Q1 2024 Kura Oncology Inc Earnings Call

Good afternoon, ladies and gentlemen, and welcome to the Q1 2020 for cure oncology financial results Conference call. At this time all lines are in listen only mode. Following the presentation. We will conduct a question and answer session. If at any time. During this call you require immediate assistance. Please press star zero for the operator.

Operator: Good afternoon, ladies and gentlemen, and welcome to the Q1 2024 Kura Oncology Financial Results Conference Call. At this time, all lines are in listen-only mode.

Speaker Change: This call is being recorded on Thursday may <unk> 2024, I would now like to turn the conference over to Pete de Spain head of Investor Relations. Please go ahead.

Operator: Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, May 2, 2024. I would now like to turn the conference over to Pete Despain, Head of Investor Relations. Please go ahead.

Pete Despain: Thanks, Chris. Good afternoon, and welcome to Kura Oncology's first quarter 2024 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'd 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.

Pete Despain: Thanks, Chris Good afternoon, and welcome to Curl oncology first quarter 2024 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.

Pete Despain: With that, I'll now turn the call over to Troy.

Pete Despain: 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 managements judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to <unk> filings with the SEC, which are available.

Pete Despain: From the SEC or on the current oncology website for information concerning risk factors that could affect the company.

Pete Despain: With that I'll now turn the call over to Troy.

Troy Edward Wilson: Thank you, Pete. And thank you all for joining us. Let's jump right in.

Troy: Pete and thank you all for joining US now, let's jump right in.

Troy Edward Wilson: Last week, we were proud to announce that Ziftomenib is the first investigational treatment to be granted breakthrough therapy designation for the treatment of NPM1 mutant AML. The FDA granted BTD for zyftomenib based on data from our ongoing COMET-001 clinical trial in patients with relapsed refractory NPM1 mutant AML. NPM1 mutant AML is a disease of significant unmet need for which there is no approved targeted therapy, and it represents approximately 30% of new AML cases annually. BTD is awarded for a drug that treats a serious or life-threatening condition and may demonstrate substantial improvement on one or more clinically significant endpoints over available therapy.

Troy: Last week, we were proud to announce that <unk> is the first investigational treatment to be granted breakthrough therapy designation for the treatment of NPM, one mutant AML the.

Troy Edward Wilson: The FDA granted CTD resistor minutes based on data from our ongoing comment 001 clinical trial in patients with relapsed refractory <unk> mutant AML NPS.

Troy Edward Wilson: NPM one mutant AML is a disease of significant unmet need for which there is no approved targeted therapy and it represents approximately 30% of new AML cases annually.

Troy Edward Wilson: <unk> is awarded for a drug that treats a serious or life threatening conditions and may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies. The designation is intended to expedite development and review of drugs, including an organizational commitment by FDA senior managers and experienced reduced.

Troy Edward Wilson: The designation is intended to expedite the development and review of drugs, including an organizational commitment by FDA senior managers and experienced review staff, as well as eligibility for rolling review and priority review. We're highly encouraged by FDA's decision to grant breakthrough therapy designation for zyptomenib, recognizing its potential as an innovative medicine for patients with NPM1 mutant AML. We look forward to working even more closely with FDA to bring zyptomenib to patients in urgent need of effective treatments as quickly as possible.

Troy Edward Wilson: Staff as well as eligibility for Rolling review and priority review.

Troy Edward Wilson: We're highly encouraged by Fda's decision to grant breakthrough therapy designation for <unk>, recognizing its potential as an innovative medicine for patients with MTM. One mutant AML, we look forward to working even more closely with FDA to bring <unk> to patients in urgent need of effective treatments as quickly as possible.

Troy Edward Wilson: Meanwhile, we're on track to complete enrollment of 85 patients in our ongoing COMET-001 registration-directed trial of ziftomenib in relapsed refractory NPM1 mutant AML by the middle of this year. Ziftomenib is also being evaluated in combination with current standards of care, including venetoclax azacitidine or citerabine plus donorubicin, commonly known as 7 plus 3, in patients In January, we reported preliminary clinical data from the first 20 patients in the dose escalation portion of the COMET-007 trial, including five newly diagnosed patients with adverse risk AML and 15 patients with relapsed refractory AML.

Troy Edward Wilson: Meanwhile, we're on track to complete enrollment of 85 patients in our ongoing comment zero-zero, one registration directed trial of <unk> in relapsed refractory <unk> mutant AML by the middle of this year.

Troy Edward Wilson: If demand is also being evaluated in combination with current standards of care, including Vanadic class, a decided dean or cytarabine plus down Aruba, commonly known as seven plus three in patients with NPM, one mutant or Kmt <unk> rearranged AML.

Troy Edward Wilson: In January we reported preliminary clinical data from the first 20 patients in the dose escalation portion of the comment zero-zero seven trial, including five newly diagnosed patients with adverse risk AML and 15 patients with relapsed refractory AML and.

Troy Edward Wilson: Ziftomenib demonstrated an encouraging safety and tolerability profile in combination with 7 plus 3 and with venetoclax plus azacitidine, enabling continuous administration of Ziftomenib while effectively mitigating the risk of differentiation syndrome. Notably, no differentiation syndrome events of any grade were reported among the first 20 patients.

Troy Edward Wilson: <unk> demonstrated an encouraging safety and tolerability profile in combination with seven plus three and with <unk> plus a society, enabling continuous administration of <unk>, while effectively mitigating the risk of differentiation syndrome.

Troy Edward Wilson: Notably no differentiation syndrome events of any grade were reported among the first 20 patients. Furthermore, no dose limiting toxicities Qt prolongation drug drug interactions or additive Milo suppression were observed.

Troy Edward Wilson: Furthermore, no dose-limiting toxicities, QTC prolongation, drug-drug interactions, or additive myelosuppression were observed. As of the January 11th data cutoff, all five newly diagnosed patients with adverse risk NPM1 mutant or KMT2A rearranged AML, treated with Ziftomenib and 7 plus 3, achieved complete remission with full count recovery for a CR rate of 100%. The overall response rate among the 15 relapsed refractory patients treated with ziftometab and venasa was 53%, including a 40% ORR among the 10 patients who had received prior venetoclax, a setting with very limited effective treatment options. The CR-CRH rate among the nine relapsed refractory patients who were menin inhibitor naive was 56%.

Troy Edward Wilson: As of the January 11th data cutoff, all five newly diagnosed patients with adverse risk NPM, one mutant or Kmt <unk> rearranged AML treated with <unk> and seven plus three achieved a complete remission with full count recovery for a CR rate of 100%.

Troy Edward Wilson: The overall response rate among the 15 relapsed refractory patients treated with <unk> was 53%, including a 40% or are among the 10 patients who had received prior venetic lacks a setting with very limited effective treatment options. The CR CRH rate among the nine relapsed.

Troy Edward Wilson: Refractory patients who were menin inhibitor naive was 56% as of the data cutoff 16 of the first 20 patients remained on trial, including all 11, NPM one mutant patients.

Troy Edward Wilson: As of the data cutoff, 16 of the first 20 patients remained on trial, including all 11 NPM1 mutant patients. Continuous daily dosing of Ziftomenib at 200 mg QD was well tolerated, and the safety profile was consistent with features of underlying disease and backbone therapy. I'm very pleased to say that our team continues to demonstrate outstanding execution.

Troy Edward Wilson: Continuous daily dosing of <unk> at 200 milligrams QD was well tolerated and the safety profile was consistent with features of underlying disease and backbone therapies.

Troy Edward Wilson: I am very pleased to say that our team continues to demonstrate outstanding execution. The 400 milligram dose of <unk> has now been cleared for both the NPM, one mutants and Kmt <unk> rearranged relapsed refractory Vanessa cohorts and enrollment for both of those subsets of the 600 milligram dose is ongoing we are all.

Troy Edward Wilson: The 400-milligram dose of Ziftominib has now been cleared for both the NPM1 mutant and KMT2A rearranged for the lapsed refractory venasa cohorts, and enrollment for both of those subsets at the 600-milligram dose is ongoing. We've also cleared the 400-milligram dose of ziftominib in the frontline adverse risk NPM1 mutant 7 plus Enrollment of the 400 mg dose in the frontline KMT2A rearranged 7 plus 3 cohort is ongoing, and we anticipate clearing that dose cohort shortly.

Troy Edward Wilson: Also cleared the 400 milligram dose of <unk> in the frontline adverse risk NPM, one mute seven plus three cohort and have escalated to the 600 milligram dose in.

Troy Edward Wilson: Enrollment of the 400 milligram dose in the frontline Kmt <unk> rearranged seven plus three cohort is ongoing and we anticipate clearing that dose cohort shortly.

Troy Edward Wilson: At this rate, we expect to identify the recommended phase 2 dose for zyftomenib in combination with venasa and in combination with 7 plus 3 by the middle of this year. Concurrently, we plan to initiate a Phase 1b expansion study with a number of combination cohorts, including Venasa in newly diagnosed NPM1 mutant or KMT2A rearranged AML, Venasa in relapsed refractory NPM1 mutant or KMT2A rearranged AML, Venetoclax in relapsed refractory NPM1 mutant AML, and 7plus3 in newly diagnosed NPM1 mutant or KMT2A rearranged AML, removing the qualifications for high-risk disease.

Troy Edward Wilson: This rate, we expect to identify the recommended phase two dose for <unk> in combination with <unk> and in combination with seven plus three by the middle of this year.

Troy Edward Wilson: Concurrently we plan to initiate a phase <unk> expansion study with a number of combination cohorts, including than Asia and newly diagnosed NPM, one mutineer Kmt <unk> rearranged AML than Asia in relapsed refractory <unk> mutant <unk> rearranged AML with <unk> in relapsed refractory.

Troy Edward Wilson: Factory NPM, one mutant AML and seven plus three in newly diagnosed NPM, one mutant or Kmt <unk> rearranged AML, removing the qualifications for high risk disease.

Troy Edward Wilson: Each phase one b combination cohort is expected to enroll independently with approximately 20 patients per cohort.

Troy Edward Wilson: Each Phase 1b combination cohort is expected to enroll independently with approximately 20 patients per cohort. In the meantime, we continue dosing patients in our COMET-008 study of zyftominib in combination with additional standards of care, including the FLT3 inhibitor diltiritinib, FLAGIDA, or low-dose ERIS-C for treatment of relapsed refractory NPM1 mutant or KMT2A re Roughly half of all patients with relapsed refractory NPM1 mutant AML have co-occurring FLT3 mutations, and the prognosis for these patients is poor.

Troy Edward Wilson: In the meantime, we continue dosing patients in our comment 008 study of <unk> in combination with additional standards of care, including the flip three inhibitor Delta written nib flag, Ida or a low dose RSC for treatment of relapsed refractory <unk> mutant <unk> rearranged AML.

Troy Edward Wilson: Roughly half of all patients with relapsed refractory <unk> mutant AML have co occurring slipped three mutations and the prognosis for these patients is poor.

Troy Edward Wilson: Preclinical data for Zift-O-Menib in combination with FLIT3 inhibitors demonstrate strong synergistic effects compared to either single agent alone. We believe a best-in-class safety and efficacy profile, as well as optimal pharmaceutical properties, will enable Zift-O-Medib to become a cornerstone of therapy for patients with acute leukemias. This belief is backed by increasing investigator enthusiasm, as evidenced by rapid enrollment across all of our ongoing Zift-O-Medib studies, and further bolstered by breakthrough therapy designation by FDA.

Troy Edward Wilson: Preclinical data for <unk> in combination with <unk> three inhibitors demonstrate strong synergistic effects compared to either single agent alone.

Troy Edward Wilson: We believe a best in class safety and efficacy profile as well as optimal pharmaceutical properties will enable <unk> to become a cornerstone of therapy for patients with acute leukemias. This belief is backed by increasing investigator enthusiasm as evidenced by rapid enrollment across all of our ongoing subdued.

Troy Edward Wilson: <unk> studies and further bolstered by breakthrough therapy designation by FDA Ulta.

Troy Edward Wilson: Ultimately, our mission is to develop Zyftomenib across the continuum of care for all patients with acute leukemias whose disease is driven by the menin pathway. We also have a growing body of preclinical data that supports attractive opportunities for men and inhibitors beyond acute leukemia. Based on internal preclinical data, we believe there may be a role for Zifto-Menib in the treatment of certain solid tumors, and we're working towards submission of an investigational new drug application for the first of these solid tumor indications in the second half of this year.

Troy Edward Wilson: Ultimately our mission is to develop <unk> across the continuum of care for all patients with acute leukemia, whose disease is driven by the men and pathway.

Troy Edward Wilson: We also have a growing body of preclinical data that supports attractive opportunities for menin inhibitors beyond acute leukemias based on internal preclinical data. We believe there may be a role for <unk> in the treatment of certain solid tumors and we're working towards submission of an investigational new drug application for the first of these solid too.

Troy Edward Wilson: <unk> indications in the second half of this year, we look forward to sharing some of the preclinical data that support this opportunity at a scientific or medical meeting later this year.

Troy Edward Wilson: We look forward to sharing some of the preclinical data that support this opportunity at a scientific or medical meeting later this year. Meanwhile, we continue to make progress toward a next-generation Menin inhibitor, which we intend to direct toward an additional, soon-to-be-disclosed indication. And we remain in a strong financial position, enabling us to invest in research, development, and pre-commercial activities to maximize the value of Zift Omeneb and support our other pipeline assets.

Troy Edward Wilson: Meanwhile, we continue to make progress toward our next generation Menin inhibitor, which we intend to direct toward an additional soon to be disclosed indication.

Troy Edward Wilson: And we remain in a strong financial position, enabling us to invest in research development and pre commercial activities to maximize the value of <unk>.

Troy Edward Wilson: And support our other pipeline assets.

Troy Edward Wilson: Now, let's turn our attention to our hardest will transfer ace inhibitor programs. We continue to build upon the impressive clinical benefit with demonstrated with Tippi Farnham as a monotherapy in patients with recurrent and metastatic head and neck cancer.

Thomas Doyle: Now, let's turn our attention to our Farnesyl transferase inhibitor programs. We continue to build upon the impressive clinical benefit we've demonstrated with tipi farnum as monotherapy in patients with recurrent and metastatic head and neck cancer. We have been evaluating the combination of TIFI-Farnab with the targeted therapy Alpelocib in PIK3CA-dependent head and neck squamous cell carcinoma in a phase one dose escalation study that we call CURRENT-HF. We remain pleased by the manageable safety and tolerability profile of tipifarnavid in combination with alpelisib, and we are encouraged by the clinical activity observed at multiple dose levels.

Thomas Doyle: We have been evaluating the combination of <unk> with the targeted therapy, I'll palisade and pick three CA dependent head and neck squamous cell carcinoma, and a phase one dose escalation study that we call currency Chet we've.

Thomas Doyle: We remain pleased by the manageable safety and Tolerability profile of TP part of it in combination without palisade and we are encouraged by the clinical activity observed at multiple dose levels.

Thomas Doyle: We expect a complete enrollment of two dose expansion cohorts to help inform selection of the optimum biologically active dose for the combination by the end of 2024, and we look forward to presenting preliminary clinical data from the current HN trial of Tipi Farnab and Delpelisib at a medical meeting in the first half of 2025. We believe the manageable safety and tolerability we've observed with the combination of tipifarnum and alpelisib also significantly de-risks the development of our next generation farnesyl transferase inhibitor, KO2806, as we begin to evaluate it in combination with other targeted therapies.

Thomas Doyle: We expect to complete enrollment of two dose expansion cohorts to help inform selection of the optimum biologically active dose for the combination by the end of 2024, and we look forward to presenting preliminary clinical data from the current HN trial of Skippy Farnell and El palisade at a medical meeting in the first half of 2025.

Thomas Doyle: We believe the manageable safety and Tolerability, we've observed with the combination of TP foreign or an hour palisade also significantly de risks development of our next generation Farnesol transfer Ace inhibitor <unk> 28, a six as we begin to evaluate <unk> in combination with other targeted therapies.

Thomas Doyle: Despite the success of targeted therapies such as tyrosine kinase inhibitors and KRAS inhibitors, a considerable need remains to drive enhanced anti-tumor activity while addressing mechanisms of innate and adaptive resistance. We are developing our next generation farnesyl transferase inhibitor, KO28F6, to address this need. KO-2806 was designed to improve upon the potency, pharmacokinetic, and physical chemical properties of tippi-farni. Last year, we presented compelling preclinical data supporting the rationale for combining KO-2806 with distinct classes of targeted therapies, including tyrosine kinase inhibitors and KRAS inhibitors.

Thomas Doyle: Despite the success of targeted therapies, such as tyrosine kinase inhibitors, and <unk> inhibitors, a considerable need remains to drive enhanced anti tumor activity, while addressing mechanisms of innate and adaptive resistance. We are developing our next generation Farnesol transfer Ace inhibitor count 28, or six to address this need.

Thomas Doyle: <unk> hundred $28 six was designed to improve upon the potency pharmacokinetic and physical chemical properties of <unk> <unk>.

Thomas Doyle: Last year, we presented compelling preclinical data supporting the rationale for combining <unk> 28, a six with distinct classes of targeted therapies, including tyrosine kinase inhibitors and <unk> inhibitors.

Thomas Doyle: In October, we began dosing patients with KO-2806 as a monotherapy in a phase one dose escalation trial that we call FIT-001. That trial uses an innovative design that enables us to begin dose escalation of KO-2806 in combination cohorts very early on in the study while continuing to dose escalate it concurrently as a monotherapy. In fact, we dosed the first patient with KO-2806 in combination with cabozantinib and clear cell renal cell carcinoma in February, just four months after KO-2806 entered the clinic.

Thomas Doyle: October we began dosing patients with <unk> 28, a six as a monotherapy in a phase one dose escalation trial that we call fit 001.

Thomas Doyle: That trial uses an innovative design that enables us to begin dose escalation of Kayo tornado six in combination cohorts very early on in the study while continuing to dose escalate concurrently as a monotherapy in fact, we dosed the first patient with <unk> hundred $28 six in combination with Cabozantinib in clear cell renal cell carcinoma in February.

Thomas Doyle: Just four months after Kao tornado 600, the clinic and.

Thomas Doyle: And we are on track to dose the first patient in combination with Adagrassiv in KRAS G12c mutated non-small cell lung cancer by the middle of this year. As a reminder, the study of KO2806 and Adagrassiv is supported by a clinical collaboration and supply agreement with Meradi, now part of Bristol-Myers Squibb. While our focus with KO2806 remains on renal cell carcinoma and KRAS-driven tumors, its rapid development progress provides us with further flexibility as we consider potential development paths forward in head and neck squamous cell carcinoma. If successful, we believe KO2806 could become the ideal combination partner for multiple targeted therapies in large solid tumor indications. With that, I'll now turn the call over to Tom for a discussion of our financial results.

Thomas Doyle: And we are on track to dose the first patient in combination without a grass it in <unk> mutated non small cell lung cancer by the middle of this year.

Thomas Doyle: As a reminder, the study of <unk> hundred 20 806 in that aggressive is supported by our clinical collaboration and supply agreement with Marathi now part of Bristol Myers Squibb.

Tom: While our focus with <unk> 28, a six remains on renal cell carcinoma, and K Ras driven tumors. Its rapid development progress provides us with further flexibility as we consider potential developed pad development paths forward in head and neck squamous cell carcinoma.

Thomas Doyle: If successful we believe <unk> 28, a six could become the ideal combination partner for multiple targeted therapies enlarge solid tumor indications with that I'll now turn the call over to Tom for a discussion of our financial results.

Thomas Doyle: Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the first quarter of 2024. Research and development expenses for the first quarter of 2024 were $36.3 million compared to $25.2 million for the first quarter of 2023. The increase in R&D expenses was primarily due to increases in clinical trial costs related to our ZIPTOMENIB and KO2806 programs.

Tom: Thank you Troy and good afternoon, everyone I'm happy to provide a brief overview of our financial results for the first quarter of 2024.

Thomas Doyle: Research and development expenses for the first quarter of 2024 were $36 3 million compared to $25 2 million for the first quarter of 2023.

Thomas Doyle: The increase in R&D expenses was primarily due to increases in clinical trial costs related to our zipped omitted and K O 20% to six programs.

Thomas Doyle: General and administrative expenses for the first quarter of 2024 were $18 2 million compared to $11 4 million for the first quarter of 2023.

Troy Edward Wilson: General and administrative expenses for the first quarter of 2024 were $18.2 million compared to $11.4 million for the first quarter of 2023. The net loss for the first quarter of 2024 was $49.5 million compared to a net loss of $34.1 million for the first quarter of 2023. This included non-cash share-based compensation expense of $8.5 million compared to $6.8 million for the same period in 2023. As of March 31, 2024, we had cash, cash equivalents, and short-term investments of $527 million compared to $424 million as of December 31, 2023.

Troy Edward Wilson: Net loss for the first quarter of 2024 was $49 $5 million compared to a net loss of $34 1 million.

Troy Edward Wilson: For the first quarter of 2023.

Troy Edward Wilson: This included noncash share based comp expense of $8 $5 million compared to $6 8 million for the same period in 2023.

Troy Edward Wilson: As of March 31, 2024, we had cash cash equivalents and short term investments of $527 million compared.

Troy Edward Wilson: Compared to $424 million as of December 31, 2023.

Troy Edward Wilson: This includes net proceeds of approximately $145 8 million from our private placement in January of 2024.

Troy Edward Wilson: This includes net proceeds of approximately $145.8 million from our private placement in January of 2024. We believe that our cash, cash equivalents, and short-term investments will be sufficient to fund our current operating plan into 2027. With that, I now turn the call back over to Troy.

Troy Edward Wilson: We believe that our cash cash equivalents and short term investments will be sufficient to fund our current operating plan into 2027.

Troy Edward Wilson: With that I'll now turn the call back over to Troy.

Troy Edward Wilson: Thank you, Tom. Before we jump into the question and answer session, let me lay out our anticipated upcoming milestones. For our MEN and inhibitor programs, complete enrollment of 85 patients in the COMET-001 registration-directed trial of ziftomenib in NPM1 mutant AML by mid-2024; identify the recommended phase 2 dose of ziftomenib in combination with venetoclax and azacitidine by mid-2024. Identify the recommended phase 2 dose of ziftomenib in combination with 7 plus 3 by mid-2024.

Troy: Thank you Tom before we jump into the question and answer session. Let me lay out our anticipated upcoming milestones for our Menin inhibitor programs complete enrollment of 85 patients in the comment Zero-zero. One registration directed trial is implemented in NPM, one mutant AML by mid 2024 identified a recommended phase II dose.

Troy Edward Wilson: <unk> in combination with venetic lacks nasal cytidine by mid 2024 identify.

Troy Edward Wilson: Identify the recommended phase II dose of <unk> in combination with seven plus three by mid 2024, and initiate a phase <unk> expansion study of Ziff to men had been combination with standards of care, including Vanadic class A's deciding in newly diagnosed NPM, one mutant or Kmt <unk> rearranged AML in the second half of 2020.

Troy Edward Wilson: Initiate a phase 1b expansion study of ziftomenib in combination with standards of care, including venetoclax, azacitidine, and newly diagnosed NPM1 mutant or KMT2A rearranged AML in the second half of 2024; and submit an investigational new drug application for ziftomenib in a solid tumor indication and present preclinical data at a medical meeting in the second half And for our farnesyl transferase inhibitor programs, we hope to dose the first patients with KO-2806 and Atagrassiv in KRAS-G12c mutated non-small cell lung cancer by mid-2024.

Troy Edward Wilson: Four and submitted an investigational new drug application for <unk> in a solid tumor indication and present preclinical data at a medical meeting in the second half of 2024 and for our Farnesol transfer Ace inhibitor programs dose. The first patients with K O 28 of six <unk> in <unk> mutated non small cell lung cancer.

Troy Edward Wilson: By mid 2024 complete enrollment of two expansion cohorts in current HN and identify the optimal biologically active dose of <unk> by the end of 2024 and present data from the current HN trial of <unk> in combination with <unk> and pick three CA dependent head and neck squamous cell carcinoma.

Troy Edward Wilson: Complete enrollment in two expansion cohorts in current HN and identify the optimal biologically active dose of tipifarnib and alpelesib by the end of 2024 and present data from the current HN trial of tipifarnib in combination with alpelesib in PIK3CA-dependent head and neck squamous cell carcinoma in the first half of 2025.

Troy Edward Wilson: The first half of 2025 with that operator, we're now ready for questions.

Operator: With that, operator, we're now ready for questions. Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press star followed by 1 on your touchtone phone. You will hear

Operator: Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press star followed by one on your touch-tone phone. You will hear a three-tone prompt acknowledging your request, and your questions will be answered in the order they are received. Should you wish to decline from the polling process, please press star followed by 2. If you are using a speakerphone, please lift the handset before pressing any key.

Speaker Change: Thank you ladies and gentlemen, we will now begin the question and answer session should you have a question. Please press star followed by one on your Touchtone phone you will hear a three tone prompt acknowledging our request and your questions will be pulled in the order. They are received should you wish to decline from the polling process. Please press star followed by two if you're using a speaker phone. Please.

Operator: Lift the handset before pressing any he's one moment. Please for your first question.

Operator: One moment, please, for your first question. Your first question comes from Jonathan Chang, Lee Ring Partners. Jonathan, please go ahead. Hi guys, congrats on the progress and thanks for taking my questions. First question: how

Operator: Your first question comes from Jonathan Chang Leerink partners Jonathan. Please go ahead.

Jonathan Chang: Hi, guys congrats on the progress and thanks for taking my questions.

Jonathan Chang: First question, how should we be thinking about the implications lift a minute getting breakthrough therapy designation on the likelihood of success of commentaries are one and the timeline for potential approval.

Operator: Yes.

Jonathan Chang: Yes, Jonathan Thanks for the question so.

Troy Edward Wilson: Yeah, Jonathan, thanks for the question. So, in terms of the implications for approval, there was a question out there, you know, in the ether, whether, you know, NPM1 mutant AML was actually, you know, of the same magnitude as KMT2A rearranged AML in terms of unmet need. And you know, as we indicated in our prepared remarks, this is the agency saying that not only is there a significant unmet need, but this is a therapy that represents the potential for substantial improvement over the standard of care.

Jonathan Chang: In terms of the the implications for.

Troy Edward Wilson: For approval.

Troy Edward Wilson: There was a question out there in the ether weather.

Troy Edward Wilson: N P M. One mutant AML was actually all of the same magnitude as Kmt <unk> rearranged AML in terms of unmet need and.

Troy Edward Wilson: As we indicated in the prepared remarks.

Troy Edward Wilson: This is the agency, saying not only is that a significant unmet need but this is a therapy that represents the potential for substantial improvement over the standard of care.

Troy Edward Wilson: Now, you know, we haven't commented specifically on our specific engagements with the FDA, other than to say, across our various studies, you know, we're engaged with the agency on a regular basis across different studies, and as we look forward to an eventual NDA submission, I think you have to believe that not only is this a validation of Zyftomeneb in terms of this patient population, but it's, you know, it That's certainly the way that we view it. It is, after all, the first and only BTD in the NPM1 subset, which is, by far and away, the larger of the two subsets.

Troy Edward Wilson: Now we haven't commented specifically on our specific engagements with the FDA other than to say across our various studies, we're engaged with the agency on a regular basis.

Troy Edward Wilson: Across different studies and as we look forward to an eventual NDA submission.

Troy Edward Wilson: I think you have to you have to believe that not only is this a.

Troy Edward Wilson: A a validation of ziff domain of in terms of this patient population, but it's.

Troy Edward Wilson: It's certainly a derisking event as we think about the submission and ultimately an application for marketing approval. That's certainly the way that we view it. It is after all the first and only BTG and the NPM, one subset, which is by far and away the larger of the two subsets in terms of timelines again.

Troy Edward Wilson: In terms of timelines, again, we've consistently said consistently what matters is that you get it, you know, at or ideally just before you complete enrollment, because what it really does is several things. It recruits the A team from the agency, which is important at a time when the agency has, you know, a lot going on, right? A lot of sponsors vying for attention.

Troy Edward Wilson: We've said consistently what matters is that you get it.

Troy Edward Wilson: <unk> or ideally just before you complete enrollment because what it really does is several things it recruits the a team from the agency, which is important at a time when the agency has a lot going on and write a lot of sponsors vying for attention you get you get their priority and they are expert review.

Troy Edward Wilson: You get priority and expert review. They work with you very collaboratively, and they basically open up other possibilities to accelerate timelines, and we've spelled out a couple of those, including rolling review and priority review. You're basically, you know, you get on the short list of priority programs at the agency. So, you know, we intend, we've said consistently, we intend to take advantage of every tool, trick, and technique we can to accelerate timelines. This is the latest one. I think it puts us in a solid position. We are exactly where we want to be in terms of enrollment.

Troy Edward Wilson: <unk>.

Troy Edward Wilson: They worked with you very collaboratively and they basically open up other possibilities to accelerate timelines and we spelled out a couple of those including Rolling review priority review you basically you get on the shortlist of priority programs at the agency. So we intend we'd said consistently we intend.

Troy Edward Wilson: To take advantage of every tool and trick and technique, we can to accelerate timelines. This is the latest one I think it puts us in a solid position, we are exactly where we want to be in terms of enrollment.

Troy Edward Wilson: You know, as we say in the heading to the sub-bullet, enrollment is nearing a close, and now we're looking forward to letting the data mature, and then all the work that goes into the submission, and then looking forward beyond that. So, hopefully that answers your question. Good, thank you.

Troy Edward Wilson: As we say in the heading to the sub bullet.

Troy Edward Wilson: <unk> is nearing a close and now we're looking forward to letting the data mature.

Troy Edward Wilson: And then and then all the work that goes into the submission and then looking forward beyond that so.

Troy Edward Wilson: Hopefully that answers your questions.

Speaker Change: Great. Thank you and just one more question for me.

Troy Edward Wilson: And just one more question for me. Can you provide any color on when we might see more ZISTO men of clinical data over the course of the year? Yeah, sure. I'm sure this is a question on a lot of people's minds.

Speaker Change: Can you provide any color on when we might see more of this tremendous clinical data over the course of the year.

Speaker Change: Yeah sure I'm sure. This is a question on a lot of People's minds. So.

Troy Edward Wilson: So, you know, we have kind of multiple, multiple things to be looking at. The last update, again, as we alluded to in the prepared remarks, was the January disclosure where we showed data from the first 20 patients enrolled in the Comet-007 study. You know, clearly, we can give an update on those patients. We are just really moving quite quickly and quite aggressively through dose escalation. I think a lot of people are looking toward what the recommended phase two dose for the different combinations and in the different populations is.

Troy Edward Wilson: We have kind of multiple multiple things to be looking at the last update again as we alluded to in the prepared remarks was the the January disclosure, where we showed data from the first 20 patients enrolled in the comment 007 study.

Troy Edward Wilson: And then what does that data look like? Does the trend, we saw, we think, pretty encouraging data from the first 20 patients in terms of safety, tolerability, combinability, and clinical activity, does that trend continue, right? Are there, aren't there, does everything look good?

Troy Edward Wilson: Clearly, we can give an update on those patients we are just <unk>.

Troy Edward Wilson: Really moving quite quite quickly and quite aggressively through dose escalation.

Troy Edward Wilson: I think a lot of people are looking toward what what is the recommended phase two dose for the different combinations and in the different populations and then what does that data look like does it does the trend. We saw we think pretty encouraging data from the first 20 patients in terms of safety Tolerability.

Troy Edward Wilson: Combined ability and clinical activity does that trend can take radar there or does everything look good and then as we alluded to obviously you turned the corner you move into the expansion cohorts.

Troy Edward Wilson: And then, as we alluded to, obviously, you turn the corner, you move into the expansion cohorts, which will take us into newly diagnosed front-line venasa, newly diagnosed 7 plus 3 without the requirements for adverse risk. That'll be sort of another tranche of data. We haven't, Jonathan, to this point been more specific. We're keeping our options open. You know, people are looking toward ECOP. We're not even yet to the late-breaking abstract deadline. We've used corporate events quite successfully. There's always ash at the end of the year.

Troy Edward Wilson: Which will take us into newly diagnosed that frontline Vanessa newly diagnosed seven plus three without the requirements for adverse risk that will be sort of another tranche of data we havent Jonathan to this point been more specific we're keeping our options open.

Troy Edward Wilson: People are looking towards the top we're not even yet to the late breaking abstract deadline we've.

Troy Edward Wilson: We've used corporate events quite successfully theres always ash at the end of the year, we may take advantage of one or several of those and when we when we have more specific guidance that we can give you will say something but that's the way. We're looking at it. We know we think we know what our audience our analysts and investors are looking for and we're going to.

Operator: We may take advantage of one or several of those. And, you know, when we have more specific guidance that we can give you, we'll say something, but that's the way we're looking at it. We know, we think we know what our audience, our analysts, and investors are looking for, and we're going to try to come out at the right times with the right data that will help give everyone confidence that we're going in the right direction.

Operator: Try to come at the right times with the with the right data that will help give everyone confidence that we're going in the right direction.

Speaker Change: Got it thanks for taking the questions.

Operator: Sure.

Operator: Your next question comes from Jason Suminski Banc of America, Jason. Please go ahead.

Operator: Sure. Thank you. Your next question comes from Jason Zemansky, from Bank of America. Jason, please go ahead.

Operator: Good afternoon. Thank you so much for taking our questions, and congratulations on the progress thus far. I was hoping maybe you could shed some light on the patients who remained on the trial. You mentioned 16 of 20 patients, including all 11 NPM1 patients, are still in the study. What happened with the four? Was it disease progression or something else? What dose were they being treated with?

Speaker Change: Good afternoon. Thank you so much for taking our questions and congratulations on the progress thus far I was hoping maybe you could shed some light into.

Operator: Patients who remained on the trial.

Operator: You mentioned 16 of 20 patients.

Operator: <unk> all 11 N P. M. One patients are still in the study.

Operator: What happened with the four.

Operator: With disease progression or or something else.

Operator: What dose where they are being treated with.

Speaker Change: Yeah, Jason Thanks for the question. So maybe just to take a step back those numbers that I cited to you where as of the January 11th data cutoff. So I was basically restating the results from that data cut of the 20 patients we.

Troy Edward Wilson: Yeah, Jason, thanks for the question. So maybe just to take a step back, those numbers that I cited to you were as of the January 11th data cutoff. So I was basically restating the results from that data cut of the 20 patients. We had, as we said, all five patients in the newly diagnosed seven plus three cohort responded.

Troy Edward Wilson: <unk> had as we said we had all five patients in the new in the newly diagnosed seven plus three cohort respond we had a significant number in the relapsed refractory.

Troy Edward Wilson: We had a significant number of relapsed refractory patients. You know, we are just sort of setting everybody's expectations that all of that data for those 20 patients was taken at a 200 milligram dose. And I think it was an open question in many people's minds as to what to expect at a 200 milligram dose. I had more than one investor say to me, well, you know, it wasn't really active at 200. I hope you can get to 600.

Troy Edward Wilson: We are just to sort of set everybody's expectations that all of that data for those 20 patients was taken added 200 milligram dose and and I think it was an open question in many people's minds as to what to expect that the 200 milligram dose I had more than one investor say to me well.

Troy Edward Wilson: It wasn't really active at 200 and I hope you get to 600.

Troy Edward Wilson: Is that, you know, it's actually active at all the doses. We did determine that the 600 milligram dose is the optimal dose as monotherapy. And the point of this experiment, this escalation, is to determine what is the optimum dose in combination. In terms of, I don't know that we gave a lot of detail at the time, Jason, about that data cut. We did have, you know, just something that we did call out at the time.

Troy Edward Wilson: Actually active it at all the doses, we did determine that the 600 milligram doses the optimal doses monotherapy and the point of this experiment. This escalation is to to determine what is the optimum dosing combination in terms of I don't know that we are that we gave a lot of detail at that time Jay.

Troy Edward Wilson: And of that data cut.

Troy Edward Wilson: We did have I'll, just something that we did call out at the time, we have one patient who crossed over from the frontline seven plus three to the relapsed refractory then Asia had a.

Troy Edward Wilson: We had one patient who crossed over from the frontline seven plus three to the relapsed refractory venasa, had a, you know, had a CR in both arms. We had another patient who Molly, I think at that time, cited who had a small bowel obstruction before the patient ever even got on Zysto. So, you know, in these heavily pretreated, particularly relapsed refractory, patients are not demonstrating a high rate of progressive disease. It's more often that they have, unfortunately, Jason, some clinical sequelae that just are associated with having advanced leukemia.

Troy Edward Wilson: Had a SCR actually in both arms, we had another patient who Molly I think at that time sided who had unfortunately had a small bowel obstruction before the patient never even got on Ziff dough. So in these in these heavily pretreated, particularly relapsed refractory.

Troy Edward Wilson: It's not evidenced a high rate of progressive disease, it's more often that they they have unfortunately, Jason some clinical sequela that just are associated with having advanced leukemia.

Troy Edward Wilson: Got it. Well, maybe just to kind of touch a little bit more on the KMT2A patients that dropped out of the trial. Was there homogeneity amongst the group? And does this read through to your expectations for ZIFTO within the, I guess, entirety of the KMT2A population?

Speaker Change: Got it well, maybe just to kind of touch a little bit more on the <unk> patients that dropped out of the trial was their homogeneity amongst the group.

Jason: And does this read through to your expectations for <unk>.

Jason: Within the entirety of the <unk> population.

Troy Edward Wilson: I so I wouldn't so again staying on that 200 milligram data set of 20 patients, I think it's too small to draw any kind of conclusion. We do, we do, you know, we did say, and we do say 200 milligrams of ZIFTO is an active dose. There's no question.

Jason: So I wouldn't so again staying on that 200 milligram dataset of 20 patients I think it's too small to draw any kind of conclusion.

Troy Edward Wilson: We do we do we did say and we do say 200 milligrams of <unk> is an active dose. There is no question is that the optimal dose I would say stay tuned we'll find out.

Troy Edward Wilson: Is that the optimal dose? I would say to stay tuned, right? We'll find out. Our view is if you can push the doses of monotherapy to 600, you should. Something that we are, that we've talked about is the potential for whole body exposure. And we think that's important in terms of both getting patients into response, Jason, and keeping them there. And obviously, that improves as you're able to go to higher doses. You get higher whole body exposure.

Troy Edward Wilson: Our view is if you can push the dose as monotherapy to 600, you should something that we are that we've talked about is the potential for whole body exposure and we think that's important in terms of both getting patients into response, Jason and keeping them there and obviously that that improves issue, we're able to go to higher doses.

Troy Edward Wilson: You get higher whole body exposure.

Troy Edward Wilson: You know, we'll, at the appropriate time, be able to walk you through the 200 dose as well as the higher doses. And then we can, you know, we can draw some conclusions as to what we're seeing. What I can say to you, and you can just tell it from enrollment, is that we don't have any toxicities. We don't have any real DDIs to speak of. That's part of, we think, why enrollment is going so quickly.

Troy Edward Wilson: We will at the appropriate time, we will be able to walk you through the 200 and dose as well as the higher doses and then we can we can draw some conclusions as to what we're seeing what I can say to you and you can just tell it from enrollment is we don't have any toxicities, we don't have any real DDI as to speak.

Troy Edward Wilson: That's part of we think why enrollment is going so quickly ziff Doe is once you've mitigated differentiation syndrome, it's actually a very easy drug to work with with these various combination regiments. So we're looking forward to updating that data.

Troy Edward Wilson: ZIFTO is, once you've mitigated differentiation syndrome, it's actually a very easy drug to work with, with these various combination regimens. So we're looking forward to updating that data. But other than the drug is, it has manageable safety and tolerability and good early evidence of clinical activity, I'm not sure I would over-interpret that 200 milligram data.

Troy Edward Wilson: Other than the drug is.

Troy Edward Wilson: It's.

Troy Edward Wilson: Manageable safety and Tolerability and good early evidence of clinical activity I'm not sure I would over interpret that 200 milligram data.

Troy Edward Wilson: Got it. Perfect. Thanks for the color.

Speaker Change: Got it perfect. Thanks for the color.

Troy Edward Wilson: Sure.

Operator: Thank you. Your next question comes from Roger Song, Jefferies. Roger, please go ahead.

Speaker Change: Thank you. Your next question comes from Roger Song Jefferies. Roger. Please go ahead.

Operator: Great, congratulations on the progress and thank you for taking the question, Troy. Maybe start with one clarification question and one follow-up question. For clarification, just to confirm, for the RP2D you are about to declare, that is in all of those four cohorts first line and relapsed reflux rate in both Vanessa and 7 plus 3, but your phase 1B trial or the phase 1B expansion trial, you plan to do only in first line Vanessa, is that correct?

Troy Edward Wilson: Great.

Speaker Change: Congrats for the progress and thank you for taking the question Troy.

Roger Song: Maybe start with the one clarification question and one follow up question for clarification just to confirm for the <unk> about you declare that is in all of those for Cole Hall first line and relapsed refractory in both the NEDA.

Operator: In the seven plus three.

Operator: But you all phase one b trial or the phase <unk> expansion trial, you planned to do only in first line than Asia.

Operator: Is that correct.

Operator: Roger I'm not sure I understand the second part of your question.

Troy Edward Wilson: Roger, I'm not sure I understand the second part of your question. Let me answer what I think is the first part, and then you can ask me the second part again.

Speaker Change: Let me, let me answer what I think is the first part and then you can ask me the second part of gas for the RP to D.

Troy Edward Wilson: Each cohort.

Troy Edward Wilson: Is enrolling independently of the others and and so and remember for everybody's sake.

Speaker Change: The way the protocol is written we don't have to go back to the agency to initiate the expansion cohorts, we need the safety monitoring committee to make a to make a determination that our recommended phase two dose has appropriate safety and tolerability to move forward into an expansion cohort. We don't have to go back in other words.

Troy Edward Wilson: For the RP2D, each cohort is enrolling independently of the others. And so, and this is important for everybody's sake, the way the protocol is written, we don't have to go back to the agency to initiate the expansion cohorts. We need the safety monitoring committee to make a determination that our recommended phase two dose has the appropriate safety and tolerability to move forward into an expansion cohort. We don't have to go back, in other words, to the FDA and ask for permission.

Troy Edward Wilson: The F D a N and asked for permission.

Troy Edward Wilson: We will.

Troy Edward Wilson: And so and those those cohorts are they're roughly all enrolling at the same rates, but theres a little bit of variability as you can tell that that Kmt two a seven plus three cohort is lagging just a little bit behind the other three.

Troy Edward Wilson: We will be validating that RP, two D and gaining more experience in the expansion cohorts and you really.

Troy Edward Wilson: As I said again, the whereas you move from escalation to expansion youre actually going into healthier quote unquote healthier patients. They still have AML, but patients who do not have adverse risk for example in the case of seven plus three or frontline patients in the case of Vanessa.

Troy Edward Wilson: We will, and so, and those cohorts are roughly all enrolling at the same rate, but there's a little bit of variability, as you can see. They still have AML, but patients who do not have adverse risk, for example, in the case of seven plus three, or frontline patients in the case of Veneza, you'd like to understand the profile of the drug in that set so that you can then make the appropriate considerations and decisions about registrational trials going forward.

Troy Edward Wilson: You'd like to understand the profile of the drug in that in that set. So that you can then make the appropriate considerations and decisions on registrational trials going forward.

Troy Edward Wilson: So, particularly in Veneza, we're not yet in the front line. We need to get there. So, that will help us clarify safety, tolerability, combinability, and activity. And enrollment's going so fast, Roger, that it shouldn't be, you know, that should be well, well underway here after we reach the RP2D around midyear. The team is just crushing it in terms of enrollment.

Troy Edward Wilson: So, particularly in venues that were not yet in the frontline we need to get there.

Troy Edward Wilson: So that will help us clarify safety Tolerability combinability and activity and enrollment is going so fast Roger that that's not going to be.

Troy Edward Wilson: That should be well well underway.

Troy Edward Wilson: After we reached <unk> around mid year. The team is just crushing it in terms of enrollment did.

Speaker Change: Did I answer your questions Yeah.

Troy Edward Wilson: Yeah, I think you answered the first part. The second part really is just to clarify what the phase 1b expansion cohort is because you mentioned the first line, first laminator combo, but how about the relapsed refractory, and the 7 plus 3? Thank you.

Roger: Yeah, I think of your answer the first part the second part really is just to clarify what is the phase one expansion cohort because you mentioned.

Troy Edward Wilson: First line first 11, Nader combo, but how about the relapsed refractory and the simplicity. Thank you.

Troy Edward Wilson: Oh, I see. Okay, I got it. Yeah.

Speaker Change: Oh I see okay got it yeah. So so the way to think about it is we will continue to evaluate the genotypes separately. So you have effectively seven arms you have venues us frontline venues NPM, one and <unk> you have relapse.

Troy Edward Wilson: So, the way to think about it is that we will continue to evaluate the genotypes separately. So, you have effectively seven arms. You have Venasa, frontline Venasa, NPM1, and KMT2A. You have relapsed refractory, again, NPM1 and KMT2A. Same thing with seven plus three, frontline, now no longer an adverse risk. And then one cohort you might have picked up on, which is ziftomenib plus venetoclax, only venetoclax, in the relapsed refractory setting. And that's one where we get a lot of interest from investigators asking the question, do you really need azacitidine?

Troy Edward Wilson: Refractory again, NPM, one Kmt <unk> same thing with seven plus three frontline now no longer adverse risk and then one cohort you might have picked up on which is ziff demand plus the net of class only been out of class in the relapsed refractory setting and that's one where we get a lot.

Troy Edward Wilson: Lot of interest from investigators asking the question do you really need as decided in India. You clearly need then but do you need as decided in given net menin inhibitors are epigenetic mechanism is a nephew genetic modifier.

Troy Edward Wilson: You clearly need Ven, but do you need azacitidine given that menin inhibitors are epigenetic? You know, their mechanism is an epigenetic modifier. We'll test that in the clinic and see. So, when you consider each of the two genotypes times those, essentially three plus the Ven-zifto combo, that gives you seven arms.

Troy Edward Wilson: We will test that in the clinic and see so when you consider Egypt, two genotypes times those.

Troy Edward Wilson: Essentially three plus the vent Ziff Doe combo that gives you seven arms, that's what we're describing Roger as the phase one b, we will not necessarily move forward with all of those into Registrational, we're gathering the safety data that activity data.

Troy Edward Wilson: That's what we're describing, Roger, as the Phase 1b. We will not necessarily move forward with all of those into registration. We're gathering the safety data, the activity data. We're already working on what the first registration enabling study look like, the second, et cetera. We'll provide more color on that, you know, likely later this year.

Troy Edward Wilson: We're already working on what do what is the first registration enabling study look like the second et cetera will provide more color on that.

Troy Edward Wilson: Likely later this year.

Roger: Excellent Okay, so thats clear now.

Troy Edward Wilson: Excellent. Okay, so that's clear now. Actually, you already partially answered my last question, the follow-up question is the registration path. Maybe can you give us a little bit, you know, in terms of timeline guidance when you will start to think about registration for either of those cohorts?

Speaker Change: Actually you already partially answer my last question a follow up question is the registration path, maybe can you give us a bit in terms of the timeline guidance. When you will start to think about the registration for either of those cohorts.

Troy Edward Wilson: Yeah, so we're already thinking about it. We're already planning for it.

Speaker Change: Yes, so we're already thinking about it we're already planning for it.

Roger: Even though we're learning we're continuing to learn about <unk> as we dose escalate and to some extent, what you're what you're waiting for as you need to be able to say to health authorities. This is the dose in the combination and this is the data that supports that dose selection that's.

Troy Edward Wilson: The point of this exercise, but you can leave that dose Roger in brackets and say this is what the design of the trial looks like pending this dose and our team is working quite intensely already to map out what is what are those registration trials look like and obviously you look at our emerging data you look at the.

Troy Edward Wilson: Even though, you know, we're learning, we're continuing to learn about ZIFTO as we dose escalate. And to some extent, you know, what you're waiting for is you need to be able to say to health authorities, this is the dose in the combination. And this is the data that supports that dose selection. That's the point of this exercise.

Troy Edward Wilson: <unk> landscape you look at what are the regulators looking for in terms of endpoints you can do the commercial considerations all of that gets folded in what I can say to you is so far.

Troy Edward Wilson: Our belief is that <unk> has the potential to be the best in class Menin inhibitor and there is nothing we're seeing thus far that takes us off of that view in terms of safety Tolerability combinability absence of toxicities Q T C drug drug interactions everything's looking good so at this.

Troy Edward Wilson: But you can leave that dose, Roger, in brackets, and say, this is what the design of the trial looks like pending this dose. And, you know, our team is working quite intensely already to map out what those registration trials look like. And obviously, you look at our emerging data, you look at the competitive landscape, you look at what the regulators are looking for in terms of endpoints, you do the commercial considerations, all of that gets folded in.

Troy Edward Wilson: So, at this point, we have a wealth of options. We clearly won't do them all, or we won't do them all at the same time. We need to prioritize, and we're doing that important work now, Roger. We'll talk more about the design. We'll probably give you our opinion on the design after we've gotten some input from the health authorities. Because we want to make sure that we bring them along, you know, as is appropriate when you're considering registrational trials.

Troy Edward Wilson: Point, we have we have a wealth of options, we clearly wont do them all or won't do them. All at the same time, we need to prioritize and we're doing that that important work now Roger will talk more about the design will probably give you.

Troy Edward Wilson: In our view on the design after we've gotten some input from the health authorities, because we want to make sure that we bring them along as there is appropriate when you're considering registrational studies.

Speaker Change: Excellent. Thank you Troy, Florida comments, that's it from us.

Troy Edward Wilson: Excellent. Thank you, Troy, for all the comments. That's it from us.

Speaker Change: Thank you next question comes from Lee Whatsapp Cantor Fitzgerald Li Please go ahead.

Operator: Thank you. Your next question comes from Li Watsek, of Cantor Fitzgerald. Li, please go ahead.

Operator: Hey, good afternoon, and congratulations on the progress. Just a couple of questions from me. Troy, could you please provide any color on whether the FDA has seen additional data for the breakthrough designation, potentially for ongoing pivotal studies as well?

Speaker Change: Hey, good afternoon, and congrats on the problem.

Operator: Sure.

Li Wang Watsek: Question from me try I Wonder if you can provide any color on whether the FDA.

Operator: Additional data.

Speaker Change: Thank you Sheng.

Li Wang Watsek: Shang potentially from the ongoing pivotal study as well.

Troy: Yeah at least so.

Troy Edward Wilson: Yeah, Lee, so you may find this answer unsatisfactory. And for that, I apologize.

Li Wang Watsek: You may find this answer unsatisfying and for that I apologize, we can't really give you specifics on our engagement with the agency.

Troy Edward Wilson: Suffice it to say they are very familiar with the benefit risk for <unk>.

Troy Edward Wilson: Been great partners with us from the beginning.

Troy: As I say, we are in active discussions with them already beginning to put the pieces in place to make sure that the modules of the NDA are lining up with their expectations I can't speak specifically to your question.

Speaker Change: I think.

Troy Edward Wilson: They don't frequently award of BTB, unless they are reasonably confident that the drug is actually going to deliver.

Troy Edward Wilson: Of the drugs that get <unk>.

Speaker Change: Breakthrough therapy designation, 90% of them go on to get approval the ones that do it's typically like a manufacturing issue or or something else, which obviously won't be the case of a small molecule.

Speaker Change: That gives you some guardrails.

Troy Edward Wilson: But.

Troy Edward Wilson: We were we're obviously thrilled by the BTG designation and particularly at two to be the first menin inhibitor and maybe the only one to actually get it.

Speaker Change: Okay. Thanks.

Troy Edward Wilson: And then for the hundreds of 400 and they dealt with it sounds like.

Troy Edward Wilson: Being cleared so I wonder if you can share any maybe early indication whether youre seeing a dose response or relative to the 200 I understand the patient population is slightly different than that.

Speaker Change: Color there would be helpful.

Troy Edward Wilson: We can't really give you specifics on our engagement with the agency. You know, suffice it to say they are very familiar with the benefit-risk analysis for ZIFT-AMENID. I mean, they've been great partners with us from the beginning. As I say, we are in active discussions with them, already beginning to put the pieces in place to make sure that the modules of the NDA are lining up with their expectations. I can't speak specifically to your question.

Speaker Change: Yeah can't really so.

Speaker Change: So we cleared it for those of you who who listen regularly the last time we had.

Troy Edward Wilson: I had the microphone in a Reg FD compliant said it I said that one of the three cohorts was open at 600 here. We are I think it's two weeks later or 10 days later now three of the four are opened my point Lee and telling you that as this data is like evolving in real time.

Troy Edward Wilson: You know, I think the FDA don't frequently award a BTD unless they're reasonably confident that the drug's actually going to deliver. Of the drugs that get breakthrough therapy designation, 90% of them go on to get approval. The ones that don't, it's typically like a manufacturing issue or something else, which obviously won't be the case for a small molecule. That gives you some guardrails, you know, but we were, you know, thrilled by the BTD designation and particularly to be the first menin inhibitor and maybe the only one to actually get it.

Troy Edward Wilson: Okay, thanks. And then for the 400 MIG dose, it sounds like it's been cleared, so I wonder if you can share any early indication whether you're seeing a dose response here relative to the 200. I understand the patient population is slightly different, but any color there will be helpful.

Troy Edward Wilson: Yeah.

Troy Edward Wilson: What is encouraging is again nothing nothing really to be concerned about.

Troy Edward Wilson: In terms of safety Tolerability drug drug interactions.

Speaker Change: I'd be careful not to get too far ahead of the data the monotherapy data Lake clearly says 600 is better than 200, we no.

Troy Edward Wilson: Yeah, I can't really, so... So, we cleared it. For those of you who listen regularly, the last time I had the microphone in a Reg FD compliant setting, I said that one of the three cohorts was open at 600. Here we are, I think it's two weeks later, 10 days later, and now three of the four are open.

Troy Edward Wilson: My point in telling you that is, this data is evolving in real time. What is encouraging is, again, nothing really to be concerned about in terms of safety, tolerability, and drug-drug interactions. But I wanna be careful not to get too far ahead of the data.

Troy Edward Wilson: We Didnt test 400, obviously, but 600 was clearly better than 200, you would expect Lee that same relationship to apply in the combination setting and so the real question is can you actually.

Troy Edward Wilson: The monotherapy data Lee clearly says 600 is better than 200. We didn't test 400, obviously, but 600 was clearly better than 200. You would expect, Lee, that same relationship to apply in the combination setting, and so the real question is, can you actually, is the safety and tolerability manageable at 600? If that's the case, then you would expect improved activity to pull through in both populations. But I'll answer the question that way rather than sort of give you an early peek at the 400 milligram cohort.

Troy Edward Wilson: Is the safety and Tolerability manageable and 600, if that's the case then you would expect.

Troy Edward Wilson: Improved activity to pull through in both populations, but.

Troy Edward Wilson: I'll answer the question that way rather than sort of trying to give you an early peek at the 400 milligram cohort.

Speaker Change: Okay. Thank you.

Speaker Change: Sure our pleasure. Thank you. Your next question comes from Brad Canino Stifle Brad. Please go ahead.

Operator: Thank you. Your next question comes from Brad Canino, of Stifel. Brad, please go ahead. Great, thank you. And it's nice to be able to focus on just your call this evening. I just want to check in on the

Troy Edward Wilson: Okay, thank you. Sure, pleasure. Thank you. Your next question comes from Brad Canino, from Stifle. Brad, please go ahead.

Bradley Patrick Canino: Great. Thank you.

Bradley Patrick Canino: To be able to focus on just your call. This evening.

Bradley Patrick Canino: I just wanted to check in on the BT D. Can you help me understand when you submitted for that designation and why it ended up at that submission date.

Bradley Patrick Canino: Yeah. So.

Operator: Yeah, so, um, not really, Brad. I mean, you, um... Just to answer the question in a general sense. In our experience, the way that BTD works is you have a pre-submission. If the agency wants you to put in a full application, they'll indicate it at that time. Otherwise, they might indicate that they'd like to see you answer questions or provide additional data. If they invite you to submit the full application, they typically get back to you in about 60 days.

Bradley Patrick Canino: Not really Brad I mean, you.

Bradley Patrick Canino: Just to answer the question in a general sense in our experience the way. The BTG works is you have a pre submission.

Operator: If the agency wants you to put in a full application they'll indicated at that time, otherwise they might indicate that they'd like to see see you answer questions or provide additional data.

Troy Edward Wilson: Again, that's the general course. One of the questions that I think were out there in the community was, what exactly is the unmet need in NPM1 mutant AML? They have been great partners ever since.

Operator: If they invite you to submit the full application they typically get back to you in about 60 days.

Operator: That's again, that's the general the General course.

Troy Edward Wilson: One of the questions that I think.

Troy Edward Wilson: It was out there in the community was what exactly is the unmet need and N. P. M <unk> mutant AML and <unk>.

Troy Edward Wilson: <unk>.

Troy Edward Wilson: I think we were very successful in convincing the agency of the view of many of the docs, which is it's particularly once you are in the relapsed refractory setting there is no difference in unmet need between <unk> and <unk>.

Troy Edward Wilson: So we've had a very constructive dialogue with the agency all the way back to I hate to say it but.

Troy Edward Wilson: The agency was very helpful. In terms of our navigating our partial clinical hold they have been great partners ever since I think they see the promise of Menin inhibitors. I think they are quite excited I don't want to speak for them, but they have been a great partner to work with.

Troy Edward Wilson: I think they see the promise of menin inhibitors. I think they're quite excited. I don't want to speak for them, but they have been a great partner to work with. And if I can ask one more question, as you're progressing through the combo dose escalation, have the enrollment rate across the different cohorts of mutations come in line with your expectations headed into the trial? Yeah, um...

Speaker Change: Okay, maybe if I could ask one more.

Troy Edward Wilson: You're progressing through the combo dose.

Troy Edward Wilson: Dose escalation of the enrollment rates across the different cohorts mutations come in line with your expectations heading into the trial. Thank you.

Troy Edward Wilson: Yeah.

Troy Edward Wilson: So the enrollment has actually been pretty even across the cohorts it it ebbs and flows.

Troy Edward Wilson: So the enrollment has actually been pretty even across the cohorts. It ebbs and flows, you know, as you go week to week. It, I'm not sure, Brad, we really, I'm not sure what our expectations necessarily were going in.

Troy Edward Wilson: As you go week to week it.

Troy Edward Wilson: I'm not sure Brad we had really I am not sure what our expectations necessarily we're going in.

Troy Edward Wilson: Certainly, we are seeing very, very strong engagement. I'll just remind everybody that, for each of these arms, if you will, it's six patients per dose. Now, some of these doses are actually over-enrolling because sometimes you have patients who have cleared screening, but you're not yet ready to put them in the next highest dose, so there may be, rather than six, we may have seven or eight or even more at a given dose.

Troy Edward Wilson: Certainly we are seeing very very strong engagement.

Troy Edward Wilson: Remind everybody that.

Troy Edward Wilson: For each of these of these arms if you will it's six patients per dose now.

Troy Edward Wilson: Some of these doses are actually over enrolling because sometimes you have patients who have cleared screening and but you are not yet ready to put them in the next highest dose. So there may be rather than six we may have seven or eight or even even more at a given dose but at a minimum when all is said and done and the escalation will have at least 72.

Troy Edward Wilson: But at a minimum, when all is said and done in the escalation, we'll have at least 72 patients. And I'm telling you now, it will be more than 72. Think about how fast that enrollment has gone. We started in July and compared it to, you know, other comparables out there, there's just been incredibly strong engagement.

Troy Edward Wilson: And I'm, telling you now it will be more than 70 to think about how fast that enrollment has gone. We started in July and look at it relative to other comparables out there theres just been incredibly strong engagement the lag in the KMT two way frontline seven plus three Brad is probably just reflective of.

Troy Edward Wilson: The lag in the KMT2A frontline seven plus three, Brad, is probably just reflective of the difference in incidence. Again, NPM1's 30%, KMT2A's probably five, it's 10% if you include all of leukemia. It's probably, you know, three to 5% in AML. That's probably what you're seeing. But it's, you know, again, it's lagging behind only, you know, only very, very briefly. We should, as we said, be clearing the 400 milligram cohort in the seven plus three KMT2A here imminently, and we expect that that one will go to 600 as well. Thank you. Your next question comes from Peter Lawson, Barclays.

Troy Edward Wilson: The difference in the incidence again, NPM, 130%, Kmt <unk>, probably five minutes, 10%. If you include all of leukemia, it's probably 3% to 5% in AML, that's probably what you're seeing but it's again, it's lagging behind.

Peter Richard Lawson: Only only very very briefly we should as we said we should be clearing the 400 milligram cohort in the seven plus three Kmt two way here imminently and we expect that that one will go to 600 as well.

Peter Richard Lawson: Thank you.

Troy Edward Wilson: Sure.

Operator: Thank you. Your next question comes from Peter Lawson, Barclays. Peter, please go ahead. Thanks for taking the question. Just around the 200 milligram dose in combination, are there any?

Troy Edward Wilson: Thank you. Your next question comes from Peter Lawson Barclays. Peter Please go ahead.

Peter Richard Lawson: Hey, Thanks for taking the question.

Peter Richard Lawson: Just around the.

Peter Richard Lawson: 200 milligram dose combination, but are there any trends emerging.

Peter Richard Lawson: From the duration on therapy between the KMT two way versus the N P M wound patients Troy.

Operator: It's early, Peter. It's early. I mean, maybe just take a step back.

Peter Richard Lawson: It's early Peter it's early I mean, the the maybe just to take a step back.

Peter Richard Lawson: It's too early if you look at these patients in general, though Peter the KMT <unk> are often younger more set more typically more frequently go to transplant. The MTM ones. The median age is like 60, so they and they oftentimes there are older and a little bit more frail, they perhaps don't go to trends.

Troy Edward Wilson: It's too early to say. If you look at these patients in general, though, Peter, the KMT2A are often younger, more typically, more frequently go to transplant. The NPM1s, you know, the median age is like 60, and oftentimes they're older, a little bit more frail, and they perhaps don't go to transplant as readily as the KMT2A. But I think it's too early to say

Troy Edward Wilson: Flat as readily as the Kmt to a I think it's too early to say what what we saw from the 200 milligram data Peter was even at that dose, which again in our view was it was a non optimized dose.

Troy Edward Wilson: What we saw from the 200 milligram data, Peter, was even at that dose, which, in our view, was a non-optimized dose, you saw meaningful clinical activity, I think better than many people expected, and you know, it certainly gave us confidence to continue escalating. A big part of KMT2A, Peter, of driving clinical benefit there is going to be this concept of whole body exposure. We think that's critically important.

Troy Edward Wilson: You saw meaningful clinical activity I think better than many people expected and it certainly gave us confidence to continue escalating a big part of the <unk> Peter.

Troy Edward Wilson: Driving clinical benefit there is going to be this concept of whole body exposure. We think that's critically important we think it gives the patients the best chance of really differentiating all of the extra medullary disease and that's the advantage that <unk> has is as we look out across the.

Troy Edward Wilson: We think it gives the patients the best chance of really differentiating all of the extramedullary disease, and that's the advantage that ZIFTO has as we look out across, you know, the competitive landscape. It's highly tissue penetrant, and it's extremely well tolerated.

Troy Edward Wilson: Competitive landscape its highly tissue penetration, it's extremely well tolerated. It is it doesn't have any other toxicities and in combination. The DFS is very well managed very well mitigate it. So I think we're optimistic Peter that as we go higher in dose that may be that may provide a benefit to both sets of patients.

Troy Edward Wilson: It doesn't have, you know, it doesn't have any other toxicities, and in combination, the DS is very well managed, very well mitigated. So I think we're optimistic, Peter, that as we go higher in dose, that may be, that may provide a benefit to both sets of patients, and whether those patients go on to transplant or not. Obviously, you know, we'll be able to say a lot more when we show you the next data installment.

Troy Edward Wilson: <unk>.

Troy Edward Wilson: And and.

Troy Edward Wilson: Whether those patients go on to transplant or not obviously, we will be able to say a lot more when we show you show you. The next data installment here.

Peter: Gotcha, and then have you seen anything in the store.

Troy Edward Wilson: And then, are you seeing anything in the side effect profile when you combine them? Is there anything that could be impacted? https://www.nasa.gov. If anything, Peter, I think it's actually helping with the backbones. Zyfto is so active in these populations that, you know, people think about, you know, if you think about how you use this, in the case of 7 plus 3, they're on for about a week, right, on chemo, and then they're on Zyfto after that. You don't have to hit them with a sledgehammer when you're giving them, you know, a potent differentiating agent, and that's both populations.

Troy Edward Wilson: When you combine.

Troy Edward Wilson: Or anything that it won't be impact in <unk>.

Troy Edward Wilson: Duration of therapy.

Troy Edward Wilson: Any cooks for me particular regiments.

Troy Edward Wilson: If anything Peter I think it's actually helping with the backbones.

Troy Edward Wilson: If does so active in these populations that.

Troy Edward Wilson: People think about if you think about how do you use this in the case of seven plus three they're on for about a week right on on Chemo and then and then they are on Ziff till after that you don't you don't have to hit them with a sledgehammer, when you're giving them a potent differentiating agent and thats both populations with Ven Asia.

Troy Edward Wilson: With Venasa, the protocol follows Venasa as it's labeled, but, you know, there's an openness among investigators to move patients off of these myelosuppressive regimens as quickly as possible. You may actually see better results, we'll see, when you combine it with Zyfto. It's early days, but Peter, we're not seeing anything in terms of safety, tolerability, side effect profiles, combinability, we're not seeing anything that's giving us any concern. In fact, if anything, it's telling us that we use the best in class language, you know, we mean it when we say it.

Troy Edward Wilson: The protocol follows then Asia as its labels, but.

Troy Edward Wilson: There's a there's an openness among investigators to.

Troy Edward Wilson: Move patients also have these milo suppressive regimens as quickly as possible you may actually see better results, we'll see when you combine with <unk>. It's early days, but but Peter were not seeing anything in terms of safety Tolerability and side effect profiles combine ability, we're not seeing anything thats.

Troy Edward Wilson: Giving us any concern in fact, if anything it's telling us.

Troy Edward Wilson: We use these best in class language.

Troy Edward Wilson: We mean it when we say it Ziff Doe now that we've put the D. S question largely to bed I think ziff does really going to be able to show you what it can do.

Troy Edward Wilson: Zyfto, now that we've put the DS question largely to bed, I think Zyfto is really going to be able to show you what it can do.

Speaker Change: Great. Thank you so much thanks for taking the questions.

Speaker Change: Pleasure. Thank you. Your next question comes from Phil Nadeau TD Cowen Phil. Please go ahead.

Operator: Your next question comes from Phil Nadeau, TD Cowen. Phil, please go ahead.

Operator: Thank you. This is Ernie Rodriguez speaking for Phil. Thanks for taking our question. I have one, we have one. With the competitors, many inhibitors launching, and even though it's in another indication, the KMT-2A, is there anything, you know, they're likely launching soon this year, later this year, is there anything on that launch that you would be looking at or any metrics or any other aspects that you would expect will be useful or informative to your strategy?

Philip M. Nadeau: We have one.

Philip M. Nadeau: With our competitors.

Operator: Indications.

Operator: <unk>.

Operator: They are likely launching.

Speaker Change: And this year later this year is there anything on that loan that you would be looking to or any metrics or any other aspects that you would expect it will be useful and informative to your strategy.

Troy Edward Wilson: Yeah, um... This may surprise you, but let me take off my current CEO hat for a second and just say, if they're able to get approval and get to market, we're going to applaud them. We're going to congratulate them. Because at the end of the day, we all do this for patients.

Operator: Yeah.

Troy Edward Wilson: And, you know, and KMT2A, which is the indication you're talking about, is a disease of high unmet need. I think that, you know, and I'll let them speak to their process and where they are. It is, you know, KMT2A is a much smaller opportunity, but it's a good indicator of the utility of menin inhibition. We'd certainly be happy that they're out educating physicians and educating the community when we're coming along with what we believe is a better menin inhibitor.

Troy Edward Wilson: And whether you look at their combo data or our combo data, you have to believe that combo is the way to go here. So while we believe that, ultimately, when we get to market with NPM1 mutant AML, we will be best in class, we also think it sets the stage for us to be best in class in combination and in maintenance. And that's how you drive a multi billion dollar peak sales potential.

Troy Edward Wilson: So we'll be paying, paying, excuse me, we will be paying careful attention, you know, watching, cheering, learning, not necessarily tracking their key performance indicators because the drugs are very different, but it will be instructive about the utility of menin inhibitors. What is clear to us is that, you know, 30% of AML patients are NPM1. We're seeing that in terms of enrollment, it's going like gangbusters. And the fact that we're seeing such strong KMT2A enrollment in the combo, I think really speaks to the potential of those regimens to drive that. Hopefully, that answers your question.

Troy Edward Wilson: It does, thanks. And another quick one on the preclinical data in solid tumors that you expect to discuss on H2? What should we expect from that? Should we be able to determine, like, which kind of solid tumors would be most amenable, or would you be, you would pursue on the clinical side? Or is it more like broad approval of the concept in a broader range of solid?

Troy Edward Wilson: What should we expect them to we are are we going to be able to determine what.

Troy Edward Wilson: Yeah, so what we're talking about, really, is epigenetic regulation of oncogenes or potential oncogenes, right? That's what you should be looking for.

Troy Edward Wilson: Are there going to be multiple opportunities? We think so, but each of them is sort of on their own. We're all still learning about epigenetic regulation, but what's clear to us is that menin, the menin-MLL interaction, appears to play a critical role both within and outside of AML. When you see this non-clinical data, and we've been working on this internally for quite some time, looking not only at ZIFTO but with other menin inhibitors as well, you'll know, it'll be very obvious to you the first place that we're going.

Troy Edward Wilson: Beyond that, I think we have to continue to be data-driven. We've been very good at putting non-clinical data out there and letting that guide the development. We're going to continue to do that. So we've really taken our time, gone to school, done the work, and are quite excited to share that data with you here in the second half of the year. If it works the way it works non-clinically, it's potentially transformational for that reason

Troy Edward Wilson: Thank you, that's helpful, and thank you for taking our questions.

Operator: Thank you. Your next question comes from Ren Benjamin, Citizens JMP. Ren, please go ahead.

Operator: Hey, good afternoon, guys. Thanks for taking the questions. You know, maybe I missed it, Troy, in your prepared remarks, but what's happening with the post-transplant program? Has that been initiated? Maybe I missed it, you know, as one of the upcoming milestones. Yeah. Just wanted to know how you're thinking about that.

Troy Edward Wilson: Yeah, thanks for asking, Ren. You did not miss it.

Troy Edward Wilson: What I can tell you is, in contrast to 001, Comet 001, and Comet 007 and 08, that trial is an investigator-sponsored trial. We've done everything as a sponsor, or not as a sponsor, but as the drug sponsor, if you will, as the company. We've done everything we can.

Troy Edward Wilson: We've put it into the investigators' hands. They're working through the last few bits of red tape. They have everything they need.

Troy Edward Wilson: As with any investigator-sponsored study, it's their study. They control the conduct. They control the timing.

Troy Edward Wilson: They control the dissemination of data. What I can tell you, Ren, is that the FDA has reviewed and cleared it. It's really now just in study startup, but it is in the hands of the investigators. We're probably not going to be in a position to guide you on enrollment there, and we're going to have to rely on them to speak about the trial.

Troy Edward Wilson: But it's going in the right direction, and let me go one step further. Just to remind everybody, we are assessing the safety and tolerability of Zyptomenib in the post-transplant maintenance setting so that we can have the appropriate discussions with health authorities about what a registration-enabling study would look like. Because we can't do everything at the same time, we've actually accepted a proposal to do it as an IST, and at this point, Ren, they're just, I think, dotting the I's and crossing the T's. I will say one other thing.

Troy Edward Wilson: Yeah, one other thing, Ren, I'll say is, of course, and this is why I wanted to add to it. We do have patients in post-transplant maintenance, both in the monotherapy setting and in the combination setting. So, you know, the way we're doing this is, our studies now permit physicians to put their patients back on zyptomimib post-transplant if they're in the various studies. The IST that I referenced is a dedicated study that would be a lead-in to a dedicated post-transplant maintenance study, which would be independent and essentially agnostic to where those patients come from. Those two strategies would then marry up to make sure that you can take patients from the front line all the way through to the maintenance setting without interruption. That's the bigger picture strategy.

Troy Edward Wilson: Got it. Thank you for that clarification.

Troy Edward Wilson: Just switching gears real quick to 2806. Yes, You know, when I look at current HN and, you know, the potential to complete enrollment in the two expansion cohorts and still identify the optimal biological reactive dose by the end of 2024, can I take that kind of a timeline and apply it to 2806? Or is 2806 such a unique molecule, you know, and very different from TIPI that maybe the entire enrollment of the combination studies is going to be a lot quicker, and we might see data a lot, a lot faster than we're seeing it currently?

Troy Edward Wilson: By the end of 2024.

Troy Edward Wilson: Can I take that kind of a timeline and apply it.

Troy Edward Wilson: One year ago.

Troy Edward Wilson: Such a unique molecule.

Troy Edward Wilson: And very different from that.

Troy Edward Wilson: That may be that entire enrollment of the combination studies is going to be a lot quicker than we might see data a lot faster than we're seeing currently.

Troy Edward Wilson: Sure, yeah, so... I would be hesitant to draw conclusions across trials about enrollment. The current HN trial, the one you're referring to, it's a handful of sites, it's a signal-seeking study really intended to answer the question, is 1 plus 1 equal to 3? I.e., Tipifarinib 1, Alpelesib 1, do you get better activity than either drug as monotherapy? I'll remind everybody, you don't really expect to see responses from either Tipifarinib or Alpelesib in PIK3CA mutant head and neck.

Speaker Change: Sure Yeah. So.

Troy Edward Wilson: Current the current HN trial, the one you're referring to is.

Troy Edward Wilson: It's a handful of sites. It's a signal seeking study really intended to answer the question is one plus one equal three.

Troy Edward Wilson: The work that's been done with Alpelesib largely resulted in stable disease, and you wouldn't expect Tipifarinib to have activity in that genotype in head and neck. So the fact that we're seeing activity at multiple doses and that we have manageable safety, tolerability, and activity to justify some dose optimization, I think is good...it says we may be able to extend beyond the work that we did with Tipi as a monotherapy and open up that patient population, but it's also, I think, highly de-risking what you should expect with 2806, because if you can combine it with The final thing, Ren, is that we don't want to go too fast. I know that sounds counterintuitive. It's actually a very good question.

Troy Edward Wilson: The work that's been done without palisade largely resulted in stable disease, and you wouldn't expect <unk> to have activity in that genotype in head and neck. So the fact that we're seeing activity at multiple doses and that we have manageable safety tolerability and activity to justify some.

Troy Edward Wilson: Dose optimization.

Troy Edward Wilson: Think is a good it says we may be able to extend beyond the work that we did with <unk> as a monotherapy and open up that patient population, but it's also I think highly derisking of what you should expect with 20 806, because if you can combine without Palo said. It gives you confidence that you can combine with weather.

Troy Edward Wilson: It's actually a very good question. If there is an opportunity in head and neck do you go with Tippi or do you go with 28, six and I would say our primary focus with 26 right now is renal cell carcinoma, and K Ras driven tumors. There are I don't even know how many K Ras inhibitors, either in the clinic or steaming into the clinic.

Troy Edward Wilson: If there's an opportunity in head and neck, do you go with Tipi or do you go with 2806? And I would say our primary focus with 2806 right now is renal cell carcinoma and KRAS-driven tumors. If there are, you know, I don't even know how many KRAS inhibitors in the clinic or coming into the clinic, they will all have the same issue. They will all have innate and adaptive resistance.

Troy Edward Wilson: We're trying to come up with an approach that basically cuts that off at the knees, and if we can demonstrate it with Atagrassiv, then we're going to have the high-class problem of which of these solid tumor indications do we pursue. We've been, Ren, very data-driven with current and just letting the patient experience sort of guide us on where to go. We're encouraged. The physicians are encouraged, The response rate in that setting is like 20% in the second line, and it's 5% or less in the third line.

Troy Edward Wilson: You know, it is as bad as pancreatic cancer. So the fact that we're seeing, you know, I think encouraging clinical activity is a good thing. It's just too early, Ren, to say what the development strategy is. Is it 2806? Is it tipiforinib?

Troy Edward Wilson: I think it does go a ways toward de-risking the overall program, and, again, if we can pull this off, you're talking about some big solid tumors. The 2806 trial is a dose escalation study, and, you know, those always have their own challenges, but, again, I wouldn't draw conclusions from one disease type to the other. Our ClinOps team has been exceptional across the board, from ZIFTO to 2806 to current. You know, they're making good progress with the FIT-001 trial. We'll likely share data next year on that study, but I think it's probably a little too early to show anything on FIT here at 24.

Operator: Excellent. Thanks for taking the question. Thank you. Your next question comes from Justin Zelin, BTIG. Justin, please go ahead.

Operator: Thanks for taking the questions. Troy, just with Comment 001, Enrollment Completed,

Troy Edward Wilson: Yeah, Justin, let us, I know this is going to be a bit unsatisfactory. Let us complete enrollment. You know, we've said we're very close. Let us complete that. And then we can give you guidance on kind of what to expect. I want to, I want to make sure we do this at the right time and the right place.

Troy Edward Wilson: We obviously want to give the, you know, the trial per protocol needs six months plus time to clean the data. I think we'll be able to answer that question better coming on the back of full enrollment. Great, that makes sense to me. And just on 2806, could we expect additional studies with other combination agents in the future? Or are you pretty comfortable with what you have right now?

Troy Edward Wilson: Yeah.

Troy Edward Wilson: Yeah, um... There's certainly a rationale, Justin, to combine it with other drug candidates. I think what we want to do is—and I'm going to just, for 30 seconds, just go a level deeper. The big takeaway from the current study is that you're driving activity in that setting both by blocking wild-type H-RAS and, we think, by blocking farnesylation of REB. REB stands for RAS Homolog Expressed in Brain. Why do I call that out?

Troy Edward Wilson: There's certainly a rationale justin to combine with other with other drug candidates I think what we want to do is.

Troy Edward Wilson: And I'm going to just for 30 seconds, just go a level deeper the big takeaway from the current study is that youre driving activity in that setting both by blocking wild type HRS and we think by blocking foreign installation of Rep ramp is it red stands for Ras homolog expressed in brain.

Troy Edward Wilson: I call that out because, if you look at the posters that we've presented, REB, de-farnesylation, or, you know, removal of the farnesyl group from REB is critical to blunting the innate and adaptive resistance that arises from KRAS inhibitors. And as I said, if you inhibit KRAS, the tumor is going to do a number of different things to try to escape. One of them is to up-regulate PIATRI kinase signaling through that pathway.

Troy Edward Wilson: Why do I call that out I call that out because that if you look at the posters that we've presented red deep foreign installation or.

Troy Edward Wilson: The removal of the fossil group from Red is critical to blunting, the innate and adaptive resistance that arises to K Ras inhibitors and as I said, if you ever if you if you inhibit K Ras the tumor is going to do a number of different things to try to try to escape one of them is to up regulate <unk> kinase signaling through that path.

Troy Edward Wilson: <unk> way blocking revpar installation is critical to blunting that effect. So if we can block Rev and current with one combination it gives us confidence that we're going to be able to block. It in a different context with a K Ras inhibitor, if that's true and we see activity and I will tell you initially Marathi now Bristol have been great.

Troy Edward Wilson: Blocking REB farnesylation is critical to blunting that effect. So if we can block REB in current with one combination, it gives us confidence that we're going to be able to block it in a different context with a KRAS inhibitor. If that's true and we see activity—and I will tell you, initially, Marotti, now Bristol, have been great clinical collaborators on this study. They've been very supportive. They've given us great input. You could imagine, Justin, using an FTI in combination with almost any KRAS inhibitor.

Troy Edward Wilson: Clinical collaborators on this study they've been very supportive they've given us great input.

Troy Edward Wilson: You would you could imagine just didn't using an STI in combination with almost any K Ras inhibitor, that's how fundamental that biology as it is on par with ship too with sauce. One that's how you think about it and it's taken US a number of years to get there, but that's the highest probably the highest best use.

Troy Edward Wilson: That's how fundamental that biology is. It's on par with SHIP-2, with SOS-1. That's how you think about it. And it's taken us a number of years to get there, but that's probably the highest best use, most valuable application of an FTI.

Troy Edward Wilson: Most valuable application of an MTI.

Speaker Change: Great. Thanks for taking my questions.

Troy Edward Wilson: Great, thanks for taking my question. Thank you. Your next question comes from George Farmer, Scotiabank. George, please go ahead. Hi, thanks for taking my question. I have two.

Troy Edward Wilson: Thank you. Your next question comes from George Farmer Scotiabank George Please go ahead.

Operator: Thank you. Your next question comes from George Farmer, Scotiabank. George, please go ahead. Hi, thanks for taking my question.

George Farmer: Alright, Thanks for taking my question I have two.

Operator: Yeah, can you ask the first part of the question again? I just want to make sure I've got the second part right.

George Farmer: Troy could you address what you think the hurdles are.

Operator: Or zip Doe approval and Tim one.

Operator: Apps refractory setting.

George Farmer: First question second question is.

George Farmer: How you think about resource allocation when developing ZIP dough in earlier lines of therapy, combining with seven plus three or Venezuela.

George Farmer: Yeah can you can you ask the first part of the question again I just want to make sure Ive got the second part is resource allocation and the first part was the hurdle rate or is that is that right, but you.

Troy Edward Wilson: The first part was the hurdle rate, is that right? But yeah, what do you think the hurdles are, Fred? Yeah. Yeah. Sure. Yeah, so I think that the hurdle rates for the NPM1 cohort, the same is true for KMT2A, by the way, you know, we've consistently said, for approval, our view is you need 20 to 30% CR-CRH, four to six months median duration of response. Would you like to do better? Yes.

George Farmer: What do you think the hurdles are for FDA approval.

Operator: Yes, yes, yes.

Fred: Factory sure, yes, so I think we think that the hurdle rates.

Troy Edward Wilson: But we've never got, you know, we and I think our competitors have consistently said, in our view, that's the bar for approval in the relapsed refractory population. It's, it's going to be different in combination. And, you know, one of the things that we expect in combination is that we expect the duration of both populations, particularly KMT2A, to improve as we go to higher doses. But, you know, when we talk about combinations, we're going to set the bar a little bit differently. But the, you know, the fact that we had a 35% CR-CRH rate in Phase 1b, again, don't get emotionally attached to 35%. That's great.

Troy Edward Wilson: For for the NPM one cohort at the same is true for <unk> by the way.

Troy Edward Wilson: We've consistently said for approval our view is you need 20% to 30% CR CRH four to six months median duration of response would you like to do better yes, but we've never.

Troy Edward Wilson: We and I think our competitors have consistently said in our view that's the bar for approval in the relapsed refractory population.

Troy Edward Wilson: <unk>.

Troy Edward Wilson: Going to be different in combination.

Troy Edward Wilson: And one of the things that we expect in combination is that we expect the duration for both populations, particularly the Kmt <unk> to improve as we go to higher doses, but when we talk about the combinations, we're going to set the bar a little bit differently, but the.

Troy Edward Wilson: The fact that we had a 35% CR CRH rate in the phase one b again don't get emotionally attached to 35% that's great you need to be 20% to 30%, but that phase <unk> data coupled with the BTG Award I think gives you confidence that we're in the right Zip code for for being able.

Troy Edward Wilson: You need to be between 20 and 30%. But that Phase 1b data, coupled with the BTD, you know, award, I think, gives you confidence that we're in the right zip code for, you know, being able to secure an approval for monotherapy. In terms of your question around resource allocation, you know, we can do it; we, Cura, on a go-it-alone basis, can probably, you know, pretty readily do one global pivotal trial. Now, if we want to really blow up ZIFTO and maximize the value, you're talking about potentially multiple pivotal trials, including frontline, including maintenance, potentially solid tumors. We've said all along that there will very likely come a time when we need the resources, both financial and operational, of a party larger than we are.

Troy Edward Wilson: To secure an approval for monotherapy.

Troy Edward Wilson: In terms of your question around resource allocation.

Troy Edward Wilson: Yes.

Troy Edward Wilson: We can do weaker on a go it alone basis can probably pretty readily do one global pivotal trial.

Troy Edward Wilson: Now if we want to really blow out ziff Doe and maximize the value you're talking about potentially multiple pivotal trials.

Troy Edward Wilson: Including frontline, including maintenance potentially solid tumors, we've said all along there they're very likely will come a time, when we need the resources, both financial and operational <unk>.

Troy Edward Wilson: You know, running global pivotal trials is facilitated if you have people on the ground in all those different countries. But at the moment, we think we can drive really meaningful value for shareholders by just continuing to execute as we have. So, you'll see us; we're already actively evaluating what is different, you know, how can we be clever.

Troy Edward Wilson: Already larger than we are.

Troy Edward Wilson: Running global pivotal trials has facilitated if you have people on the ground in all those different countries.

Troy Edward Wilson: At the moment, we think we can drive really meaningful value for shareholders by by just continuing to execute as we have one of the things you want to understand is what what's the safety tolerability activity and some view into durability, both for NPM one N <unk>.

Troy Edward Wilson: As you go to frontline because the longer that is both whether patients go to transplant or not that's going to help inform the commercial models and and really we think drive the value. So you'll see us we're already actively evaluating what are different how can we be clever how can we take advantage.

Troy Edward Wilson: How can we take advantage of everything the health authorities have to offer, and be efficient about the first combination pivotal trial? I think we're providing a really good foundation that will inspire physicians to have confidence that ZIFTO can be used readily with these different combinations, right? And that's the starting point; you give them comfort that they can use it safely. It can be given orally once a day. There are no other complications. And, and then, and then you just let the efficacy and the clinical activities speak for themselves.

Troy Edward Wilson: <unk> of <unk>.

Troy Edward Wilson: Of everything the health authorities have to offer be efficient about.

Troy Edward Wilson: The first combination pivotal trial I think we're providing a really good foundation that that will inspire physicians to have confidence that <unk> can be used readily with with these different combinations right and that's the starting point is you give them comfort that they can use it safely it can be given orally once a day.

Troy Edward Wilson: Sure.

Speaker Change: Okay. Thank you.

Troy Edward Wilson: Thank you. There are no further questions at this time. I will now turn it back to Troy Wilson for closing remarks.

Troy Edward Wilson: Great, thank you. Thank you all once again for joining the call today. We'll be participating in the Bank of America Healthcare Conference in a couple of weeks, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Tom, or me. Thank you, and have a good evening, everyone.

Speaker Change: Great. Thank you. Thank you all once again for joining the call today, we will be participating in the bank of America Health Care conference in a couple of weeks and we look forward to seeing many of you. There in the meantime, if you have any additional questions. Please feel free to contact Pete Tom or me. Thank you and have a good evening everyone.

Speaker Change: Thank you ladies and gentlemen. This concludes your conference call for today, we thank you for participating and ask that you. Please disconnect your lines.

Operator: Thank you. Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your lines.