of ourselves. That's in December. And I think as we get closer, we can provide more guidance on what we're looking to talk about. I think at this stage of the game, it's an execution story, right? We're getting our sites open. We're enrolling patients and hoping to be in a position that we've got some data to talk through in December. So this is more about our plans and our expectations at this point. And as we get closer to the conference, of course, we can narrow that down and talk a little more specifically.

The second part of your question of what would define success in this first proof-of-concept study, that's a pretty wide-ranging one. And I might ask Dr. Hamdy to chime in on his thoughts. Ahmed?

Sure. Thanks, Jim. Well, I mean, as Jim mentioned earlier, we are trying to change the CLL treatment paradigm. As mentioned, BTK inhibitors only gets patients to partial responses with MRD positivity. So we're aiming hopefully to deepen that response and see that patients are going in the right direction towards a complete remission and hopefully, MRD-negative.

We still don't understand the kinetics of response in the combination where we are aiming to inhibit both pathways, the BCR signaling pathway and the TLR pathway, aiming to inhibit the NF-kappaB pathway, which is the driver of the disease at a much deeper level. So we have to dose a lot more patients to understand how fast that conversion from PR to CR happens. And I don't intend to venture there just yet, but I'm quite hopeful that by ASH, we will have some meaningful data to present.

Yes. Let me expand on that a little bit more because I know, at least for some of the investors who may be listening to this call, a little reminder is helpful. So as Dr. Hamdy mentioned, we know there are 2 pathways driving disease in these patients, the BCR pathway and the TLR pathway. We know that historically, the standard of care is BTKi, right? BTKi blocks the BCR pathway. And it works, right? You're blocking 1 of the 2 pathways driving diseases. That said, it's also why patients are only getting partial response. They're not getting complete remission because they're only blocking 1 of the 2 pathways.

So what we've seen in our previous studies and what we're certainly seeing in our ongoing study in primary CNSL, another NHL subtype that's -- the standard of care is BTKi. If you add emavusertib to it, if you add a blockade of the TLR pathway on top of the blockade of the BCR pathway, you get deeper responses. We've seen complete remission. We've seen time-limited treatment. Our goal is to see if we can repeat that success across all 5 of the subtypes of NHL where BTKi gets used. The biggest of them by far is, of course, CLL.

And to Dr. Hamdy's point, we're very excited about getting into that study and seeing what effect we can have. But at this stage, we're learning. The mechanism tells us that it should work. Our previous studies tell us it should work, and we can't wait to see the data, frankly. So I hope that longer explanation is helpful.

And may I ask a follow-on -- follow-up?

Please. Of course.

Have you dosed your first patient yet in this study?

So we haven't disclosed that yet. What we are saying for now is that we are in the process of initiating the study. We've got our sites opening up in the U.S. and Europe, and our hope is to have data by the time we get to ASH. And we're going to try and get out of the path of month-by-month reporting on where are we in enrollment, if that's all right.

There are no further questions at this time. I will now turn the call over to Jim Dentzer. Please continue, sir.

Thank you, and thank you, everyone, for joining today's call. And as always, thank you to the patients and families participating in our clinical trials, to our team at Curis for their hard work and commitment and to our partners at Aurigene, the NCI and the academic community for their ongoing collaboration and support. We look forward to updating you again soon. Operator?

Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good afternoon, ladies and gentlemen, and welcome to the Curis Third Quarter 2025 Business Update Conference Call. [Operator Instructions] This call is being recorded on Thursday, November 6, 2025. I would now like to turn the conference over to Diantha Duvall, Chief Financial Officer. Please go ahead.

Thank you, and welcome to the Curis Third Quarter 2025 Business Update Call. Before we begin, I would like to encourage everyone to go to the Investors section of our website at www.curis.com to find our third quarter 2025 business update press release and related financial tables. I'd also like to remind everyone that during the call, we will be making forward-looking statements, which are based on current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. For additional details, please see our SEC filings.

Joining me on today's call are Jim Dentzer, President and Chief Executive Officer; Dr. Jonathan Zung, Chief Development Officer; and Dr. Ahmed Hamdy, Chief Medical Officer. We will also be available for a question-and-answer period at the end of the call.

I'd like to now turn the call over to Jim.

Thank you, Diantha. Good afternoon, everyone, and welcome to Curis' third quarter business update call. We continue to make steady progress in our TakeAim Lymphoma study, which is evaluating emavusertib in combination with ibrutinib in patients with primary CNS lymphoma, one of the most rare and most difficult to treat of the NHL subtypes.

As a reminder, the TakeAim Lymphoma study is a single-arm study with an ORR endpoint that adds emavusertib to a patient's BTKi regimen after they have progressed on BTKi monotherapy. And after collaborative discussions with the FDA and EMA, we expect the study to support accelerated submissions in both the U.S. and Europe. Over the next 12 to 18 months, we'll be focused on enrolling the additional patients we'll need to support those submissions.

If you recall, last quarter, we engaged with a number of KOLs who are excited and highly supportive of expanding our emavusertib studies into additional NHL subtypes. They were especially interested in exploring emavusertib's potential to fundamentally change the treatment paradigm for CLL patients where the current standard of care is BTKi monotherapy.

BTK inhibitors have become the standard of care in CLL and NHL because of their ability to help patients achieve objective responses. However, these responses are typically partial responses, not complete remission. The unsurprising result is that patients who are treated with a BTK inhibitor end up having to stay on it in chronic treatment for the rest of their lives. Additionally, since patients never achieve complete remission, many of these patients develop BTKi resistant mutations and ultimately, their disease progresses.

At Curis, we're looking to improve upon the current standard of care by adding emavusertib to a patient's BTKi regimen, enabling patients to achieve deeper responses and potentially come off treatment, reducing the risk of developing BTKi resistant mutations and improving a patient's overall quality of life.

The first step in testing this hypothesis in CLL is to initiate a proof-of-concept study in patients currently on BTKi monotherapy who have achieved a PR, but have been unable to achieve complete remission or UMRD. We have submitted the study protocol to the FDA. We're working to activate clinical sites, and we expect to enroll our first patient in late Q4 or early Q1 with initial data expected at the ASH Annual Meeting in December 2026.

Now let's turn to AML. Abstracts for the December ASH meeting were released on Tuesday, including the abstract for our ongoing AML triplet study, which is evaluating the triple combination of emavusertib with azacitidine and venetoclax in AML patients who have achieved complete remission on aza-ven but remain MRD positive.

The data in the abstract are for the first 2 cohorts, patients who received emavusertib for 7 or 14 days in a 28-day cycle in addition to their aza-ven treatment. As of July 2, 2025, 10 patients with a median age of 71 were enrolled, 4 in the 7-day cohort and 6 in the 14-day cohort. MRD conversion to undetectable levels occurred in 4 of 8 evaluable patients within 5 to 8 weeks of adding emavusertib.

Among the patients who remained MRD positive, 1 patient achieved a 40% MRD reduction and none showed disease progression. Two dose-limiting toxicities, CPK increase and neutropenia occurred in the 14-day cohort, but both resolved.

We're very encouraged by the initial readout from these first 2 cohorts and the exciting potential of combining emavusertib with aza-ven in frontline AML to enable more patients to achieve undetectable MRD. We continue to explore different dosing regimens for this triplet combination, and we look forward to reporting our progress. As you can see, we've had a very exciting and productive quarter and have a lot of exciting updates coming at the SNO and ASH conferences over the next few weeks.

With that, I'll turn the call back over to Diantha for the financial update. Diantha?

Thank you, Jim. Curis reported a net loss of $7.7 million or $0.49 per share for the third quarter of 2025 as compared to a net loss of $10.1 million or $1.70 per share for the same period in 2024. Curis reported a net loss of $26.9 million or $2.19 per share for the 9 months ended September 30, 2025, as compared to a net loss of $33.8 million or $5.77 per share for the same period in 2024.

Research and development expenses were $6.4 million for the third quarter of 2025 as compared to $9.7 million for the same period in 2024. The decrease was primarily attributable to lower employee-related clinical consulting, research, manufacturing and facility costs. Research and development expenses were $22.4 million for the 9 months ended September 30, 2025, as compared to $29.6 million for the same period in 2024.

General and administrative expenses were $3.7 million for the third quarter of 2025 as compared to $3.8 million for the same period in 2024. The decrease was primarily attributable to lower employee-related costs. General and administrative expenses were $11.2 million for the 9 months ended September 30, 2025, as compared to $13.4 million for the same period in 2024.

Curis' cash and cash equivalents were $9.1 million as of the end -- as of September 30, 2025, and the company had approximately 12.7 million shares of common stock outstanding. Based on our current operating plan, we believe that our existing cash and cash equivalents should enable us to fund our existing operations into 2026.

With that, I'd like to open the call for questions. Operator?

[Operator Instructions] Your first question comes from Sara Nik with H.C. Wainwright.

Congrats on the ongoing progress. My question was regarding your CLL program. And if you -- any color you could provide on the FDA discussions and protocol you submitted. Were you mostly aligned with primary endpoints and study design? Any granularity you can provide as of now would be helpful.

Thank you, Sara. Thanks for the question. I'll start, and I'll ask Dr. Hamdy to chime in as well. So we're very excited about that study. So as you know, we did have a dose escalation study where we tested across different subtypes in NHL. Our first expansion was in PCNSL and the second one is going into CLL. Obviously, as we move into CLL, it's a much larger indication. And of course, there's a much wider circle of interest among the KOLs. Ahmed, do you want to talk a little bit more about the CLL study in particular?

Sure. Sara, it's Ahmed. So basically, we're trying to address the unmet medical need in the CLL community, which is basically getting patients to a time-limited treatment with the combination of emavusertib plus a BTK inhibitor in patients who are currently on a BTK and have only achieved a PR with MRD positive. So -- and we're aligned with the FDA there, and we intend to have a small dose escalation at 100 milligram and expanding into our 200-milligram Phase II dose.

Your next question comes from Li Watsek with Cantor.

And I guess just for the Phase II CLL trial, can you maybe just talk a little bit about the size of the study and in terms of the delta you want to achieve in terms of the CR rate?

And then second is just how you're thinking about resource prioritization at this point, especially as you think about the resources that you might need to move forward with the CLL study versus the frontline AML study?

Sure. So again, why don't I start on CLL, I'll ask Dr. Hamdy to talk a little more detail and then maybe have Diantha talk a little bit about resources. So first, on CLL, we are anticipating a study design at this point in time that anticipates 40 patients. But of course, as we saw in PCNSL, the unmet need is so clear, we're hoping to be able to see a signal long before we get to that point.

As a reminder, patients on BTKi monotherapy in CLL, they get PRs. They don't get CRs. They certainly aren't getting MRD either. So what we're looking to do in that population is demonstrate simply that by adding emavusertib, by blocking both pathways, not just one, but both pathways that are driving disease that we can end up seeing deeper responses. So that's deeper PRs, and we hope also that we'll see CRs and MRD.

Ahmed, do you want to chime in a little bit more on that?

I think you said it all, Jim. The whole concept here that you don't see CRs in -- with BTK. And obviously, you don't see MRD negative. So getting patients to a CR, and I think anything north of 20% would be very exciting. But obviously, we're going to have to wait until we see a treatment effect in our trial and plan accordingly. But we are very hopeful that the dual blockade of inhibiting the TLR pathway along with the BCR pathway would have a much more profound effect on the NF-kappaB and therefore, getting patients to a deeper response in MRD negative.

Yes. Thank you. And Diantha, would you mind spending a moment talking about the resources?

Absolutely. So Li, as you can appreciate, our current priorities are clearly to continue the PCNSL trial and obviously launch the newly initiated CLL trial. And also, as you can appreciate, we'll be looking to bring in additional capital prior to the end of the year. We've been pretty clear about that over the last 6 months. So neither of those things should be a surprise. So that's sort of where we're thinking about our resource allocations.

Yes. And in overall messaging, Li, we continue to move forward with great progress in PCNSL. And I think the investor interest, not just in PCNSL with the [indiscernible] approval, but the ability to move the needle in CLL. It seems to be a very reachable goal and because of the market opportunity, a very exciting goal. So look forward to hearing from us more about that over the next 8 weeks.

Your next question comes from Yale Jen with Laidlaw & Company.

I've got 2 here. First of all, in terms of the CLL study, what would you think about the safety side? In other words, in the combination, was there any sort of speculated AE may happen? And how would you think about the mitigation for that? And then I have a follow-up.

Okay. Again, let me start, and I'll ask Dr. Hamdy to add to it. So I think the critical issue for us is going to be, do we see any DDI with the BTK inhibitors. And as you know, we have a great deal of confidence given that we've already tested a number of patients in NHL with ibrutinib, and we aren't seeing DDI. In fact, at the doses that we're testing 100 and 200 milligrams with [indiscernible], it seems to be a very clean profile.

Ahmed, would you like to add to that?

Yes. I mean, again, you said it all, Jim. But yes, I mean, we have approximately 25 patients, if not more, combined with ibrutinib. And as you know, ibrutinib is probably would be the most unselective of all approved BTKs, and we have not seen any additive toxicities and we expect not to see any additive toxicity with the other BTK inhibitors. Of course, we're going to be doing some PK work in GDI following any potential toxicities, but I don't think there's any additive toxicities that we expect.

Okay. Great. That's very helpful. And maybe just one more question here. In terms of the SNO meeting in a few days, what should be the investor sort of expectation to talk about?

Yes. So obviously, we're going to have to be a little careful not to front run the conference. But thank you, Yale, for your interest in that. Yes, we're going to have several posters, 3 of them available at the SNO conference in PCNSL, but also SCNSL. Dr. Grommes and Dr. Nayak, in particular, will be talking about PCNSL. So I think what you can expect to see there is learn a little bit more about what we've seen over the last 6 months in that study. And of course, the secondary CNS lymphoma even harder to treat, that will be brand new. So I think on both fronts, it should be a really exciting conference for us. Thank you.

There are no further questions at this time. I will now turn the call over to Jim Dentzer for closing remarks.

Thank you, operator, and thank you, everyone, for joining today's call. And as always, thank you to the patients and the families participating in our clinical trials, to our team at Curis for their hard work and commitment and to our partners at Aurigene, the NCI and the academic community for their ongoing collaboration and support. We look forward to updating you again soon. Operator?

Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your lines.

Good afternoon. I'm Jim Dentzer, the CEO of Curis. Thank you for taking time today to learn more about us. Over the next 25 minutes, I'll walk through a summary of our progress to date.

Before I begin, I'd like to remind everyone that during the presentation, we'll be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and actual results may differ materially. For additional details, please see our SEC filings.

While Curis has a broad pipeline of novel cancers, focusing our efforts on emavusertib, the first-in-class IRAK4 inhibitor with broad application in lymphoma, leukemia and solid tumors. We now have proof-of-concept data in 34 patients with PCNSL and the second proof-of-concept data set with 21 patients in AML with both studies demonstrating a significant improvement over standard of care.

More to the point, we believe that these 2 studies represent the tip of the iceberg. The proof-of-concept results in PCNSL, one of the toughest NHL subtypes to treat, give us confidence that it will also work in other NHL subtypes, including CLL.

Similarly, the proof-of-concept results in relapsed/refractory AML give us confidence that it will also work in frontline AML.

Curis is one of the most experienced leadership teams in biotech with each of us having over 20 years of experience developing novel drugs at Dicerna, Biogen, BMS and Merck. The newest member of our team, Dr. Ahmed Handy, brings experience of developing both and the # 2 BTK inhibitor as the CMO of Pharmacyclics and also at Acerta. Ahmed is spearheading our push into CLL, and we are very glad he chose to join the team earlier this year.

This slide highlights emavusertib's novel mechanism of action and there is multiple unmet medical needs in lymphoma and leukemia. On the right side of the graphic, we see how emavusertib blocks both the TLR and pathways, the 2 pathways driving disease in AML.

On the left side of the graphic, we see the BCR and TLR pathway, 2 pathways in CLL and NHL. In this setting, emavusertib is used in combination with the BTK inhibitor to enable a dual blade. BTK inhibitors block the BCR pathway and emavusertib blocks the TLR pathway.

With that, let's walk through the data that demonstrate how important this novel mechanism is. We'll start with the opportunity in CLL and NHL. IRAK4 is a compelling target in CLL and NHL because of its ability to downregulate NF-kappaB in a way that's independent from and synergistic with standard of care.

In the graphic on the left, we see that NF-kappaB overactivity is what's driving disease in NHL. And 2 pathways are driving that overactivity. One is the BCR pathway, which is addressed by BTK inhibitors; the other is the TLR pathway. That's addressed by emavusertib. We all know that BTK inhibitors work, and they can provide high response rates, but we also know that they struggle to get complete responses.

We believe this is block 1 of the 2 pathways driving disease in CLL and NHL. In the graphic on the right, we see the preclinical data supporting this thesis. Both drugs induce tumor reduction in monotherapy, but it is only when we combine them that we see the strongest activity and the deepest responses.

When we look at the unmet need in CLL and NHL, we have to start with the understanding that everyone loves BTK inhibitors for a reason. They changed the game in NHL and have become an $11 billion industry that grew 20% last year.

But BTK inhibitors have 2 key drawbacks. First, their inability to provide complete responses means chronic lifelong therapy for patients with the heightened risk of acquiring treatment-resistant mutations. And second, BTK inhibitors come with side effects like bruising, bleeding, fatigue and cardiac issues that are particularly difficult for older patients.

More recent therapies like the BCL2 anti-CD20 combination, which was approved in 2019, have suggested the promise of a one-and-done or a fixed duration treatment, which is very compelling. Unfortunately, those treatments also come with a very difficult side effect profile. And over the last 6 years, they've been unable to displace BTK inhibitors as standard of care. With emavusertib, we have a therapy that has the potential to provide the good outcome promise of BCL2 and CAR-T but with an oral, oral therapy and a much more attractive safety profile.

The clinical program for emavusertib in CLL and NHL was designed in anticipation of the potential for accelerated filing. In Part A, we explored dose escalation across multiple NHL subtypes. In Parts B and C, we're focusing specifically on PCNSL [indiscernible]. Part B supports an accelerated approval path with a single-arm study adding emavusertib to a patient's BTKi regimen directly after they progressed on BTKi monotherapy. And Part C supports the confirmatory path with a randomized study in BTKi-naive patients.

In Part A, the dose escalation part of the study, we saw a clear pattern of activity across multiple NHL subtypes. Monotherapy and lower doses are active, and there's a steady increase in activity as we go to higher doses and to combination. Among the NHL subtypes, we selected PCNSL as the subtype to pursue for our fastest path to first label because the regulatory opportunity is so clear. PCNSL is an orphan indication. It's the hardest NHL subtype to address, and there are currently no drugs approved for it.

So in these early data, we saw an emerging pattern of activity across multiple NHL subtypes. What then happened is we expanded into PCNSL? We see this in Parts B and Part C. What happened is that the emavusertib continued its encouraging pattern of anticancer activity.

In the BTKI naive group, the emavusertib ibrutinib combination outperforms the data published for ibrutinib monotherapy, 63% versus 39%. In the BTKi experienced group, these are patients who've progressed on BTKi monotherapy, so we wouldn't expect any tumor reduction if they stayed on it. We saw clear reduction in 11 of 17 patients and objective responses in 7 of them.

The duration of responses we can see on the right looks encouraging as well. 3 of 4 CRs have lasted longer than 6 months, and 1 patient has been in remission for over 400 days and another patient for over 800.

[indiscernible] across all of our studies. The [ safety table ] on this slide includes specifically with NHL. Treatment was well tolerated. There's no dose-limiting myelosuppression and no BDI.

As we push forward into PCNSL, the obvious next step is to expand into the other NHL subtypes wherever BTKi is used. We know BTK inhibitors work and that they can provide high response rates, but they struggle to get complete responses. When we add emavusertib to a BTK inhibitor, we can get complete responses. Given the clarity of emavusertib's mechanism and the clear pattern of activity we're seeing even in the hardest to address NHL subtype, we look forward to expanding across NHL wherever BTK inhibitors are used.

We expect to enroll our first patient in CLL by year-end. As we said earlier, we look to provide the outcomes promised by BCL2 and anti-CD20 but with a better safety profile. The 53% MRD potential with BCL2 and anti-CD20 is compelling, but its difficult safety profile has prevented it from displacing BTKi since its 2019 approval. Our goal is to bridge that gap, maintain the safety profile of the established $11 billion standard of care but deepen its efficacy and enable patients to achieve complete remission or the potential for MRD negativity.

From a regulatory perspective, we see the world is changing. The FDA and EMA are increasingly receptive to MRD as a clinical endpoint. To be fair, this is a relative [indiscernible]. But emavusertib's potential to deepen responses, eliminate minimal residual disease and enable time-limited treatment seems well timed with where regulatory authorities want to go.

In summary, BTK inhibitors are great. They change the game in NHL, but they come with limitations, including the need for chronic lifelong therapy and difficult side effects. With emavusertib, we can make the already clear market leader an even more effective therapy by [indiscernible] with emavusertib. And that's the NHL story.

Let's now move on to AML. As [indiscernible] into AML, we find that emavusertib [indiscernible] unique molecular opportunity. In AML, both IRAK4 and FLT3 are target of interest with both of them driving disease in AML. Why is this important? Let's walk through them.

In the graphic on the right, [indiscernible] you see the TLR pathway and the FLT3 pathway drive disease in AML and that emavusertib blocks both of them. Let's walk through these 2 pathways individually to better understand how important this novel mechanism is. First, we'll start with IRAK4.

It's important to note that there are 2 isoforms of IRAK4. IRAK4 short is the wild type and IRAK4-Long is oncogenic. This distinction is demonstrated in the 4 gray boxes on the left side of the slide. The box in the upper left is the control. The box in the upper right shows that knocking out IRAK4 stops leukemic activity.

In the lower right, we see that adding back the wild type. IRAK4-Short has no effect. And in the box on the lower left, we see that adding back the oncogenic isoform, IRAK4-Long, restarts leukemic activity. The red and blue graphic on the right side of the slide shows why the identification of IRAK4-Long as an oncogene was so important in [ in AML ]. these data are from cancer genome [ models ], and they show that IRAK4-Long is expressed in nearly all patients with AML.

Now we're not suggesting IRAK4 is the only driver of disease in AML, of course, not. There are a lot of drivers in AML. What we're suggesting is that IRAK4 is an important driver. It's expressed in nearly every patient and the current standard of care doesn't address it.

Now let's look at FLT3, which is mutated in 1/3 of patients with AML and more specifically, why combining FLT3 inhibition with IRAK4 inhibition is so effective. The graphics on this slide are from the 2019 Melgar paper, which we think does a great job of articulating why FLT3 inhibitors as a class aren't more effective in treating AML patients who harbor FLT3 mutation.

In the graphic on the left, we see that IRAK4 activity increases after treatment with a FLT3 inhibitor. In the middle graphic, we see that blocking either IRAK4 or FLT3 in monotherapy can induce tumor reduction, but the effect is temporary. You need to combine IRAK4 and FLT3 to get the longer, deeper response.

In the graphic on the right, we see the logical extension that blocking both IRAK4 and FLT3 results in extended [indiscernible]. So given the strong synergy between IRAK4 and FLT3, 1/3 of the patient population with FLT3 AML represents a clear opportunity for emavusertib.

In the frontline setting, composite CR rates are typically around 60% with fit patients receiving chemo plus midostaurin or quizartinib and unfit patients receiving ven/aza. The fit and unfit populations converge in the relapsed/refractory setting, where patients will typically receive quizartinib and the expected composite CR rate drops to 21%.

In our study, we targeted patients who had progressed after they had failed a FLT3 inhibitor. In the salvage line setting, we might expect that the composite CR rate would drop again, perhaps to 10% or lower. As we now know, our data were quite a bit better than that.

In the waterfall on the left, we see the [indiscernible]. Swimmer plot in the middle, we see that these responses came quickly and were durable. And in the chart on the right, we see how these data compared to the current standard of care. Even though the majority of patients treated with gilteritinib were naive to FLT3 inhibition and the majority of patients on emavusertib had already failed on a FLT3 inhibitor. Emavusertib clearly outperformed gilteritinib, the current standard of care for patients with FLT3 AML.

Just as we saw in NHL, the safety data are equally encouraging. To date, we've dosed over 225 patients across all of our studies. The table on this slide includes the 102 patients with AML that were treated with emavusertib. Treatment was well tolerated and no dose-limiting myelosuppression was observed.

We're currently working with key opinion leaders to design a registrational head-to-head study randomizing against gilteritinib. It's a big study. So we want to ensure that we have sufficient financing before we kick it off, but it's designed to demonstrate that emavusertib is the next-generation best-in-class treatment for all patients with FLT3 AML. And that's it for leukemia.

In short, emavusertib is a novel drug with a compelling monotherapy opportunity in a genetically defined population with the potential to establish a new standard of care for AML patients with FLT3 mutation. We want to repeat our FLT3 AML study this time in a head-to-head against gilteritinib. We think we can [indiscernible]. As I mentioned [indiscernible], the primary focus of our work has been in NHL and AML, but we're also working with several partners in academia and the NCI on the potential for emavusertib in solid tumors.

In preclinical studies, emavusertib has been shown to potentiate both chemotherapy and immunotherapy in solid tumor malignancies. Emavusertib is being evaluated in 5 investigator-sponsored trials in solid tumors. We expect preliminary data from these studies to begin later this year. And as these data mature, we hope to gain a better sense of emavusertib's potential in the competitive landscape and the scope of the potential opportunity in solid tumors.

Now that we've walked through emavusertib's potential in NHL, AML and solid tumors, let's review some of the high-level corporate information. Inclusive of the financing in July, we finished Q2 with roughly $17 million, and we have a strong IP position with Comp of Matter to 2035 before any extensions.

In closing, novel targets in biotech are rare, especially ones with such wide commercial potential. All of us at Curis are grateful for the opportunity to develop this first-in-class, and we believe best-in-class novel therapy for patients with cancer. Thank you for your time today. We appreciate the opportunity to provide this update on our progress.

Hey, everyone. Welcome to our next session with Curis. My name is Li Watsek, a biotech analyst here at Cantor. I'm very pleased to have Jim Dentzer, CEO of Curis, with us today. Maybe start, I'll just hand it over to Jim to give us some quick overview.

Thank you. I appreciate it, and thank you for having me.

Yes, the overview of Curis is we're really at an exciting crossroads. So we've got one drug that we're funding. We've got a pretty good pipeline, but one drug is all of our resources, all of our time and all of our money, and it's an IRAK4 and FLT3 inhibitor. Its utility is in NHL and in AML. Maybe in solid tumors as well. We have a bunch of studies funded by the NIH in solid tumors. But what most investors are focused on right now is NHL. So we've got a proof-of-concept data set in PCNSL of 34 patients, that look quite compelling. It's an add-on therapy to BTK inhibitors. You may remember that in NHL, disease is driven by NF-kappaB. And NF-kappaB is in turn driven by 2 pathways, BCR and TLR. BTK inhibitors block one of the pathways, we block the other.

So we are approaching all of the NHL subtypes just as we approach PCNSL, which is the smallest subtype. Use a BTK inhibitor block BCR pathway, use our drug to block the TLR pathway, and it should lead to higher response rates and potentially complete remission.

So right now, as I say, the proof-of-concept data is in PCNSL with 34 patients, but we recently announced that we're moving into CLL as well. And that's where most people's attention is because it's the largest indication within NHL.

Yes. We're certainly going to talk about CLL just in a little bit. But going back to PCNSL, so that's the CNS lymphoma. It's a small subset of lymphoma population. And I'm not sure many investors are super familiar with sort of the treatment regimen here and unmet needs. Maybe, Jim, you can talk a little bit about that and where do you think you can fit in, in this landscape?

Sure. So you're exactly right. Most people don't pay attention to PCNSL. It is the smallest of the 6 NHL subtypes. Standard of care in frontline is chemo and radiation. And then once you progress, standard of care is ibrutinib. It's the only BTK inhibitor currently in the NCCN guidelines as standard of care in relapsed/refractory PCNSL. And that's because it has the best BBB penetration, blood-brain barrier penetration data.

Our view is that while BTK inhibitors work, the largest study ever conducted was a study in France, showed an ORR of 39% in those patients. We believe we can improve that by adding emavusertib. So far, in a small population, we've got an ORR of 63%, so quite a bit better.

And in the secondary data set of patients who are on a BTK inhibitor and failed, so now their brain tumors are growing, we find that in the majority of patients, we can reverse the disease, shrink the tumors and get responses in 27% of them so far. And that's in a patient population who doesn't -- they don't have an alternative. There is no standard of care once you fail BTK. So they would likely be going to hospice, and yet we're getting patients into complete remission. So it's very exciting. It's just a very small market.

Okay. So it sounds like you guys believe that you might be able to get accelerated approval based on a single-arm study. And obviously, you've shown some nice data early. And you're going to have an update for us later this year, maybe set the expectations for us what the bar for success might be?

Sure. So yes, you're exactly right. It's a Phase I/II study, but we now know as of a couple of months ago that both agencies have accepted it as pivotal. All we need to do is add more patients. And how many patients do we need? That's a statistics question, but the answer is somewhere between 45 and 60.

So what we reviewed with FDA and EMA was that if we have a lower bound of 10%, then we need to have an ORR of 20% in 45 patients -- I'm sorry, 22% in 45 patients or 20% in 60 patients. So as long as we're in that 20% to 22% ORR range, 45 to 60 patients is the right end to get a 95% confidence in enroll. As I say, right now, we're at 27%. So we're in good shape moving forward. The hardest part moving forward is not data related about whether the molecule is working. It's finding the patients because it's an ultra-rare disease. But both agencies have agreed now that the current study is pivotal.

Okay. So in terms of enrollment, Jim, like what can you do in terms of maybe try to accelerate the enrollment a little bit just given there's some challenges here.

Sure. It's all about the number of sites. So there are -- we've got 30 sites now globally, Europe, U.S. and 3 sites in Israel. With 30 sites, our expectation to hit our goal is we need 1 patient per site per calendar year. So we'll talk to the investigator at MSK, for example. And they'll say, how many patients do you need? And the answer is we need 1, in 2025 from you. Now some sites will have 2 or 3 patients, some sites might not have any. But as long as we get 1 patient per site per calendar year, we'll hit our goal, which is full enrollment in 12 to 18 months, follow them for another 6 months and get their data and file an NDA. And you're exactly right, it's an accelerated approval single-arm study. And then we will follow it with a confirmatory study that's randomized. It will be randomized against ibrutinib. But that study, of course, can take much longer and likely will.

Okay. Just given recently the FDA put out the new guidance for oncology drugs and seems to have a very strong focus on OS. And as you think about single-arm trial for accelerated approval, do you see any risks there in terms of what the agency wants to see? Do they want to see OS benefit? Obviously, in single arm, it's not reliable. But just based off your interactions with the agency, do you see any sort of shifting the bar at all?

Yes. So the short answer is there is always uncertainty whenever you're dealing with the regulatory agency, but especially in the current environment, there's not a whole lot of constancy, and that is a concern. I'd say in our case, in PCNSL, we are less concerned, and we're less concerned for a couple of reasons.

First, it's an ultra-rare indication where there are currently no drugs approved. So patients do receive ibrutinib because there are NCCN guidelines, but there are actually no drugs approved. So we would be the first one. And that's encouraging. Both agencies are eager to have a drug that has gone through all of the regulatory testing needed. And I think they're willing to be more flexible rather than if we were going after a disease where we're the fourth or fifth drug to market.

The second thing is in PCNSL, we're talking about tumors in the brain. Unfortunately, survival statistics are fairly grim. So these patients don't live for very long. They'll respond fairly well to chemo and radiation in frontline. But by the time they get to second line on a BTK inhibitor, their survival is typically measured in months.

So if we needed to pivot in our discussions with the regulatory authority, we're already going to include survival statistics. But if they wanted to put more weight on survival, in our case, it wouldn't take very long to generate those data because the patients don't live very long.

Okay. And Jim, you talked about confirmatory trial. And I know the agency also has some requirement for recruitment of confirmatory trial to support AA. So I think you mentioned before the Part C of the study where you have BTK-naive patients could potentially serve as confirmatory study. Have you had that discussion with the FDA and how feasible that would be?

So we've had the high-level discussions with FDA and EMA, and they're both supportive. We need to have more discussions about confirmatory trial design. That said, you're exactly right. We designed Part B and Part C to support accelerated approval and confirmatory approval or full approval intentionally. So Part B is in the experienced patients. These are the patients who failed ibrutinib and don't have an option. That will be a single-arm study. We leave them on ibrutinib, add ema to it and see if we can reverse their disease.

And then for the confirmatory study, that needs to be randomized. And because it's randomized, it will have to go online earlier. You can't have one arm of your study being ibrutinib if they just failed ibrutinib.

So both agencies agreed with that approach. They like the idea of randomizing against ibrutinib. Again, we have a very small patient population that's been treated so far. But as I say, versus an expectation of 39%, we're at 63%, I think that's very encouraging. And certainly, we would expect that over time, we'd see a consistent result in survival as well. But we need to have a more detailed discussion with FDA to follow up on the high-level discussion about exactly what that clinical design looks like.

If they are consistent, what they did in accelerated was they said our existing data count, the Part B data can roll in and be included in the NDA. I expect that they'll do the same thing with Part C in an indication where there are no drugs approved, if we already have a population that's being treated and being treated successfully, as long as the criteria are the same, it is reasonable for them to allow us to expand Part C and that becomes the confirmatory study.

I guess when are you going to maybe approach the FDA to sort of have more follow-up discussions around the confirmatory study?

That's over the coming year. I mean we've already started that study. We're enrolling it now. So there's no big rush to have that discussion with FDA since we already know directionally that we had the high-level discussion and they were fine. Our view is let's go to them when we have some data. So we have some small end, but we would like to go back to them over the coming year, and we'll give them an update of here's where we are on the single-arm study, and here's where we are on the randomized study.

Now that you see these data and they're hopefully going to be consistent with what they've seen in the past, they would be amenable to coming to the same conclusion, which is the current population as long as you haven't changed the enrollment criteria, should be amenable to inclusion in the confirmatory design, which means Part B was converted into the pivotal. Presumably, Part C will be converted into the confirmatory. A worst-case scenario, if they say no, it just means the confirmatory study takes longer, which isn't the end of the world because you'll already be approved. But for patient's sake, it'd be nice if we could include them.

Have you had any high-level discussion in terms of size of the confirmatory study and what the primary endpoints might be?

So size, no, primary endpoint is almost certainly a survival endpoint, whether it's PFS or OS.

OS. Okay.

Yes. And in either one, because in PCNSL, the survival stats are fairly grim. Prognosis is difficult for these patients, we don't have a strong feeling between PFS and OS. We had a discussion with FDA and EMA already, as I said. And as long as it's one of those two, I think both agencies will be fine. So we'll look to lock that down, as I say, when we have the follow-up discussion.

Okay. Just in terms of the time line for the Part B, and Jim, you mentioned ideally, you're going to have one patient per site per year and you have 30 sites and perhaps you're going to enroll other patients in 12 to 18 months. As we think about when to expect the top line, number one, any interim analysis? And two is help us understand after you finish enrollment, what the final top line could come in?

Yes. So it's an open-label study. So we are able to provide updates every 6 months at ASH and at ASCO, if that's what investors would like to see. Now we've just given an update in midyear. So while we're planning on having a presentation at ASH, just to put expectations into perspective, when you're talking about adding a patient a month, it's not a dramatic update. The conclusion before was the drug is effective. The conclusion at ASH is going to be the drug is effective. It's not a big movement of the needle.

That said, as we get closer to the 45 patients, it will be very encouraging for us and for investors to know that things are on track, and that we continue to be above that 20%, 22% hurdle. And right now, I think we are. And even if every patient that we enroll over the next 3 months, does not do well, we would still be above that. So I'm actually not -- I'm not seeing that that's going to be a big needle mover for investors. But certainly, over the 12- or 18-month time frame, it will be.

Okay. I think one interesting update from your Q2 is you're going to initiate a new trial in CLL. I think that's really interesting opportunity. Maybe talk to us about the thought process behind that? And where do you see the opportunity is?

Sure. So there's been a lot of excitement about that, which is interesting. We're in a pivotal study in PCNSL and every question we've gotten over the last 2 months from investors has been about CLL. Not shocking, CLL is much larger. I mean PCNSL is maybe a $500 million, $600 million market. CLL, of the $11 billion in BTK, $7.7 billion of it is CLL. So of course, that's where all the interest is.

So we're going at it with two primary thoughts. The first is the biology for NHL holds through all 6 subtypes. And that is the disease is fundamentally driven by NF-kappaB overactivity. Two pathways drive it. One is addressed by BTK inhibitors, the other is addressed by us. So we would go with a combo therapy in CLL, the same as we did in PCNSL, and we would look to have the same outcome, meaning when you add emavusertib to BTK, it makes BTK better. You get higher response rates, deeper responses. And presumably, that will lead to better long-term clinical benefit as well.

Specifically, the unmet need in CLL, while there are exciting developments scientifically, things like venetoclax or obinutuzumab or CAR-T, this one-and-done idea is really compelling. They don't have a whole lot of traction among patients for various reasons. They're difficult. The side effect profile is tough. CAR-T in particular, you need to have a site that's capable of doing it. The market is still a BTKi market. And that's despite the safety effect profile. And the safety effects are very concerning for an elderly population. So the lead side effects for BTK are bleeding, bruising, fatigue, cardiac events. It's exactly what you don't want as an elderly patient.

What we look to do by adding ema to a BTK inhibitor is to provide that same kind of outcome that you'd get with CAR-T or VO, but with an oral-oral regimen. And that's really compelling for patients. They want to be able to move to either a CR or MRD negative so that they can take a time-limited approach to BTK treatment. You can stay on ema as a maintenance therapy, get them into CR with the doublet and then drop the BTK. And if the disease comes back, add the BTK back in, knock it back down, and then go on that sign curve.

And the value for that is two reasons, is twofold. Time-limited treatment is important because the side effects of BTK are so difficult to tolerate, but also BTKs as monotherapy don't get you to complete remission, they get you to partial response. And as long as disease is active and you're in chronic therapy, you have the opportunity for the disease to mutate and mutations in CARD11, CD79B, these BTK-resistant mutations mean that you run the risk that your BTK will stop working.

So for those reasons, we want to be able to offer the one-and-done kind of outcome that you can get with a CAR-T, but do it with an oral-oral therapy. That's our goal.

Okay. So the population you're going to look at is the patients have been exposed to BTK inhibitor, but they don't get good response to BTK. Is that the population you're going to have?

Yes. We want to -- a patient -- so we look for patients that are already on a BTK, which is effectively all of them. Who are in partial response, but have not been able to get to CR and are still MRD positive. Again, that's virtually all of them. Patients don't get CRs or MRD negativity on BTK monotherapy.

So we'll take those patients in. Once they're stable in PR, we'll leave them on whatever BTK they're on, any 1 of the 4, we'll add emavusertib to it and see if we get the same outcome that we do in PCNSL. Are we deepening the response? Can we get them from PR to CR? And can we convert them from MRD positive to MRD negative? If so, that is a -- that has the potential to fundamentally change the treatment paradigm in CLL. And we need the data to show that we can do it. But given our experience in PCNSL and given the limited data we have in Waldenström, CLL and Mantle Cell in our earlier Part A study. We feel pretty good about it.

Okay. So I think the study or the patient population you're looking at is sort of like in between the first line and second line. It's not patients that progress or become refractory to BTK. It's just inadequate response to BTK. You talk about CR rate, MRD activity rate. Can you use these endpoints to support approval? Or do you have to get the PFS and OS benefit as well?

So obviously, we need to have this discussion with FDA. I think certainly, over the last 12 to 18 months, there's been a big move towards MRD as an endpoint. We know of at least 6 different studies in CLL that have used MRD as an endpoint. publications as recent as 2 months ago, one of the lead publications talking about using MRD as a novel endpoint in clinical trials was co-authored by Prasad. So I think there will be -- since he's running, right, the FDA, I think we're expecting to get a favorable view. But as I would say, MRD negativity is a recent goal and a recent clinical endpoint for clinical studies.

So we need to have that discussion with FDA to be sure that they're okay with that. But my anticipation would be that's where the market is going.

Okay. Just looking at the landscape of CLL right now, obviously, BTK has been the standard of care for the longest time, but we're seeing, for instance, the doublet is moving into the front-line in combination with BCL-2. And then we also have BTK degrader coming shortly after that, that has shown really, really strong data that probably can even max out the front-line treatment. And then there are several BTK inhibitors out there. So this landscape is definitely evolving. So as you think about designing a trial, which BTK to choose from, like how are you thinking about that? What is the impact on the trial design from your standpoint?

Yes. So there are a couple of different interesting nuggets to your question. So I'll address the first one first.

So there are some really interesting scientific approaches. BCL-2 is one. As I said, venetoclax, the leading BCL-2 gets combined recently with anti-CD20 with obinutuzumab. And I would say that and CAR-T are both really interesting scientifically. They haven't had much traction in NHL to date. The lion's share of the revenue is the lion's share of patients still go on BTK inhibitors. I think the reason for that is the side effect profile is considerable, both for venetoclax and obinutuzumab and also for CAR-T. And that's been the primary reason why we hear from investigators that they're resistant.

Within BTK, I think you're right, there are some really interesting degraders that are coming along. Our view would be whether you block the BCR pathway with a BTK inhibitor, or a BTK degrader, has no impact on us. It's just how well do you block that BCR pathway. We block an entirely different pathway. It's complementary, but it's the toll-like receptor path. Whether you use a degrader or an inhibitor to block the BCR pathway, you're not blocking the toll-like receptor path. We do.

So our view would be today, there are 4 approved BTK inhibitors. There will likely be another 2 over the coming years, and there may well be a degrader or 2 that get approved. Our view would be pick your favorite way to block the BCR path, write a script for that, then write a script for emavusertib to block the TLR path, and it will provide a better outcome.

So far, that's what the data we have support. And I would presume that moving forward, it should be a very compelling approach for physicians and patients.

Okay. Do you have MRD negativity data from your existing...

So we don't, and it's a little premature. It's one of the things, of course, that we want to have in hand before we go have the discussion with FDA about that. But presumably, what we would be able to do is every instance that we've gone after the combination within non-Hodgkin's of emavusertib and a BTK inhibitor has led to higher efficacy, has led to being able to convert to CRs and has led to long-term survival, whether it was preclinical, clinical data in PCNSL or admittedly small M, but in other indications in NHL, Waldenström, CLL, Mantle Cell. My presumption would be that it would be consistent for us to see patients go to MRD negativity as well, but we need a higher level of N to get there. And specifically in CLL, if that's the indication that we want to have MRD, we need to have some patient data first.

So right now, our goal is to get our first patient dosed by year-end. We'll have an interim readout by midyear. And presuming that we see a consistent result in those data, we would, of course, go take those data and talk to FDA and try to lock down what the endpoint would be in a registrational study.

How many patients will we get to middle of next year?

I would guess -- so it's a question of how many do we have on drug and have on drug long enough that we'll start to see patient results. And I'd say somewhere in the mid-teens is likely by midyear, somewhere closer to 25 or so would be a good number for year-end by next year. But you may remember in PCNSL, we saw clear signs of activity in just the first 10 to 15 patients. My hope would be in CLL, we'll see the same thing. In the first 10 to 15 patients, we should see that we can add to the efficacy of a BTK inhibitor.

So I assume you're going to report the CR rate and MRD negativity.

Yes, we would report whatever we have.

Okay. And what should be the bar here?

I'm sorry.

What's the bar here, in terms of CR rate and MRD negativity?

Yes. So it's premature. I think our goal long term, and so let's kind of step back from there. Our goal long term is to get patients to have time-limited treatment as an option, that we can get them to the point where their disease is controlled, whether it's complete remission or MRD negative, that they can safely stop taking their BTK inhibitor for a period of time, 6, 12, 18 months. Can they go off the BTK inhibitor for a period of time safely? And then if their disease comes back, go back to the doublet, add the BTK back in and then follow that curve as they go. That's the end goal.

I would suggest that CR and MRD negative are indicators of whether or not we're on track. They certainly would be endpoints from a clinical perspective, but more importantly, they're biomarkers of have we had sufficient success with the patient that we can get to that end goal, which is time-limited treatment.

So we'll be collecting all the data that we can on these patients. Certainly, in the early days, it will not just be a smaller end, but smaller opportunity for complete remission and MRD negative, but we'll be looking for everything that we can point to, to suggest that we've got something that's additive. And then as the data set builds over time, of course, we'll find the data very interesting, but we would take those data right to the regulatory authorities, as I mentioned.

So it sounds like at ASH this year, you guys are also going to share some combo data in AML. So that's ema plus aza-ven. What the expectation should be for that data readout? And as you balance different indications, obviously, CR is a great opportunity. So how are you thinking about prioritization indication to go into?

Yes. So two things. First, within AML, our goal is to give status update of patients. And again, what we're looking to do is something similar to what we're doing in NHL. In NHL, we're combining with BTK and looking to add to its efficacy. In AML, we're looking to add to aza-ven and add to that efficacy. Whether we can get a higher response rate, deeper response rate, MRD negativity, all of these things is what we're going to be looking for. MRD negative would be the ideal. But in a small data set, are we showing indications that we can do that? That's first and foremost.

The second thing is, of course, we know that BCL-2 inhibitors, venetoclax, in particular, are really difficult to dose. They lead to a lot of side effects, and it's hard just to get aza-ven to work well together. With the triplet, there's a lot of work that needs to be done to adjust the regimen to make sure that you've got a triplet profile that patients can tolerate for an extended period of treatment time. And that will be something that's an ongoing portion of the trial, of course.

But in this interim readout, can we see, even though we've only got a couple of patients in and a couple of the regimens tried out, are we already seeing signals that we've got something that can provide a benefit for patients by adding ema to aza-ven. That's what we're hoping to present.

Okay. Great. Thank you so much.

Thank you.