This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk03: Ladies and gentlemen, thank you for standing by and welcome to the Cura Oncology fourth quarter and full year 2020 earnings conference call. At this time, all participant lines are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded and if you require any further assistance, please press star 0. I would like to hand the conference to your speaker today, Pete DeSpain. Please go ahead, sir.
spk01: Great. Thank you, Victor. Good morning, and welcome to CURL Oncology's fourth quarter and full year 2020 conference call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer, and Dr. Mark Grasso, our Chief Financial Officer and Chief Business Officer. Jim Bosta, our Chief Legal Officer, Dr. Steven Dale, our Chief Medical Officer, Kirsten Flowers, our Chief Commercial Officer, and Kathy Ford, our Chief Operating Officer, are also with us and available to answer questions. Before I turn the call over to Dr. Wilson, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Cura's filings with the SEC, which are available from the SEC or on the Cura Oncology website for information concerning risk factors that could affect the company. I'd also like to point your attention to our newly updated corporate presentation, which can be found in the Investors section of our website. With that, I'll now turn the call over to Dr. Troy Wilson, President and CEO of Cura Oncology. Troy?
spk09: Thank you, Pete, and thank you, everyone, for joining us this morning. We're a precision medicine company with two clinical stage oncology drug candidates for which we own global commercial rights. Our menin inhibitor, KO539, and our farnesyl transferase inhibitor, Tipifarnib. Each of our drug candidates targets oncogenic driver mutations in indications of high unmet need, and we're pursuing an accelerated development and fast-to-market strategy. Our pipeline also includes an emerging next-generation farnesyl transferase inhibitor program that we believe will target innovative biology to address indications of high unmet need through rational combinations. We're also in a stronger financial position than ever before with more than $600 million in cash, which we believe provides us with sufficient resources to advance our programs through multiple value inflection points. And we have a talented and proven team with the oncology drug development and commercialization expertise required to be successful. Now, let me take you through each of our programs, beginning with our menin inhibitor, KL539. In December, we reported preliminary clinical data from our Phase I-II Comet 001 clinical trial of KL539 at the American Society of Hematology annual meeting. These data were highlighted by single-agent activity in an all-comer population of patients with relapsed or refractory acute myeloid leukemia, including patients with NPM1 mutations, and KMT2A rearrangements. KO539 also demonstrated a favorable safety and tolerability profile with no drug discontinuations due to treatment-related adverse events and no evidence of QTC prolongation. Since the ASH presentation, we've continued to enroll patients in the phase one dose escalation portion of the trial as KO539 continues to demonstrate compelling clinical activity and a wide therapeutic window. we've completed the 600 milligram dose cohort and are currently evaluating an 800 milligram dose cohort. Meanwhile, we recently sought FDA feedback regarding the design of the registration-directed portion of our trial. In the context of those discussions, FDA guided that we should consider determining a minimum safe and biologically effective dose in our ongoing phase one trial. FDA also agreed we should modify our primary endpoint from CR-CRI to CR-CRH, and incorporate transfusion independence as a secondary endpoint in order to align the endpoints with those that would be meaningful for patients and acceptable for registrational intent. Based on this feedback, we plan to amend our COMET-001 trial protocol to include two Phase I expansion cohorts while we continue to evaluate KO539 in dose escalation. We expect these Phase I expansion cohorts to include a minimum of 12 patients each at doses that have already met the safety threshold to help us to determine a minimum safe and biologically effective dose. Furthermore, we plan to enrich each of these Phase I expansion cohorts with both NPM1 mutant and KMT2 rearranged relapsed or refractory AML patients. This should help us to further characterize the efficacy of KL539 in these target populations and better inform a recommended phase two dose. Determination of an optimal recommended phase two dose is among the most critical decisions for an early stage clinical program. With these changes to the trial protocol, we have the opportunity to move into genetically defined expansion cohorts prior to reaching a maximum tolerated dose to obtain a larger data set in an enriched population and to more confidently determine a recommended Phase II dose, thereby increasing the likelihood of success for the program. We believe that the clean safety and tolerability profile, the encouraging signs of clinical activity, and the wide therapeutic window of KL539 support a potential best-in-class profile, both as a monotherapy and in combination. We continue to actively engage with our key opinion leaders and global steering committees to further define a comprehensive clinical development plan for KL-539, including a potential third expansion cohort, combination studies in the front line, and a pediatric development strategy. We intend to move these efforts forward aggressively, pending determination of a recommended phase two dose, and we look forward to providing updates to you along the way. Now let's turn our attention to our farnesyl transferase inhibitor, tififarnic. Earlier this morning, we were very pleased to announce that tibifarnib has been granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic atrius mutant head and neck squamous cell carcinoma, or HNSCC, with a variant allele frequency greater than or equal to 20% after disease progression on platinum-based chemotherapy. The breakthrough therapy designation is based upon data from our Phase II RUN-HN trial which was recently accepted for publication in an upcoming issue of the Journal of Clinical Oncology. As a reminder, the RUN-HN trial showed an objective response rate of approximately 50%, a progression-free survival of six months, and a median overall survival of 15 months. As a point of reference, the objective response rate for the three FDA-approved therapies for the treatment of HNSCC in the second line ranged from 13% to 16%, with a median progression-free survival of two to three months and a median overall survival of five to eight months. This breakthrough therapy designation acknowledges both the dire unmet need for patients with recurrent or metastatic HRAS mutant HNSCC and the promise of tipifarnib to provide clinical benefits to these patients. Benefits of breakthrough therapy designation include more frequent meetings and communications with FDA, intensive guidance on an efficient drug development program, eligibility for rolling review of an NDA submission, and an organizational commitment involving senior managers from FDA. We anticipate the breakthrough therapy designation will help to facilitate the development and ultimate approval of tibifarnib for the treatment of HNSCC patients. To that end, we remain focused on conducting our AIM-HN registration-directed trial and bringing tipifarnib to the market as quickly and as efficiently as possible. In addition, we're also leveraging new advances to expand the use of tipifarnib in combination with other oncology therapeutics to address larger patient populations and pursue earlier lines of therapy. Among these potential combinations, we've prioritized the combination of tipifarnib and an inhibitor of the enzyme PI3 kinase alpha in patients with HNSCC. Our preclinical data suggests that HRAS and PI3 kinase alpha are codependent oncogenes in HNSCC and that combining tipifarnib with a PI3 kinase alpha inhibitor has the potential to provide meaningfully better antitumor activity than inhibiting either target alone. We believe the total addressable population for tipifarnib may be as high as 50% of HNSCC. We continue to prepare for a Phase I-II proof-of-concept study of tipifarnib in combination with a PI3 kinase alpha inhibitor in patients who have HRAS overexpressing, PIK3CA mutated, and or PIK3CA amplified HNSCC, and we expect to initiate this study in the second half of 2021. Breakthrough therapy designation from FDA is the latest milestone in our effort to pioneer the use of farnesyl transferase inhibitors to treat patients with cancer. We view farnesyl transferase inhibition in oncology as a potentially valuable therapeutic and commercial franchise, one that has the potential to deliver multiple opportunities for additional indications. Over the past several years through our internal efforts and a network of academic collaborations, we've uncovered some compelling opportunities for farnesyl transferase inhibitors in combination with other targeted therapies. These efforts have both revealed some exciting new areas of biology and underscored to us the opportunity for a greater investment in this therapeutic class. Last year, we initiated a discovery stage program to develop a next-generation farnesyl transferase inhibitor. Our goal is to deliver a drug candidate that has comparable potency and selectivity and improved pharmacokinetic and physical chemical properties relative to tipifarnib. I'm pleased to report we've already identified multiple advanced lead compounds and expect to nominate a development candidate for IMD-enabling studies in mid-2021. We intend to direct this next-generation FTI at new biology and larger oncology indications, and we look forward to sharing our progress and our plans with you later this year. With that, I'll now turn the call over to Mark Grasso for a discussion of our financial results for the fourth quarter and full year 2020.
spk05: Thank you, Troy, and good morning, everyone. I'll provide a brief overview of our financial results here on the call and invite you to review our 10-K file today for more detailed discussion. Research and development expenses for the fourth quarter of 2020 were $17.5 million compared to $13.5 million for the fourth quarter of 2019. R&D expenses for the full year 2020 were $60.4 million compared to $47.8 million for the prior year. The increase in R&D expenses was primarily due to an increase in clinical development and manufacturing-related activities related to our KO539 program, personnel costs, and other expenses. General and administrative expenses for the fourth quarter of 2020 were $8.8 million compared to $5.5 million for the fourth quarter of 2019. DNA expenses for the full year 2020 were $31.5 million, compared to $19.7 million for the prior year. The increase in DNA expenses was primarily due to increases in pre-commercial planning expenses, personnel costs, and on-cash share-based compensation. Net loss for the fourth quarter of 2020 was $26.2 million, compared to a net loss of $17.9 million for the fourth quarter of 2019. Net loss for the full year 2020 was $89.6 million compared to a net loss of $63.1 million for the prior year. Net loss for the fourth quarter and full year 2020 included non-cash share-based compensation of $3.7 million and $12.8 million, respectively. This compares to $2.4 million and $9.4 million for the same periods in 2019. Our cash, cash equivalents and short-term investments were $633.3 million as of December 31st, 2020, compared with $236.9 million as of December 31st, 2019. This includes net proceeds of approximately $324.1 million from our public offering completed in December 2020. Based on our current plans, We believe that our current cash, cash equivalents, and short-term investments will be sufficient to fund current operations into 2024. With that, I will now turn the call back over to Troy.
spk09: Thank you, Mark. Before we jump into the question and answer session, let me lay out our anticipated milestones for the year ahead. For KL539, initiation of genetically enriched Phase I expansion cohorts in mid-2021, and additional Phase I data from Comet 001, in the second half of 2021. For tipifarnib, initiation of a Phase I-II proof-of-concept study in combination with a PI3 kinase alpha inhibitor in the second half of 2021. And for our next-generation farnesyl transferase inhibitor program, nomination of a development candidate in mid-2021. With that, operator, we're now ready for questions.
spk03: As a reminder, ladies and gentlemen, to ask a question, you will need to press star 1 on your telephone. And to withdraw your question, press the pound key. Our first question will come from the line of Jonathan Chang from SVB Lyric. You may begin.
spk12: Hi, team. This is John Barrett on for Jonathan. Thanks for taking my questions. What drove this decision to dose escalate to 800 milligrams? And what is your plan moving forward with dose escalation? Do you still expect to reach RP2D by the end of the quarter? Or do you plan to define a dose taken to these expansion cohorts and continue the dose escalation in parallel?
spk09: Yeah, thanks, John, for the question. And you alluded to the answer at the end of your question. So we're doing two things simultaneously. The first is continuing to dose escalate. We have been very pleasantly surprised at the lack of toxicity that we've seen. and the potential for good safety and tolerability in a wide therapeutic window. As we indicated in the prepared comments, we're currently evaluating the 800 milligram cohort. Depending on the outcome of that cohort, we, along with the safety review committee, will make the determination of whether to continue the escalation. But as it stands today, we don't see anything that would prevent us from doing that. Simultaneously, we're in the process of amending the protocol to enroll those two phase one expansion cohorts that we mentioned that will comprise NPM1 mutant and KMT2 rearranged patients. And that's really, John, an effort to both try to identify a minimum safe and efficacious dose and really the titrate for efficacy. What we're seeing is You know, good activity across the dosing cohorts, good safety and tolerability. We need now really to focus down on which of those cohorts is actually optimum from the standpoint of moving forward with a recommended Phase II dose into the registrational portion of the study.
spk12: Got it. So will you be using the 600 milligram dose in those expansion cohorts and just trying to get additional data at that dose and then potentially moving up to 800 when you pass through that safety threshold in the dose escalation? Or are you going to be waiting until 800 passes through the safety and then using the 800 as the dose expansion cohort dose?
spk09: Yeah, John, it's a good question, and it's one for which I think at this point we don't have a precise answer. You know, the point here is to be able to evaluate at least a couple of different doses. Just to remind everyone, The 200-milligram cohort, we showed data at ASH in December, and in that cohort, we had one NPM1 mutant patient who had a complete remission, a second NPM1 mutant patient who had morphologic leukemic-free state as best response. So that appears to be, at least on the lower bound, a good potential going-forward dose. To your question on the upper bound, I think that's going to be data-driven by the data that comes out of the 800-milligram cohort, and it'll be a discussion among, you know, Stephen, who's on the call with us today, our clinical team, and, of course, the investigators. At this point, don't have an exact answer for you, but I think you're thinking about it in the right way, a lower dose, a higher dose, and then using these Phase I expansion cohorts to titrate for efficacy.
spk12: Got it. And just one more quick one. Given the 539 update is now in the second half, will this still just be focused on the dose escalation data, or might we see some initial expansion cohort data?
spk09: Yeah, it's hard to say at this point. I think what we'd like to be able to do when we, you know, give the next data update is to provide a fuller picture of the Phase I experience for the compound. And, you know, that would include pharmacokinetic data and exposure, of course, the safety and tolerability, and then the efficacy. I think it's too early to say. It will take us, John, you know, at least a couple of months. We're guiding toward initiating the phase one expansion cohorts around the middle of the year, and that's just the time that it takes to amend the protocol and FDA review and then implement the amendment at the sites that, you know, we have currently enrolling COMET001. So, you know, we are looking forward to providing a data update. It's just a little bit early at this point to say exactly what data will be included in that update. But we'll continue to keep you and others on the call, you know, informed as we continue to progress.
spk12: Got it. Thanks and congrats on the continued dose escalation. Thanks. Thank you.
spk03: Our next question comes from the line of Marty Oster from Credit Suisse. You may begin.
spk02: Thanks, operator. Thanks for taking the question. Troy, I think I have a three-parter. I just want to clarify a couple things. In terms of the update on the timing of the next update from Comet, is that just a function of the dose escalation continuing longer than you expected and you want to have that kind of complete picture at the next update. I know it actually talked about having something early in 2021. Second question was on the change in protocol. I just want to make sure I'm understanding clearly kind of what evolved in kind of your, from your thinking and from your discussions with FDA that kind of deviated from the original plan. And again, it's just getting back to the dose window being a lot wider than expected and needing to kind of clarify that down before embarking on the registration path. And then finally, I guess, getting back to the common feature here, what is your evolved understanding of the kind of wide therapeutic index you're seeing with KO539, and do you think this is a class feature, or is there something kind of unique to the molecule that you're, that was kind of triggering efficacy at such a lower level than expected? Thanks.
spk09: Sure, yeah, so thanks for the questions, and let's take them in turn. So with respect to the timing of the next update, You're exactly right. We have been, I think, surprised pleasantly at the ability to continue to dose escalate. And although we've seen encouraging signals of activity at lower doses, there's definitely a desire among both the investigators and members of our team to push the dose, to understand, you know, are we getting better efficacy? Are we getting more efficacy? and also to help define the properties of the compound. And I'm going to take the third question in turn. We don't know whether it's a class effect or is it specific to KO539, this wide therapeutic window. As we've said in the past, preclinically, there really wasn't anything in the GLP toxicology that suggested a dose-limiting tox that we might expect. What we've done is to evaluate each cohort of patients as we've escalated, and we've been, again, very surprised at how benign the safety profile is. There were some questions early on, as all of you on the call remember. There were some AEs in the 200-milligram cohort, including pancreatitis and some other AEs. Those, we believe, were idiosyncratic to that patient, We haven't seen any evidence of any of those AEs in other patients as we've escalated. Now, we can't escalate indefinitely. There will come a point when we've maxed out exposure or the pill burden just becomes too great, but we don't think we're there yet. And then the second question that you asked was, you know, what's the rationale for the change in protocol and what evolved in our thinking? And it was... it really came out of a discussion with FDA. So we sought feedback from FDA on the entire registrational design. In the context of those conversations, FDA and we discussed identification of a minimum safe and efficacious dose. And the rationale for that is twofold. That's really the agencies of all thinking around these targeted therapies. You want to give enough drug that you're driving maximal efficacy, maximal pharmacologic benefit, and not too much. That's true as a monotherapy. It's even more important in combination. And it's our view that, you know, I don't want to speak for FDA, but certainly everyone anticipates that menin inhibitors will be used in combination with other agents like venetoclax and azacitidine. You know, one wants to have a minimum safe and efficacious dose, to give you the maximum therapeutic window, the greatest chance to combine with those other agents. And the only way to do that is to enroll these Phase I expansion cohorts. What we've seen as we've continued to enroll is, remember, that the Phase I dose escalation to this point has been open to all comers. And we literally are getting, you know, it's an alphabet soup of different genetic backgrounds. we're perhaps getting at most one patient per cohort who's really relevant, an NPM1 mutant or a KMT2A. That's enough to give you some encouraging breadcrumbs. It's not enough to be able to make a determination as to whether one dose is better than another because you just don't have enough data points to relate a dose exposure activity correlation. So the way we're going to get around that is to enroll these two expansion cohorts, one at a lower dose, one at a higher dose. Again, through a discussion with FDA, we've modified the endpoints now such that the patients in those phase one expansion cohorts have the potential to be included when the trial rolls over into a trial for registrational intent. So I think it's taking longer because the compound's better tolerated than we expected, and we really want to make sure that we zero in at the right dose to give us the greatest chance of success as a monotherapy and the greatest likelihood of success as a combination therapy. And by going into these enriched cohorts, we're optimistic that that should give us the data that we need to determine which of these doses that we've evaluated, all of which have cleared the the safety hurdle, which of them are optimum on a going-forward basis. So that's a long answer to your question, but hopefully it gives you some additional color.
spk02: Yeah, do you mind just a quick follow-up? I just wanted to try to restate what you just said and make sure I'm getting the message correctly. On the high end, you feel comfortable that the Phase I escalation is establishing safety, and so for monotherapy, you expect that you're going to get better efficacy at higher doses, and that's the upper end of what you want to test. On the lower end, what you want to do then is double check and enrich population, whether some of those early CR signals were potentially just fortuitous or lucky. You want to make sure those were real signals for future combination potential use.
spk09: I think that's, yeah, I think that's right. Maybe to restate your restatement, you know, what we're really doing in this phase one expansion is we're now titrating for efficacy. So in a typical phase one escalation, the stopping criteria would be tox. We're not seeing tox, so we've continued to escalate. Because we're in an all-comers population, it's difficult to titrate between different cohorts unless you're in an enriched population. That's what the expansion cohorts will allow us to do. If we see equivalent activity at 200 milligrams and a higher dose, for example, I think the view might be to go with the lower dose, the minimum safe and efficacious dose. But we need the data package to be able to make that. That's a data-driven decision. I think from the standpoint of you know, looking at the program, folks should feel confident that, you know, we had, in our view, very encouraging activity at 200 milligrams. And, you know, that's continued. And we've only seen now, you know, a wider and wider therapeutic window. No evidence of QT prolongation, no cardiac talks, none of the AEs that were, you know, observed in the 200 milligram cohort. So it's lining up nicely. It is taking a little bit longer, but we're doing the drug development that we believe will maximize the value of the program, both as a monotherapy and combination.
spk02: Thank you, Troy. Sure.
spk03: Thank you. Our next question will come from Peter Lawson from Barclays. You may begin.
spk10: Thanks for taking the questions. Troy, just on, I guess, recommended phase two dose, when do you think we see that? Will we get that ahead of the second half data, and do you think we get different recommended phase two doses for NPM1 and all the rearrangements?
spk09: Yeah. Yeah, so let's take, Peter, two good questions. Take the second one and then the first. There's nothing that suggests to us at this point that different doses are needed for NPM1 mutant patients and KMT2 rearranged. Now, admittedly, we have an expanding data set, I think that's an answer that will be forthcoming in these expansion cohorts because we anticipate that we'll enroll both NPM1 and KMT2 rearranged, and so we'll have a better sense of that. But at this point, there isn't anything we've seen preclinically or clinically that suggested we need different doses. With respect to your first question on timing of the RP2D, So we've been a little vague about the specific doses, and that's really out of respect for the Safety Review Committee. We don't want to get ahead of the Safety Review Committee and come out and tell you what we think the doses are going to be. It appears 200 milligrams is probably a good lower bound. The upper bound, I think, has yet to be defined, but that is pending review by the Safety Review Committee. We've tried to provide as much transparency as we can going along. You know, with these phase one expansion cohorts are intended to enroll a minimum of 12 patients. So, you know, once we're into those cohorts, I think we'll have a better idea. I think it's just a little bit early to say exactly what the timing of nomination of an RP2D is versus, you know, presenting data. We're moving as aggressively as we can. It's all hands on deck to get this amendment done. We're adding additional sites to the study to help us drive enrollment. At this point, we have more patients than we have slots, but we also recognize we're going to narrow the aperture as we now focus on NPM1 and KMT2A. So everything's going in the right direction, Peter. It's just a little bit early to be able to say exactly what the timing of the RP2D versus the next data update.
spk10: Thank you. And just switching gears on to the final, when do we see, I guess, the next data or when do you think you'll be ready for filing?
spk09: Yeah, it's a great question. You know, we're thrilled at the Breakthrough Therapy designation and really appreciate the agency's acknowledgement of the unmet need. As we've said in the past, the registrational study, you know, it continues to enroll. The changes that we made to the protocol we think have really helped, both to drive enrollment and to ensure a higher likelihood of success. We're really pleased now, you know, that the agency wants to be actively involved with us in the development, and we hope, you know, the ultimate approval of Tipi Farnib. We're not yet at a point where we can give guidance on the timing of enrollment or data. But, you know, we're definitely, we think the study's going in the right direction. And, you know, the next thing on deck, Peter, as we mentioned, is going to be the combination study. And there's a lot of excitement there within the investigator community. So I would expect that's the next thing you'll see. But we'll continue to provide updates as much as we can. Okay. Thanks. Thanks for taking the questions. Yeah, thank you.
spk03: Our next question comes from the line of Konstantinos Afrilak from Stifel. You may begin.
spk04: Hey, thanks for taking my questions. Just looking for further color on the wide therapeutic window for KO539. It seems like the answer is no, but can you say explicitly whether you've seen any DLTs thus far? I've got a quick follow-up.
spk09: Yeah, so we can't comment specifically, Konstantinos, as to whether we've seen any DLTs. We certainly continue to escalate. So, you know, I think that's encouraging. We're now at 4x the dose. And, you know, I would say it looks good. You never, you know, as I've joked before, you know, every day is a new day. But we're not seeing, what's important is typically with toxicities, you'll see them build in over time. You know, you might see grade 1, and then as you go higher, you see grade 2 or grade 3. we're not even seeing a regular pattern of grade one across these patients. So we think that that wide therapeutic window will continue. As I mentioned in the answer to a previous question, at some point we're going to reach a limit where it's just infeasible to continue dose escalating, but we don't think we're there yet. We're still pushing it as hard as we can, looking at exposure, at safety and tolerability, at activity, and at some of the other aspects, such as, you know, pill burning. And so far, everything's looking, you know, all the lights are looking green.
spk04: Thanks for that. And then do you still plan to open a cohort exploring KO539 in patients with, you know, the miscellaneous genetic abnormalities, including SETD2? You know, would that cohort also need to have its own dose titration?
spk09: Yeah, so the answer is yes, we do. We do anticipate opening that cohort in the registrational portion of the study. We don't want to do that now for the simple reason that we're still defining the selection rules of that third cohort, and we're trying to reduce this analysis down to single variables. So as we've said, we've established good safety and tolerability at every cohort, Now we need to titrate for efficacy, so we're going to try to keep the patient composition relatively fixed with NPM1 and KMT2A and vary dose. That should give us the data then to be able to make the, you know, the PK exposure dose decision. At that point, we can fix the recommended phase 2 dose and then roll into what we would expect, three cohorts, KMT2A, NPM1, and that third cohort. that will be in the portion of the study that is for registrational intent. We're not going to do it while we're still trying to fix the RP2D down because it just introduces uncertainty, and we think it's better to get to that RP2D in the two populations where we have high confidence of clinical, you know, of recurrent clinical benefit. Got it. Thank you. Sure. Thank you, Constantine.
spk03: And our next question will come from Ryan Benjamin from J&P Securities. You may begin.
spk11: Hey, good morning, guys. Excuse me. Thanks for taking the questions. Maybe just a couple. Troy, if you rerun the analysis on the patients that you've seen that you've already talked about with the new modified endpoints that you've discussed with the FDA, what do you see? you know, does it change at all? I guess related to that, how many patients now have been evaluated? So in the 600 milligram dose, was it, I thought in the past we were thinking about six patients were going to be enrolled because we thought that was going to be the final dose, but is that still the case or did you only do three and now we're going to another three at 800? And I guess finally just thinking about, you know, exposure, What kind of exposure are you seeing? And you mentioned pill burden, you know, could limit dose. Are there any thoughts about reformulating the pills so that you might be able to put more per pill?
spk09: Yeah. So let me take the first couple questions, Ren. They're actually going to be the second and third question, and I'll let Stephen comment on the end point because he's probably better positioned than I am. In terms of the numbers of patients, the cohorts are designed to enroll a minimum of three patients and up to five patients. And that, you know, nothing has changed there. You're typically getting anywhere between three and five patients in a given cohort. It just depends on whether they all make it through the, you know, through the cycles. So, you know, I don't think we were enrolling six patients. We're continuing to escalate, again, at a minimum of three. And we give the investigators up to five. to ensure that we don't have patients that make it all the way through and then can't get on the study. That same thing will be true at 800 and likely true if we go higher than 800. In terms of the exposure, we're continuing to see increases in exposure as we go up. We haven't plateaued on exposure yet. What we don't know is whether that increased exposure is actually driving better activity, and that's really kind of the question that we have to answer in the Phase I expansion cohorts. If we had reached a plateau on exposure, that could be another criteria that would help us to define the RP2D. We're not there yet, although it feels as though we're getting closer. The final question, I think, which was the first question you asked, is if we re-ran the analysis looking at the patients from the standpoint of CR-CRH versus CR-CRI, would anything have changed? And I'll ask Stephen Dale, who's on the line with me, Stephen, if you could answer Wren's question on that as to whether we would have gotten a different answer with the revised endpoints we've discussed with the agency.
spk07: Yeah, so thank you, Troy. Hi, Wren, that's a very good question. So the amendments to the endpoint, the chiefly the one where we are changing from a CRI to CRH, where both actually, in effect, both composites and both of these endpoints are as a complete remission, but the only difference between the two is dependent on the absolute neutrophil count and the platelet count. There is a nominal difference between the two. To answer the question of if we were to reanalyze the data, would we see any differences, it It's difficult to answer that yet because we haven't run all of the analysis on all these data sets to say the difference. There would be no difference in the criteria for those responses that we've seen and already discussed previously regarding complete remission. So those that are CR, those meet the exact same criteria. For where we may see a difference between CRI and CRH, we can certainly look and we'll be looking at those data further, but to date we haven't done those analysis rankings.
spk11: Got it. Okay. Yep. That makes sense. And then Troy, if I could sneak one in, how many sites will you have up and running between, you know, kind of now and, um, by the time you have the expansion codes?
spk09: Yeah, it's a good question. So at the moment I think we have seven or eight sites that are up and running between the U S and France. Uh, Ren, I would anticipate we'll, we'll go to, you know, anywhere between sort of 12 and 20. Um, really with a focus on the U.S. sites initially because those can move a bit quicker with the amendment. But Kathy Ford and our clinical operations colleagues are very focused on this. And these sites are just waiting for the opportunity to enroll patients. And so we're anticipating bringing them online with this amendment to help drive enrollment initially in the phase one expansion cohorts, and then they'll just roll into the registrational cohorts if and when we get there.
spk11: Terrific. Thanks for taking the questions.
spk09: You're welcome.
spk11: Thanks, Ren.
spk03: The next question comes from Phil Nadeau from Cowan & Company. You may begin.
spk06: Good morning. Thanks for taking my question, and congrats on the progress. Just a couple from us. First, on the design of the expansion cohorts or the phase one cohorts, I guess it's unclear to me what's different between the two cohorts. Are the cohorts divided based on the mutation or are they different doses?
spk09: Yeah, they're different doses. So they will be open to either NPM1 or KMT2 rearranged patients. We're not going to try to pre-specify a blend of those two populations. We'll take the patients as they come. What will separate the two cohorts is that they'll be evaluated at different doses.
spk06: Got it. Okay. And then the doses in the cohorts themselves, those are fixed. So one will be low, one will be high?
spk09: That's the intent. Correct. That's the intent. You really want to be able to evaluate a range to try to draw a conclusion as to whether a higher dose or a lower dose. The agency's feedback to us was, given the profile of the compound, given the activity you've seen and the wide therapeutic window, we would advise you to target a minimum safe and efficacious dose. So there will be, you know, we think scrutiny on the lower dose. The question is whether you then leave any efficacy on the table at a higher dose, and that's what we're going to try to tease out as we're titrating for efficacy in these Phase I expansion cohorts. We think the good news and one of the things we're pleased about with the FDA's feedback is we'll come out of these cohorts, obviously, with a very robust understanding of the recommended Phase II dose as we then move into the registration-directed portion. And so that will give us increased confidence in the overall success of the program as we're going through this. We had thought we would need to get to an RP2D, and then move to the expansion cohort. The FDA has basically done us a great favor in allowing us to evaluate these enriched populations at a couple of different doses to help refine that RP2D.
spk06: Got it. And you said before you could use some of the data from these as part of the efficacy portion of a filing. Does that assume that basically you'd use the patients who are at the recommended phase two dose in these cohorts as part of that efficacy filing? Could you use, is it possible to use a different data from a different dose as part of that filing?
spk09: Yeah, I mean, for, so all of the patients will likely be included for safety, of course. I think your question is really at efficacy. And sort of two important points. I mean, the thought would be that, you know, the patients at the RP2D would be the ones that would be included. But of course, the FDA is going to look at every patient and you're going to include every patient in an eventual filing. The other thing, of course, is, you know, this will ultimately be a review issue as it always is for FDA. So FDA is guiding us to ensure that those patients have the potential of being counted or, you know, being included in the ultimate registrational cohort. But that's, you know, I don't want to misrepresent, that's ultimately going to be an FDA review issue. But it allows us, you know, as we're, as we start enrolling these Phase I expansion cohorts, to move more quickly, more aggressively against that ultimate endpoint, which we're very focused on.
spk06: Got it. Okay. And this is kind of a follow-up on a prior question. So it sounds like you've determined the low dose that's going to go into these expansion cohorts. The high dose, has that been determined yet, or does that rely upon the continued dose escalation that's ongoing at 800 milligrams?
spk09: Yeah, I would say we have ideas on the lower dose. We're very, you know, we have a great partnership with the Safety Review Committee. I wouldn't want the Safety Review Committee to think that we'd already made the decision ahead of having the conversation. We're, you know, we're going to look at the continued data from the Phase I escalation and then make a determination. In our view, you know, 200 milligrams is a dose where we're seeing very encouraging signs of clinical activity, but we need to have that discussion with the Safety Review Committee. So, you know, I would say, you know, we're leaning in that direction. We haven't yet finalized it, but what we're trying to communicate to folks is think about a lower dose in the range of 200, think about a higher dose, you know, 600 to 800, but that's pending further data, you know, further data being generated, and then, of course, the, you know, the appropriate discussions with our with our safety review committee and our internal colleagues.
spk06: Great. Last question, just kind of a follow-up on Martin's question as to the rationale why the FDA and you are doing this. We've seen a lot of dose escalations over the years, and usually in oncology there isn't a lower effective dose that's identified. And when people want to do that for combination studies, there's a separate phase one that is conducted. So I guess the question is kind of, Why now? Why do it as a monotherapy? Is there something about the profile that makes it particularly important, for example, like the SIP interaction or anything else? Again, it seems a little aggressive to be doing it this early in a development program if the real concern is about combination therapies later.
spk09: Yeah, it's a good question. Let me ask Stephen Dale if he can comment on It's certainly not unusual, but let me ask Stephen if he can comment on the rationale and sort of the discussions that we had with the agency on that point.
spk07: Yeah, no, thank you, Troy. Yeah, so no, thanks for the question. It's an excellent one. So in essence, yeah, so in essence, what we have here is amount to a Phase Ib element to the Phase I study with our Phase I expansions. Indeed, in escalation and in Phase I protocols, it's often the case where sometimes this is done to expand out at different doses, especially where you're looking to titrate or look closely for efficacy, so where the Phase Ia in escalation is safety-driven. The expansions allow us to be both safety- and efficacy-driven. So with the expansions, we continue to assess for safety and tolerability But as Troy has mentioned, but really also having the opportunity now to look and assess the efficacy in a target patient population. So these are in RICS patients in the all-comers population in the escalation. We're not getting purist view in terms of those target patients. So the expansions also give us the opportunity to look in a larger data set. In this case, it's in at least 12 patients, which also gives us the opportunity to further characterize PK. There's certainly nothing around SIP that's driven any of this. This is to really hone down to try and assess more accurately efficacy in a target patient population. And then cumulatively work out and look at the benefit-risk ratio, because this will play an important role in determining the recommended Phase II dose.
spk06: Got it. That's very helpful. Thanks for taking my questions, and congrats again on the progress.
spk12: Sure. Thank you.
spk03: Thank you. Our next question will come from Tyler Van Bern from Piper Sandberg.
spk13: Let me begin. Hey, guys. Good morning. I have a couple for you. I guess the first one is just a follow-up to Phil's last question. Just to be clear and make sure we're covering all of our bases, the Comet protocol amendment recommended by the FDA, that was not specifically due to a new safety event or DLT like pancreatitis or something that we haven't seen yet.
spk09: Correct. In fact, the opposite, Tyler. It was due to the fact that we're not seeing any toxicity that's allowing us to set the dose. So not only is it not an unexpected toxicity event, it's It's in fact the lack of toxicity. You know, we could take the compound forward at any of the doses we've evaluated. We now need to turn to the question of which of them is best to be able to drive efficacy.
spk07: And Troy, if I can just add as well to that, you know, and the fact that all the doses that are going to be used in the expansion are all doses that have met the safety threshold in the escalation. it again is testimony to how well tolerated and how wide the therapeutic window is.
spk13: Okay, that's helpful. And then the second one is just, again, related to these expansion cohorts. I understand, based upon the existing expansion, that it could make sense to use 200 mg as the lower bound, but how do you accurately pick the upper bound? You know, if the goal is to generate the minimum effective dose with precision, Wouldn't a potential dose escalation in genetically defined patients or potentially even intrapatient dose escalation be helpful or informative since, as you stated, this initial escalation is generating breadcrumbs on the side of efficacy?
spk09: Yeah. That's a great question, Tyler. This question is spot on. Let me ask Stephen if he can comment on that.
spk07: Yeah. So, no, it's another great question. So, To do a dose escalation, in essence, it's typically, if it's a 3 plus 3 design, it's safety-driven. And the agency is fairly consistent with dose escalations being done in an all-commerce population, which has been done now. The question as to how to select the dose to do the expansions in, which, of course, have the enriched population, it's something which will have to be decided in terms of discussion with the Safety Review Committee. But When making those decisions, it's important to note that those are chiefly based on a benefit-risk assessment. So we look at clinical activity at that given dose. We also look at the safety, and we also look at what available pharmacokinetic data we have, and the decision then of which dose to select will then be depicted and agreed with the Safety Review Commission. It's very similar when you're deciding and determining your You recommended phase two dose as well when you have more data, but those decisions will have to be agreed with our SRC committee. So hopefully that puts a little more color on what we're trying to do here.
spk13: Okay, so you guys just have a very high level of confidence that the exposure that you observe in these all-comer patients is going to give you an accurate read on what will be efficacious in genetically defined patients.
spk07: Yeah, no, absolutely. But it's important to note that whilst we've seen and we've discussed this previously, we see a dose-related increase in exposure. We see some degree of concentration-related increase in exposure. What we haven't seen today, as we previously said, is a plateau as well. So the data that we're ongoing in monitoring, we're trying to see whether or not that we hit that plateau in exposure. So it's a factor in the decision, yes. Okay, thanks so much for taking the questions. Thanks, Tyler.
spk03: And as a reminder, that's a star one for any questions. Star one. Our next question comes from Joe Panginis from H.C. Wainwright. You may begin.
spk08: Hey, good morning, guys. Thank you for taking the question. I have one question at this point, and it's just curious. Troy, if I heard you correctly, did you say the expansion patients, the 12 or the 25, have the opportunity to be included in a potential registration study? And specifically, are you ready to discuss, at least from an early standpoint, some broad strokes about FDA potential feedback as to the size of that study?
spk09: Yeah. So, Joe, the intent in aligning the endpoints in the Phase I expansions with the endpoints in the registrational study is to permit those patients – potentially to be included. As I mentioned, you know, that's ultimately, you know, up to the FDA. That'll be a review issue. But we're going to do everything we can. We're going to treat those patients as though they were in the registrational portion from the standpoint of the filing. And, you know, there's definitely a desire to be able to move quickly here. In terms of the size of the trial, you know, I think what we've guided to is, you know, three potentially three different registrational cohorts, one in NPM1, one in KMT2A, and one in a third cohort. And the number of patients is anywhere from sort of 40 to, you know, up to 100, depending on the level of activity that we see. So the trial will have sizing to allow you to basically expand the population, you know, given a given level of clinical activity in those populations. We still have some work to do to finalize the details on the portion of the study that's for registrational intent. I think we'll be in a position to talk about that later in the year. But, you know, it's consistent with what's been done with other targeted therapies. Here you just have, you know, multiple genetically defined subsets.
spk08: Got it. Thanks, Troy.
spk09: Sure.
spk03: Thank you. And I'm not showing any further questions at this time. I'd like to turn the call over to Troy Wilson for any closing remarks. Great.
spk09: Thank you, Operator, and thank you all once again for participating in the call. We're going to be at a number of virtual investor conferences over the next couple of weeks, beginning with the SBB Lyric Global Healthcare Conference tomorrow, and we'll look forward to speaking with many of you then. In the meantime, if you have any additional questions, of course, you can always reach out to Pete, to Mark, or to me. and we're happy to connect with you. Thanks again, and have a good day, everyone.
spk03: Ladies and gentlemen, this concludes today's call. Thank you for participating. You may now disconnect.
Disclaimer