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spk02: Good day, everyone, and welcome to the CINDEX first quarter 2021 earnings conference call. Today's call is being recorded. At this time, I would like to turn the call over to Megan Myers of Argo Partners. Please begin.
spk03: Thank you, Operator. Welcome and thank you to those of you joining us on the line and the webcast this afternoon for a review of CINDEX's fourth quarter 2021 Financial and Operating Results. I'm Megan Myers with Argo Partners, and with me this afternoon to discuss the results and provide an update on the company's progress are Michael Metzger, Chief Executive Officer, Dr. Briggs Morrison, President and Head of R&D, and Alex Nolte, Chief Accounting Officer. Also joining us on the call today for the question and answer session is Dr. Peter Ordunlik, Chief Scientific Officer, and Dr. Anjali Ganguly, Chief Business Officer. This call is being accompanied by a slide deck that has been posted on the company's website, so I would ask you to please turn to our forward-looking statements on slide two. Before we begin, I would like to remind you that any statement made during this call that are not historical are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important business factors, including those discussed in the risk factor section in the company's most recent quarterly report on Form 10-Q, as well as those reports filed with SEC. Any forward-looking statements represent our views as of today, March 1st, 2022 only. A replay of this call will be available on the company's website www.syndax.com following this call. With that, I'm pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.
spk08: Thank you, Megan, and thank you to everyone joining us in today's call and webcast. Before we turn to the deck, let me start my comments by first welcoming Kate Madigan to Syndax as our new Chief Medical Officer. Kate completed her formal education and training at Dartmouth and USC and has had a distinguished professional career at some of America's most prestigious pharmaceutical firms. We are truly honored to have her joining our team, and you will hear more from her on future calls. I would also like to take this opportunity to thank Michael Myers for his exceptional contributions to Syndax over the past seven years. Michael has flawlessly led the development of both of our programs into their registration trials. Michael is committed to seeing Syndax successfully transition into its next phase of growth and we are grateful that he will remain an active advisor to the company. Now, turning to slide three, 2021 was a truly transformational year for Syndax. We initiated registration trials for both of our lead programs, SMDX5613 and Axotilimab. We entered into a global partnership and collaboration with a world-class partner, Insight, on Axotilimab to expand the potential for this program. And we ended the year with an exceptionally strong balance sheet following $152 million upfront payment from our collaboration and $81.2 million in net proceeds from our December offering, following strong data disclosures for both of our lead programs at the 2021 American Society of Hematology Medical Conference. Especially given the current challenging market backdrop, we are starting 2022 with an extremely solid balance sheet position. This gives us the resources to expand both of our assets into new indications and the flexibility to aggressively pursue business development opportunities to augment our pipeline with potential best in class molecules. Slide four provides a high level summary of our current corporate priorities as we strive to realize a future in which people with cancer live longer and better than ever before. The momentum is really building its index. Our three pivotal phase two trials for SMDX5613 our highly selective Menden inhibitor, which we call Augment 101 cohorts 2A, 2B, and 2C, is progressing very well and is actively enrolling patients. For axotilamab, our antibody against CSF1R, enrollment is ongoing in our pivotal Agave 201 trial, and we are now underway working closely with our new partner, Insight, to maximize the value of this important program. I want to emphasize that we now have two registrational programs ongoing for two first-in-class and potentially best-in-class medicines for two areas of important unmet medical need. It is an enormously exciting time for the company as we anticipate filing potentially two NDAs in 2023 and are starting to expand the organization to support the commercial launch of both 5613 and Axotilimab in the United States. Let's now turn to slide five and provide further details on where we are with S&D X5613. First, we have opened three single-arm Phase II trials that FDA has agreed may each serve as a pivotal trial. Each of these single-arm Phase II trials represent an independent path to a separate indication. Augment 101 Cohort 2A will enroll patients with relapsed refractory MLR-ALL. Cohort 2B will enroll patients with relapsed refractory MLR-AML. And Cohort 2C will enroll patients with relapsed refractory MPM1-AML. Each trial is open to patients aged one month or older, and each trial will enroll independent of the other two. We may seek additional regulatory approval for S&D X5613 based on the results of any one of these trials should one trial enroll faster than the others, or we may seek initial regulatory approval with any two or all three, just depending on when they complete enrollment. We are happy to report that additional site initiation and patient accrual across the cohorts is going extremely well. We are very optimistic that we will be able to complete enrollment in at least one of these cohorts this year. Given our current trajectory and our view of the landscape, we anticipate being the first company to achieve regulatory approval for a Mennon inhibitor. Needless to say, we believe being first to market is extremely important and accretive to the long-term value of Syndax. We have agreement with FDA Now, for each trial, the primary endpoint will be the percentage of patients achieving CRCRH, with secondary endpoints including durability of CRCRH response, transfusion independence, overall survival, and safety. Importantly, the trial design allows patients to be treated with 5613 after bone marrow transplant, a design feature that allows us to start to understand the role of 5613 in the post-transplant maintenance settings. We also have agreement with FDA on the statistical design of each trial. Each trial enrolls 64 patients and up to 10 pediatric patients. Finally, we have agreement with FDA that 163 milligrams every 12 hours given with a strong CYP3A4 inhibitor is an appropriate phase two dose, and that is the dose we are using in each of these trials. We know that the vast majority of eligible patients are on a strong CYP3A4 inhibitor, and in an effort to enroll the cohorts as quickly as possible, at least one cohort to complete this year, we have now prioritized the enrollment of these patients versus those not on a strong CYP4 inhibitor. Once one cohort closes to enrollment, we plan to increasingly focus on accumulating the data required for labeling, which includes the necessary dose adjustment, often referred to as the ARMA dose. Let me remind you that this CLIMFARM data is not in any way limiting on our ability to enroll and complete the pivotal trial. Beyond the Augment Pivotal Program in relapsed refractory disease, slide six highlights some of the additional opportunities we are exploring with 5613, all of which build on the excellent safety and efficacy profile we have thus far seen with 5613. The panel on the left highlights the trial we are planning in collaboration with the Leukemia and Lymphoma Society, otherwise known as LLS. They have selected 5613 as the first Mennon inhibitor to be tested specific targeted therapy for patients with MLR or MPM-1 AML in their umbrella trial that they call BEAT-AML. The collaboration we have agreed to with them will test 5613 in combination with venetoclax and azacitidine in newly diagnosed AML patients who are unfit for induction chemotherapy and will consist of a Phase I followed by a Phase II-III trial, which could serve as the basis for a regulatory filing. Our scientists have generated preclinical data that supports the benefit of menin inhibition in combination with chemotherapy. And therefore, the middle panel of the slide highlights a trial to explore the use of 5613 in combination with standard salvage chemotherapies used for pediatric patients with ALL or AML that we are calling Augment 102. And the panel on the right illustrates a third trial that explores the activity in 5613 in patients with AML who have MRD-positive disease. This trial is being conducted as part of the Intercept Master Clinical Trial being led by the Australian Leukemia and Lymphoma Group. The Intercept Trial is focused on investigating novel therapies to target early relapse and clonal evolution as preemptive therapy in AML. The trial will enroll patients with measurable residual disease progression following initial treatment. A group of patients at very high risk of relapse that represent an important unmet medical need. A general observation in the treatment of cancer is that the earlier in the patient's disease course that you treat, the better patients do and the longer the patients stay on medicine. The Intercept Trial is a very creative approach to treating patients early in their disease course. I will also note that 5613 is the first MENIN inhibitor to be included in the Intercept AML Master Clinical Trial. We believe the selection of 5613 for inclusion into two Master Clinical Trial protocols highlights the enthusiasm that investigators have shown for treating patients with acute leukemias with 5613. As mentioned on our last quarterly call, we are excited to expand the clinical opportunities for 5613 beyond the initial approval in relapsed refractory acute leukemias. Slide 7 highlights our goal as a company to be first to market in relapsed refractory disease and then be first to garner additional value-enhancing indications by expanding the use of 5613 into newly diagnosed and maintenance settings in patients with MLR and MPM1 mutant acute leukemias. We see the opportunity to treat patients with these forms of mutant acute leukemia, which account for up to 40% of the eligible patient population, as early in their treatment journey as possible, and then drive them into remission and maintain them in that state for months, if not years. That emerging paradigm for men in inhibition is what will enable this to be one of the most important new franchises in heme malignancies and why we are so keen to invest in 5613 at this stage. Let me now turn to axotilamab, our potentially best-in-class monoclonal antibody therapy targeting CSF1 receptor. Slide 8 is our pivotal trial for axotilamab in CGBHD. This trial is the axotilamab for graft-versus-host disease trial called Agave 201. The trial is enrolling patients with CGVHD whose disease has progressed after two prior therapies. Patients must be at least six years of age and have met overall entry criteria. This is a pivotal dose-ranging trial in which patients will be randomized to one of three treatment groups, each investigating a distinct dose of axotilamide given either every two weeks or every four weeks. The primary endpoint is overall response rate using the 2014 NIH consensus criteria for CGBHD. Secondary endpoints will include duration of response and validated quality of life assessments using the Lee symptom scale. Enrollment to the study is going quite well, and we are on track to deliver top line data in the first half of 2023. We were also delighted to announce during the quarter that Syndax and Insight closed our global collaboration that brings together two companies with a solid track record of innovation to accelerate and maximize the development of axotilamab. As you know, we presented our Phase I-II CGBHD data at ASH in December of last year, which received a very positive reaction and further underscored its best-in-class profile. Through our collaboration, Syndax and Insight will pursue an expanded set of indications in CGBHD and other fibrotic diseases. The development plan calls for the partners to design novel combinations with axotilamab in InsightsJAC inhibitors with a goal of establishing axotilamab in earlier settings within CVHD and expanding its market opportunity. As we previously mentioned was our intention, Syndex will initiate a robust Phase II trial in IPF in the fourth quarter of this year. The first expansion outside of establishing CGBHD as a BCHET into other fibrotic diseases where we believe axotilumab could have a significant impact. Successful development in IPF could lead to an additional approval and a very important indication of considerable value and would provide support to axotilumab and other fibrotic-driven diseases that the parties could explore over the course of the collaboration. Slide 9 highlights our view of the broad clinical and commercial opportunity for axotilumab. We believe chronic GVHD represents a high unmet medical need and an important commercial opportunity, with approximately 14,000 patients suffering from CGVHD in the U.S. today. The recent approvals of Jacofe and Cadman's Belimucidil will begin to delineate the commercial opportunity in CGVHD. Despite recent advancements in this area, to our knowledge, axotilamab is the only agent in clinical development that specifically targets the monocyte macrophage lineage. Both Syndax and Insight believe the data generated to date with axotilamab suggests it has the potential to play an important role in the treatment of CGBHD, both as a monotherapy and given its safety profile in combination with complementary medicines such as jacofi and other JAK inhibitors within the Insight portfolio. Through combinations in the frontline setting, as well as the opportunity to expand to ex-U.S. markets, we envision the CGVHD opportunity more than doubling, as shown on this slide. As we move Axotilimab into additional indications, starting with IPF, we really see Axotilimab contributing materially to the value of our company moving forward. Finally, slide 10 summarizes the transactions that led to the acquisition of Menin MLLR and Axotilimab program. We believe these transactions underscore our robust capabilities to identify and evaluate high-value differentiated assets, as well as the clinical development expertise to bring these compounds through key value inflection points. We anticipate in 2022 that we will be able to continue to expand our pipeline through product acquisitions or in licensing of quality differentiated assets. We expect to remain among preferred partners of such transactions. I'll now like to turn the call over to Alex to review our financial results. Alex?
spk04: Thank you, Michael. Let me now take a few minutes to discuss our financial results for the fourth quarter and the full year of 2021. The results of our operations for the fourth quarter of 2021 and the comparison to the prior year quarter are included in our press release, so I won't repeat them in these remarks. Additional financial details are available in our fourth quarter and full year report on Form 10-K, which will be filed today. I would like to point out that our net profit for the quarter was $96.2 million, or $1.81 per share, compared to our net loss of $20.4 million, or $0.44 per share, for the same period last year. This difference is primarily attributed to the change in license revenue generated by from the collaboration agreement with Insight. Turning to slide 11, we ended our fourth quarter with $439.9 million in cash and cash equivalents, including net proceeds of approximately $81.2 million from our public offering completed in December of 2021, and with 59 million shares and pre-funded warrants outstanding. This cash balance also includes $152 million in proceeds from the December closing of the collaboration agreement with Insight. Our current cash runway now extends into the second half of 2024 and supports our expanded development and early commercialization plans for both the Exotelamab and the Menin programs during this period and provides us flexibility for continued business development. Looking ahead, I'd like to provide financial guidance for the first quarter and full year of 2022. For the first quarter of 2022, we expect R&D expense to be $30 to $35 million, and total operating expense to be $38 to $42 million, including $4 million of noncash stock compensation expense. For the full year 2022, we expect R&D expense to be $130 to $140 million, and total operating expense to be 160 to 170 million, including approximately 14 million of non-cash stock compensation expense. The increase in R&D and operating expense in 2022 compared to the prior year period is driven by the expansion of both Exitilinib and Mennon into registration trials, expansion into new indications, and initiation of pre-launch commercialization activities. This guidance does not currently reflect any potential offset by the cost-sharing offset of Exotelum operating expenses with our partner Insight, and we will continue to update guidance over the course of the year as we move forward with this collaboration. With that, let me now turn the call back over to Michael.
spk08: Great. Thanks, Alex. Let me close the call by again noting that this management team has been focused on obtaining regulatory approval for drugs that extend and improve the lives of people with cancer and other diseases, and we consider having two ongoing registration programs to be a major achievement. We are also really excited about the broad franchise opportunities for both programs beyond their initial registration indications. We believe S&D X5613 could have broad utility across a wide range of clinical settings in acute leukemia and possibly in a number of others as well. Our immediate goal as a company is to be the first to market in relapsed refractory disease and then to garner additional value-enhancing indications by expanding the use of 5613 into newly diagnosed and maintenance settings in patients with MLLR and MPM1 acute leukemias. And axotilamab also holds the promise of a broad franchise opportunity in various lines of therapy in CGVHD and across a broad range of fibrotic diseases starting with IPF. We have a strong balance sheet to aggressively advance our programs and achieve key upcoming milestones. We remain optimistic in 2022 that we can continue to identify and bring in novel molecules to deepen our portfolio. We have a proven track record of delivering on this pillar of our corporate strategy, and I believe this is a core strength of our company. We could not accomplish all that we have without our wonderfully talented team here at Syndex, our collaborators, and most importantly, the patience, trial sites, and investigators involved with our clinical programs. In addition, I would like to thank our committed long-term investors who are helping us build this great company. With that, I would like to open the call for questions.
spk02: As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile our Q&A roster Our first question comes from Phil Nadeau with Callen and Company. Please proceed.
spk00: Good afternoon. Thanks for taking my questions, and congrats on a very productive year. First, a question on the 5613 no CYP3A4 dose. I want to make sure I understand the strategy. It sounds like you're saying patients who are not on a CYP3A4 inhibitor probably won't be enrolled in the trial for some time. but that's okay because you just simply need to identify the dose through pharmacokinetic measures and actually having clinical data from patients who aren't on CYP3A4 inhibitors is less of a requirement for filing. Is that correct?
spk08: Yeah, maybe I'll start and bring some comment also, but thanks for the question. So, look, I think the priority, as we've seen, most of the patients seem to be on strong CYP3A4 inhibitors, antifungals, and our priority is to get the trial enrolled, each of the cohorts enrolled as quickly as possible. And so, as a result of the dynamics of what I just described, we're prioritizing getting it done versus collecting all the ClinPharm information in this trial. So, We are seeing some patients that are not on a strong CYP3A4 inhibitor, but the cadence of that is not prioritized. We're not prioritizing putting them on the trial versus getting as many patients in as we can to complete it as early as we can. And what you said was correct. I think we want to get the information together, the ClinPharm information together, in order to you know, complete the trial, ultimately complete the trial for labeling purposes, but that's, you know, once we submit the NDA. But that's, you know, once we have one of the cohorts fully enrolled, we'll turn our attention to bringing more of those patients in. They're just harder to find.
spk00: Got it. Okay. And have you identified a dose yet, or are there complications in figuring out what dose should be the dose that is ultimately submitted?
spk08: No. No, there's been no trouble identifying a dose. I think it's just a matter of, you know, accumulating more patients. That's all.
spk00: Got it.
spk08: As you know, we have identified, you know, two doses that meet the RP2D as part of the Phase I. So, you know, we've identified it active doses. It's just a matter of, you know, putting on enough patients who are not on a strong CYPR-A4 inhibitor.
spk00: And that's put enough patients on in order to figure out the dose that you want to register. Correct.
spk08: Well, the PK, what PK matches our RB dose?
spk00: Perfect. Yep. Okay. That's very helpful. Second question, also on the pivotal trials. In terms of the pace of enrollment, I think in the past you've said MLR, AML patients are like that. That group is likely to enroll more quickly because of the competing trials. Is that still your expectation? Is that the cohort that we should expect to see data from first?
spk08: Yeah, I think we said, Phil, that the AML cohorts, we didn't differentiate between MLR and PM1. We just said that our expectation is the AML cohorts will enroll faster than ALL cohorts. And as I said in my remarks, We expect to enroll at least one, maybe two, hopefully fully this year. So we're not saying exactly which ones will enroll faster than the others, but that was the kind of guidance we had given, and we're sticking with that.
spk00: Perfect. And then last question on XTLMAP. You referenced the two recent approvals and the fact that those launches could inform you about the GVHD market. We're curious, what do you expect to learn most from those launches, you know, aside from the revenue trajectory, which we'll all see, but in terms of, like, location of patients, access to reimbursement, desire to be treated, what do you think will be most informative about those launches as you contemplate Exatel Maps commercialization?
spk08: Yeah, maybe I'll ask Anjali, our chief business officer, to comment on that.
spk11: Sure. Thanks, Michael. Thanks, Phil, for the question. I think, you know, a big part of the launches too is the awareness of new drugs in this space because for so long it's been dominated by generic entry and the defining of a treatment algorithm for chronic GVHD I think is an ongoing and evolving event. And so that alone I think is really helpful for the space and for, you know, being able to position axotilamab within the treatment algorithm when it is approved in, we're hoping, the 2024 timeframe. So, you know, beyond the items that you mentioned, reimbursement, pricing, adoption, you know, understanding who are the physicians that are likely to be the decision makers or key influencers in this space and early adopters will also be very helpful, but I think even building awareness of these new drugs and agents and how they can help patients is also part of the process that we're watching.
spk00: Perfect. Thanks for taking our questions, and congrats again on the progress.
spk08: Thanks, Phil.
spk02: Thank you. Our next question comes from Bert Haslett of BTIG. Please proceed.
spk10: Hi, thank you, and thanks for taking my question. Just with regard to 5613 and the expanded opportunities, in particular the master protocol trials, BDML and Intercept, could you just give a little bit more granularity with regard to timing and when we might get a sense of initial data for really any of those studies, including Augment 102?
spk08: Yeah, thanks, Bert. Thanks for the question. Maybe I'll ask Dr. Briggs-Morrison to comment on this as well. Hey, Bert.
spk07: Thanks for the question. So all three of those trials will be starting in the first half of this year. Again, for each of them, for the first two, the LLS trial and the combination chemotherapy trial, there's a phase one portion to pick a dose. And the data that is used to support the dose, you know, could be available, let's say, for BAML early part of next year, potentially also for 702. Intercept is not a combination trial. It's just monotherapy. And so it's really a question of when we'll have some early data on converting MRD positive to MRD negative. Again, I would think perhaps by middle of next year there might be something.
spk10: Okay, terrific. Just shifting gears to Axotilamab for a question. With regard to the IPF study, could you provide any more granularity on the Phase II effort there? I know it's early days, but I would very much love to understand a little bit more of the scale and scope of the work there.
spk08: Yeah, sure. Thanks, Bert. Maybe I'll ask Briggs to comment a little bit more on that as well.
spk07: Yeah, so Bert, we'll give a lot of details as we typically do once we have FDA endorsement on the trial and we're sort of opening the trial. I would say our general, the general approach that we've been advised by experts in the field is that if you're going to study IPF, you just have to study IPF. And you have to do, you know, an endpoint, FEC endpoint-driven trial that's about a year in duration. And so that's, you know, the sample size and some of the details we'll go through with you after we, you know, get endorsement and we're up and running the trial. But you should think of it as, you know, a year-long trial with FEC as the primary endpoint. We've looked at a talk with many experts about sort of surrogate biomarkers that you could use you know, to sort of do an intermediate time point. And the advice that we've gotten is that none of those have really been well validated, and there may be just as high a false positive as a false negative. And the best thing to do is if you really believe that you have an active agent, just go ahead and do the full one-year trial. So that's the current thinking, but we'll give you a lot more details once we open up the trial. Okay, great.
spk10: And then just one big picture question. You've had some intriguing success with the licensing of 5613N, axotilumab. Is there a common theme here with regard to therapeutic area, oncology, fibrotic disease? You know, you've, again, had some unique success. How are you thinking about additional business development efforts more broadly?
spk08: Yeah, thanks for that question too, Bert. You know, look, I think the theme for us has been identifying molecules that are sort of, we think, best in class differentiated molecules. And we have never sort of drawn a line saying that, you know, they're heme versus solid tumor or one modality versus the other. I think we're most interested in targeted therapy for oncology. Having said that, I think we are really looking for molecules at a time point in their development, generally on the earlier side, late preclinical, early clinical, where we can use our expertise in terms of clinical development, translational medicine, in order to make a big difference with these molecules. You know, right now we are on the heme side of the equation in terms of what we're developing, and there is some synergy between call points between our molecules, which is great. but I wouldn't rule out a broader kind of opportunity set within oncology, you know, maybe perhaps in solid tumors as well. So as you know, it's a competitive field, and it's hard enough to find molecules that you feel are worthy of resources and a team's time. So we're hunting hard, and we expect we'll be able to identify hopefully one or more molecules this year and continue building the pipeline.
spk10: Terrific. Thanks for the call. I look forward to more progress. Thank you.
spk08: Thank you, Bert.
spk02: Thank you. Our next question comes from Yigal Nochalmavitz of Citi. Please proceed.
spk09: Hi, Tim. This is Ashik Mubarak. I'm on for Yigal, and thanks for taking my question, and congrats on all the progress. I guess can you talk a little bit about the ex-U.S. opportunity for 5613? And do you think the expansion cohort data may be sufficient for a filing there as well, or perhaps you'll need another control study? And also just curious about how the BEAT AML cohorts might play into a European strategy. Thanks.
spk08: Yeah, maybe I'll ask Briggs to comment on our European strategy as well. And I took it to mean not necessarily a commercial opportunity, but you were thinking more in terms of trial and development, correct?
spk09: Correct.
spk08: Thanks, Asher. Greg?
spk07: Yeah, yeah, great. Thanks so much for the question. Your instincts are quite right here that, you know, the regulatory environment in Europe is different, and so the single-arm so-called palliative trial with CRCRH and durability may not be enough, but it may. So we're in, you know, discussions with regulators about what it'll take to get the drug approved in the EU. I think your point about beat AML, since that is, as we move into the randomized phase two portion, that is a randomized trial with sort of standard of care as the control arm, so that could play into it. But I would say, you know, stay tuned for more information on the European strategy. It will be different from the U.S.
spk09: Okay, great. That makes a lot of sense. And I guess, could you, is there any color you can share on maybe the status of the Acetilamab-JAK inhibitor combo?
spk08: Yeah, thanks for the question. As I think I said in my remarks, we're kicking off, we have kicked off our collaboration with Insight, and I think we're in the design phase of putting those trials together. And so we'll have more to say in future calls, but we hope one or more trials are initiated this year in combination with one or more of their JAK inhibitors. We haven't specified, they haven't specified as to which ones as of yet, but stay tuned.
spk09: Okay, great. Thank you very much.
spk08: Thank you.
spk02: Thank you. Our next question comes from Justin Walsh of the Riley Securities. Please proceed.
spk06: Hi. Thank you for taking the questions. I know that BEAT AML has a pivotal portion, but I was wondering if you can provide some comments on how Augment 102 and Intercept could lead to label expansions. Specifically, do you think that the data for these trials could support an expansion on their own or maybe just inform the design of larger trials?
spk08: Yeah, thanks for the question, Justin. I'll turn it to Briggs once again.
spk07: Yeah, no, Justin, I think the second two are more to inform future trials. It's getting a dose for the combination with chemotherapy in the refractory setting, and I think Intercept will give us a sense of what the MRD positive to MRD negative conversion rate is, which will allow us to sort of power a definitive trial.
spk06: Got it. Thanks. One more question for me. So you mentioned potential benefits of being first to market with a novel drug. It's pretty obvious, but can you maybe provide some color on how you plan to lay the groundwork to take maximum advantage of this? And sort of related to that, any thoughts on any potential label differences between your asset and any fast follower MEN and MMLR inhibitors that could come to the market?
spk08: Yeah, thanks, Justin. Great questions. In terms of label differences, I think it's a little early. I'll just take that question first. It's a little early to be speculating about label and how our molecule may be different than our competitors. I think at this stage, we're the only ones that have really shown much data in the clinical setting. And so I think we need to kind of wait and see what others show and how our drug continues to develop. Needless to say, I think we're in a very favorable position, and in terms of seizing the opportunity to expand, I think we made comments, and then I think you've become accustomed to us hearing about the different trials we're doing in the frontline and the maintenance setting. I think strategy here is obviously to get the drug approved and relapse refractory disease, expand into the frontline setting in combinations. I think what's very nice about our molecule is that you can add our drug onto regimen. We hope to be able to add it onto regimens that already exist, you know, to be able to accommodate the MLR or NPM1 mutation types. And so, you know, the opportunity to add in the frontline setting and then recapture patients in the maintenance setting and perhaps keep them on drug for a long period of time in order to keep their disease at bay. That's a vision we have for this molecule, and so we're going to continue to do those trials and look at combinations that position us both in the unfit frontline setting is perhaps the fit as well, and then moving in parallel into the maintenance setting. I'll also note that one important feature of the phase two pivotal trials that we're running now is that patients can go back on therapy after going through stem cell transplant, and that will be an opportunity to see, you know, how patients do in the, call it, maintenance setting, although we'll have to run, and I think we've said before, we'll be running additional maintenance trials. But it will give us an early look into you know, how patients do post-transplant and perhaps give an indication of how long they can actually stay on treatment, which we expect to be, you know, we hope quite a long period of time. So that's just a general, I think that's a general landscape of how we'll be approaching.
spk06: Great. Thanks for taking the questions. Thank you, Justin.
spk02: Thank you. Our next question comes from Joel Beatty of Baird. Please proceed.
spk05: Hi, thanks for taking the questions. First one is on the registrational trial of 5613. Just to clarify, what happens now when a patient screens for enrollment but is not on a CYP3A4?
spk08: They are allowed to be admitted to the trial. Thanks, Joel, for the question. They're allowed to be admitted to the trial. I think that there's no change to that. I think the point being that we're not holding spots for patients who are not on a strong CYP3A4 inhibitor. In fact, we're enrolling almost on a first-come, first-served basis, and it just so happens that the vast majority of patients are on a strong CYP3A4 inhibitor. I think the idea is that it might be a little bit slower to enroll patients who are not on a strong CYP3A4 inhibitor in the scheme of this trial, and that's what I meant by my remarks. We're not prioritizing them versus others who are on a strong CYP3A4 inhibitor, and there is in no way an impact on our ability to complete the trial. It's more of a submission issue and a labeling issue for dose adjustment that we're going to have to figure out in the course of the next while as the trial continues, what those ClinPharm questions and answers are. So that's the kind of long-winded answer to your question.
spk05: Dad, I appreciate that. It makes sense. For exotelamab, how much dose-finding work needs to be done for the IPF setting versus jumping right into a more robust study of efficacy?
spk08: Yeah, that's a great question. Maybe I'll ask Briggs to comment there.
spk07: Yeah, so thanks, Joel. The current thinking, which again we'll have to validate with the FDA when we finalize the protocol, is that we would not do dose ranging in the IPF trial. We would take a dose that we think gives us maximal pharmacodynamic effect. So as you know, in agave, There are three different arms, the 0.3, the 1, and then the 3 every four weeks. So the 1 mg per kg, as you saw in our ass data, looks like a very, very good dose. It gives us optimal PKPD, very good efficacy. So the current thinking is that we would not do dose ranging. We would just simply do a proof-of-concept trial at roughly that dose. So, again, we'll say more about that once we have that finalized. But our view is that's a really good dose to be able to test the concept. And obviously, if the trial is positive, there may need to be similar to Agave 201. Some additional regulators may want some dose ratio. But I think for us, it's a proof-of-concept trial where we just take one dose.
spk05: Great. Thank you. Thank you, Joel.
spk02: Thanks. Thank you. Our next question comes from Peter Lawson of Barclays. Please proceed.
spk01: Thanks for taking the questions. Thanks for the updates. Just around the CYP3A4 strong weak arms, how many patients would you need that aren't on a strong CYP3A4 inhibitor for refining?
spk08: Yeah, maybe I'll ask Briggs. Thank you for the question, Peter. Let me ask Briggs to answer that.
spk07: Right. So, Peter, the question is, you know, how many patients' worth of data at a dose that we feel comfortable saying that there's sufficient PK to, you know, label. We think it's probably in the, you know, let's call it 12 to 15 range of not on a strong CYP3A4 inhibitor and then a separate group that's on a moderate. As Michael pointed out, the pivotal trial At this stage, they'll all be on a strong inhibitor. So it's a question of probably in the 12th to 15th should give us enough understanding of the PK to be able to inform the dose.
spk01: Okay. How is that tracking? Is that significant? Right.
spk07: So as Michael said, I think our decision was that we're prioritizing enrollment of the registration trial. And the main reason to prioritize enrollment of the registration trial is so that we have good durability data, right? Because once we finish enrolling all of those patients, then it's six months after the last patient is when we do the data cut. And we'd like to have, you know, as much durability as possible for labeling purposes. So at this point, the preference is put, the focus is, the decision is put people on who are on a strong septic heart inhibitor and don't worry about the non or the moderates. Once the, at least one cohort is fully enrolled, then that patient population where we've already fully enrolled, we will then enroll additional patients with a none or a moderate. So I'm not sure if it's, to your question, if it's ahead or behind, but we've made a strategic decision that we're going to prioritize getting everybody in onto the pivotal trial because that will allow us to get the durability that we need.
spk01: Got you. Thank you. Would physicians have a problem as putting a patient on a strong CYP3A4 inhibitor, even if they didn't require it? So you kind of had almost like a label. That's right.
spk07: That's right. So right now, actually, there are patients who come into the trial who are not on a strong, and in order to get onto the trial right now, they need to be on a strong. So the physician just switches them. But it's actually not that many. Most of the patients, whatever the The voriconazole and posaconacol seem to be the preferred agents anyhow. So most patients are already on a strong CYP3A4 inhibitor, but every physician we've taught, every investigator on the trial has said, well, they need to be on a strong inhibitor to go on. I'll put them on a strong inhibitor. Not a problem.
spk01: Perfect. Thank you. And then just kind of a final question around the strong weak CYP3A4. The BEAT, the Augment 102 and the Intercept, does that, have a requirement or will it have a requirement for a strong CYP3A4 inhibitor?
spk07: Right. So for beta-AML and 702 right now, again, because the dose that we have agreement with the FDA is with a strong inhibitor, those patients will be on it. Again, that's standard of care in those populations because they're, you know, similarly get put on antifungals. In the intercept trial, It's not a requirement that they be on a strong CYP3A4 inhibitor. These are patients who are in morphologic remission, and so they actually don't necessarily need a nasal. So that one, you know, there's an option to be on the trial without being on a strong inhibitor.
spk01: Great. Okay. Thanks so much. Thanks for all the details. Thank you, Peter. Thank you, Peter.
spk02: Thank you. I would now like to turn it back to Michael Metzger for closing remarks.
spk08: Great. Thank you, DeeDee. And thank you to everybody who participated on the call today. We look forward to seeing many of you at the upcoming conferences in March. I know there are a handful of those. And with that, I wish you all a very, very nice evening.
spk02: This concludes today's conference call. Thank you for participating, and you may now disconnect.
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