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spk08: Good day, everyone, and welcome to the CINDEX fourth quarter and full year 2023 earnings conference call. Today's call is being recorded. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number five on your telephone keypad. If you would like to withdraw your question, press star and the number five once again. At this time, I would like to turn the call over to Sharon Clary, Head of Investor Relations at Syndex Pharmaceuticals.
spk04: Great. Thank you, Operator. Welcome, and thank you all for joining us today for a review of Syndex's fourth quarter and full year 2023 financial and operating results. I'm Sharon Clary, and with me this afternoon to provide an update on the company's progress and discuss financial results are Michael Metzger, Chief Executive Officer of Dr. Neil Gallagher, President and Head of R&D, and Keith Goldan, Chief Financial Officer. Also joining us on the call today for the question and answer session are Dr. Peter Ardenlik, Chief Scientific Officer, and Dr. Anjali Ganguly, Chief Business Officer. This call is accompanied by a slide deck that has been posted on the investor page of the company's website. You can now turn to our forward-looking statements on slide two. Before we begin, I'd like to remind you that any statements 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 factors, including those discussed in the risk factors section in the company's most recent annual report on Form 10-K, as well as other reports filed with the SEC. Any forward-looking statements made represent our views as of today, February 27, 2024 only. A replay of this call will be available on the company's website, www.syndax.com, following its completion. With that, I am pleased to turn the call over to Michael Metzger, Chief Executive Officer of Syndax.
spk15: Thanks, Sharon, and thank you to everyone joining us on the webcast. 2023 was a year of tremendous progress in execution for Syndax, marked by the delivery of positive pivotal data and regulatory submissions for both Revimenib and Axotilamab. We look forward to continuing this momentum in 2024 with two potential approvals and commercial launches. Syndex is firmly on the path to distinguishing itself as a commercial stage SMIDCAT biotechnology company. And with opportunities to expand well beyond the initial indications for Revumenib and Axotilimab, we envision creating long-term value with these franchises for years to come. On slide three, let me take a moment to review some recent accomplishments. With Revimenib, our highly selective menin inhibitor, we made significant clinical and regulatory progress in the fourth quarter. At the 2023 American Society of Hematology annual meeting in December, we presented robust data from the Phase I and Phase II portions of the Augment 101 trial that included a late-breaking oral presentation highlighting pivotal results from the KMT2A acute leukemia cohort, as well as multiple phase one combination trials that demonstrated Revumentib's ability to safely and effectively combine with standards of care. In late December, we announced the submission of an NDA filing for Revumentib under the FDA's Real-Time Oncology Review, or RTAR program, for the treatment of adult and pediatric relapsed or refractory KMT2A-rearranged acute leukemia. Submitting the NDA under RTOR ensures early engagement with the FDA throughout the review process, helping to de-risk the submission and provide a potentially expedited timeline to reviewment of approval. We expect to receive a PDUFA action date for reviewment of this quarter, which should align with a third quarter approval date. For axotilamab, our anti-CSF1R antibody, I'm excited to announce today that the FDA granted us priority review and a PDUFA action date of August 28, 2024, for the treatment of chronic graft-versus-host disease, or GVHD, after failure of at least two prior lines of systemic therapy. Positive data from the pivotal Agave 201 trial presented at a plenary scientific session at ASH in December formed the basis of the BLA submission. And last quarter, we also initiated a Phase II double-blind randomized clinical trial for the treatment of idiopathic pulmonary fibrosis, or IPF, that Neil will later detail in this call. Financially, we are in a very good position. We strengthened our balance sheet in the fourth quarter with an additional $258 million in cash, and Keith will go into more detail in our financials later in this call. We continue to prepare for commercialization in 2024. Our first mover advantage is of high strategic importance, and we are busy ensuring that we successfully execute two first and best-in-class drug launches. For Revimenib, we are focused on pre-launch activities, and we are finalizing our go-to-market strategies for both Revimenib and Exotilamab that we look forward to communicating in the coming months. In January, we exercised our option under our agreement with our partner Insight to co-commercialize Axotilamab in the United States and provide 30% of the commercial effort as there is a considerable benefit to promoting two products simultaneously to a highly overlapping and targeted physician-prescriber universe. 2024 is shaping up to be a historical year for Syndax as we prepare to launch two first and best-in-class products, and I am confident that we have the expertise, resources, and determination to achieve our goals. Now let's turn to slide four, and I'll begin a recap of some recent clinical data for Revumenev that investigators presented at the ASH annual meeting in December. There was significant excitement for Revumenev in the reaction to the data that investigators presented, which clearly demonstrated Revumenev's potential to become a cornerstone for the treatment in NPM1 and KMT2A acute leukemia. The data presentations have translated to continued strong enrollment in our clinical trials through additional engagement from the medical community, as well as additional requests for investigator-sponsored trials that could ultimately expand the use of the drug once approved. In the late-breaker presentation for the Augment 101 pivotal trial, we indicated that KMT2A acute leukemia patients achieved clinically significant responses to treatment with a high overall response rate of 63%, and responses were observed across all major subgroups. Revumentum delivered a high rate of deep responses with a CRCRH rate of 23%, 70% of which were MRD negative. At the time of the data cutoff, the median duration of CRCRH response was 6.4 months based on a Kaplan-Meier estimate with 46% or six patients remaining in response. Moving to slide five. In the Augment 101 trial, 39% of the overall responder population proceeded to a stem cell transplant, which is higher than historical benchmarks in this population of less than 5%. Many of these patients proceeded to transplant prior to achievement of a CRCRH. At the time of the data cutoff, 71% of patients who underwent a transplant had either restarted Revimentib or were eligible to restart as maintenance therapy. A few of these patients had been receiving maintenance treatment for as long as eight months, with several continuing on therapy, highlighting the potential for long-term treatment with Revumatic. Physicians with whom we have engaged are impressed by Revumatic's ability to induce rapid tumor clearance in heavily pretreated patients, enabling many of them to undergo a potentially curative bone marrow transplant. Treating physicians have repeatedly told us that they want to use Revumative as early as possible during treatment to bring more patients to transplant and then extend responses by continuing treatment following transplant engraftment. We unanimously heard from KOL's At Our Ash investor event and continue to hear from physicians today their belief that continued use of Revumative post-transplant should lead to the best possible outcomes, and it is an attractive option for these patients. Turning to slide six. The final pivotal cohort of the Augment 101 trial continues to enroll relapsed or refractory MPM1 mutant AML patients. It is designed to enroll 64 patients and up to 20 pediatric patients. With multiple presentations highlighting the consistency of Menin inhibition across MPM1 mutations and KMT2A rearrangements as a monotherapy agent, and in combination with standards of care, we continue to see the excitement building for Revimenib and MPM1. We are quite pleased with the recruitment in the trial and are reaffirming our guidance of expected completion of enrollment in the late first quarter or early second quarter of this year. We expect to report top-line data from the trial in the fourth quarter of 2024, and importantly, we continue to look forward to a potential approval in 2025 based on an SNDA filing for NPM-1 following Revu-Medim's anticipated initial approval in KMT2A acute leukemia. The Phase I MPM-1 data that we've reported for Revimenib supports our conviction that Revimenib could be an important treatment for this AML population. Across monotherapy and in combination, we've generated consistent results between KMT2A and MPM-1 acute leukemias. In the Phase I portion of Augment 101, 50% of MPM-1 patients achieved an overall response and 36% achieved a CR or CRH response. And importantly, all patients with a CR-CRH were MRD negative. Consistent with the KMT2A population, Revimenib also enabled a high percentage of MPM1 responders to proceed to transplant, 43%, and responses have been durable. This is despite many of the patients failing prior venetoclax therapy and receiving prior stem cell transplants. It's worth noting that Revimenib has been well-tolerated in patients with relapsor refractory MPM1 AML, In the Phase 1 results, there were no Grade 4 or 5 QT prolongations, no patients experienced more than Grade 2 differentiation syndrome, and no patients discontinued due to treatment-related adverse events. Now, turning to Slide 7, we believe that RevuMeta will form the backbone of treatment for patients with KMT2A and MPM1 acute leukemias. Our clinical strategy extends beyond the initial relapse or refractory indications and into the frontline and post-transplant maintenance settings through combinations with approved therapies. In the frontline setting, there are basically two broad categories of patients, those who are fit and can tolerate intensive chemotherapy, and those who are deemed unfit for intensive chemotherapy and would traditionally receive venetoclax plus azacitidine. Our frontline strategy is to add Revumenev onto standard of care treatments to show that Revumenev can be used effectively in combination, thereby increasing efficacy without negatively impacting the tolerability or safety profile of those regimens. We started combination development with venetoclax plus azacitidine in frontline unfit AML population in the BEAT AML trial. The trial is expanding to validate the recommended phase two doses, and we expect to have an additional data update for this trial later this year. In parallel, we are planning the venetoclax plus azacitidine pivotal trial that we expect to initiate by year end. To address frontline AML patients fit enough to tolerate intensive chemotherapy, we initiated a Phase I dose escalation trial of Revumetib in combination with standard of care induction therapy known as 7 plus 3. Here, we also anticipate identifying an RP2D for Revumetib and initiating a pivotal trial for this combination soon thereafter. On slide 8 is the data from the BEAT AML trial, a Phase I trial being conducted by the Leukemia and Lymphoma Society. In this trial, frontline AML patients who are unfit for induction chemotherapy are dosed with a triplet of revumentib, venetoclax, and azacitidine in 28-day cycles. In an interim look at data from 13 patients, 100% achieved a complete remission, or CRC, and all patients for whom we had an MRD assessment achieved an MRD negative response. This is significantly higher than what would be expected from venetoclax plus azacitidine alone based on the results of the VIALA-A trial where patients achieved a 66% CRC rate and only 24% achieved an MRD-negative response. Importantly, I'd like to emphasize that there was no impact on the safety or tolerability observed by adding Revimediv to this doublet regimen. Turning to slide nine. Gravimenta was also evaluated in another all-oral venetoclax combination among patients with relapsorefractory AML. Interim data from this trial, known as SAVE-AML, was conducted by investigators from the MD Anderson Cancer Center and presented at ASH. The SAVE trial evaluated the oral combination of revimenev, venetoclax, and a fixed-dose combination of dacitabine and cetaziridine in relapse or refractory AML or mixed phenotype acute leukemias. In the interim presentation, nine patients with either NPM1, KMT2A, or NUP98 mutations were enrolled into the trial. These patients had received a median of three prior lines of therapy, and over half of them had received prior venetoclax and prior hypermethylating agents. At the interim assessment, 100% of patients achieved a response and 78% achieved a complete remission. Importantly, responses were observed across all three patient subsets, NPM1, KMT2A, or NUP98. This triple combination was also well-tolerated at both active doses of Revimed in the trial, including the current monotherapy RP2D, with no new or increased safety signals observed beyond what would be expected with venetoclax and a hypomethylating agent. Now to slide 10. KMT2A and MPM1 acute leukemias represent up to 40% of all AML patients, and there are no FDA-approved targeted therapies for this population. Inclusive of the expansion opportunities, there is the potential to address upwards of 12,000 MPM1 and KMT2A acute leukemia patients across various settings. We believe relapse or refractory KMT2A acute leukemia alone represents a $750 million market opportunity in the U.S. The annual incidence of KMT2A acute leukemia is about 2,600 patients, and the majority are refractory to frontline standard of care treatments. We estimate a median duration of therapy across the treated population of approximately nine months, and we believe the clinical data supports pricing competitively with other targeted therapies in AML, such as the FLT3 or IDH inhibitors. We anticipate that with the only age and disease agnostic label in KMT2A acute leukemia, along with no other treatment options approved in this population and no near-term competition, Revimenib should become the treatment of choice for patients with relapsed or refractory KMT2A acute leukemia. We expect that our first mover advantage and the experienced physicians will gain treating patients with Revimenib could extend meaningfully beyond KMT2A and allow us to build a formidable franchise in the next few years, augmented by a second indication in MPM1 AML. Our market research suggests that if approved, oncologists are likely to prescribe Revumetib as either their second or third-line agent of choice for the treatment of NPM1 AML. We estimate that this population would be slightly larger than the relapsed or refractory KMT2A acute leukemia population, and based on our Phase I results, we also believe overall efficacy and treatment duration will be consistent between the KMT2A and NPM1 relapsed or refractory populations. Having two distinct market segments in acute leukemias available to us, KMT2A and NPM1, would create a total accessible population of somewhere between 5,000 and 6,500 patients in the relapsed or refractory setting and an addressable market opportunity approaching $2 billion in the U.S. Beyond acute leukemia, we are also investigating the opportunity to expand to solid tumors. Our proof-of-concept signal-seeking phase 1 clinical trial in metastatic colorectal cancer is ongoing. This trial is based on preclinical science that supports the role of menin-KMT2A interaction in beta-catenin-driven tumors. We are following these patients and expect to provide an update on the progress of the dose escalation phase of the trial in the second quarter of 2024. we would perceive single-agent activity reflected as responses or prolonged stable disease as encouraging in this third-line patient population. Let me now turn to axotilamab, our monoclonal antibody targeting the CSF1 receptor beginning on slide 11. As noted earlier, we're thrilled that the BLA for axotilamab in adult and pediatric patients with chronic GVHD after failure of at least two prior lines of systemic therapy has been given a PDUFA action date of August 28, 2024 by the FDA. Data from the Global Pivotal Agave 201 trial formed the basis for this application. The Agave 201 trial, which was showcased during the Plenary Scientific Session at ASHE, met its primary endpoint of overall response rate by cycle 7, day 1, using the 2014 NIH consensus criteria for chronic GVHD across all three dose groups. The overall response rate was 74% at a dose of 0.3 milligrams per kilogram administered every two weeks. The responses were durable, with a median duration of response not yet reached at the time of data cutoff, and 60% of responders were still responding at one year. Axotilinab was well-tolerated in the trial with a low 6% rate of discontinuation. The most common adverse events were consistent with the on-target effects observed in prior trials. Axotilinab is differentiated from other approved therapies for chronic GVHD in that it is the first investigational chronic GVHD treatment to target inflammation and fibrosis through the inhibition of disease-associated macrophages. On slide 12, you will note that responses, including CRs, were seen across all organs involved, and notably in fibrosis-dominated organs, including esophagus, joints, fascia, and lung. Over 85% of patients reported a reduction in chronic GVHD-related symptom burden in agave 201, which supports the potentially pronounced impact this mechanism can have on patients suffering from chronic GVHD. These results reinforce its potential as a first and best-in-class CSF1R monoclonal antibody in chronic GVHD. I'll now turn the call over to Neil to speak about the IPF trial that we started in late fourth quarter, as well as the scientific rationale for the use of axotilamab in IPF.
spk03: Neil? Thank you, Michael. Turning to slide 13. We're excited about the opportunity to expand the development of axotilamab into fibrotic diseases such as idiopathic pulmonary fibrosis, where the monocyte microphase cell lineage plays a key role. iPS is a chronic fibrosing lung disease for which there are limited treatment options. Only two drugs have been approved, and both have only been shown to slow but not halt or reverse disease progression. The only opportunity for a cure is lung transplant, which is limited to less than 5% of patients. With the estimated U.S. prevalence of IPF growing to over 180,000 people by 2026, there is an increasing need for new, well-tolerated, and effective medications. There are several reasons why we are excited to pursue fibrotic disease outside of chronic GVHD and why we have confidence that axotilamide may provide meaningful benefit in IPF. There is a growing understanding of the important role that macrophages play as a master regulator of the fibrotic process. There's a wealth of preclinical and clinical data indicating that the CSF1 signaling pathway may play an important role in the development of pulmonary fibrosis. One such preclinical dataset from an in vivo bleomycin pulmonary fibrosis model is shown in the panel on the left. The bleomycin model is commonly used to investigate the potential of therapies to address lung fibrosis, and in this experiment, animals were treated with an anti-CSF1R antibody, or saline control, nine days after the administration of bleomycin. The histological section on the top left shows a normal lung with extensive white airspace. Conversely, the bleomycin-treated lung has extensive fibrosis, as indicated by the dark-colored material. Strikingly, the lung treated with bleomycin and then therapeutically with an anti-CSF1R antibody in day 9 has significantly less fibrosis than markedly preserved white airspace. Analysis of the extent of fibrosis using the ASHCROSS score indicates that significantly less damage to the lungs occurs in the presence of the anti-CSF1R antibody. Even more encouraging are the clinical data for axotilamab in patients with pulmonary manifestations of chronic GVHD, where clinically notable improvements in lung function have been observed. The panel on the right shows the data originally presented at the American Thoracic Society meeting last year from patients in the Phase I to chronic GVHD trial of axotilamab who had GVHD-related bronchiolitis obliterans syndrome, or BOS. As you can see, most patients experienced improvements or slowing of decline of pulmonary function, which is very unlikely to occur spontaneously. These data, in conjunction with the organ-specific data from the Agave 201 trial presented earlier, strongly support the therapeutic potential of axotilumab in interstitial lung diseases, including IPS. Turning to slide 14. Here we lay out the design of our recently initiated multinational phase two trial of axotilamab in ICF. It's a 26-week double-blind, placebo-controlled, and multi-center trial, which aims to include 135 patients randomized two-to-one to receive 0.3 milligrams per kilogram of axotilamab every two weeks or placebo on a background of standard of care. The primary endpoint is the annualized rate of decline in forced vital capacity, or FEC. Key secondary endpoints include disease progression, quality of life specific to patients with obstructive airways disease and others. We believe this study is robustly designed to demonstrate proof-of-concept fraxipitilumab and IPF, thereby enabling us to advance the molecule into phase three pivotal development potentially. Let me now turn the call back to Michael.
spk15: Thank you, Neil. Turning now to slide 15. which highlights the broad clinical and commercial opportunity for axotilamab. Approximately 14,000 U.S. patients suffer from chronic GVHD, 50% of whom require treatment beyond second line due to disease progression, inadequate response, or disease manifestations that aren't wholly addressed with current treatment. There are no cures for this advanced population of chronic GVHD patients, and patients who are initially treated with corticosteroids are then cycled through a variety of additional therapies. While patients may be treated with any of the approved therapies, the order in which they are used may depend on the physician's experience with how a given agent may address specific manifestations of the disease. Newer entrants, Jackify and Resiroc, have had successful commercial launches, which speaks to the unmet need in chronic GVHD and the substantial commercial opportunity for a differentiated agent such as exotilamide. Axotilamab suppresses monocyte-derived macrophage activation and proliferation, which may provide more comprehensive control of the disease than currently approved therapies. Addressing inflammation and fibrosis in one mechanism of action is a key differentiator and also supports moving axotilamab earlier in the treatment paradigm to potentially prevent organ damage before it occurs. Because axotelimab is an antibody, drug-drug interactions are expected to be minimal, and axotelimab's unique mechanism of action may offer the benefit of being an ideal combination partner with standard-of-care therapies currently used for the treatment of chronic GVHD. The opportunity to expand to ex-U.S. markets and into other high-value indications could build significant additional value for axotelimab over the next few decades. We're looking forward to the insight-led initiation of additional trials of axotilamab, including a Phase II combination trial with Jacify and a Phase III combination trial with corticosteroids, which is expected to commence in mid-2024. I'll now turn the call over to Keith to review our financial results. Keith?
spk02: Thank you, Michael. Turning to slide 16. As Michael mentioned earlier, in the fourth quarter, we strengthened our balance sheet, adding $258 million, providing strong validation of Syndex's potential from both existing as well as new high-quality institutional investors. The $600 million on the balance sheet at year end is expected to provide cash runway through 2026. Turning to the income statement, operating expenses for the fourth quarter were $77.9 million, comprised of $55.1 million of research and development expense and $22.8 million of selling, general, and administrative expense in line with guidance. Looking forward, our financial strength enables us to focus on the execution of advancing our pipeline and achieving an exceptional launch of RevuMedUp and Axotelmab later this year. Keeping in mind that we've always embraced a disciplined approach to resource allocation, I'd like to provide financial guidance for the first quarter and full year 2024. For the first quarter, the company expense expects research and development expense to be $56 to $62 million, and total operating expenses to be $82 to $88 million. For the full year 2024, the company expects research and development expenses to be $240 to $260 million, and total operating expenses to be $355 to $375 million, including approximately $43 million of non-cash stock compensation expense. With that, let me now turn the call back over to Michael.
spk15: Thank you, Keith. As you have heard during the call, 2023 was a landmark year for growth and execution. As evidenced by our positive pivotal trial readouts and two regulatory submissions for our two lead drug candidates, both of which are first and potentially best-in-class treatments, this is only the beginning of what's to come for Syndex. We are in a significant transition into a fully integrated biopharmaceutical company serving multiple patient populations of high unmet need. Both programs offer the potential for broad franchise opportunities beyond their initial registration indications, adding to Syndex's long-term growth potential. We have ambitious goals and milestones that I've set out for 2024 and that are laid out on slide 17. I'm confident that we have the right plan and team in place to execute on them. As always, I'd like to express my sincere appreciation to the CINDEX team, collaborators, and most importantly, the patients, trial sites, and investigators involved with our clinical programs. Through your important work, we are getting closer to delivering on our mission of improving the lives of patients with cancer. I'd also like to thank our committed long-term investors who continue to share in our vision and support us in building Syndex. With that, I'd like to open the call for questions. Operator?
spk08: At this time, I would like to remind everyone in order to ask a question, press star, then the number five on your telephone keypad. If you would like to withdraw your question, press star and the number five once again. We'll pause for just a moment to compile the Q&A roster. Our first question comes from Peter Lawson with Barclays. Please go ahead. Your line is open.
spk05: Hi, this is Cheyenne for Peter. Congrats on all the progress. But you've announced that for axotilamab, can you comment on expectations for your launch in 3Q? And related to that, it sounds like you're still expecting a 3Q potential approval for the menin inhibitor. Are you expecting that to be potentially positioned for sales in 3Q, or is this potentially dependent on you receiving priority? Thank you.
spk15: Thanks, Shay, for the question. So first off, I think you broke up a little bit on the second question. Do you want to take the first question? Yeah, sure.
spk02: So thanks for the question, Shay. This is Keith. So for axotilumab third quarter, you know, we have the PDUFA. When the FDA actually approves the drug is still a question. As we've laid out earlier in the year, we've opted into the co-promotion, and as Michael said earlier, into the co-promotion of axotilumab. So we'll be ready with our sales force, you know, prior to the approval of either product. So as you can see by looking at LinkedIn or looking at our website in the careers section, we're currently recruiting for all of the territory managers. So that's public knowledge. So we'll have them on board and trained up prior to approval of either product. With respect to your question around the timing of the initiation of revument of revenue. And we'll have to wait until later this quarter when we receive the PDUFA date, PDUFA action date from the agency. And I think at that time we'll have a better idea of when to expect the initiation of revument of revenues. Does that answer your questions?
spk08: Our next question comes from Anupam Rama with JP Morgan. Your line is now open.
spk12: Hey, guys. Thanks so much for taking the question. Maybe expanding on Keith's comments just now, just remind us of where you are in terms of the Salesforce sales team build-out. What are some of your pre-commercial kind of plans here in the near term? And then maybe just on expenses, how we think about the growth here quarter over quarter looking to 2024, especially on the SG&A line as we think about the launches.
spk15: Thanks for the question. Maybe I'll take the first part in terms of Salesforce build-out, and then I'll leave the rest to Keith to answer. So I think, as we've said in the past, we're building out our commercial organization to accommodate both the launch of Revumative, and now we've opted into the the co-promote with Insight around axotilamab to provide up to 30% of the FTEs for that effort. You know, it's an overlapping, as I said, my remarks, overlapping and highly targeted call point. And so the opportunity here is with, you know, roughly 40 to 50 representatives to cover the U.S., You know, quite extensively and also cover both products. So that's the build out of that Salesforce will continue until the time of right up until we have approval on on both agents, which, as Keith mentioned, we have a PDUFA at the end of August for. And we expect the PDUFA imminently for revenue as well. So we have, you know, we'll be ready well in advance of both of those to put the sales force in place. And leadership has been hired and is doing extensive work to get ready. Maybe Keith, do you want to handle the second point?
spk02: Yeah. So Anupam, with respect to your question on SG&A expense, We gave guidance today on total OPEX for the year, 355 to 375. That includes noncash.com. And then for R&D, the 240 to 260. So, you know, based on that, you can, you know, it's circa 100 slightly higher in total SG&A for the year. You know, last year we ended the year SG&A totaling about $67 million, and about $22 million of that was in the fourth quarter. So, you know, the reps, I think you can assume, you know, we're recruiting now. I think it would be, you know, a reasonable assumption to assume they're definitely on board for the second half of the year in advance of both launches. um you know take a take a reasonable uh cost per rep per year you know and add that on um and and i think you can pretty simply kind of work out the math of the sgna growth for the year you know from 66 67 million this year to 100 next year um and given the fact that we've given first quarter guidance of total opex and r d expense as well But, yeah, you know, definitely the second half of the year will be the additional commercial field force. You know, we have the G&A infrastructure in place from, you know, HR, finance, IT. That infrastructure is well in place. It's going to be the reps plus the A&P to go with that.
spk15: Thanks so much for taking our questions. Thanks, Anupam. Thanks, Anupam.
spk08: The next question is from the line of Phil Nadeau with TD Cohen. Your line is now open.
spk10: Good afternoon. Thanks for taking our questions, and congrats on the progress. A couple on the ASH data and then a follow-up on XTLMAP. So in terms of the ASH data, there are two controversial aspects that we keep debating with investors, and I'm curious to get your thoughts on those. First, in SaveAML, I know you said that there was no additive toxicity involved, by adding Revimenib to the background regimen. Not everyone agrees, so could you address the neutropenia rates that you would expect? I think you showed 56% at ASH. What would ASTX727 do alone? And then second, on BAML, again, there's some concerns about the combinability, particularly the dose of Revimenib going forward in light of the SIP interaction that Venn has. How will you determine the Phase II dose through BAML, and what type of dose adjustments would you anticipate once that Phase II dose is found?
spk15: Phil, thanks for the question. I think I'm going to turn it over to Neil so he can make a comment first about SAVE, and then he'll address the question you brought up about BAML. Thank you.
spk03: Yeah, so I think the first thing to remember is that the trial, the SAVE trial, accrued a very heavily pretreated population. So two-thirds of patients had failed prior then, a third had been, or over half of them had been transplanted. So this is a patient population, a median number of prior therapies of three to four. And therefore, the cytopenia rate that was observed is, according to the investigators, and not only the investigators in the study, but others, entirely consistent with what you would expect with uh with ven and oral decided then you know in that particular patient population i mean if there's been some comparison to you know a less heavily pre-treated population that that may be in people's minds that's just not a valid comparison like you have to look at the patient population that was included in the trial and therefore that's why we can you know the investigator has stated his confidence and we agree with them that that the cytopenia rate was consistent with what would be expected uh from the backbone In terms of beat AML, I'm not sure that I understand why you think that there's a challenge around dose selection. So just to reiterate for the entire audience, there were two doses of Revimenib tested in all three of the combination trials. that we reported out at the investor event at ASH, right, or was also reported at ASH itself. Dave AML was presented independently of our event as well. So the two doses that were included in all three combination trials were 113 milligrams twice a day and 163 milligrams twice a day. Different patient populations Obviously, in the B and AML trial, they were newly diagnosed. Save, we've just discussed, they were heavily pretreated relapsed refractory. And in ARGMENT-102, they were heavily pretreated relapsed refractory patients. And in all three trials, the dose-limiting toxicity windows for both doses were cleared. Okay? So, and with respect to B and AML, So what the group is now doing is expanding those cohorts to further refine what the RP2D would be for a phase three trial. And we stated, you know, many times publicly that it is our intention to proceed to that phase three by the end of the year. So just one final point. Those two doses, 113 and 163, 163 milligrams is the presumptive monotherapy full dose. when administered with a strong CYP3A4 inhibitor, okay? And 113 milligrams is also highly active. Also, you have to recall that venetoclax and azacitab in the beta-AML trial was administered at full dose. So there's, you know, the... There's no question in our mind that the combinability of Revumena with Veneza in the newly diagnosed setting, as well as in the other two settings, you know, it's clear.
spk10: That is very helpful. It makes it clear. And then last question, just on AxotelMap sales and marketing. I think in your prepared remarks you said Syndex is responsible for 30% of the marketing efforts. In the answer, I think, to Anupam's question, you said 30% of FTEs. How are the marketing efforts – how is 30% of marketing efforts defined? Is that specifically 30% of FTEs, or are there other metrics that CINDEX needs to deliver as well, such as touch points with physicians or call points or something else?
spk02: Yeah. Turn it over to Keith. Go ahead. Yeah, Phil, thanks for the question. So apologies if I wasn't clear or if we weren't clear. So the – Our partnership agreement with Insight stipulates that we have the ability to contribute 30% of the promotional effort. So from a sales call point perspective, we'll be delivering 30% of that effort. So I mentioned it before in FTEs because I didn't want to speak like in the number of reps, but we will be delivering 30% of that Salesforce effort. But don't forget, it's a combined P&L, right? So we'll put the cost of that 30% effort into the combined P&L. Insight will put their 70% of the cost of their effort into the P&L. And then any advertising promotion expenses incurred by Insight, because they are taking the lead from that perspective, would go into that joint P&L. And the bottom of that joint P&L, call it the commercial profitability of the product, is split 50-50. Perfect. That's very helpful. We pick up 50%. They pick up 50%.
spk16: Thanks again for taking our questions. Thank you, Phil. Thanks, Phil.
spk08: question comes from Brad Canino with CFO. Your line is now open.
spk11: Good afternoon. You've provided peak sales opportunities, but how do you see the KMT2R launch playing out this year? You know, things in terms of number of patients that are available in the relapsed refractory setting, where they're concentrated, and what to expect for the pace of uptake?
spk15: Brad, thanks for the question. I think maybe a little early to start speculating about sales ramp and projection, and we'll reserve the ability to give a little bit more guidance as we get closer to commercialization. I think, as we stated in our remarks, we think KMT2A is a really I'd say compelling opportunity commercially in the sense that we'll have a first-to-market, best-in-class product to address patients even earlier than they were tested in the clinical trial. So we're talking 2,600 patients overall, probably about 2,000 of which are treated in the relapsed refractory setting. We believe that we'll have the opportunity to address the vast majority of those patients. And as we've pointed out, in previous discussions that these patients are in dire need of therapy. Many of them can go to transplant, hopefully, through the use of treatment with Revimenib, and then potentially back on treatment in a post-transplant setting. So there is, we think, a highly addressable population. Physicians seem to be quite motivated to use the drug. And so we've seen that in our trials, but we've also heard that from physicians. So I think this sets up as a really interesting new opportunity for a drug to come to market with really no competition at this current point to get in the way of a very successful launch. So that's how we see it today in terms of projections and launch and ramp. We'll maybe preserve that for future discussions.
spk08: Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is now open.
spk09: Hey, guys. Thanks for taking my question. I had one on the first line setting for every minute in combination with 7 plus 3. In your opinion, what is the right way to view frontline combo data with menin inhibitors and 7 plus 3, and specifically given that one would expect very high CR rates, presumably on top of 7 plus 3 already, you know, what are other benchmarks that you're looking for in your own study, you know, including MRD status, for example, transplant rates, or any other efficacy measures that are important in your opinion?
spk15: Michael, thanks for the question. Important one, certainly, to get a handle on. I think the 7 plus 3 regimen, as you know, is highly effective in frontline patients, NPM1 and KMT2A patients initially respond. Upwards of 80% of patients respond to those treatment. However, they don't usually respond for long. So there's relapse that happens with most of those patients. Things to look for beyond just CR rates, CR-CRH, of course, would be MRD and transplant rates, which we would be looking for. Obviously, we've seen high rates of both in relapsed refractory patients. Now we would be moving to frontline, and you'd expect to see equal or better rates of MRD and certainly transplant in earlier line settings. And so I think those are some really important measures. Duration of treatment, of course, seven plus three is a short course. The ability to treat with Revimenib and keep patients in remission for an extended period of time is obviously something that we'd want to do. that we'd want to see of course it's it's it's new days right we haven't you haven't seen a meta inhibitor perform in the front line seven plus three um as of yet so i think it would be you know up to us to kind of set the trend for what uh what the bar looks like there but um certainly from a cr perspective um you in in a safety perspective you you kind of know what you'd want to see relatively clean relatively clean profile and highly effective, but you need to continue on, and she'd see deep, durable responses as well. Neil, do you want to add anything?
spk03: Yeah, maybe just two things I would add to that. And I think there may have been a regulatory context to the question about what the potential endpoint could be. It's certainly too soon to talk about that. I think Michael has mentioned, you know, MRD-CR is another certainly an endpoint of interest. you know, whether or not it could be an approvable endpoint remains to be seen. And we will, of course, be engaging in discussions with the agency, you know, as we move closer to having now initiated our dose ranging trial, as we move closer to initiating our phase three trial. And then the only other add that I would make would be, you know, if you look at, the seven plus three trials that have been conducted really, you know, over the last, you know, sort of 10 to 12 years, going back as far as my description, they've all included maintenance phases. And you could assume that any seven plus three trial that we would conduct would also include a maintenance phase. And in support of that, what we have seen, recall that what we've seen in the relapsed refractory setting post-transplant, is patients who've remained on therapy for protracted periods of time, speaking to the tolerability of Revimenib in a last refractory setting. And therefore, we anticipate that as we move towards the newly diagnosed setting, that patients who would be, for instance, given monotherapy maintenance after induction consolidation therapy would probably, would most likely tolerate the medicine very well as well, or the molecule rather.
spk16: Okay, thank you. Thank you, Michael.
spk08: Our next question comes from Yigal Nachumovitz of Citi. Your line is now open.
spk13: Hi, guys. This is Ashik Mubarak. I'm for Yigal. Thanks for taking my questions. I had a few on axotilumab. I guess first, congrats on the PDUFA date. I'm just wondering how involved you are in the regulatory process from this point out. Obviously, we know Insight is leading the proceedings, but will you be part of the mid-cycle review? Will you be able to weigh in on labeled negotiations? How should we think about that?
spk15: Yeah, Ashley, thanks for the question. Look, we're very involved with, obviously, with Exotilamab. We generated the data, and it's been a very close collaboration with Insight, and so we are involved in the regulatory process. and are working with them closely to get this drug approved in all facets. So you're thinking about label negotiations and things like that. We are, I'd say, suffice to say, very involved with what's going on. So that's an exciting development for the company, and obviously we have great experience with the molecule and want to think that we're involved. So that's certainly what it is. Was there a second part to your question, or did I cover it?
spk13: No, that's very clear. I wanted to ask another one on IPF. Maybe I'm forgetting or simply just don't remember this from prior calls, but I know you're evaluating the 0.3 make per kick dose, which was obviously the dose that looked best in Agave 201. I'm just wondering what kind of gave you confidence that's the right dose specifically for IPF. I guess why didn't you need to do dose optimization work or is the disease biology really similar enough that you felt confident enough not to do that. Obviously, we're dealing with a different endpoint here, so just curious what your thoughts are.
spk03: Yeah. Hi, it's Neil. I'll take the question. So, no, it's a good question. We did have a long, you know, a long discussion internally about the dose selection. So, a couple of things. You know, quite clearly, the 0.3 milligram dose in Agave, in the Agave trial, was superior to the other two doses. And, you know, we don't need to, you know, sort of go back over that. It's quite clearly the superior dose in terms of efficacy as well as tolerability. And, you know, what we have talked about a number of times over the past year, and particularly before we announced the details of the IPF proof of concept trial that we talked about today, was that we were looking for an efficient trial design. And therefore, the most efficient trial design, which would get us to a robust proof of concept answer, you know, efficiently, meaning efficiently in terms of the design of the trial, but also in the time to execute the trial, was the one that we've described today. And we felt that on the balance of, you know, the balance of everything, that it was reasonable to go ahead with one dose in this trial, and that those should be 0.3 milligrams. I think to one point that you alluded to, yes, I think that there is sufficient overlap from a biological perspective to have made that decision, and that sort of partly led us to that decision.
spk15: Right. Maybe I'd add on to that that you probably know that we did extensive dose ranging in the course of the phase one as well as the pivotal trial. We've also looked at early on, we looked at healthy volunteers. We know how this antibody behaves and the effect that it has on the macrophage. And so I think the understanding the pharmacology here and therefore how we think it would translate to patients in IPF kind of gave us some, you know, I think some good confidence that 0.3 would be the appropriate dose in addition to what Neil has added. Very helpful. Thanks very much.
spk08: Thank you. You're welcome. Our next question comes from the line of Jason Zemanski from Bank of America. Your line is now open.
spk07: Hey, guys. This is Alex Hammond on for Jason. Thanks for taking my question. Appreciating it somewhat early, but with regards to your regular submission for revuminib, can you provide some color on what you expect to be included in the label? Are the eight efficacy-evaluable ALL and PAL patients with a 12.5% CR, CRH enough to warrant a tumor-agnostic label? And what are your basic expectations on potential safety monitoring requirements for DS and QTC prolongation? Thank you.
spk15: Maybe I'll turn it over to Neil. We talked a little bit about the label and then maybe talk about any kind of safety. Sure.
spk03: Well, our anticipation is that the label, I mean, let me just pre-stage what I'm about to say by reminding everyone that we got BTD back in December 2022 for, came to a and ALL adults and kids. So, you know, the development program moving forward from there, and that was based on Phase 1 data, the development program moving forward from there was based around that premise that we would have a potential for a broad indication. As you know, we actually pooled cohorts 2A and 2B, and the submission for KM22A relapsed leukemia is based on that pooled analysis, which of course includes AML, ALL, adults, as well as pediatric patients. So our anticipation is, and of course, the agency has been fully in luck, you know, sort of coming on that journey with us, you know, the whole way, including from BTD, before BTD, through BTD and onwards. So that's the indication that we're looking for. So not the exact words, but came to a rearranged acute leukemias in adults and children. With respect to your second question about safety monitoring, we don't – so, first of all, you know, from a class perspective or a broad class, meaning targeted therapies in AML, you know, we anticipate – we would probably anticipate a boxed warning for differentiation syndrome, you know, since that, you know, is typical of these agents in class, right? It's on target. We know it happens, the agency knows it happens, so that's that. We do not anticipate, we anticipate a warning and precaution for QT, but that's it.
spk08: Our next question comes from Kalpit Patel with B. Riley. Your line is now open.
spk16: Yeah, hey, good afternoon and thanks for taking the question. Maybe a couple on the 7 plus 3 combo study. Can you give us some color on what dose of Revimenib you're planning to start with? And then the second question is, how should we think about the enrollment split between the KMT2AR and the NCM1 population in that combo study? Would it be a 50-50 split, or are you anticipating a skewing of the KMP2A patients as they're more fit?
spk15: Yeah, maybe I'll take the second question. I'll give the first one to Neil. Yeah, so I think you just said it. In terms of KMP2A versus NPM1, we don't really know, but I think it's, you know, the KMP2A patients overall are more fit than unfit, right? So that's where they skew. Whether or not we have, you know, skewing in our population of patients to KMT2A or not, we don't know at this point, but we do expect representation of both. And Neil, do you want to talk about the 7 plus 3 combo starting dose?
spk03: Yeah. So, and just one thing to add on, it doesn't really matter how, you know, the split between KMT2A and MPM1 patients in the first instance, right? What we're actually seeking to demonstrate is that if the combinability of Revimenibud 7 plus 3. And as we mentioned a little bit earlier on in the call, in all of the combination trials that we've described thus far, there have been two doses tested, 113 milligrams and 163 milligrams. And those are the doses or the equivalent doses without CYP3A4, that strong CYP3A4 that we will be testing in the 7 plus 3 trial as well. I mean, we know We know based on the comments that we made earlier on and, you know, data that we've presented before, we know that they're combinable with chemotherapy and also venetofax-based HMA therapy.
spk08: Our next question comes from the line of Justin Zeland with BTIG. Your line is now open.
spk14: Great. Thanks for taking our question. This is Jeet Mukherjee on for Justin. Maybe just coming back to axotilumab, was hoping you could provide a little bit of a sense of the opportunity for axotilumab and IPS, a subset of patients perhaps best suited for this therapy and what you'd be looking for from an efficacy perspective.
spk15: Yeah. I don't know if, Anjali, do you want to take that question?
spk01: Yeah, sure. I can start. And, you know, I will preface this by saying that we need a little bit more efficacy data to really hone in the expectations. But I think we know that, you know, as Neil mentioned on the call, there's two drugs that are approved. And though a lot of patients cycle through both of them and sometimes see them added on to one another, All they do is slow the decline. They're not actually treating the disease, and so there is still a huge unmet need in the marketplace. There are a very large number of IPF patients out there today, even in the U.S. alone, and we would expect to be able to, you know, we're doing the trial to add on to standard of care, so we'd be looking at a second or third line utilization. And I think we would expect, based on positive data, to get significant uptake in that population because of the large unmet need.
spk14: Got it. That's helpful. And maybe just one more on axotilamab. Is there any additional color perspective on the combo studies you're doing with ruxolitinib and steroids in collaboration with Insight and just what you'd be looking there from an efficacy and safety perspective to move one or both of those forward ultimately?
spk15: Angela, do you want to follow on there?
spk01: Yeah, sure. So, you know, again, it's exotilinab bringing this strong fibrotic effect to bear on patients and hopefully helping to manage the impact of the disease on organs and therefore potentially shifting the courses of the disease. is what we're trying to change with that combination therapy. So moving up earlier, could you really have a bigger impact on patients and their overall disease profile going forward? We anticipate getting some data out of this trial in the coming years, and I think that would govern, you know, what the uptake would really look like. But This is something that physicians are telling us they're really looking for. Right now, the only thing they have is steroids. And unfortunately, those do as much harm as they do good. And so if you could get strong efficacy out of that combination, could you minimize the use of steroids and bring Xtelmab up to an earlier population? I mean, we know the current estimated prevalent pool is about 14,000 patients, and so you could access a big chunk of that population with good data.
spk14: Thanks for taking our questions.
spk08: Our next question comes from George Farmer with Scotiabank. Your line is now open.
spk06: Hi there. This is Chloe on for George. Thank you for taking our questions. Two from us on RevuMedib. So do you have any sense on whether the FDA is intending to hold an ODAC meeting to discuss the approval package in CAMT2AR AML or ALL? And secondly, could you speak to the prospects for other indications for revumenib?
spk15: Great, Chloe, thank you for the question. So in terms of an ODAC, we don't expect that the FDA will hold an ODAC for Revimenib. From time to time, for new mechanisms, they do that more as a showcase than they do for any other reason. But we don't expect, and we haven't received any word from the FDA to indicate that we would have an ODAC. So I think that's the answer to your first question. And then secondly, you had asked about prospects for additional indications I presume that means outside of leukemia, and as I mentioned in my previous remarks, we are looking at revumentive in colorectal disease, third-line metastatic colorectal cancer. As a monotherapy agent, it's obviously a very difficult disease state, and we're We're going to have some data in the second quarter of this year to first get at whether there's sufficient activity there as a monotherapy agent and how the drug performs. There is this thesis that we're pursuing a beta-continued upregulated drug tumor types, which is a broadly implicated phenomenon through a lot of different cancers. Colorectal cancer is one, and so there could be other cancers that we look to see whether they're susceptible to revimative treatment. So stay tuned. There may be more to come. I think the first step here is certainly the colorectal cancer trial that we're running.
spk06: Okay, got it. Thank you.
spk15: Thank you.
spk08: This concludes our question and answer session. I will now turn the floor over to Mr. Michael Metzger for any additional comments or closing remarks.
spk15: Thank you all. We appreciate you tuning in tonight, and we look forward to seeing you at our planned investor events, including the upcoming Cowan and Barclays healthcare conferences in March. And with that, I wish you all a very pleasant evening. Thank you.
spk08: This concludes today's conference call. Thank you, and you may now disconnect.
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