Kura Oncology Inc (KURA) 2020 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Kura Oncology Fourth Quarter and Full Year 2020 Earnings Conference Call. (Operator Instructions) Please be reminded that today's conference is being recorded. (Operator Instructions)

I would now like to hand the conference to your speaker today, Pete De Spain. Please go ahead, sir.

Great. Thank you, Victor. Good morning, and welcome to Kura 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. Marc Grasso, our Chief Financial Officer and Chief Business Officer. Jim Basta, our Chief Legal Officer; Dr. Stephen 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 Kura's filings with the SEC, which are available from the SEC or on the Kura 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 Kura Oncology. Troy?

Thank you, Pete, and thank you, everyone, for joining us this morning. We're a precision medicine company with 2 clinical stage oncology drug candidates for which we own global commercial rights, our menin inhibitor, KO-539 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, KO-539. In December, we reported preliminary clinical data from our Phase I/II KOMET-001 clinical trial of KO-539 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. KO-539 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 I dose escalation portion of the trial as KO-539 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 I 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 KOMET-001 trial protocol to include 2 Phase I expansion cohorts, while we continue to evaluate KO-539 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 KO-539 in these target populations and better inform a recommended Phase II dose. Determination of an optimal recommended Phase II 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 KO-539 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 committee to further define a comprehensive clinical development plan for KO-539, including a potential third expansion cohort, combination studies in the frontline and a pediatric development strategy. We intend to move these efforts forward aggressively pending determination of a recommended Phase II dose, and we look forward to providing updates to you along the way.

Now let's turn our attention to our farnesyl transferase inhibitor, tipifarnib. Earlier this morning, we were very pleased to announce that tipifarnib has been granted breakthrough therapy designation from FDA for the treatment of patients with recurrent or metastatic HRAS 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 6 months and a median overall survival of 15 months.

As a point of reference, the objective response rate for the 3 FDA-approved therapies for the treatment of HNSCC in the second line range from 13% to 16% with a median profession-free survival of 2 to 3 months and a median overall survival of 5 to 8 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 benefit 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 tipifarnib for the treatment of HNSCC patients. To that end, we remain focused on conducting our AMHN 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 the 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 underscore 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 IND-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 Marc Grasso for a discussion of our financial results for the fourth quarter and full year 2020.

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 filed today for a 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 KO-539 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. G&A expenses for the full year 2020 were $31.5 million compared to $19.7 million for the prior year. The increase in G&A expenses was primarily due to increases in pre-commercial planning expenses, personnel costs and a non-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 31, 2020, compared with $236.9 million as of December 31, 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.

Thank you, Marc. Before we jump into the question-and-answer session, let me lay out our anticipated milestones for the year ahead. For KO-539, initiation of genetically enriched Phase I expansion cohorts in mid-2021 and additional Phase I data from KOMET-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.

(Operator Instructions) The first question will come from the line of Jonathan Chang from SVB Leerink.

This is John Barrett on for Jonathan. 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?

Yes. Thanks, John, for the question. And you alluded to the answer at the end of your question. So we're doing 2 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 2 Phase I 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 to titrate for efficacy. What we're seeing is 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.

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 get -- when you pass-through that safety threshold in the dose escalation? Or are you going to be waiting until 800 that passes through the safety and then using the 800 as the dose expansion cohort dose?

Yes, John, it's a good question. And it's one for which I think, at this point, we don't have a precise answer. The point here is to be able to evaluate at least a couple of different doses. To -- just to remind everyone, the 200-milligram cohort, we showed data at ASH in December. And in that cohort, we had 1 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 will be a discussion among Stephen, who's on the call with us today, our clinical team and, of course, the investigators. At this point, I 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.

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?

Yes. That's a -- it's hard to say at this point. I think what we'd like to be able to do when we give the next data update is to provide a fuller picture of the Phase I experience for the compound. And 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, at least a couple of months. We're guiding toward initiating the Phase I expansion cohorts around the middle of the year. And that's just the time that it takes to amend the protocol, FDA review and then implement the amendment at the sites that we have currently enrolling KOMET-001.

So 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 informed as we continue to progress.

Got it. And congrats on the continued dose escalations.

Our next question comes line of Marty Auster from Credit Suisse.

Troy, I think I have a 3-parter. I just want to clarify a couple of things. In terms of the update on the timing of the next update from KOMET, the -- 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 at ASH, you 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, just getting back to the dose window being a lot wider than expected and you need to kind of clarify that down before embarking a 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 KO-539? 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?

Sure. Yes. 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, is there -- 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. I don't -- we don't know whether it's a -- you asked is it a class effect or is it specific to KO-539, 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 that -- 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. And -- but we don't think we're there yet.

And then the second question that you asked was, 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 agency's evolved 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 -- 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 -- 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. The -- 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 -- it's an alphabet soup of different genetic backgrounds. We're perhaps getting at most 1 patient per cohort, who's really relevant, the 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 1 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 2 expansion cohorts, one at a lower dose, one at a higher dose. We've -- again, with -- through a discussion with FDA, we've modified the endpoints now such that the patients in those Phase I expansion cohorts have the potential to be included when the trial rolls over into a registrational -- a trial for registrational intent.

So I think it's taking longer because the compound is 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 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.

Yes. Do you mind, just a quick follow-up. I just want 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'd expect that you're going to get better efficacy at higher doses and at the upper end of what you want to test. On the lower end, what you want to do with them is double checking enriched population, whether some of those early CR signals were potentially just fortuitous or lucky, and you want to make sure those are real signals for future combination potential use?

I think that's -- yes, I think that's right, maybe to restate your restatement. What we're really doing in this Phase I expansion is we're now titrating for efficacy. So in a typical Phase I 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 looking at the program, folks should feel confident that we had, in our view, very encouraging activity at 200 milligrams and that's continued, and we've only seen now a wider and wider therapeutic window. No evidence of QT prolongation, no cardiac talks, none of the AEs that were 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.

Our next question will come from the line of Peter Lawson from Barclays.

Troy, just on, I guess, recommended Phase II dose, when do you think we'll see that? Will we get that ahead of the second half data? And do you think we'd get different recommended Phase II doses for NPM1 and all the rearrangements?

Yes. Yes. So let's take, Peter -- so two good questions. I take the second one and then the first. There's nothing that suggest 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 will 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, what we're -- 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 with -- these Phase I expansion cohorts are intended to enroll a minimum of 12 patients.

So 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 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 there's a -- everything is 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.

And just switching gears on to tipifarnib. When do we see, I guess, the next data? Or when do you think you'll be ready for filing?

Yes. It's a great question. We were thrilled at the breakthrough therapy designation and really appreciate the agency's acknowledgment of the unmet need. As we've said in the past, the registrational study 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 that the agency wants to be actively involved with us in the development, and we hope the ultimate approval of tipifarnib. We're not yet at a point where we can give guidance on the timing of enrollment or data. But we're definitely -- we think the study is going in the right direction. And 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.

Our next question comes from the line of Konstantinos Aprilakis from Stifel.

Just looking for further color on the wide therapeutic window for KO-539. It seems like the answer is no, but can you say explicitly whether you've seen any DLTs thus far? And I got a quick follow-up.

Yes. So we can't comment specifically, Konstantin, as to whether we've seen any DLTs. We certainly continue to escalate. So I think that's encouraging. We're now at 4x the dose. And I would say it looks good. You never -- as I've joked before, 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 might see grade 1. And then if you go higher, you see grade 2 or grade 3. We're not even seeing a regular pattern of grade 1 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, its safety and tolerability, adaptivity and at some of the other aspects, such as pill burden. And so far, everything is looking -- all the lights are looking great.

And do you still plan to open a cohort exploring KO-539 in patients with the miscellaneous genetic abnormalities, including SETD2? Would that cohort also need to have its own dose titration?

Yes. 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 we've -- 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 PK exposure dose decision. At that point, we can fix the recommended Phase II dose and then roll into what we would expect 3 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 2 populations where we have high confidence of clinical -- of recurrent clinical benefit.

Our next question will comes from the line of Ren Benjamin from JMP Securities.

Maybe just a couple. If you -- Troy, if you rerun the analysis, right, on the patients that you've seen -- that you've already talked about with the new modified endpoints that the FDA is -- that you've discussed with the FDA, what do you see? 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 6 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 3 and now we're going to another 3 at 800?

And I guess, finally, just thinking about exposure, what kind of exposure are you seeing? And you mentioned pill burden could limit dose. Are there any thoughts about reformulating the pills so that you might be able to put more per pill?

Yes. So let me take the first couple of questions, Ren. They're actually going to be the second and third question, and I'll let Stephen comment on the endpoint 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 3 patients and up to 5 patients. And that -- nothing has changed there. You're typically getting anywhere between 3 and 5 patients in a given cohort. It just depends on whether they all make it through the cycles. So I don't think we were enrolling 6 patients. We're continuing to escalate, again, at a minimum of 3 and we give the investigators up to 5 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. But we are -- 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 we -- it feels as though we're getting closer.

The final question, I think, which was the first question you asked is, if we reran 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 Ren's question on that as to whether we would have gotten a different answer with the revised endpoints we've discussed with the agency.

Yes. So thank you, Troy. Ren, that's a very good question. So the amendments to the endpoint, [but chiefly] the one where we are changing from a CRi to CRh, were both actually in effect of 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 one to the question of if we were to reanalyze the data, would we see any differences? It's difficult to answer that yet because we haven't run all of the analysis on all these data sets to see 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 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, Ren.

Got it. Okay. Yes, that makes sense. And then, Troy, if I could sneak one in. How many sites will you have up and running between kind of now and by the time you have the expansion cohorts?

Yes. It's a good question. So at the moment, I think we have 7 or 8 sites that are up and running between the U.S. and France. Ren, I would anticipate we'll go to anywhere between sort of 12 and 20 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 have been -- 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 I expansion cohorts, and then they'll just roll into the registrational cohorts if and when we get there.

Your next question will come from the line of Phil Nadeau from Cowen and Company.

Congrats on the progress. Just a couple from us. First, on the design of the expansion cohorts or the Phase I cohorts, I guess, it's unclear to me what's different between the 2 cohorts? Is -- are the cohorts divided based on the mutation? Or are they different doses? What they're...

Phil they're -- yes, they are different doses. So they will be open to either NPM1 or KMT2-rearranged patients. We're not going to try to prespecify a blend of those 2 populations. We'll take the patients as they come. What will separate the 2 cohorts is that they'll be evaluated at different doses.

Got it. Okay. And then the doses in the cohorts themselves are -- those are fixed. So one will be low, one will be high?

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, 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.

The -- we think the good news and one of the things we're pleased about what 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 and allowing us to evaluate these enriched populations at a couple of different doses to help refine that RP2D.

Got it. And you said before you could use some of the data from these as part of the efficacy portion of the filing, does that assume that -- basically, you'd use the patients who are at the recommended Phase II 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?

Yes. 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 2 important points. I mean the thought would be that the patients at the going -- 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 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 being included in the ultimate registrational cohort, but that's -- I don't want to misrepresent. That's ultimately going to be an FDA review issue. But it allows us -- as we start enrolling these Phase I expansion cohorts, just to move more quickly, more aggressively against that ultimate endpoint, which we're very focused on.

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?

Yes. I would say we have ideas on the lower dose. We're very -- 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 going to look at the continued data from the Phase I escalation and then make a determination.

In our view, 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 I would say 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, 600 to 800, but that's pending further data being generated, and then, of course, the appropriate discussions with our safety review committee and our internal colleagues.

Great. Last question, just kind of 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 I that is conducted. So I guess the question is kind of why now? Why do it as a monotherapy? Is there a -- is there something about the profile that makes it particularly important, for example, like the [CYP] 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?

Yes, 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.

Yes. No. Thank you, Troy. Yes -- so no, thanks for the question. It's an excellent one. 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 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 enriched patients in the all-comers population in the escalation. We're not getting pure risk 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 [CYP] that's driven any of this. This is to really home 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.

Got it. That's very helpful. And congrats, again, on the progress.

Our next question comes from Tyler Van Buren from Piper Sandler.

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 KOMET 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?

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, in fact, the lack of toxicity. 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.

And Troy, if I can just add as well to that. 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, again, is testimony to how well tolerated and how wide the therapeutic window is.

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? 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?

Yes. It's a -- let me -- that's a great question, Tyler. This question is spot on. Let me ask Stephen if he can comment on that.

Yes. 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-comers population, which has been done there. The question is 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 one 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 recommended Phase II 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.

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?

Yes. 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've 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.

(Operator Instructions) Our next question comes from the line of Joe Pantginis from H.C. Wainwright.

I have one question at this point. And I was just curious, Troy, if I heard you correctly, did you say the expansion patients, the 12 or the 12, 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?

Yes. 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, that's ultimately up to the FDA. That will 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 there's definitely a desire to be able to move quickly here.

In terms of the size of the trial, I think what we've guided to is 3 -- potentially 3 different registrational cohorts, 1 in NPM1, 1 in KMT2A and 1 in a third cohort. And the number of patients is anywhere from sort of 40 to up to 100, depending on the level of activity that we see. So the trial will be -- will have sizing to allow you to basically expand the population 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 it's consistent with what's been done with other targeted therapies. Here, you just have multiple genetically defined subsets.

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. 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 SVB Leerink Global Healthcare Conference tomorrow, and we 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 Marc or to me, and we're happy to connect with you. Thanks again, and have a good day, everyone.

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