Kura Oncology, Inc. (KURA) Earnings Call Transcript & Summary

Good morning, good afternoon, everyone. My name is Troy Wilson, and I am the President and CEO of Kura Oncology. It's a pleasure to welcome all of you today to our investor event, where we'll be discussing the data that was just presented at the American Society of Hematology meeting just a few minutes ago. I want to take a minute before we get started and just introduce the other participants on the line. I'm joined by Dr. Stephen Dale, Kura's Chief Medical Officer; Dr. Bridget Martell, Kura's Senior Scientific Advisor; Dr. Eunice Wang, one of the key investigators on the study from Roswell Park; Dr. Ghayas Issa from MD Anderson; Dr. Francis Burrows, who's our VP of Translational Research. Dr. Blake Tomkinson, our Head of Portfolio Strategy and Program Management. I believe I've covered all of the participants. Before we get started, obviously, just need to make a forward-looking statement. The presentation and the comments that you hear today are going to be subject to forward-looking statement language. We would refer you to either the SEC's website or our website for more information about Kura Oncology and about the risks and uncertainties within investment in the company. If we look at the agenda, we're going to get started with an overview of the program and the development time line. I'll do that. I'm going to hand it over to Stephen to introduce the investigators for the KOMET-001 study. And then Dr. Wang will take us through the AML treatment landscape and an overview of the KOMET-001 study. She and Dr. Issa will then discuss a number of the KOMET-001 case studies and the data summary. Stephen will, after the data has been presented, talk about the KO-539 expansion opportunities. We're quite excited to be moving this forward. And then we're going to, of course, have a Q&A session, where you'll be able to submit questions through the chat box, and we're going to make an effort to try to answer as many of the questions as we can. So just to level set everyone, today's discussion will be about KO-539. Just to remind you all, this is one of the 2 major value pillars at Kura Oncology. On the left-hand side of this slide here, we have a summary of our tipifarnib program. This is our farnesyl transferase inhibitor targeting HRAS mutant solid tumors. As you know, this program has received Fast Track designation from FDA. We are currently in a registration directed study, the AIM-HN study in patients who have relapsed and/or refractory head and neck squamous cell carcinoma. We are looking forward to broadening out the patient population by starting a combination study around the middle of next year that will combine tipifarnib with PI3-kinase alpha inhibitor to treat a -- potentially a much broader population of head and neck squamous cell patients. On the right-hand side is really what we're here to talk about today. This is our program, KO-539, of course, targeting specific genetic subsets of acute leukemia. This program has received orphan drug designation from the FDA. And as you'll see, we think we have the opportunity to address a significant patient population in acute leukemias from the relapsed/refractory setting all the way potentially to the frontline and beyond. And we're going to talk about several of the specific genetic subtypes as Dr. Wang and Dr. Issa go through the data today. Before I turn it over to Stephen, I just want to remind everyone of the development time line. So in the early 2000s, our academic collaborators at the University of Michigan, [ Dr. Grembecka ] and Dr. [indiscernible] began an effort to try to develop small molecule inhibitors of the menin-MLL interaction. And in 2014, through an introduction from the Leukemia & Lymphoma Society, we met the 2 of them and ended up both in-licensing the program and engaging in a program of collaborative research with them, the output of which was a series of compounds that have been the subject of a number of publications that you can see here, including MI-503 and KO-382. It was during this 2.5-year period, the KO-539 was optimized and ultimately underwent IND-enabling talks. I'll also remind you, in this time period, Scott Armstrong and colleagues discovered the relationship between menin-MLL and the NPM1 mutations that forms the basis for some of the data that we'll talk about today. The investigational new drug application was cleared in early 2019. We began this Phase I study in September of that year, and we're just delighted that Dr. Wang presented the data on behalf of her colleagues, the other investigators on the study just a few minutes ago at the ASH presentation. So with that, I'm going to transition now to Stephen Dale, our Chief Medical Officer, and let him take it from here. Stephen?

Yes. Thank you, Troy. Thank you very -- very nice summary. Again, welcome to everybody. I think, just wanted to say just a couple of words. I joined Kura 3-or-so months ago. And I've got to say it was a true honor. Troy and I were talking early a few nights ago. And just going over some of the reasons why I joined. And I have to say even before I joined the organization, having worked a number of major pharma in oncology research over many years, I was so impressed with the team and the genuine passion and desire the company has to bring in new cancer medicines to our patients. In fact, it was more than palpable. It was contagious. So I just wanted to share that with you in the pipeline, the innovation and the true spirit of follow the science, it was just exactly as it should be and always looking for right target right patient. So I think it's important. I just wanted to share that before we do move on. So with that said, it's a great pleasure, I'm able to introduce 2 esteemed speakers who are with us tonight. We have Dr. Wang, Chief of the Leukemia Service at Roswell Park Cancer Center and Associate Professor of the Department of Medicine in New York. And also Dr. Issa, Medical Oncologist, Department of Leukemia and Genomic Medicine at MD Anderson Cancer Center and also Assistant Professor of the Department of Leukemia. And Dr. Wang will now speak to us about the treatment landscape in relapse/refractory AML. Thank you, Dr. Wang.

Good morning. I appreciate everybody taking the time to be here today for this presentation. So acute myeloid leukemia is an aggressive hematologic malignancy, which occurs in approximately over 13,000 individuals each year in the United States. Treatment of this malignancy is highly complicated by numerous factors. These include the aggressive clinical nature of this disease with death occurring within weeks to months. And also includes the diverse biological heterogeneity of this cancer as well as the fact that many of the patients at diagnosis are of advanced age, specifically between the ages of 67 to 70 years of age at diagnosis. Now more than half of these individuals, despite all of our treatment modalities will develop relapsed or refractory disease. And the outcomes of these individuals represents an urgent unmet need. Shown here are the national guidelines for the management of individuals with relapse and refractory AML. As you can see here, the first step is at the time of disease recurrence is to have a comprehensive genomic profiling done again on the tumor type to determine whether this individual might be eligible for numerous targeted therapeutics, which have been approved for the treatment of relapsed AML over the last 3 years. Shown here are those targeted therapies, gemtuzumab, an antibody drug conjugate against CD33, ivosidenib and enasidenib, which represent IDH1 and IDH2 inhibitors, respectively, and gilteritinib, which is a potent FLT3 inhibitor. In addition, we have -- for patients who do not express any of these surface antigens or who do not have any of these specific mutations, we always have chemotherapy, supportive care and transition to hospice. How do patients fare with these outcomes? As shown here on the left-hand side, despite all of these modalities and despite the approval of multiple new agents since 2017, the outcomes of patients with relapsing/refractory AML remain dismal. On the left-hand side, you can see the survival curves of individuals receiving conventional chemotherapy, both intensive cytarabine, anthracycline-based therapy as well as low-dose epigenetic therapy. Shown on the right-hand side are the outcomes of targeted therapy for relapsed/refractory leukemia. As you can see here, the overall response rate of patients receiving these targeted therapies only is less than 50%, ranging from 27% to 42%. In addition, we see that individuals here, despite the advances that we've made are expected to live less than 12 months from the treatment initiation with these targeted therapies. Inhibition or genetic disruption of the menin-KMT2A gene interaction may represent the next cutting-edge novel therapeutic approach for treatment of acute leukemias. Just to remind you, the histone lysine and methyltransferase KMT2A is rearranged in 5% to 10% of acute leukemias, and this encompasses both de novo and secondary leukemias as well as therapy related and pediatric disease. Binding of the protein menin to this KMT2A complex results in upregulation of different promoters, HOXA9 and MEIS1, leading to leukemia genesis in the majority of these patients. As you can see here, drugs that inhibit menin, such as the KO-539, therefore, have the ability to block this interaction and, therefore, lead to downregulation of these promoter genes, resulting in differentiation, maturation and cell depth. In addition to the efficacy of these agents expected in patients with MLL-rearranged leukemias, we also have identified a central role for men in KMT2A or MLL interactions and other tumor types, the most prominent of which is NPM1-mutant AML. NPM1-mutant AML occurs in up to 1/3 of patients at the time of diagnosis. In addition, there is a less prominent but still described roles from menin-KMT2A interactions and AML with other mutations, including IDH1, IDH2, TET2, DNMT3A and FLT3. KOMET-001 is a Phase I first-in-human study of KO-539. KO-539 is an oral, novel, potent daily inhibitor of menin, which is being studied in adults with relapse and refractory AML agnostic to the oncogenic mutation type. This study is divided into 2 cohorts. The Phase I cohort has the objective of assessing safety, tolerability and determining a recommended Phase II dose or maximum tolerated dose. The Phase I trial is also designed to describe any evidence of early preclinical or clinical activity in these patients. The Phase II expansion cohorts involving 18 patients each will evaluate the efficacy of the recommended Phase II dose in patients with both NPM1-mutant disease as well as in patients who have KMT2A-rearranged AML. Continuous daily dosing of KO-539, as you saw in the oral presentation, has been to date, been very well tolerated with a manageable safety profile. Currently, there's been no drug discontinuations due to treatment-related adverse events, no evidence of QTc prolongation and no evidence of interactions with CYP3A4 inhibitors. As you can see here that the toxicities have largely been manageable and include increased lipase, pancreatitis, decreased neutrophil count, deep venous thrombosis and tumor lysis. In addition, we've seen a number of grade 1 and 2 toxicities, including nausea, rash and diarrhea. Shown here are the data presented in 12 patients as opposed to 8 in the ASH oral abstract. Receiving KO-539 in cohorts of drug ranging from 50 to 400 milligrams. In this table, we present updated information, shown in blue are the 6 patients out of these 12 who have demonstrated what we would consider some evidence of clinical activity following drug treatment. This includes 2 CRs, one morphological leukemia-free state, one stable disease; and two decreased peripheral blasts and decreased hydrea requirement. To remind you, all of these patients had relapsed and refractory disease that had failed between 2 to 7 prior lines of therapy, thereby constituting a very high-risk, poor prognostic patient population. You can see that activity was observed in three patients, 2 of which had NMP1 mutation and 1 patient who had a KMT2A rearrangement. In addition, clinical activity was seen in 3 patients who had neither NPM1 or KMT2A rearrangement. Of note also, just again to remind you, activity was seen regardless of the co-administration of CYP3A inhibitors. Moving on, we'd like to show you some data on specific patient cases to better illustrate the encouraging clinical activity that we've seen so far. So I'd like to lead off by describing this patient which was my patient. This individual was the first human to receive KO-539 in this clinical trial at a dose of 50 milligrams per day. He was a 71-year-old gentleman who had traveled over 1.5 hours to come to our facility for novel therapeutics. He had acute myeloid leukemia, which have failed 2 prior lines of therapy, including cytarabine and anthracycline-based induction as well as venetoclax and azacitidine. At the time of presentation, he had over 50% blasts, was taking a concomitant azole for a prior history of fungal pneumonia and was in excellent performance status. After initiation of therapy, he demonstrated evidence of clinical activity, as shown by decreasing dependence on an oral cytotoxic agent, hydroxyurea and evidence of grade 3 tumor lysis, suggesting tumors -- leukemia cells were undergoing apoptosis. Unfortunately, he subsequently was admitted for a history of hypoxia, which was believed unrelated to treatment. And given the distance from his home, he decided, therefore, to withdraw further therapy and return home for supportive care and hospice treatment. My colleague, Dr. Issa from MD Anderson will now take the reins to discuss the other patients that we'd like to present today.

Thank you, Dr. Wang. So my goal is to tell you again why we are so excited about this new class of inhibitors and specifically this compound. So I'm going to go through some of these cases. So this is patient #2. This is a 69-year-old man with mutations SETD2 and RUNX1. And as a background, RUNX1 is an adverse risk factor in AML. It is enriched in leukemias that have progressed from myelodysplastic syndrome, so essentially conferring an adverse risk. And this patient had 2 lines of therapy, decitabine as a standard of care and investigational agent. In this case, this is immunotherapy abate against CD33, which is expressed on leukemia. He received the 100 milligram dose, which was subsequently increased to 200. And as you can see from the top, this patient had immense clinical benefit. So despite the adverse risk factors, despite that this patient had progressed on 2 lines of therapy, this patient had a complete remission, MRD positive, and it was sustained for multiple cycles of therapy. So this is important for multiple reasons. First, this is exciting because this patient is refractory, as I said. But also it's because we show activity here and a genotype that is not NPM1 and MLL rearranged, which is the most studied in the preclinical models, but essentially highlights that menin inhibition could be important for a larger group of AML. To date, this would be the first if RUNX1 is the target and here would be the first targeted therapy against RUNX1 mutation. So very important. This patient did have a Grade 3 DVT, but it is not uncommon for leukemia patients to develop DVT like all cancer patients. So going to patient #3. This is a 44-year-old woman with mutations in NPM1, DNMT3A, and FLT3 tyrosine kinase domain. This triad of mutations is the most common co-occurrence in AML and is also the worst co-occurrence in AML. It leads to the worst prognosis. And this patient had 7 lines of therapy, including standard of care and investigational agents. And not shown here, this patient has relapsed following transplant. So highly refractory disease. He was treated on the 200-milligram dose and achieved a complete remission, MRD negative. So this is incredibly exciting, because this disease is refractory, as I mentioned. But it also -- it settles a debate about the proof-of-concept on targeting NPM1. So -- and here, we show that using this inhibitor in patients that have NPM1 could achieve a complete remission MRD negative. And the other point established is despite the genetic context of co-occurring mutations with NPM1, an example here, FLT3, so regardless of that genetic contacts, there was a response by targeting NPM1, which potentially could be important because NPM1 could precede in the development of leukemia other mutations. So we would be targeting the founding clone in this case. This patient had pancreatitis, that resolved with medical management. He had been receiving other medications. So it's possible that other medications could have caused this at the same time, although we can't rule that out. So this other patient, patient #4. This is a 73-year-old woman with NPM1, FLT3-ITD. Again, this pattern of co-occurrence. And this time, this patient had received the standard treatment for the FLT3 mutation or FLT3-driven AML. So had 7+3 standard of care with midostaurin, the approved FLT3 inhibitor and then had decitabine with gilteritinib, which would be the more potent FLT3 inhibitor. And despite this, had relapse. So in this setting, this would be a refractory disease that have progressed on FLT3 inhibitor. And so despite being resistant, despite progressing on FLT3 inhibitor, this patient had a response. In this case, this is the leukemia-free state or [ molecular ] leukemia-free state, which means that the blast percentage went down to less than 5% -- or morphologic leukemia-free state and had no adverse events. So in summary, KO-539 is a potent and selective inhibitor of the menin-KMT2A complex, and it's well tolerated with a manageable safety profile to date. The observed toxicities appear to be reversible and manageable, and we have seen no evidence of QTc prolongation. KO-539 demonstrated encouraging signs of clinical activity in multiple genetically defined subgroups of AML. The pharmacokinetics and clinical activity do not appear to be affected by co-administration of a CYP3A4 inhibitor, and we continue to enroll patients in dose escalation, currently evaluating the 600 milligram cohort. We anticipate that we would determine the recommended Phase II dose in the first quarter of 2021. I will pass it on to Dr. Dale.

Thank you, Dr. Issa. So just as we sort of come to a close and our final slide in the primary presentation, we thought it would be useful to share with you our multiple expansion opportunities in acute leukemias. And as Dr. Issa has already called out, we anticipate to get the recommended Phase II dose in Q1 of next year. That enables us to move into stage 1 of our Phase II expansion in the first instance, which means there are 2 primary cohorts. The first expansion cohort will be in patients with KMT2A rearrangements and the second in patients with NPM1-mutant disease. But as well as those 2 primary cohorts. As we look at further stages in the Phase II expansion, then it's looking also to look and explore another cohort of cohort 3, which is going to look at potential other subtypes of other genetics. And that's a piece of work which is ongoing at the moment. But also as well as looking at relapsed/refractory AML, we're also looking to expand the indications and looking at frontline opportunities as well. So in the adult population, expanding out to look at potential for other combinations with frontline therapy with standards of care. But in addition to prosecuting development in AML, we recognize deeply the unmet medical needs in childhood AML. And with that in mind, we're also looking to prosecute development in pediatric AML. So that would look to both relapsed/refractory disease, but also in frontline therapy as well. And as we sort of come down the list and then to look at other disease areas, so other acute leukemias. In this instance, one of those would be acute lymphocytic leukemia. And I think it's important that the overall message here is that we have an ongoing commitment to all these areas of high unmet medical need, which we continue to prosecute development of KO-539. And with this, it concludes all of our prepared formal remarks, to which, I hand back to Troy.

Great. Thank you, Stephen. At this point, we're going to take as many questions from the audience as we can. There are -- last, Pete told me there were more than 160 people on the webcast, and there's a long list of questions. So we're going to try to get through as many as we can. And I want to start with this one that's come in. The question is, how would you characterize the activity of KO-539 relative to other targeted drugs for acute myeloid leukemia at a similar stage of development. And I'll ask Dr. Issa and Dr. Wang to comment on that. And maybe Dr. Issa, we can start with you and then transition to Dr. Wang.

As I mentioned, this is very exciting because just to give a context, so this is an oral medication that's being developed for a highly aggressive disease in the relapsed setting, where options are limited. So for example, MLL-rearranged AML has no good targeted therapy options. And NPM1 would be the largest genotype that is in AML. So essentially, there's an unmet need. There's an oral drug with very manageable side effects. And most exciting is that even in the first phases of Phase I, we are seeing activity that justifies the preclinical context of targeting menin-MLL. And in addition to the predictive NPM1 or MLL-rearranged leukemia, we are seeing activity in other genotypes, so potentially expanding the indication of using menin-MLL inhibition. So compared to other drugs that are -- that have been developed or are at this stage, this is very exciting, it's comparable to, I would think of like, IDH inhibitors or FLT3 inhibitors. So again, very exciting.

Thank you. Dr. Wang?

So I'd like to just echo the comments made by my colleague. I think we've seen over the last 3 years the development of multiple targeted agents for AML, specifically IDH inhibitors and FLT3 inhibitors. And those agents, unfortunately, only work in patients that have disease driven by those specific mutations. The promise of this drug is remarkable in that it could be equivalent more similar to what we're seeing with venetoclax, where it has activity across mutational subtypes, which I think is highly exciting. The fact that we're seeing any activity at this early stage is remarkable because this is a drug that in preclinical studies, we expected not to have any evidence of clinical activity to 600 milligrams. So up to 400 milligrams to have half of the patients who had up to 7 lines of therapy shows any evidence of any signal, I think, is remarkable at this early stage. I've done a lot of Phase I drugs, and we typically do not see responses at some of the early levels, and that is suggestive of the exquisite sensitivity potentially of different AML subtypes to perturbation on this particular pathway.

Thank you, Dr. Wang. And in your answer, you actually anticipated, I guess, the next question. And the question from the audience is, you saw evidence of clinical activity at 50 milligrams and a complete response at 100 milligrams, but your predicted efficacious dose with 600 milligrams, how do you explain this? Francis Burrows, who's our VP of Translational Research. Francis, would you like to try to address this question for the audience?

Sure. Yes. I think there -- what's really -- basically going on here is that, for a nice change, the human patients seem to be more sensitive than the kind of patients I treat, the 4-legged version. And that's because there is preferable decay in human relative to the animals. So our prediction of the 600 mg is the human efficacious dose. It's based upon the efficacy studies in the mouse, how much we needed to cure some of these animals and then physiologically based PK on allometric scaler, which are state of the art for how to do that, but are imperfect tools in some ways. In this case, the prediction did not account for the time-dependent CYP3A4 inhibition, that we recently observed, which indicates that 1 or more of the primary metabolite of KO-539 is an inhibitor of CYP3A4. And since that is the primary metabolic pathway of metabolism of KO-539, this in turn results in significant accumulation of the parent drug in the blood, and we hypothesized even more so at the primary disease site in the bone marrow. So we're currently doing additional modeling and analysis of PK. As you see, we're expanding cohorts to look at more patients. And we seek to understand better the exposure of KO-539 in its primary metabolite and understand the PK study state.

Great. Thank you, Francis. There was just a quick question that came in about the potential to dose escalate to 600 milligrams or higher. I hope it was clear from this presentation. We're now evaluating patients in the 600 milligram dose escalation cohort. So nothing to say as of this point, obviously, because that's passed the data cutoff, but did want to address that question? The next question is actually a 2-part question. And I'll ask maybe Dr. Wang and Dr. Dale to respond to this. So the first question is, can you rule out the concomitant effect of CYP3A4 inhibitors on the activity of KO-539 based on this early data set? That's question #1. And question #2 is, do you foresee any issues combining with venetoclax given the CYP3A4 interaction? Dr. Wang, would you like to get us started on this question?

Sure. So again, it's a limited data set, and it's early days. But I think based on the data that we have so far, I think I'm reasonably confident that the PK and exposure of KO-539 is unaffected by concomitant administration of, for example, antifungal medicine CYP3A4 inhibitors. I do think that right now, when we look at the overall PK, as we go up on the dose, we do see a proportional increase in drug exposure as we would expect. But I think that in my limited, again, opinion based on the small numbers of patients, I don't foresee that it would be a problem to -- as I mentioned in the ASH oral abstract to explore combinatorial approaches with drugs such as venetoclax. So that I would be interested in Dr. Dale's input into these topics as well.

Stephen, would you add your thoughts?

Yes. No, no, absolutely. Thank you, Dr. Wang. Completely agree. And as well, in terms of the CYP3A4 patient, we've taken a number of samples, PK samples and looked across the board of patients who are receiving concomitant AZOLS, both moderate CYP3A4 inhibitors and strong CYP3A4 inhibitors and compared those with patients that have received no azole therapy. And what we see is actually, overall, we see no difference in pharmacokinetic parameters. And indeed, exposure overall remains constant. So AUC remains flat, which we see no added effect if a patient is on concomitant azole therapy.

That's great. Thank you, Stephen. So the next question is as follows. Based on the preliminary clinical data reported to date, how does KO-539 compare to SNDX-5613? Maybe I'll take this question. I think we just want to start by saying, look, it's ideal if patients have multiple options. These are patients, a very high unmet need, and we want to give them as much -- as many options as we possibly can. If you look at the preclinical data, the 2 compounds appear to be comparable. They're both very potent. They're selective and they're capable of driving responses in multiple genetic subtypes. The differentiation -- it's very early days. These are early data sets, but the differentiation appears to be more in the drug-like properties, tolerability, pharmacokinetics exposure and potentially the ability to combine. As you know, KO-539 continues to be given on a once-daily regimen, 5613 by contrast, as far as we understand, is given twice a day. In terms of tolerability, all of the toxicities that we've observed to date are reversible and manageable. It's still early, but we're very encouraged by the safety and tolerability profile that we're seeing. And importantly, we're not seeing any evidence of QTc prolongation. In terms of the potential to combine, this is a question that we get from all directions. As both Stephen and Dr. Wang commented, although KO-539 is metabolized by CYP3A4, that metabolism appears independent to [ vasos ]. And from our perspective, given the comfort that most hematologists, oncologists have in working in an environment where there are moderate or strong CYP3A4 inhibitors, we don't foresee any issues developing 539, either as a monotherapy or in combination. So I think it's early days. We're incredibly encouraged by the data set that we've shared. We look forward, as Stephen mentioned in his slide, to aggressively pursuing the multiple expansion opportunities that we enumerated. And we think potentially, KO-539 has a chance to be a best-in-class compound. Obviously, more data to come. With the next question, the question is, what can you tell us about the 2 patients in the 200-milligram cohort who were not evaluable for efficacy? Dr. Wang, could I ask you to address that? I think that was one of your slides.

Yes. No, thanks, Troy. So this is a good question. I think it's good to always examine the patients that we don't necessarily present all the data on. Unfortunately, both of these patients passed away prior to complete evaluation, prior to day 28. And I think that, again, highlights the incredible clinical aggressiveness [ in for prognosis ] of these patients. And how remarkable it is that we even saw any results that suggested clinical efficacy in the remaining patients. The one patient who had KMNT2A rearranged patient. One of my individual patients received the drug for '21 days and had what looked like very upward disease progression. His blast count went up. He was hospitalized for pneumonia and acute kidney injury and then he unfortunately passed away. The second patient who had a CD33 mutation received KO-539 for '19 days. He was in hospital, but was a younger gentleman. And again, lived about 3 hours away and requested to go home. When he went home to spend time with his family, unfortunately, developed gastritis symptoms, was hospitalized for that and that rapidly progressed to an antibiotic-associated C. diff colitis. So he unfortunately was not able to complete 21 days of drug. We think both of those patients had evidence of ongoing disease. And we do think that both of those tests were unrelated to treatment.

Thank you, Dr. Wang. Dr. Issa, maybe I can direct this next question to you from the audience. How would you characterize the toxicities observed to date? Is there any potential cause for concern as you move to the 600 milligram cohort?

Yes. So far, this drug is really well tolerated, especially for a first-in-class drug, where -- we're starting in humans, and we're not sure whether what we predicted and modeled is going to apply. So most patients are having no side effects. And the side effects that we've seen are manageable. And again, everything should be taken into context. Within AML, this compares really well to other drugs that are essentially targeted therapies. So it seems that this drug is tolerated by patients and would be an ideal candidate for combination therapies with the approved treatments for AML.

Thank you, Dr. Issa. The next question is, how long do you expect it will take to complete the 600 milligram cohort? Do you expect to determine the recommended Phase II dose at that point? Stephen, could I ask you to address that question?

Yes. Thanks, Troy, Of course. Of course. This is a question, I guess, asked quite a lot. We continue to be on a Phase IA dose escalation. The 600 milligram cohort continues to enroll patients. Each cohort in the study has 3 patients, but where we have multiple patients in screening, up to 5 patients [indiscernible] to a cohort. So this is ongoing. And of course, the whole purpose of the Phase IA study is to ensure that we don't have DLTs. And so far, as we've talked about, we have a highly encouraging safety and tolerability profile. In terms of the Phase II recommended dose that we've spoken about, that remains to be said, but we anticipate that we'll have that by Q1 next year.

Great. Stephen, while I have you, I think there's a second question from the audience. How many patients do you expect to enroll in the expansion cohorts? And what is the bar for efficacy? That's part one. Part two is, are the expansion cohorts designed to be registrational? Would you take those two?

Okay. Yes, sure. Thank you, Troy. So the Phase II expansion has -- actually has 3 stages. But in terms of the number of patients in stage 1 of the expansion, so that will be 18 patients. So 18 patients per cohort per genetic subtype. So in terms of the benchmark that we're looking for, the primary endpoint of the Phase II study is a composite. It's a composite of CR and CRI. And the levels of response rate that we're looking for are between 25% and 30% to move forward. So that answers the -- sort of the second part or the first part 1A, then the cohorts or the parts of the Phase II, which are registrational. The first part is a proof of principle. And the second and third stages of the Phase 2 will be pivotal. So at the moment, we're going into phase, the first phase of the Phase II expansion once we get the recommended Phase II dose.

Great. The next question from the audience is, can you tell us more about this potential third expansion cohort? This is the one, Stephen, that you're referring to, how big do you estimate this additional population to be. Francis -- Dr. Francis Burrows, could you take this question maybe for the audience?

Sure, Troy. Thanks. So obviously, we are very encouraged by the activity that we observed in the patient with SETD2 and RUNX1 co-mutations. The SETD2 can be linked to the menin-MLL pathway through the -- its effects on the binding of the complex to DNA. That's very exciting. And the RUNX1 was unexpected, certainly to me. But since we have, in addition, observed some biologic activity in another patient with RUNX1 mutation, it appears that there may be something there. In fact, if you look at the AML databases that are out there, you can see that there are actually significant numbers of cases that exhibit MEIS1 overexpression, but lack a mutation in NPM1 or a rearrangement in KMT2A, which suggests that perhaps combinations of recurrent AML mutations other than NPM1 and MLL could combine to activate the menin-MLL pathway and drive disease via upregulation of the Homes gene program. So we're excited to build on the work we've done already. We've initiated a couple of large preclinical collaborations with leading labs at Sloan Kettering and MD Anderson, and we're going to try and find out as much as we can in anticipation of potentially enrolling the third cohort as part of our expansion into the Phase II portion of the trial.

Great. Thank you, Francis. The questions keep pouring in. We're not going to -- we're clearly not going to get to all of them, but I'm going to do my best to get through as many as I can. The next question is, can you tell us about your pediatric development strategy? When do you expect to begin dosing pediatric patients? Dr. Bridget Martell, who's actually been the clinical lead on this program from long before the compound was ever in the clinic and has been shepherding it to this point. Bridget, would you like to address the question on pediatric development? And what our thoughts are there?

Sure, Troy, I would love to do that. Again, I think that we've all talked about the biggest rate limiter for moving into pediatrics is going to be finding the recommended Phase II dose that will allow us to calculate the appropriate doses for children. Because it's an oral agent, so those children that can actually take an oral medication, we can move immediately into pediatric enrollment strategy. However, it's going to be determinant on that recommended Phase II dose. And we're encouraged to think about enrollment for pediatric program for a number of different acute leukemia, and we're very excited to start thinking about that next year. So we'll be giving you updates as -- in 2021 as appropriate.

That's great. And Bridget, while I have you on the line, maybe just another question. It appears that you move to a 3+3 design in cohort three, was this by design or due to the observation of DLT. Can you comment on that?

Yes, I can. That's a great question and a very important one. It was not related to the observation of DLT, that would require us to move to a 3+3 design based on a modified [indiscernible] probability index. It was actually due to the need to characterize the pharmacokinetics. And as you can tell by the [indiscernible] that Dr. Wang gave, it was very well thought through with regard to looking at prior results. And this is very important for us to determine some of the characters, the compound with regard to a CYP3A4 inhibitor, that gave us great information to move forward to the subsequent cohorts.

That's great. Thank you, Bridget. The next question is, what is your strategy for moving into the frontline? Where do you see KO-539 ultimately fitting in within the treatment paradigm? Dr. Stephen Dale, could you take that question for us?

Yes. Of course. Thanks, Troy. It's a good question. It's an important question and it links, of course, to the final slide. So without doubt, there's a strong interest from investigators and KOLs alike in combining KO-539 with multiple frontline therapies. We're currently conducting preclinical work. I think that's important to state -- to look at the different options that we have and together more evidence ex vivo in terms of how we may do these combinations. It's also important to note as well that we continue and will continue to get a feedback from both clinical and regulatory experts on potential trial designs because we have to get the balance right as well in terms of getting that trial design, which will enable us to gather and game registration, which is an important factor. So that's something that we'll continue to get advice on that as well. And back to the fact that given all of the encouraging safety and tolerability data that we have and already the highly encouraging level of both biological and clinical activity that we're seeing, we're very excited about the possibility of combining KO-539 with another agent or other agents in the firstline setting.

Great. Thank you, Stephen, for that. I'm going to direct a question to Dr. Wang and Dr. Issa. And Dr. Wang, maybe I'll ask you to take it first. And that is several folks have asked, can you talk about the advanced nature and the rapidly progressing aspect of this disease and how that sort of confounds interpretation of these early data sets? Maybe give folks some color on your experience with patients in this setting for each of you.

So this is a very clinically aggressive disease. The -- when you measure in the laboratory the cell cycling and the half-life for some of these acute myeloid leukemia cells, it's really measured in a matter of hours. So I'll give you a real life example. I saw a patient of mine. He was 81 years old. He had received 2 cycles of venetoclax-azacitidine, which as we know, with the VIALE-A trial is a new standard of care for those elderly individuals. He had after cycle 1 evidence of some cytoreduction, but still some disease burden there. So we went ahead and gave him a second cycle, and he came back to my clinic for a second bone marrow biopsy after cycle 2. We did that bone marrow, his white count was 2, his hemoglobin was 8, platelets were a little bit low. He was fine. Performance status was probably 1 or 2. He was commuting from about half an hour away. So we did that bone marrow. Unfortunately, what it showed is about 70% leukemia blasts. So we brought -- we were bringing him back in the distance -- in 5 to 7 days to discuss his marrow results and I saw him on Wednesday. On Monday, I received a phone call that he had presented to an outside emergency room with a white count of 113 with 70% blasts. By the time we had transferred him here, he had evidence of an LDH level of 14,000. He is in active tumor lysis with creatinine of 2.5. And again, a white count of over 100 with 70% or 80% blasts. And unfortunately, that gentlemen with very refractory/relapsed disease went on to hospice care. As we know from the MD Anderson Group, Dr. Issa can speak more cogently than I can about that example. Patients who are refractory and relapsed [indiscernible] induction or reinduction really have an overall survival, I believe, that's less than 3 months. Maybe, Dr. Issa, you could address that from your perspective. Is that something that we're seeing in patients that are refractory to venetoclax-azacitabine?

Dr. Issa?

Yes. Relapse after AML is after treatment with venetoclax is very aggressive and very few treatment options. So like the example you had mentioned, median survival is a month, maybe 3 months, 4 months. And to sort of echo what you were saying about the nature of AML, I can highlight the 2 genotypes and indicate that both MLL and NPM1 mutation, NPM1 when it's co-occurring with the 3 is a presentation of a very high white count, where we have to act immediately. So unlike other cancers, in AML, the time matters and time to therapy could be very important. And when we have effective therapy, it's like this menin inhibitor would be exciting.

Oh, oh, we interrupted you, Dr. Issa, go ahead and finish the thought. Sorry for that.

That's okay. Just saying that I'm excited about menin inhibitors because essentially, these are highly refractory patients with these genotypes and the addition to the treatment armamentarium in AML of menin inhibitor would be incredibly helpful for these patients.

Terrific. Thank you. The next question, Stephen, I think I'm going to direct this to you, but feel free to call on others if you think it's appropriate. And the question is, based on the data that we're seeing thus far, how are we thinking about determining a recommended Phase II dose? Is it potentially 200 milligrams, 400 milligrams? How do we go about -- how will we go about that determination given the data set? Can you [indiscernible]?

Yes. Sure. Thanks, Troy. Yes. It's -- and again, it's a good question. And this is often asked, when you're in a situation, when you're in dose escalation and you're continuing to escalate. And you're not getting to the point of maximum tolerated dose yet and in the absence of DLT, which, of course, is a highly positive situation to be in. And to this -- at this point, we don't know if we're going to hit MTD or not yet. In terms of assessing, which is the right recommended Phase II dose, of course, we've said already that the 600 milligram cohort is still enrolling at the moment. So we've still got data sets that we need to evaluate for those patients. But in the absence of an MTD, and as I say, with a caveat that we don't know that yet, then it has to be based on evaluating overall across the different dose cohorts, safety and tolerability data, coupled with the clinical pharmacology and coupled with the efficacy data. And those all get added up in terms of assessing the benefit risk. And this is a standard practice in this type of situation. But at the moment, we're still in dose escalation. We're still enrolling patients at 600. It's highly positive data in terms of safety and tolerability, and we'll continue to collect those data until we finish the cohort 600 milligrams.

Great. Thank you, Stephen. Francis, I think I'm going to direct this question to you. The question is, is the complete response observed in the NPM1 patient due to NPM1 or KMT2D?

Yes. Guy, I'm the right guy for that. Thanks, Troy. So just to step back a moment, as you've seen, we usually use the term MLL rearrangement to describe the type of AML that we developed this drug for. And now MLL, which stands for mixed lineage leukemia is now called by a much more technical name, KMT2A, which signifies that it's the #2 lysine methyltransferase. In this family, KMT2D is a related -- rather closely related enzyme that actually performs quite different functions. And hence most importantly, in AML, it is not recurrently mutated, it doesn't play a similar role to KMT2A. It is the mutations in our [indiscernible] function and are primarily associated with B-cell lymphoma. So it looks like it should be on pathway, so to speak, but it's not. In the case of the NPM1, we know that, that is the driver mutation here. And as both Dr. Issa and Dr. Wang have mentioned, for me as well, the most exciting timing that we've seen is that the presence of co-mutations, which confer particularly poor prognosis when combined with NPM1. Actually seems, if anything, to reinforce the addiction to this pathway. And there's possible reason for that in as much as a number of these mutations actually do feed into the menin-MLL pathway at a mechanistic level. So for example, a loss of function of DNMT3A can result in up-regulation of HOXA9 and MEIS1, because normally, the effect of that active enzyme would be to restrict the ability of the menin-MLL complex to buy into those promoters. The same applies to the mutant form of IDH1 and 2. So we see that despite the presence of multiple co-mutations, which are all highly oncogenic, the dependency on the pathway is not reduced. And if anything, is strengthened. So again, I think it comes back to the fact that we've referred to a couple of times, that this interaction and the activity that's complex is essentially the founding lesion of the disease and is central to everything else. So the addition of extra co-mutations over and above the NPM1 or indeed the MLL rearrangement does not seem to radically affect the activity of the drug.

Great. Thank you, Francis. The next question is a bit of an unfair question, but can you comment on the status of the third NPM1 mutant patient? And maybe I'll take that question. As indicated in Dr. Wang's presentation, the data cutoff was as of early November. We can't comment on anything observed post the data cutoff for obvious reasons. If we -- we can't pick and choose, and we would have to clean all of the data on every patient. There's another part of the question, is there anything different about that NPM1 mutant patient? There isn't anything overtly different. Just to remind the audience, and I think Dr. Issa and Dr. Wang both said it very well. This is a very sick population, very relapsed/refractory population. These patients are at very high unmet need, and these are small numbers. We will provide an update on this data set at an upcoming medical meeting. We will also make an announcement when we reach the recommended Phase II dose. Obviously, we're still, as Stephen indicated, in dose escalations. So we're not there yet. But you can anticipate that we will provide an update on all of the patients on the study at the next appropriate opportunity. So I appreciate that question. We have 1 or 2 more minutes. I'm going to try to take 1 or 2 more questions. Stephen, this is a question that's come in, I think, for you maybe to address. And that is, are we concerned at all about the ability to combine with venetoclax given that venetoclax is a substrate for CYP3A4 and KO-539 is an inhibitor or the metabolite is an inhibitor of CYP3A4. Can you take that question?

Sure. Yes, of course. Now, that's a good question. And we've spoken about KO-539 and all its metabolites being both time-dependent inhibitor of CYP3A4 and the substrate. And the question of combining with a compound which is metabolized by CYP3A4 is a good one. The easiest way to address this is actually, look, if one looks at the label for venetoclax. And there are two great examples, which are given in the instructions in the label for venetoclax. And in combination, so when you combine venetoclax, which is metabolized, it's a substrate for CYP3A4. When you combine it with a strong CYP3A4 inhibitor and the frame of reference that is given in the label for venetoclax is posaconazole. And it's a simple dose modification. In this case, it's a dose reduction of venetoclax to 70 milligrams. And indeed, if it's combined with other strong CYP3A4 inhibitors, then the dose reduction of venetoclax is down to 100 milligrams. So there is already -- and there are other examples as well, where it can be very effectively managed when you combine a compound, which has inhibitory properties. CYP3A4 with a compound, which is metabolized by the same P450 enzyme system. And other examples as well, KO-539 is not the only example of [indiscernible]. Another common example of a compound, which is also part of polypharmacy and cardiovascular meds is verapamil. Verapamil is also a time-dependent inhibitor of CYP3A4 and a substrate, and that's combined with many different compounds is streaming for AF and hypertension. So answer to the question, this can be very effectively managed.

Thank you, Stephen. With that, I think we've come to the end. We're just actually -- we're over the hour at this point. So I want to thank, first of all, Dr. Wang and Dr. Issa for their participation as well as all of the investigators on the study. We, of course, want to thank the patients and their families. And I want to thank my colleagues, Dr. Bridget Martell, Dr. Francis Burrows, Dr. Blake Tomkinson; and of course, Dr. Stephen Dale. And then finally, I want to thank all of you. We didn't get to every question. I trust we will. We're, of course, available. You can talk to -- you can reach out to me, Pete De Spain or Marc Grasso, if you want to have further discussion. Thank you all. Thank you for the participants, and thank you all for participating in today's investor update. Thank you.