Kura Oncology, Inc. Q2 FY2022 Earnings Call

Good day, and welcome to the Kura Oncology Second Quarter 2022 Conference Call. Today's conference is being recorded. At this time, I would like to turn the conference over to Pete De Spain, Senior Vice President of Investor Relations. Please go ahead, sir.

Thank you, Sarah. Good afternoon and welcome to Kura Oncology's second quarter 2022 conference call. Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer; and Tom Doyle, our Senior Vice President of Finance and Accounting. Before I turn the call over to Dr. Wilson, I would like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the Company. With that, I'll now turn the call over to Troy.

Thank you, Pete, and thank you all for joining us this afternoon. Last year, as we continued in dose escalation with our menin inhibitor ziftomenib in an all-comer population of patients with relapsed or refractory acute myeloid leukemia, we sought FDA feedback regarding the design of our registration-directed trial. In the context of those discussions, FDA advised we spend more time in our Phase 1 study to identify an optimal dose. Guidance we now know was part of a broader FDA initiative in oncology drug development aptly named Project Optimus. In agreement with FDA, we enrolled a Phase 1b study with two-dose expansion cohorts, 200 milligrams and 600 milligrams, each comprised of 12 patients with NPM1 mutant or KMT2A rearranged relapsed refractory AML. I'm pleased to report we've nearly completed our assessment of these patients in the expansion cohorts for efficacy, safety and tolerability, as well as pharmacokinetics and exposure, and we believe we've identified a recommended Phase 2 dose for ziftomenib. We're working diligently to gather the data package for submission to FDA and look forward to sharing the recommended Phase 2 dose for ziftomenib later this year, pending the agency's review along with top line data from the Phase 1b study with a more complete dataset reserved for presentation at a medical meeting in the fourth quarter. In the meantime, enrollment in KOMET-001 has continued and we're pleased to announce that we've enrolled an additional 18 patients in the Phase 1b study in less than three months that what we believe to be the recommended Phase 2 dose, an indication of the continued enthusiasm surrounding ziftomenib among investigators and patients. We continue to believe data from all patients treated at the recommended Phase 2 dose will have potential to contribute to the registrational patient population. In parallel with our efforts to advance ziftomenib's monotherapy, we've been working to operationalize a series of combination studies in the relapsed and frontline settings. We've designed these studies to assess the safety, tolerability and therapeutic activity of ziftomenib in combination with current standards of care in AML, including venetoclax and azacitidine, FLT3 inhibitors and standard induction cytarabine, daunorubicin chemotherapy, commonly referred to as 7+3. We remain enthusiastic about the potential for ziftomenib in the treatment of acute leukemias as we prepare to transition into the Phase 2 registration-directed portion of KOMET-001 and initiate our combination studies pending determination of our recommended Phase 2 dose. Although our menin program continues to capture much of the attention, we remain just as motivated by opportunities for farnesyl transferase inhibition in oncology, one of the first therapeutic applications of an FTI as a targeted therapy with via direct inhibition of an oncogenic protein namely HRAS. We've demonstrated the potential for tipifarnib to drive durable responses in recurrent and metastatic HRAS mutant head and neck squamous cell carcinoma or HNSCC, and our ongoing AIM-HN registration-directed trial continues in that indication. More recently, we've begun efforts to build upon the initial monotherapy activity of tipifarnib with a focus on overcoming drug resistance. Late last year, we initiated the current HN study designed to evaluate the combination of tipifarnib and alpelisib, an inhibitor of PI3 Kinase alpha in selected HNSCC patient cohorts. We believe that HRAS and PI3 Kinase alpha are co-dependent oncogenes in HNSCC, and the combination of the two inhibitors has potential to provide improved antitumor activity relative to the inhibition of either target alone. The combination also had potential to increase the total addressable population for tipifarnib to as much as 50% of patients with recurrent and metastatic HNSCC. The initial cohort of the current HN study includes patients with PIK3CA-dependent HNSCC, and I'm pleased to report that we recently dosed the first patient in a second cohort comprised of patients with HRAS overexpression. Our goal with the current HN trial is to identify a recommended Phase 2 dose and schedule for the combination in each patient cohort. We are encouraged by the preliminary safety and tolerability of the combination, as well as early evidence of clinical activity, and we believe we may be in a position to share preliminary proof of mechanism data from patients in the PIK3CA-dependent HNSCC cohort later this year. Beyond HNSCC, we continue to elucidate the role of FTIs in preventing or delaying the emergence of resistance for certain classes of targeted therapy with potential to drive deeper and more durable responses in large solid tumor indications. One of these emerging combination opportunities was unveiled earlier this year at the American Association for Cancer Research Annual Meeting, the preclinical data generated through a collaboration with INSERM support potential for tipifarnib to prevent emergence of resistance to osimertinib and other potent EGFR inhibitors in EGFR-mutant non-small cell lung cancer. We're preparing to initiate a Phase 1 study of tipifarnib in combination with osimertinib in EGFR mutated non-small cell lung cancer, which we call KURRENT-LUNG later this quarter. We intend to perform initial clinical evaluation of tipifarnib and osimertinib together valuable experience in data, while in parallel advancing KO-2806, the lead development candidate in our next generation FTI program through IND enabling studies. KO-2806 represents a next-generation farnesyl transferase inhibitor with improved PK, exposure and bioavailability relative to tipifarnib. In addition to combining FTIs with EGFR inhibitors, we continue to investigate combinations with other potent targeted therapies in preclinical studies that may represent additional opportunities. We intend to evaluate KO-2806 in combination with these targeted therapies and we remain on track to submit an IND application for KO-2806 in the fourth quarter. With that, I'll now turn the call over to Tom for a discussion of our financial results.

Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the second quarter 2022. I invite you to review our 10-Q filed today for a more detailed discussion. Research and development expenses for the second quarter of 2022 were $24.3 million, compared to $21.1 million for the second quarter of 2021. The increase in R&D expenses was primarily due to increases in our clinical trial costs related to our ziftomenib program and personnel cost. General and administrative expenses for the second quarter of 2022 were $11.1 million, compared to $12.6 million for the second quarter of 2021. The decrease in G&A expenses was primarily due to the decreases in personnel costs and professional fees. Net loss for the second quarter of 2022 was $34.8 million, compared to a net loss of $33.7 million for the second quarter of 2021. As of June 30, 2022, we had cash, cash equivalents and short-term investments of $450.3 million, compared to $518 million as of December 31, 2021. Based on our operating plan, we continue to believe that our cash, cash equivalents and short-term investments will fund current operations through 2024. With that, I now turn the call back over to Troy.

Thank you, Tom. Before we jump into the question-and-answer session, let me lay out our anticipated milestones for 2022. For our menin inhibitor program, determine the recommended Phase 2 dose for ziftomenib in consultation with FDA and report top line data from the Phase 1b study later this year. Present updated data from KOMET-001 at a medical meeting in the fourth quarter. And for our FTI programs, initiate the Phase 1 KURRENT-LUNG study of tipifarnib plus osimertinib this quarter and submit a new investigational new drug application for KO-2806 in the fourth quarter. With that, Sarah, we are now ready for questions.

Thank you. We'll take our first caller from Jonathan Chang, SVB Securities.

Hi, guys, thanks for taking my questions. First question, on timing of the top line ziftomenib data, can you provide any additional color on how you're thinking about when to disclose the top line data?

Sure, Jonathan. Thanks for the question. As we indicated, Jonathan, our goal here is to determine the recommended Phase 2 dose in consultation with FDA. We're at a point where we are completing our assessment and preparing to submit the package to FDA that should happen shortly. What we don't have as much visibility into is the process and the timeline by which FDA reviews that. Unlike, for example, in the case of an IND submission there isn't a 30-day clock. We certainly believe that we're going to submit a package that should address all of their questions, we will stand ready if they have additional questions or need us to look at the data in any different way. At this point, I think that the best we can say is we're probably looking at late in Q3, it could potentially slip into Q4, just depending on the timing with FDA.

Got it. Thank you. And I guess, are you able to provide any color on the identification of the RP2D and the regulatory interactions. I guess, what boxes remain to be checked before officially declaring the RP2D?

Yes. So maybe just to take a quick step back, we undertook this Phase 1b study really as an exercise in dose optimization, and this was part of the FDA's initiative around Project Optimus, it's becoming standard for targeted therapies. I can tell you with our view now having conducted the Phase 1a and the Phase 1b that the Phase 1b was absolutely the right thing to do. We’ve gathered a tremendous amount of information about the clinical activity, the safety and tolerability, you know, the PK, in addition to how to manage the on target adverse effects such as leukocytosis and differentiation syndrome. So it was absolutely the right thing to do. I think we're going to emerge from this in our view with a very strong data package supporting the recommended Phase 2 dose, we still want to jump the gun at this point. And it isn't so much Jonathan, a check the box exercise as it is. The FDA is looking for information relating to clinical activity, safety and tolerability, pharmacokinetics and exposure really across all the patients enrolled in the study to this point, but with a particular emphasis on the Phase 1b patients and integrating that and analyzing that to really make a strong recommendation that supports advancement as a monotherapy and that sets the dose for any and all future combination studies, that's why this is so critically important. And I can't stress enough, I think we did, although it took a bit longer, given the profile we have with ziftomenib and given what we were seeing absolutely the right experiment to do.

Got it. Thank you. And just last question for me. On the additional 18 patients enrolled in KOMET-001 since May. How many of these patients could we see data on for the top-line disclosure and for the fourth quarter medical meeting presentation? Thank you.

Yes, that’s a good question, Jonathan. From the beginning, our intention has been to conduct the Phase 1b study using the same endpoints that will eventually be utilized in the registration phase of Phase 2, as guided by the FDA. The data we are collecting is intended to be reliable, as these patients are expected to be part of the registration totals. We are treating them accordingly, which is crucial because it’s important to ensure that the data we receive from the sites is robust and accurate. Ultimately, we hope this data will be part of our submission. This also applies to the additional 18 patients and all subsequent patients we plan to enroll. We are weighing the incremental value of sharing additional data against the potential risk of having to replace those patients. When you share data from significant patients in a registration study, you place those patients at risk if you continue to cut the data. Therefore, at this point, I don’t expect that you will see more than the initial 12 patients in each cohort in the top-line results. At ASH, we will present data from both the Phase 1a and Phase 1b studies, but it’s not our current expectation to go beyond the initial 12 patients in each cohort. For now, we may be able to provide qualitative insights, but we are doing everything we can to maintain momentum and close the gaps without putting those patients at risk.

Makes sense. Thanks for taking the questions.

Our pleasure, Jonathan. Thank you.

Thank you. And next we'll move on to Tiago Fauth with Credit Suisse.

Thank you for the question and for acknowledging our progress. I realize you may be limited in what you can share at the moment. However, could you provide any qualitative insights regarding the enrollment ratio between the two genetic subtypes and whether it aligns with previous experiences from competitors? Additionally, can you discuss the consistency of efficacy response across these two subpopulations? I'm also interested in the future of the FTI franchise. With 2806 expected to enter the clinic in Q4, or possibly Q1 depending on the IND filing, and having recently started the combination trials for tipifarnib alongside both alpelisib and EGFR, do you plan to develop these combinations simultaneously? Would it be beneficial to establish proof-of-concept with tipifarnib and potentially advance 2806 for our registration trial? I'm curious if there are any specific characteristics that would make tipifarnib a preferable candidate for our combination strategies and how you foresee this evolving over time. Thank you.

Thank you, Tiago. I appreciate your questions. Let me address them one by one. Regarding enrollment, it tends to vary, but we observe a reasonably healthy balance between NPM1 and KMT2A rearranged patients. At any point in time, the distribution appears more balanced than the expected four or five to one ratio, which indicates significant interest from physicians in enrolling both groups. We anticipate strong enrollment as we move into Phase 2 for the registrational cohorts. Concerning activity, our expectations remain steady. We envision the cohorts being around 50 to 75 patients each, which aligns with our statistical design aimed at meeting or exceeding a 20% to 30% clinical response rate, with four to six months of durability and transfusion independence being a secondary goal. This patient count should be sufficient for successful Phase 2 results in both KMT2A and NPM1. On the third part of your question regarding the strategy for FTIs, you raise an important point. We aim to address multiple objectives simultaneously. First, we focus on data generation; we believe combining FTIs with other targeted therapies may yield the best results. We have seen exciting preclinical data, and we want to test whether clinical outcomes reflect those findings. Secondly, we consider the regional and global development and commercialization strategies. We believe we can advance the tipifarnib-alpelisib combination in the U.S. and Europe into a registrational study if the data supports this, working closely with Novartis, with whom we maintain a strong collaboration. As for osimertinib or other potential opportunities, we are also evaluating 2806. The current lung study provides an opportunity to determine whether we see early indicators that align with our preclinical findings regarding delaying resistance to osimertinib. If the data is positive, our goal would be to present 2806 as a strong option alongside tipifarnib and make progress with osimertinib. This represents a significant potential opportunity, even by targeting a fraction of the osimertinib population. Given the novel biology and the farnesylated targets involved, we believe it's worthwhile to mitigate clinical risks with tipifarnib while also exploring combination strategies in the Phase 1 study for 2806, where we anticipate including any EGFR inhibitor. We will continue our preclinical research and pursue our clinical strategies with confidence. Ultimately, we believe 2806 has promising advantages as an FTI, but given the high unmet need in recurrent metastatic head and neck cancers, if we see strong data supporting the tipifarnib and alpelisib combination, we will certainly explore that pathway. Should that scenario unfold, we would consider it a positive challenge for us. Did I address all parts of your question, or is there anything else I missed?

Yes. Thanks again for taking the question. Appreciate it.

Pleasure.

Thank you. And next we'll move on to Peter Lawson, Barclays.

Great. Thank you. Thanks for taking the questions. Troy, just the 200 milligram dose, which do you think sets you better for first line in combination use? And then is there anything you're seeing in the data that makes you the menin data? Anything that makes you incrementally more positive for unconventional more negative?

Yes, that's a great question, Peter. To address the first part of your query, our primary focus is on safety and tolerability, as this remains a Phase 1 study. While we are collecting data aligned with registrational endpoints and are eager to progress, we understand that safety is our priority. We feel confident in the safety profile at both doses and have the flexibility to adjust dosing as necessary. We are also assessing clinical activity, pharmacokinetics, and pharmacodynamic markers, and we look forward to sharing our findings. You'll see some preliminary results soon, with a more comprehensive presentation at ASH. We believe this sets up nicely for both monotherapy and potential combinations. In response to Jonathan's question, we feel it was the right approach to take. As we transition from 1A to 1B, we have observed leukocytosis and, although it's uncommon, some cases of differentiation syndrome. To those unfamiliar, leukocytosis may seem like disease progression, especially in patients who have previously failed multiple treatments and then start on a menin inhibitor. It can appear that the peripheral blood counts are increasing, but we've learned that this doesn't necessarily indicate progression. Instead, it's a sign that the cells are doing what they are supposed to do when their MLL interaction is blocked, as they move into the bloodstream and eventually die off after a couple of weeks. This insight is crucial for understanding both monotherapy outcomes and combination scenarios, as it's important to identify the source of any effects observed in combination treatments. Regarding the second part of your question, our enthusiasm remains strong. I aim to keep a consistent outlook. We are optimistic about ziftomenib and are eager to share further data. We are fully engaged in Project Optimus and look forward to discussing these findings with the FDA to ensure alignment. I believe we will be in a favorable position as we present the top-line data and medical conference results, reinforcing a clear path forward for both monotherapy and potentially becoming the best in class when used in combination. Time will reveal the outcome.

Great. Thanks so much.

Our pleasure.

Thank you. We'll move on next to Roger Song with Jefferies.

Thank you for the question. I would like to clarify what Troy mentioned about starting to enroll an additional 18 patients in the RP2D arm on May 6th. Can you confirm if this means that you have already determined the RP2D in May based on the profile you were observing at that time?

Yes, Roger. And I'm going to be very different here to the FDA on this. The protocol as was originally agreed to with the FDA gave us the flexibility to enroll 12 patients at each of the two doses and then to continue enrollment in either cohort, depending on the way the data went. And so we've done exactly that. We've enrolled the 24 patients that where we've nearly completed the assessment, we've continued enrolling at what we believe to be the optimum dose. I want to choose my words carefully out of respect for the agency, we'll be able to come back and tell you that is the recommended Phase 2 dose once we have their alignment. But obviously, we feel at this point that the data is trending in the right direction that we want to try to both give every patient the best chance for clinical benefit or benefit risk, if you will. And as I've said in response to the earlier question, to try to close any gaps on enrollment and maintain the momentum for the program.

Thank you. The next question pertains to regulatory interactions. I understand you have completed your data analysis for those 24 patients. Have you received any guidance or had any discussions with the FDA regarding the RP2D package? And what kind of data are you considering including in that package?

Yes, that's a very good question, Roger. So as part of the discussions when we were agreeing with FDA on the design of the Phase 1b study, they were very clear at what they were looking for as far as the data coming out of the Phase 1b in terms of assessing benefit risk. And I have characterized that in kind of the three columns of efficacy data, safety and tolerability, pharmacokinetics and exposure. And then any other data we want to include to help support the benefit risk at what we would feel is the appropriate recommended Phase 2 dose. Nothing there has changed. We have regular interactions with the FDA, I don't want to get into the specifics, but nothing on that guidance has changed at all. Where we are is this data has to be again sanctified, right? These are patients that we hope and expect will ultimately be able to be included in a registrational package. So as we're pulling data out of the site, as we're pulling it out of the vendors, we have to make sure it's clean. We have to make sure it all ties out. I don't think the answer is going to change, Roger, between now and when we ultimately submit the package. But the FDA is looking for a level of credibility, of excellence, of professionalism that we intend to meet or exceed. And they were clear with their instructions on what they’re looking for. We're going to deliver them that. We're also going to then Roger as every company I suspect does, we'll prepare for any other questions they might have, right? So they get the data. Do they want to look at it in different way? Do they maybe have a question about cutting it this way or that way. This is the kind of scenario planning that you do and our team is all over that. We'll be ready to provide the FDA any additional information that they need or any further analysis to help support the recommended Phase 2 dose. We found them to be very collaborative and to be very clear on what they need and we're hoping we can move through this as efficiently as possible.

Yeah, that's very good. Great, maybe just very quick last one. Maybe just to confirm this additional 18 patient on the optimal dose additional 18 patient won't be part of this RP2D package or FDA not requiring or not asking for the data from those 18 patients?

Yes, to clarify, the FDA has authority over all patients in every study. They can request any information they deem necessary. Specifically regarding safety, any updates must be communicated to them. However, we believe that the 24 patients in the Phase 1b group at the 200 milligram and 600 milligram doses will be sufficient for our needs. We will provide further safety updates if required. We do not anticipate the need for ongoing data cuts, but we will collaborate with the FDA as requested, although we don't expect that to be necessary initially.

Very good. Okay, great. I think that's it from us. Thank you. Thank you, Troy.

Thanks, Roger.

Thank you. And next we'll move on to Li Watsek with Cantor Fitzgerald.

Hey, guys. Thanks so much for taking my questions. I guess one question on ziftomenib. I mean, you finished enrollment in May and now in August, I guess for, you know, differentiation syndrome, we know that typically occurs early in treatment. So, I guess, is it safe for us to doing that, like, there's less risk now for seeing, I guess, serious cases?

Yes, I'm happy to address that. Earlier this year, we experienced a partial clinical hold due to a case of differentiation syndrome. We put revised guidance in place for managing the condition. As trials have progressed, we’ve noticed that while differentiation syndrome does occur, it happens infrequently. Moreover, when it does occur, its severity seems to have diminished compared to before we implemented the new guidance. Our aim has been to equip investigators and clinicians with the necessary tools to manage differentiation syndrome and leukocytosis, keeping them at mild to moderate levels rather than allowing them to escalate to severe grades. We’ve made significant progress in this regard as the trials have advanced. Experts among physicians, who have the most experience with the drug, have become more adept at identifying and addressing these issues, similar to the learning curve seen with venetoclax and tumor lysis syndrome. Overall, we are witnessing a trend towards less frequent and less severe differentiation syndrome, and we expect this to improve further as we explore combinations with cytoreductive agents, like cytarabine, which can help manage counts. We feel optimistic about being competitive in this area, and while the trials are ongoing, we see the indicators moving in a positive direction.

Okay, great. Thank you for the color. I guess my second question is about tipifarnib combination. I mean you mentioned from the Phase 1, I guess current head and neck study, you've seen some preliminary, I guess, activity. So I wonder if you can expand a little on that? I guess what have you seen so far that gives you the confidence that the activity is real? And maybe remind us what a benchmark is? You know, so I guess A, you mentioned that you might, I guess, present some data later this year. Can you give us a sense of what we should expect?

Sure. That's a great question, and it has three parts. Let me address them one at a time. Generally, our team has a long history of working with the MAP kinase and PI3 kinase pathways across various agents. The industry has largely struggled to combine inhibitors from these two pathways due to overlapping toxicity issues. Therefore, it’s significant that we’re observing an acceptable safety and tolerability profile, which I view as a considerable advancement; this was an area where I anticipated the greatest risk, as preclinical models have their limitations in predicting toxicity. Currently, we are in the dose escalation phase, and we are encouraged by the safety and tolerability outcomes so far, as this has traditionally been a hurdle for most combinations targeting these pathways. Importantly, we are also seeing early signs of clinical activity, which means we are observing tumor regression, the clinical endpoint we are aiming for. When we talk about proof of mechanism, we are looking for observable results in a select group of patients that reflect the preclinical data we've previously shared. Our corporate presentation, available on the AACR website, highlights the synergistic activity between alpelisib and tipifarnib across all four subsets of head and neck cancer, including the two HRAS-dependent and two PIK3CA-dependent subsets. Even early in the dose escalation, we are noticing promising signs. In the PIK3CA population, tipifarnib is inactive, while our treatment maintains stable disease. Therefore, if we observe tumor regression or durable responses, it's a positive trend. This is how we anticipate updates later this year. I would distinguish this from proof of concept, which we reserve for when we reach the recommended Phase 2 dose schedule and conduct an expansion cohort to measure overall response rates. We expect to have that proof of concept data around mid-next year. Regarding what constitutes a successful threshold, we believe that achieving around 30% confirmed objective responses or higher places us in a favorable position to consider advancing this combination relative to current standard treatments for recurrent and metastatic head and neck cancer. Currently, the three approved agents—Opdivo, Keytruda, and Cetuximab or Erbitux—offer monotherapies that may result in responses in the teens or low 20s range. If we can outperform that with an oral regimen, it would be a significant development, allowing us potentially to treat up to 50% of recurrent metastatic head and neck cancer cases.

Great. Thank you so much.

Thank you. And next we’ll move on to Reni Benjamin with JMP Securities.

Good afternoon everyone. I appreciate your questions and congratulations on the progress. Troy, to start off, can you provide more insights into the FDA review? Are you expecting them to validate the RP2D you've chosen and your strategy moving forward? Or are you anticipating more guidance, as in providing them with the data sets for a collaborative decision on the appropriate RP2D going forward?

Yes, Ren, thank you for the question. We are awaiting input from the FDA and hope they will evaluate and agree with our recommendation. We plan to present them with our recommendation and allow them to respond, rather than seeking their initial input and creating uncertainty. It’s important to remember that the FDA must approve any registrational plan, which includes agreeing on the registrational dose. This is a necessary step before we can proceed with the registrational aspect of the KOMET-001 study or initiate any combination studies. To answer your specific question, Ren, we will present what we consider to be the minimal safe and effective dose according to Project Optimus, along with the supporting data, and will seek their feedback and address any questions. That is our proposed approach.

Got it. And will you be discussing the registrational study and obtaining FDA approval for that, or will that be addressed in a later conversation after this discussion is completed?

No, you're absolutely right, Ren. So it's option one in your options. We will look to gain alignment from the FDA on the path forward in the registrational study as a monotherapy.

Perfect. Okay. Switching gears to the current lung study, can you discuss the preclinical work and what specific resistant mutations seem to be affected by tipifarnib? I recall that T790M and 797S mutations are typical mutations associated with resistance to osimertinib. I'm trying to get a clearer understanding of that. Additionally, I know that you'll be measuring ctDNA as a biomarker for efficacy, but can it also be used to track resistance?

Yes, those are both excellent questions, Ren. What seems to be evolving is a shift away from focusing solely on EGFR and osimertinib for a moment. You often ask why we don't see complete responses with powerful signal transduction inhibitors like osimertinib or KRAS, and instead observe partial responses. This is a question I have pondered for over 15 years while working on various targets. One potential explanation is the existence of drug-tolerant cells. When treated with a strong inhibitor like osimertinib, there exists a subset of cells that are not eliminated. These cells are able to adapt by fundamentally rewiring themselves, allowing them to continue cycling in the presence of the drug. They achieve this drug-tolerant state through a farnesylated protein. Once these cells develop resistance mutations, they can then thrive even when osimertinib or another EGFR inhibitor is present. Osimertinib is notably the most significant player in this space, which is why we have started with it. This process of redifferentiation and the resulting drug tolerance is dependent on farnesylation as well. When osimertinib is combined with tipifarnib in patients who have not previously been treated with osimertinib, preclinical data suggest that this combination prevents those drug-tolerant cells from entering a drug-tolerant state, making them more susceptible to osimertinib. Clinically, I'm uncertain whether we will achieve complete responses, although some preclinical data indicate that it may be possible in certain contexts. It appears this phenomenon is not limited to just EGFR inhibitors; it may also apply to other powerful signal transduction inhibitors such as ALK and BRAP inhibitors. By preventing drug tolerance, we can delay the onset of resistance, thus stopping this subset of cells from cycling and developing drug resistance. The key is to act before resistance occurs. If you wait until resistance has developed, as most therapies do, it may be too late. The hope is that we can significantly extend the median progression-free survival of osimertinib, aiming for a 50% increase, which would be a major improvement for patients. We are not the only ones pursuing this strategy, but osimertinib represents just the beginning; the phenomenon of farnesylation-dependent drug tolerance may occur across several small molecule drug targets, which bodes well for tipifarnib and 2806 and suggests promising returns over the next few years.

Got it, which as leads me to focusing on what you're going to look for, particularly for a go no, go decision, because it seems like median PFS would be way too long?

Yes and no. I apologize for not addressing your question about ctDNA in my earlier response. We are indeed looking into ctDNA, which stands for circulating tumor DNA, and our team at AstraZeneca, along with clinical investigators, understands its profile. For those on the call, ctDNA allows us to avoid solid tumor biopsies since it relies on blood tests. This method enables us to monitor the disappearance of the mutant allele, such as T790M, as well as the reemergence of resistant alleles. It serves as a way to gauge what's happening, similar to measuring MRD negativity in AML cases. We're focusing on ctDNA, and if results progress positively, we may expedite our efforts. Ultimately, progression-free survival is the most relevant endpoint, although osimertinib has an extended progression-free survival period. The potential benefit here is significant, especially with the combination of tipifarnib and 2806, which we believe offers superior clinical benefits compared to osimertinib alone. We are exploring ways to reach these endpoints faster. For instance, with KRAS, could we extend the median time to relapse from six or eight months to potentially ten or twelve months? Stay tuned, as we are conducting extensive preclinical research in this area. We've made great strides from targeting HRAS to now addressing a whole family of farnesylated proteins that contribute to drug resistance. This is a compelling narrative, and we anticipate sharing more details, likely early next year following the menin update.

Got it. There's one final question for us. Translational continues to, I guess, gain in more and more popularity. We're noticing more papers, kind of, focusing in on this mechanism of action, especially in different diseases, including neurological ones, like Alzheimer's and the like. I know that you guys don't necessarily want to branch out there, but I'm kind of curious, do you have any BD discussions? Do you have any inbounds with interest, kind of, to partner your FTI library?

I don't want to go into specific discussions. The papers from the University of California in Santa Barbara are very interesting, especially concerning tau proteins. We're working on a brain penetrant FTI. I won't comment on any partnership discussions at this time. Once we have the capability to block farnesyl transferase, there are many collaborations in progress, like the osimertinib project that came from an intern in France who had insights into farnesylation biology and required our molecular expertise and drugs. We have other similar examples, so I suggest you stay tuned.

Great. Thanks for taking the questions.

Pleasure.

Thank you. And next, we will take Eva Privitera with Cowen.

Hi. Thanks for taking our questions. Back to the upcoming topline disclosure for ziftomenib. I know you had previously mentioned that it will include composite CR. Can you remind us if it will also include MRD status? Or any of the PK and exposure data?

Yes, Eva, thank you for the question. Regarding the top line data, we are anticipating CR, CRH, and CRC rates. To be completely honest, we have not yet made a decision on MRD status. We are very encouraged by our observations, but that is an area where we haven't reached a conclusion. If it is not included in the top line data, you will see it at ASH. The PK and exposure data isn't really suitable for a top line summary; it is probably better reserved for a more comprehensive discussion of the clinical data at ASH. So I would suggest we wait until then.

Great. Thank you. And will the efficacy be broken down by genetic subtypes?

It will. Yes, it will and you'll see it certainly I think both in the top line and in ASH.

Great. Thank you. And just one more point of clarification. You had mentioned in your remarks that you expect 50 to 70 patients in each of the registrational cohorts for each genetic subtype. Would this be in addition to the 30 from the Phase 1b at the RP2D, since those patients can be counted for the registrational data?

Yes. The question is that we will need 50 to 75 patients who meet the criteria for inclusion. That's the focus, and it aligns with the 20% to 30% CR and CRH rate we are targeting. The patients enrolled so far represent a mix of the two genetic types. In total, we will need about 50 to 75 patients per cohort, and we are trying to enroll as many as possible. However, some patients may be excluded or not counted by the FDA, so we often overenroll to account for that. Regarding the equivalence of activity between the two genotypes, we plan to run similarly sized cohorts, which should indicate consistency without going into specific details.

Perfect. That's very helpful. Thank you.

Our pleasure. Thank you, Eva.

Thank you. And there are no further questions. So that will conclude our question-and-answer session today. I would now like to turn the conference back over to Dr. Troy Wilson, President and Chief Executive Officer for any additional or closing remarks.

Thank you, Sarah. And thank you all once again for joining our call today. We'll be participating in the Wedbush Path Grow Healthcare Virtual Conference next week, look forward to seeing a number of you there. In the meantime, if you have additional questions, please feel free to contact Pete, Tom or me. Thank you again and have a good evening everyone.

Thank you. And that does conclude today's teleconference. We do appreciate your participation. You may now disconnect.