Good morning. Good afternoon, everyone. My name is Troy Wilson, 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 with an 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 timeline.
I'll do that. I'm going to hand it over to Stephen to introduce the investigators for the KOMET-001 study. 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 a data summary. Stephen will, after the data's been presented, talk about the KO-539 expansion opportunities.
We're quite excited to be moving this forward. 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. Just to level set everyone, today's discussion will be about KO-539. Just to remind you all, this is one of the two 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 the PI3 kinase alpha inhibitor to treat 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. 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. 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 timeline. In the early 2000s, our academic collaborators at the University of Michigan, Dr. Grembecka, and Dr. Cierpicki, began an effort to try to develop small molecule inhibitors of the menin-MLL interaction.
In 2014, through an introduction from The Leukemia & Lymphoma Society, we met the two 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 two and a half year period that KO-539 was optimized and ultimately underwent IND-enabling tox.
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. With that, I'm going to transition now to Stephen Dale, our Chief Medical Officer, and let him take it from here. Stephen?
Thank you, Troy. Thank you for a very nice summary. Again, welcome to everybody. I think I just wanted to say just a couple of words. I joined Kura three or so months ago, and I've got to say, it's a true honor. Troy and I were talking only a few nights ago and just going over some of the reasons why I joined.
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 that the company has for bringing new cancer medicines to our patients. In fact, it was more than palpable. It was contagious. I just wanted to share that with you.
The pipeline, the innovation, and the true spirit that followed the science, it was just exactly as it should be and always looking for right target, right patient. I think it's important. I just wanted to share that before we do move on. With that said, it's a great pleasure, I'm able to introduce two esteemed speakers who are with us tonight.
We have Dr. Wang, Chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, and Associate Professor of the Department of Medicine in New York. Also Dr. Issa, a Medical Oncologist, Department of Leukemia and Genomic Medicine at MD Anderson Cancer Center, and also Assistant Professor of the Department of Leukemia. Dr. Wang will now speak to us about the treatment landscape in relapsed refractory AML. Thank you, Dr. Wang.
Good morning. I appreciate everybody taking the time to be here today for this presentation. Acute myeloid leukemia is an aggressive hematologic malignancy which occurs in approximately over 13,000 individuals each year in the U.S. 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. It 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 67-70 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 relapsed and refractory AML.
As you can see here, the first step is at the time of disease recurrence, is to have 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 three years.
Shown here are those targeted therapies, gemtuzumab, the 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 relapsed 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%-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 N-methyltransferase KMT2A is rearranged in 5%-10% of acute leukemias. 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 leukemogenesis 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 death.
In addition to the efficacy of these agents expected in patients with MLL-rearranged leukemias, we also have identified a central role for MENIN-KMT2A or MLL interactions in other tumor types, the most prominent of which is NPM1 mutant AML. NPM1 mutant AML occurs in up to a third of patients at the time of diagnosis.
In addition, there is a less prominent but still described roles for MENIN-KMT2A interactions in 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 relapsed and refractory AML agnostic to the oncogenic mutation type. This study is divided into two 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 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, 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 eight 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 six patients out of these 12 who have demonstrated what we would consider some evidence of clinical activity following drug treatment. This includes two CRs, one morphologic leukemia-free state, one stable disease, and two decreased peripheral blasts or decreased hydroxyurea requirement.
To remind you, all of these patients had relapsed and refractory disease that had failed between two to seven prior lines of therapy, thereby constituting a very high-risk, poor prognostic patient population. You can see that activity was observed in three patients, two of which had an NPM1 mutation and one patient who had a KMT2A rearrangement.
In addition, clinical activity was seen in three 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 CYP3A4 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. 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 an hour and a half to come to our facility for novel therapeutics. He had acute myeloid leukemia, which had failed two 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 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 tumor's 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. My goal is to tell you again why we are so excited about this new class of menin inhibitors and specifically this compound. I'm going to go through some of these cases. This is patient number two. This is a 69-year-old man with mutations SETD2 and RUNX1. As a background, RUNX1 is an adverse risk factor in AML. It is enriched in leukemias that have progressed from myelodysplastic syndrome, essentially conferring an adverse risk.
This patient had two lines of therapy, decitabine as a standard of care and an investigational agent. In this case, this is immunotherapy, BiTE against CD33, which is expressed on leukemia. He received the 100-milligram dose, which was subsequently increased to 200. As you can see from the top, this patient had immense clinical benefit.
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. This is important for multiple reasons. First, this is exciting because this patient is refractory, as I said. Also, it's because we show activity here in a genotype that is not NPM1 and MLL rearranged, which is the most studied in the preclinical models.
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 in here, it would be the first targeted therapy against RUNX1 mutations, so very important. This patient did have a grade 3 DVT. It is not uncommon for leukemia patients to develop DVT like all cancer patients. Going to patient number three.
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, it's also the worst co-occurrence in AML. It leads to the worst prognosis. This patient had seven lines of therapy, including standard of care and investigational agents. Not shown here, this patient has relapsed following transplant, highly refractory disease. He was treated on the 200 milligram dose achieved a complete remission MRD negative.
This is incredibly exciting because this disease is refractory, as I've mentioned, it also settles a debate about the proof of concept on targeting NPM1. In here we show that using this inhibitor in patients that have NPM1 could achieve a complete remission MRD negative.
The other point to establish is despite the genetic context of co-occurring mutations with NPM1, an example here, FLT3. Regardless of that genetic context, there was a response by targeting NPM1, which potentially could be important because NPM1 could precede in the development of leukemia other mutations. 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 it out. This other patient number four. This is a 73-year-old woman with NPM1 FLT3-ITD. Again, this pattern of co-occurrence. This time this patient had received the standard treatment for a FLT3 mutation or FLT3-driven AML.
Had seven plus three standard of care with midostaurin, the approved FLT3 inhibitor, then had decitabine with gilteritinib, which would be the more potent FLT3 inhibitor. Despite this, had relapsed. In this setting, this would be a refractory disease that had progressed on FLT3 inhibitor. 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, sorry, leukemia-free state, and had no adverse events. In summary, KO-539 is a potent and selective inhibitor of the MENIN-KMT2A complex, it's well-tolerated with a manageable safety profile to date. The observed toxicities appear to be reversible and manageable, 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. 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. Now I'll pass it on to Dr. Dale.
Thank you, Dr. Issa. Just as we sort of come to a close in our final slide in the primary presentation, we thought it'd be useful to share with you our multiple expansion opportunities in acute leukemias. 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 two primary cohorts.
The first expansion cohort will be in patients with KMT2A rearrangements and the second in patients with NPM1 mutant disease. As well as those two primary cohorts, as we look at further stages in the phase II expansion, it's looking also to look and explore another cohort with cohort 3, which is going to look at potential other subtypes of other genetics.
That's a piece of work which is ongoing at the moment. Also, as well as looking at relapse refractory AML, we're also looking to expand the indications and looking at frontline opportunities as well. In the adult population, expanding out to look at potential for other combinations with frontline therapy with standards of care. In addition to prosecuting development in AML, we recognize deeply the unmet medical needs in childhood AML.
With that in mind, we're also looking to prosecute development in pediatric AML. That would look to both relapse refractory disease, but also in frontline therapy as well. 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.
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. 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. Pete told me there were more than 160 people on the webcast. There's a long list of questions. We're going to try to get through as many as we can. 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? I'll ask Dr. Issa and Dr. Wang to comment on that. 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. For example, MLL-rearranged AML has no good targeted therapy options, and NPM1 would be the largest genotype that is in AML. 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. In addition to the predicted NPM1 for MLL-rearranged leukemia, we are seeing activity in other genotypes, so potentially expanding the indication of using menin-MLL inhibition. Compared to other drugs that have been developed or are at this stage, this is very exciting.
It's comparable to, I would think of IDH inhibitors or FLT3 inhibitors. Again, very exciting.
Thank you. Dr. Wang?
I'd like to just echo the comments made by my colleague. I think we've seen over the last three years the development of multiple targeted agents for AML, specifically IDH inhibitors and FLT3 inhibitors. 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 till 600 milligrams.
Up to 400 milligrams, to have half of the patients who had up to seven lines of therapy shows any evidence of any signal, I think is remarkable at this early stage. We typically do not see responses at some of the early levels. That is suggestive of the exquisite sensitivity, potentially of different AML subtypes to perturbation of this particular pathway.
Thank you, Dr. Wang. In your answer, you actually anticipated, I guess, the next question. 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 was 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. Yeah. I think 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 four-legged version. That's because there is preferable PK in human relative to the animals. Our prediction of the 600 mg as the human efficacious dose was based upon the efficacy studies in the mouse, how much we needed to cure some of these animals, and then physiologically based PK and allometric scalar, which are state-of-the-art to help 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 one or more of the primary metabolites of KO-539 is an inhibitor of CYP3A4.
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. We're currently doing additional modeling and analysis of PK. As you see, we're expanding these cohorts to look at more patients, and we seek to understand better the exposure of KO-539 and its primary metabolites and understand the PK at steady 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. Nothing to say as of this point, obviously, because that's past the data cutoff, but did want to address that question.
The next question is actually a two-part question. I'll ask maybe Dr. Wang and Dr. Dale to respond to this. 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 number one. Question number two 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. 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 medicines, 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.
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 abstract, to explore combinatorial approaches with drugs such as venetoclax, although I would be interested in Dr. Dale's input into these topics as well.
Stephen, would you like to add your thoughts?
Yeah, no, absolutely. Thank you, Dr. Wang. Completely agree. As well, in terms of the CYP3A4 piece, we've taken a number of samples, PK samples, and looked across the board of patients who are receiving concomitant azoles, both moderate CYP3A4 inhibitors and strong CYP3A4 inhibitors, and compared those with patients that have received no azole therapy. What we see is actually, overall, we see no difference in pharmacokinetic parameters. Indeed, exposure overall remains constant. AUC remains flat, which we see no additive effect if a patient's on concomitant azole therapy.
That's great. Thank you, Stephen. 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 with very high unmet need, and we want to give them as many options as we possibly can. If you look at the preclinical data, the two 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. 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 of azoles. 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. 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. 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 two 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.
Yeah. No. Thanks, Troy. That's 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. I think that, again, highlights the incredible clinical aggressiveness and poor prognosis of these patients and how remarkable it is that we even saw any results that suggested clinical efficacy in the remaining patients. T
he one patient who had KMT2A rearranged patient, one of my individual patients, received the drug for 21 days and had what looked like very awkward disease progression. His blast count went up. He was hospitalized for pneumonia and acute kidney injury, he unfortunately passed away. The second patient, who had a TP53 mutation, received KO-539 for 19 days.
He was in hospital but was a younger gentleman and again, lived about three 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 progress to an antibiotic-associated C. diff colitis. He unfortunately was not able to complete 21 days of drug. We think both of those patients had evidence of ongoing disease. We do think that both of those deaths 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?
Yeah. 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 in models is going to apply. Most patients are having no side effects, and the side effects that we've seen are manageable. Again, everything should be taken into context. Within AML, this compares really well to other drugs that are essentially targeted therapies. 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?
Yeah. Thanks, Troy. Of course. This is a question that gets asked quite a lot. We continue to be in phase I-A dose escalation. The 600 mg cohort continues to enroll patients. Each cohort in the study has three patients. Where we have multiple patients in screening, up to five patients can be added to a cohort. This is ongoing. Of course, the whole purpose of the phase I-A study is to ensure that we don't have DLTs. 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, 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? Could you take those two?
Thank you, Troy. The phase II expansion actually has three stages. In terms of the number of patients in stage 1 of the expansion, so that will be 18 patients. 18 patients per cohort, per genetic subtype. 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. The levels of response rate that we're looking for are between 25% and 30% to move forward. That answers the first, part 1a. 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 II will be pivotal.
At the moment, we're going into the first phase of the phase II expansion once we get the recommended phase II dose.
Great. Thank you. 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? Dr. Francis Burrows, could you take this question maybe for the audience?
Sure, Troy. Thanks. Obviously, we're very encouraged by the activity that we observed in the patient with SETD2 and the RUNX1 co-mutations. The SETD2 can be linked to the menin-MLL pathway through its effects on the binding of the complex to DNA. That's very exciting. The RUNX1 was unexpected, certainly to me. Since we have, in addition, observed some biologic activity in another patient with a 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 up-regulation of the HOX/MEIS gene program.
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. We're going to try and find out as much as we can in anticipation of potentially enrolling this 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 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, 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 for those children that can actually take an oral medication, we can move immediately into a pediatric enrollment strategy. However, it's going to be determined on that recommended phase II dose. We're encouraged to think about enrollment for pediatric program for a number of different acute leukemias, and we're very excited to start thinking about that next year. We'll be giving you updates in 2021 as appropriate.
That's great. Bridget, while I have you on the line, maybe just another question. It appears that you moved to a three plus three design in cohort 3. Was this by design or due to the observation of a 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 a DLT that would require us to move to a three plus three design based on a modified toxicity probability interval. It was actually due to the need to characterize the pharmacokinetics. As you can tell by the ASH presentation that Dr. Wang gave, it was very well thought through with regard to looking at prior AML, and this is very important for us to determine some of the characteristics of the compound with regard to a CYP3A4 inhibitor. It gave us great information to move forward to the subsequent cohort.
That's great. Thank you, Bridget. The next question is, what is your strategy for moving into the front line? Where do you see KO-539 ultimately fitting in within the treatment paradigm? Dr. Stephen Dale, could you take that question for us?
Yeah, of course. Thanks, Troy. It's a good question. It's an important question, and it links, of course, to the final slide. Without doubt, there's a strong interest from investigators and KOLs alike in combining KO-539 with multiple frontline therapies. We're currently conducting pre-clinical work, I think that's important to state, to look at the different options that we have and to gather 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 gather 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 a trial design which will enable us to gather and gain registration, which is an important factor. That's something that we'll continue to get advice on that as well.
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 first-line setting.
Great. Thank you, Stephen, for that. I'm going to direct a question to Dr. Wang and Dr. Issa. 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.
Sure. This is a very clinically aggressive disease. 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. I'll give you a real-life example. I saw a patient of mine, he was 81 years old. He had received two cycles of venetoclax and cytarabine, which as we know with the VIALE trials and the standard of care for those elderly individuals.
He had, after cycle one, evidence of some cytoreduction, but still some disease burden there. We went ahead and gave him a second cycle, and he came back to my clinic for a second bone marrow biopsy after cycle two. We did that bone marrow. His white count was two, his hemoglobin was eight. Platelets were a little bit low. He was fine.
Performance status was probably a one or a two. He was commuting from about half an hour away. Unfortunately, what it showed is about 70% leukemia blasts. We were bringing him back, given the distance, in five to seven days to discuss his marrow results. I saw him on a 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 has an active tumor lysis with a creatinine of 2.5, a white count of over 100 with 70% or 80% blast. Unfortunately, that gentleman with very refractory relapse disease went on to hospice care.
As we know from the MD Anderson group, and Dr. Issa can speak more cogently than I can about that example, patients who are refractory and relapsed to venetoclax induction or reinduction really have an overall survival, I believe that's less than three months. Maybe, Dr. Issa, you could address that from your perspective. Is that something that we're seeing in patients that are refractory to the venetoclax and azacitidine?
Dr. Issa?
Yeah. Relapse after AML, after treatment with venetoclax, is very aggressive and very few treatment options. Like the example you had mentioned, median survival is a month, maybe three months, four months. To sort of echo what you were saying about the nature of AML, I can highlight the two genotypes and indicate that both MLL and NPM1 mutation, NPM1 when it's co-occurring with the three, is a presentation of a very high white count where we have to act immediately. Unlike other cancers, in AML, time matters, and time to therapy could be very important. When we have effective therapy, it's like this menin inhibitor would be exciting.
Uh-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. The addition to the treatment armamentarium in AML of a 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. 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 will we go about that determination given the data set? Can you address that?
Yeah, sure. Thanks, Troy. Again, it's a good question. 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. In the absence of DLTs, which of course is a highly positive situation to be in. 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.
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. Those all get added up in terms of assessing the benefit risk. This is a standard practice in this type of situation. 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 am 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, I think I am the right guy for that. Thanks, Troy. 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. Now, MLL, which stands for mixed lineage leukemia, is now called by a much more technical name, KMT2A, which signifies that it's the number two lysine methyltransferase in this family.
KMT2D is a rather closely related enzyme, but actually performs quite different functions, and most importantly, in AML, it is not recurrently mutated. It doesn't play a similar role to KMT2A. The mutations are loss of function and are primarily associated with B-cell lymphoma. It looks like it should be on pathway, so to speak, but is not.
Okay.
In the case of the NPM1, we know that that is the driver mutation here. As both Dr. Issa and Dr. Wang have mentioned, for me as well, the most exciting finding 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. There's a 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. For example, a loss of function of DNMT3A can result in upregulation of HOXA9 and MEIS1, because normally, the effect of that active enzyme would be to restrict the ability of the menin-MLL complex to bind to those promoters. The same applies to the mutant form of IDH1 and 2. 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.
Again, I think it comes back to the fact that we've referred to a couple of times that this interaction and the activity of this complex is essentially the founding lesion of the disease and essential to everything else. 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, can you comment on the status of the third NPM1 mutant patient? 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. We can't pick and choose, we would have to clean all of the data on every patient.
There's another part to the question, is there anything different about that NPM1 mutant patient? There isn't anything overtly different. Just to remind the audience, I think Dr. Issa and Dr. Wang both said it very well, this is a very sick population, a very relapsed refractory population. These patients are at very high unmet need, 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 escalation, so we're not there yet. You can anticipate that we will provide an update on all of the patients on the study at the next appropriate opportunity. Appreciate that question.
We have one or two more minutes. I'm going to try to take one or two 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. Yeah, of course. No, that's a good question. We've spoken about KO-539 and all its metabolites being both a time-dependent inhibitor of CYP3A4 and a substrate. 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 exemplars which are given in the instructions in the label for venetoclax and in combination.
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.
Indeed, if it's combined with other strong CYP3A4 inhibitors, then the dose reduction of venetoclax is down to 100 milligrams. There are other examples as well where it can be very effectively managed when you combine a compound which has inhibitory properties of CYP3A4 with a compound which is metabolized by the same P450 enzyme system.
Other examples as well, KO-539 is not the only example. Actually, another common example of a compound which is also part of polypharmacy in 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 treatment for AF and hypertension. In 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 over the hour at this point. 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. 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 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.