Q2 2024 Kura Oncology Inc Earnings Call
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Operator: Good day, and welcome to the Q2 2024 Kura Oncology conference call. All participants will be in listen-only mode. Should you need assistance, please signal the conference specialist by pressing the star key, followed by 0. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Pete DeSpain, Head of Investor Relations. Please go ahead.
[inaudible]
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Speaker Change: Good day and welcome to the Q2 2024 Cure Oncology conference call. All participants will be in listen-only mode. Should you need assistance, please signal the conference specialist by pressing the star key followed by 0.
Pete Despain: Great. Thank you, Amy. Good afternoon, and welcome to Kura Oncology's second quarter 2024 conference call. Joining me on the call are Dr. Troy Wilson, our President and CEO, and Tom Doyle, our Senior Vice President of Finance and Accounting. Before I turn the call over to Troy, 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 FCC, which are available from the FCC or on the Kura Oncology website, for information concerning risk factors that could affect the company.
Operator: Good day and welcome to the Q2 2024 Kura Oncology Conference Co. All participants will be in listen only mode. Should you need assistance please signal the conference specialist addressing the stock key followed by zero.
Troy: Please refer to <unk> filings with the SEC, which are available from the FCC on the oncology website for information concerning risk factors that could affect the company with that I'll turn the call over to Troy.
Troy Wilson: With that, I'll turn the call over to Troy. Thank you.
Operator: After today's presentation there will be an opportunity to ask questions. To ask a question you may press star then one on your telephone keypad. Would draw your question please press star then two.
Troy Wilson: Thank you, Pete, and thank you all for joining us. This past quarter was highlighted by strong execution across the organization as we continue to generate a robust clinical data package to support broad development of our Menin Inhibitor Program, beginning with Dr. Menin. In April, Zyptomeda became the first investigational therapy to be granted breakthrough therapy designation by FDA for the treatment of relapsed, refractory, NPM1 mutant acute myeloid leukemia. FDA awarded BTD based on data from our COMET-001 trial, recognizing hip dementia's potential as an innovative medicine for patients with this devastating disease. In May, we announced completion of enrollment in the registration-directed portion of Comet-001, enrolling more than 85 NPM1 mutant AML patients in fewer than 16 months. We believe this important milestone reinforces Zika Med's potential best-in-class program.
Troy: Thank you Christine and thank you all for joining US this past quarter was highlighted by strong execution across the organization as we continue to generate a robust clinical data package to support broad development of our Menin inhibitor program beginning with system minutes in April documented became the first investigational therapy.
Operator: Please note this event is being recorded.
Pete D'Spenne: I would now like to turn the conference over to Pete D'Spenne. Head of investor relations, please go ahead. Great, thank you Amy.
Pete D'Spenne: Good afternoon and welcome to Q2 2024 conference call. Joining me on the call are Dr. Tori Wilson, our president and CEO and Tom Doyle, our senior vice president of finance and accounting. Before I turn the call over to Tori, I'd like to remind you that today's call will include forward looking statements based on current expectations. Such statements represent management 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 FEC which are available from the FEC or on the Kura Oncology website for information concerning risk factors that could affect the company.
Troy: Granted breakthrough therapy designation for treatment of relapsed refractory NPM, one meeting acute myeloid leukemia.
Troy: FDA awarded BTB based on data from our comment 001 trial, recognizing <unk> potential as an innovative medicines for patients with this devastating disease.
Troy: The announced completion of enrollment in the registration directed portion of comment 001 enrolling more than 85% in <unk> mutant AML patients in fewer than 16 months. We believe this important milestone reinforces with committed potential best in class profile.
Troy Wilson: With that I'll turn the call over to Tori. Thank you Pete and thank you all for joining us. This task order was highlighted by strong execution across the organization as we continue to generate a robust clinical data passage to support broad development of our men in inhibitor program beginning with the minute.
Troy Wilson: As a reminder, NPM1 mutant AML represents approximately 30% of new AML cases annually and is a disease of significant unmet need for which there is no approved targeted therapy. With the COMET-001 study now fully enrolled, we look forward to sharing top-line data early next year as we continue to work closely with FDA to expedite the development and review of just a minute as a monotherapy. Meanwhile, we continue to evaluate ZIF-Committed in combination with current standards of care in patients with both NCM1 mutant and KNP2A rearranged AML.
Troy: As a reminder, NPM one leading AML represents approximately 30% of new AML cases annually and has a disease of significant unmet need for which there is no approved targeted therapy with.
Speaker Change: With the common zero one study now fully enrolled we look forward to sharing top line data early next year as we continue to work closely with FDA to expedite development and review of just a minute as a monotherapy.
Troy Wilson: In April, that the metad became the first investigational therapy to be planted for the therapy designations for treatment of relapse, refractory, NPM1 mutant acute myeloid leukemia. FCA awarded BPD based on data from our comet zero zero one trial, recognizing that demands potential as an innovative medicine for patients with this devastating disease. It may be announced completion of enrollment in the registration director portion of comet zero zero one enrolling more than 85 NPM1 mutiny and patients in fewer than 16 months.
Troy: Meanwhile, we continue to evaluate <unk> in combination with current standards of care in patients with both NPM, one mutant <unk> rearranged AML.
Troy Wilson: Earlier this year, we reported preliminary clinical data from 20 patients enrolled in the Phase 1 dose escalation portion of our COMET-007 trial. This amendment demonstrated an encouraging safety and tolerability profile, as well as meaningful evidence of clinical activity when administered in combination with Cytarabino plus Donorubicin, commonly known as 7 plus 3, as well as with Phenetoclax plus Azacitabine. Notably, no differentiation syndrome events of any grade were reported.
Troy: Earlier this year, we reported preliminary clinical data from 20 patients enrolled in the phase one dose escalation portion of our comments <unk> seven trial.
Troy: <unk> demonstrated an encouraging safety and tolerability profile as well as meaningful evidence of clinical activity when administered in combination with cytarabine postpone rubinsohn, commonly known as seven plus three as well as with the medical X plus a decidedly.
Troy Wilson: We believe this important milestone reinforces the estimated potential best in class profile. As a reminder, NPM1 mutant AML represents approximately 30% of new AML cases annually and is a disease of significant unmet need for which there's no approved targeted therapy. With the comet zero zero one study now fully enrolled, we look forward to sharing top line data early next year as we continue to work closely with FCA to expedite development and review of the fermented as among the therapy. Meanwhile, we continue to evaluate the fermented in combination with current standards of care in patients with called NPM1 mutiny and K and C2A rearrange AML.
Troy: Notably no differentiation syndrome events of any grade were reported Furthermore, no dose limiting toxicities PTC prolongation drug drug interactions or additive Milo suppression were observed continuous daily dosing of <unk> at 200 milligrams was well tolerated and the safety and Tolerability.
Troy Wilson: Furthermore, no dose-limiting toxicities, QTC prolongation, drug-drug interactions, or additive myelosuppression were observed. Continuous daily dosing of Zift-O-Mana at 200 mg was well-tolerated, and the safety and tolerability profile was consistent with features of the underlying disease and back health therapy. Since that update, our team has continued to demonstrate outstanding execution, and the COMET-007 study has now enrolled more than 100 patients. I'm pleased to report that the safety, tolerability, and clinical activity of ZYFTA-MEDEV continue to support advancement into both the fit and unfit frontline population.
Speaker Change: File was consistent with features of underlying disease in back of therapies.
Speaker Change: Since that update our team has continued to demonstrate outstanding execution and the common zero-zero. Seven study has now enrolled more than 100 patients I am pleased to report that the safety Tolerability and clinical activity of <unk> continue to support advancement into both the fit and unfit frontline populations.
Troy Wilson: Earlier this year, we reported preliminary clinical data from 20 patients enrolled in the phase one dose escalation portion of our comet zero zero seven trial. Just a minute demonstrated an encouraging safety intolerability profile as well as meaningful evidence of clinical activity. One administered in combination with therapy and post on a little distance, commonly known as seven plus three, as well as with the metaclacks plus a society. Notably, no differentiation syndrome events could any grade will report it furthermore, no testimony toxicities, key to sequel on gations, drug interactions, or additive mild suppression work served.
Troy Wilson: Two of the four cohorts have cleared the 600 milligram dose and advanced into the Phase 1b expansion study. The two remaining cohorts are expected to clear the 600 milligram dose and advance shortly as well. The Phase 1b expansion study includes multiple combination cohorts, most notably Ziptometed plus Venasa in newly diagnosed NPM1 mutant or KMT2A rearranged AML, as well as Ziptometed plus 7 plus 3 in newly diagnosed NPM1 mutant or KMT2A rearranged AML, removing the requirement for patients to have high-risk disease. Each combination cohort is enrolling independently, and we expect to enroll approximately 20 patients
Speaker Change: Two of the four cohorts of cleared the 600 milligram dose and advanced into the phase <unk> expansion study. The two remaining cohorts are expected declared a 600 milligram dose and advanced shortly.
Speaker Change: The phase one the expansion study includes multiple combination cohorts, most notably <unk>, then Asia in newly diagnosed <unk> mutant or A&P <unk> rearranged AML as well as with <unk> plus seven plus three in newly diagnosed NPM 1 million or <unk> rearranged AML.
Troy Wilson: Continuous daily dosing of zip-domended at 200 milligrams is well tolerating and the safety and tolerability profile was consistent with features of underlying disease and back up therapy. Since that update, our team has continued to demonstrate outstanding execution and the Comet 007 study is now enrolled more than 100 patients. I'm pleased to report that the safety, tolerability, and clinical activity is optimistic, continue to support advancement into both the fit and unfit frontline populations.
Speaker Change: Removing the requirement for patients to have high risk disease.
Speaker Change: Each combination cohort is enrolling independently and we expect to enroll approximately 20 patients per cohort.
Speaker Change: We believe the phase <unk> expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with both <unk>.
Troy Wilson: We believe the Phase 1b expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with both NPM1 mutant and KMT2A rearranged AML in both the fit and the unfit population. We look forward to presenting updated data from the COMET-007 combination trial of diphthermia at a medical meeting later this year. It should be a meaningful update.
Troy Wilson: Two of the four cohorts have cleared the 600 milligram dose and advanced into the phase 1D expansion study. The two remaining cohorts are expected to clear the 600 milligram dose and advanced shortly. The phase 1D expansion study includes multiple combination cohorts, most notably the Comet Prosveneza in newly diagnosed NPM1 UV or KMP2A Rearranged AML, as well as the Comet plus 7 plus 3 in newly diagnosed NPM1 UV or KMP2A Rearranged AML, removing the requirement for patients to have high risk disease.
Speaker Change: And <unk> rearranged AML in both the fit and unfit population.
Speaker Change: We look forward to presenting updated data from the comment 007 combination trial of <unk> at a medical meeting later this year it should be a meaningful update.
Troy Wilson: Each combination cohort is enrolling independently and needs set to enroll approximately 20 patients per cohort. We believe the phase 1D expansion study will continue to lay the groundwork for helping us to redefine the current standards of care for newly diagnosed patients with both NPM1 UV and KMP2A Rearranged AML in both the fit and unfit populations.
Troy Wilson: In addition to the progress our team has made with the COMET-007 study, we continue to dose patients in our ongoing COMET-008 study of Zipf-Demented in combination with additional standards of care, including the FLIP-3 inhibitor GILTS-Ritmin, as well as FLAG-IDA and low-dose Cyparabine. Roughly half of all patients with relapsed or refractory NTM1 mutant AML have co Preclinical data for zyptomanib in combination with fit-free inhibitors have shown strong synergistic effects compared to either single agent alone.
Speaker Change: In addition to the progress our team has made that comment 007 study we continue to dose patients in our ongoing comments 008 study of <unk> in combination with additional standards of care, including the <unk> three inhibitor gets written in as well as flag Ida and low dose cytarabine.
Speaker Change: Roughly half of all patients with relapsed or refractory NPM, one mutant AML of co occurring slipped three mutations and the prognosis for these patients is poor.
Speaker Change: Preclinical data for <unk> in combination with <unk> inhibitors have shown strong synergistic effects compared to either single agent alone.
Speaker Change: When we look across the fifth.
Troy Wilson: When we look across the fit, unsit, and flip remutant AML front-line populations, we believe a best-in-class safety and activity profile and optimal pharmaceutical properties could enable Zika Menage to become a cornerstone of therapy for patients with acute leukemias. Ultimately, our mission is to develop Zika Menage across the continuum of care for all patients with acute leukemias whose disease is driven by the men and cow
Speaker Change: Debt and flipped reviewed in AML frontline populations, we believe the best in class safety and activity profile and optimal pharmaceutical properties could enable <unk> to become a cornerstone of therapy for patients with acute leukemia.
Troy Wilson: We look forward to presenting updated data from the Comet 007 combination trial of this experiment at a medical meeting later this year. It should be a meaningful update.
Troy Wilson: In addition to the progress our team has made with the Comet 007 study, we continue to dose patients in our ongoing Comet 008 study, including the fit 3 inhibitor guilt written in as well as flag item and low dose state therapy. Once the half of all patients with relapse or refractory NPM1 UV and AML have co-occurring lip remutations and the prognosis for these patients is poor. Preclinical data for Zythromatode in combination of fit 3 inhibitors has shown strong synergistic effects compared to either single agent alone.
Speaker Change: Ultimately our mission is to develop Cisco minute across the continuum of care for all patients with acute leukemias, whose disease is driven by the <unk> pathway.
Speaker Change: Over the past couple of years, we've generated a growing body of preclinical data that supports opportunities for menin inhibitors beyond the keep the pds, including the.
Troy Wilson: Over the past couple of years, we've generated a growing body of preclinical data that supports opportunities for men and inhibitors beyond acute leukemias, including the potential for zika menis in certain solid tumors. Earlier today, we announced FDA clearance of our investigational new drug application for zircomenib in combination with imatinib for treatment of advanced gastrointestinal stromal tumors. GIST is the most common form of sarcoma, characterized as kit-dependent solid tumors.
Speaker Change: The potential <unk> in certain solid tumors earlier today, we announced FDA clearance of our investigational new drug application for <unk> in combination with a magnet for treatment of advanced gastrointestinal stromal tumors.
Speaker Change: <unk> is the most common form of sarcoma characterize kicked dependent solid tumors kit inhibitors are associated with favorable outcomes for patients with Jess and Imatinib is the frontline standard of care in this patient population for.
Troy Wilson: When we look across the fit, unfit, and fit 3 new NAML frontline populations, we believe the best in class safety and activity profile and optimal pharmaceutical properties could enable Zythromatode to become a cornerstone of therapy for patients with acute leukemia. Ultimately our mission is to develop Zythromatode across the continuum of care for all patients with acute leukemia as these diseases driven by the men in pathway. Over the past couple of years we've generated a clothing body of preclinical data that supports opportunities for men and inhibitors beyond acute leukemia including the potential for Zythromatode in certain solid tumors.
Troy Wilson: Kit inhibitors are associated with favorable outcomes for patients with GIST, and imatinib is the front-line standard of care in this patient population. For patients who progress on imatinib, subsequent treatment options consist of other kit inhibitors. However, these options are limited by moderate efficacy and challenging tolerability.
Speaker Change: For patients who progress on Imatinib subsequent treatment options consist of other kit inhibitors. However, these options are limited by moderate efficacy and challenging tolerability.
Troy Wilson: The Menin-MLL complex regulates KIT expression in GIST cells, and Menin inhibitors display additive therapeutic activity in combination with imatinib in a imatinib-sensitive GIST model. Our preclinical data suggest Lyft-A-Minute has potential to re-sensitize patients to Imatinib and induce deep, durable responses. Building upon an initial report from the Armstrong Lab, we've generated a substantial amount of preclinical data that further support the opportunity for zyftominobib GIFs. We look forward to presenting these data for the zyftominobib-imatinib combination at an upcoming scientific meeting.
Speaker Change: Lamented MLS complex regulates expression in <unk> cells, and Menin inhibitors display additive therapeutic activity in combination with Imatinib in Imatinib sensitive just models.
Speaker Change: Our preclinical data suggests lift a minute has potential to re sensitize patients through a magnet and induce deep durable responses.
Troy Wilson: Earlier today we announced FDA clearance of our investigational new drug applications for Zythromatode in combination with a magnet for treatment of advanced gastrointestinal stromal tumors. Just as the most common form of sarcoma characterizes kick-dependent solid tumors. Kid inhibitors are associated with favorable outcomes for patients with GIFs and a magnet is the frontline standard of care in this patient population. For patients who progress on a maintenance, subsequent treatment options consist of other kidding inhibitors.
Speaker Change: Building upon the initial report from the Armstrong line, we've generated substantial amount of preclinical data that further support the opportunity for just a minute and Jess we look forward to presenting these data for the <unk> combination at an upcoming scientific meeting.
Troy Wilson: And following the IND clearance announced this morning, we plan to initiate a proof of concept study evaluating zyftominobib in combination with imatinib in patients with advanced GIFs after failure of imatinib early next year. If successful, the potential opportunity in JITS appears to be mutationally agnostic, enabled by Zip2Manage's favorable pharmaceutical properties and an addressable market as significant as our frontline opportunities in
Speaker Change: And following the IND clearance announced this morning, we plan to initiate a proof of concept study evaluating <unk> in combination with Imatinib in patients with advanced gifts after failure of a magnet early next year.
Troy Wilson: However, these options are limited by moderate efficacy and challenging tolerability. The men in MLL complex regulates kit expression in gist cells and men in inhibitors display additive therapeutic activity in combination with a magnet in a magnet's sense of gist models. Our preclinical data suggests lift a minute has potential to re-sensitize patients through a magnet and induce deep, durable responses.
Speaker Change: If successful the potential opportunity in jet appears to be mutation really agnostic enabled by <unk> favorable pharmaceutical properties with an addressable market as significant as our frontline opportunities in AML.
Speaker Change: In June we reported preclinical data supporting the potential therapeutic utility of Menin inhibitors in the treatment of diabetes and new findings were presented at the American Diabetes Association scientific sessions in Orlando.
Troy Wilson: In June, we reported preclinical data supporting the potential therapeutic utility of menin inhibitors in the treatment of diabetes. The new findings were presented at the American Diabetes Association Scientific Sessions in Orlando. Type 2 diabetes is marked by an inadequate number of functional pancreatic beta cells, which results in insufficient insulin production leading to hyperglycemia. This amendment demonstrated meaningful levels of glycemic control in the preclinical in vivo model, including reduced fasting blood glucose levels and percent HbA1c within 27 days, as well as consistent improvement in both insulin sensitivity and insulin production.
Troy Wilson: Building upon an initial report from the on-strong lab, we've generated substantial amount of preclinical data that further support the opportunity for gist and men in gist.
Speaker Change: Type two diabetes is marked by an inadequate number of functional pancreatic beta cells, which results in insufficient influence production leading to hyperglycemia.
Troy Wilson: We look forward to presenting these data for the gist and men in the magnet combination that ended up coming science of the meeting. Following the IND clearance announced this morning, we plan to initiate a proof of concept study evaluating zip-nominated in combination with a magnet in patients with advanced gist after failure of a magnet early next year. If successful, the potential opportunity in gist appears to be mutationally agnostic, enabled by zip-nominated favorable pharmaceutical properties within a dressable market as significant as our frontline opportunities in AML.
Speaker Change: Mr managed demonstrated meaningful levels of <unk> control.
Speaker Change: Preclinical in vivo model, including reduced fasting blood glucose levels and percent HVA, one see within 27 days as well as consistent improvement in both <unk> and insulin sensitivity and insulin production.
Speaker Change: The preclinical data showed that the effects of <unk> were fully maintained following dose discontinuation, suggesting restoration of beta cell mass.
Troy Wilson: The preclinical data shows that the effects of ZIF-demented were fully maintained following dose discontinuation, suggesting restoration of beta cell mass. A decline in pancreatic beta cell function and or mass has been defined as a key contributing factor to disease progression in type 2 diabetes.
Speaker Change: And decline in pancreatic beta cell function <unk> mass has been defined as a key contributing factor to disease progression in type two diabetes.
Troy Wilson: In June, we reported preclinical data supporting the potential therapeutic utility of men in inhibitors in the treatment of diabetes.
Troy Wilson: The new findings were presented at the American Diabetes Association Scientific Sessions in Orlando. Type 2 diabetes is marked by an inadequate number of functional pancreatic beta cells, which results in insufficient insulin production leading to hyperglycemia. Zip-nominated demonstrated meaningful levels of glycine control in preclinical individual model, including reduced fasting blood glucose levels and percent HBA1C within 27 days, as well as consistent improvement in both insulin sensitivity and insulin production. The preclinical data shows that the effects of zip-nominated were fully maintained following dose discontinuation, suggesting restoration of beta cell mass.
Tom Doyle: Notably, in human islet microtissues originating from donor samples, zeta-menib-induced beta-cell proliferation, while non-beta-cell proliferation was not detectable, demonstrating menin is a viable therapeutic target for beta-cell mass-specific expansion. We're advancing multiple next-generation menin inhibitor drug candidates targeting type 2 diabetes and potentially type 1 diabetes, and we expect to nominate the first of these next Now, let's turn our attention briefly to our Farnsworth Transposase Inhibitor Program.
Speaker Change: Notably in human ILEC micro tissues originating from donor samples <unk> induced beta cell proliferation, while non beta cell proliferation was not detectable demonstrating manan as a viable therapeutic target for beta cell mass specific expansion.
Speaker Change: We are advancing multiple next generation Menin inhibitor drug candidates targeting type two diabetes and potentially type one diabetes and we expect to nominate the first of these next generation development candidate in early 2025.
Speaker Change: Now, let's turn our attention briefly to our Farnesol transfer inhibitor programs.
Tom Doyle: Despite the success of targeted therapies, a considerable need remains to drive enhanced anti-tumor activity while addressing mechanisms of the maintenance of active resistance. We're developing our next-generation farnesyl transferase inhibitor, KO-2806, to address PE. 2806 is designed to improve upon the potency, pharmacokinetic, and physical chemical properties of earlier FTI drug candidates. Last year, we presented compelling preclinical data supporting the potential for KO2806 to address mechanisms of innate and adaptive resistance in distinct classes of targeted therapies, including tyrosine kinase inhibitors and KRAS inhibitors.
Speaker Change: Despite success of targeted therapies are considerable need remains to drive enhanced anti tumor activity, while addressing mechanisms of the maintenance active resistance with developing our next generation Farnesol tax based inhibitor payout 25 steps to address these needs.
Troy Wilson: A decline in pancreatic beta cell function, AML mass, has been defined as a key contributing factor to disease progression in Type 2 diabetes. Notably, in human eyelid micro-tissues originating from donor samples, just the men have induced beta cell proliferation, while non-beta cell proliferation was not detectable. Demonstrating menin is a viable therapy to target for beta cell mass-specific expansion.
Speaker Change: 186 is designed to improve upon the potency pharmacokinetic and physical chemical properties of earlier STI drug candidates last year, we presented compelling preclinical data supporting the potential for til 'twenty six to address mechanisms of innate and adaptive resistance in distinct classes of targeted therapy.
Troy Wilson: We are advancing multiple next-generation menin inhibitor drug candidates targeting Type 2 diabetes and potentially Type 1 diabetes, and we expect to nominate the first of these next-generation development candidates in early 2025.
Speaker Change: You Couldnt tyrosine kinase inhibitors, and <unk> inhibitors late last year, we began dosing patients with pay a 20% <unk> as a monotherapy in a phase one dose escalation trial that we call that 001.
Tom Doyle: Late last year, we began dosing patients with KR2806 as a monotherapy in a Phase I dose escalation trial that we call FIT-001. FIT-001 uses an innovative design that enabled us to begin dose escalation of 2806 in combination cohorts very early on in the study, while continuing to dose escalate it concurrently as a single agent. In February, we dosed the first patient with KO-2806 in combination with cabozantinib in clear cell renal cell carcinoma just four months after KO-2806 entered the clinic.
Speaker Change: 001 uses an innovative design that enabled us to begin dose escalation of <unk> in combination cohorts very early on in this study while continuing to dose escalate concurrently as a single agent and.
Troy Wilson: Now, let's turn our attention briefly to our financial transfer rate inhibitor programs. Despite success of targeted therapies, a considerable need remains to drive enhanced anti-tumor activity while addressing mechanisms in the maintenance-active resistance. We're developing our next-generation financial transfer rate inhibitor, K-O-2086, U-S-B-D. 1806 is designed to improve upon the potency, pharmacokinetic and physical chemical properties of earlier FTI drug candidates. Last year, we presented compelling pre-clinical data supporting the potential for CARE-28O6 to address mechanisms of innate and adaptive resistance in distinct classes of targeted therapies, including tyrosine tiny inhibitors and CARE-resin inhibitors.
Speaker Change: In February we dosed the first patient with <unk> in combination with Cabozantinib in clear cell renal cell carcinoma, just four months after care 2008 of 600 to clinic and I am pleased to report we recently dosed the first patient in its combination study without <unk> in <unk> mutated non small cell.
Tom Doyle: And I'm pleased to report we recently dosed the first patient in a combination study without aggressive treatment for KRF-T12C mutated non-small cell lung cancer. As a reminder, the study of KO2806 and adegrassib is supported by a clinical collaboration and supply agreement with MARATI, now at Bristol-Myers Squibb. If successful, we believe KO2806 could drive enhanced anti-tumor activity and become an ideal combination partner to multiple targeted therapies in large, solid tumor indications. Meanwhile, we continue to evaluate the combination of tipifarnib with the targeted therapy alpelastim in PIK3CA-dependent head and neck squamous cell carcinoma in a Phase I dose escalation study that we call Current HN.
Speaker Change: Lung cancer as a reminder, the study of 28, 6% and <unk> is supported by our clinical collaboration and supply agreement with Marathi now of Bristol Myers Squibb company.
Speaker Change: If successful we believe <unk> 2086 could drive enhanced anti tumor activity and become an ideal combination partner some multiple targeted therapies in large solid tumor indications.
Troy Wilson: Late last year, we began dosing patients with CARE-28O6 as a monotherapy, in a phase one dose escalation file that we call 5-001. 5-001 uses an innovative design that enabled us to begin dose escalation of 20-06. In combination cohorts, very early on in the study, while continuing to dose escalate concurrently as a single agent. In February, we dose the first patient with CARE-28O6 in combination with capigantinant, in clear cell renal cell carcinoma, just four months after CARE-28O6 entered the clinic.
Speaker Change: Meanwhile, we continue to evaluate the combination of skippy Barnard with targeted therapy, Allison in Pip VCA dependent head and neck squamous cell carcinoma in a phase one dose escalation study that we call current HN.
Tom Doyle: We remain pleased by the manageable safety and tolerability profile of tipifarnib in combination with alpelastim, and we're encouraged by the clinical activity observed at multiple dose levels. We remain on track to complete enrollment in the two expansion cohorts to help inform selection of the optimal biologically active dose for the combination by the end of this year. And we look forward to presenting preliminary clinical data from the current HN trial of Tipifonam and Alkalisib at a medical meeting in the first half of 2025. With that, I'll turn the call over to Tom for a discussion of our financial results.
Speaker Change: We remain pleased by the manageable safety and Tolerability profile of <unk> in combination with <unk> and we're encouraged by the clinical activity observed at multiple dose levels.
Troy Wilson: Then, I'm pleased to report you recently dose the first patient in its combination study without a grafted, in CARE-C12C mutated, non-small cell lung cancer. As a reminder, the study of CARE-28O6 and had a grafted, is supported by a clinical collaboration and supply agreement with Maraudi, now a Bristol Myers-Squid Company. If successful, we believe CARE-28O6 could drive an handstand, eat your activity, and become an ideal combination partner to multiple targeted therapies in large, solid tumor indications.
Speaker Change: We remain on track to complete enrollment of two expansion cohorts to help inform selection of the optimal biologically active dose for the combination by the end of this year and we look forward to presenting preliminary clinical data from the current HN trial of typify him and he'll tell us they've been a medical meeting in the first half of 2025 was that.
Speaker Change: I will turn the call over to Tom for a discussion of our financial results.
Tom Doyle: Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the second quarter of 2024. Research and development expenses for the second quarter of 2024 were $39.7 million compared to $28.2 million for the second quarter of 2023. The increase in R&D expenses was primarily due to increases in clinical trial costs related to our ZyptoMinid and KO-2806 programs.
Tom: Thank you Troy and good afternoon, everyone I am happy to provide a brief overview of our financial results for the second quarter of 2020 for.
Troy Wilson: Meanwhile, we continue to evaluate the combination of Cippy-Farned with the targeted therapy health pelicans, in PIC3CA dependent head and neck swelling cell carcinoma, in a phase one dose escalation study that we call current HN. We remain pleased by the manageable safety and tolerability profile of Cippy-Farned in combination with alcalacim, and we're encouraged by the clinical activity observed at multiple of those levels.
Tom: Research and development expenses for the second quarter of 2024, or $39 7 million compared to $28 2 million for the second quarter of 2023.
Speaker Change: The increase in R&D expenses was primarily due to increases in clinical trial costs related towards system unit and <unk> 26 programs.
Troy Wilson: General and administrative expenses for the second quarter of 2024 were $16.7 million compared to $11.8 million for the second quarter of 2023. The net loss for the second quarter of 2024 was $50.8 million compared to a net loss of $37.2 million for the second quarter of 2023. This included non-cash, share-based compensation expense of $8.4 million compared to $7 million for the same period in 2023. As of June 30, 2024, we had cash, cash equivalents, and short-term investments of $491.5 million compared to $424 million as of December 31, 2023. 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 turn the call back over to Troy. Thanks, Tom.
Speaker Change: General and administrative expenses for the second quarter of 2024, or $16 7 million compared to $11 8 million for the second quarter of 2023.
Troy Wilson: We remain on track to complete enrollment of the two expansion cohorts to help inform selection of the optimal biologically active dose for the combination by the end of this year.
Speaker Change: Net loss for the second quarter of 2024 was $58 million compared to a net loss of $37 2 million for the second quarter of 2023.
Troy Wilson: And we look forward to presenting preliminary clinical data from the current HN trial of Cippy-Farned and alcalacim at a medical meeting in the first half of 2025.
Speaker Change: This included noncash share based compensation expense of $8 4 million.
Tom Doyle: With that, I'll turn the call over to Tom for a discussion of our financial results. Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the second quarter of 2024. Research and development expenses for the second quarter of 2024 were $39.7 million compared to $28.2 million for the second quarter of 2023. The increase in R&D expenses was primarily due to increases in clinical trial costs related to our zip-dominant and KO-28-06 programs.
Speaker Change: Compared to $7 million for the same period in 2023.
Speaker Change: As of June 32024, we had cash cash equivalents and short term investments of $491 5 million.
Speaker Change: Compared to $424 million.
Speaker Change: As of December 31, 2023, we believe that our cash cash equivalents and short term investments will be sufficient to fund our current operating plan into 2027.
Tom Doyle: General and administrative expenses for the second quarter of 2024 were $16.7 million compared to $11.8 million for the second quarter of 2023. Net loss for the second quarter of 2024 was $50.8 million compared to a net loss of $37.2 million for the second quarter of 2023. This included non-cash surveys compensation expense of $8.4 million compared to $7 million for the same period in 2023. As of June 30th, 2024, we had cash, cash equivalence and short-term investments of $491.5 million compared to $424 million as of December 31st, 2023.
Speaker Change: With that I'll turn the call back over to Chuck.
Troy Wilson: Before we jump into the question and answer session, let me just quickly lay out our anticipated upcoming milestones for our Menin Inhibitor Program. Present updated data from the Comet-007 trial of Diff Demented in combination with Venasa and 7plus3 at a medical meeting in the fourth quarter of 2024. Report top-line data from the Comet-001 registration-directed trial of Diff Demented in NCM1 mutant relapsed refractory AML in early 2025, and present preclinical data supporting the opportunity for GIST for this amendment in GIST at a scientific meeting in the second half of 2024.
Chuck: Thanks, Tom.
Speaker Change: Before we jump into the question and answer session. Let me just quickly lay out our anticipated upcoming milestones for our Menin inhibitor programs.
Speaker Change: Present updated data from the commentary of zero seven trial of <unk> in combination with Vanessa seven plus three at a medical meeting in the fourth quarter of 2024 report topline data from Comet 001 registration directed trial of <unk> in <unk> mutant relapsed refractory AML in early 'twenty five.
Speaker Change: Present preclinical data supporting the opportunities suggest for this amended ingest excuse me at a scientific meeting in the second half of 2024.
Troy Wilson: Initiate a proof-of-concept study evaluating zyptomenib and imatinib in patients with advanced GIFs in the first half of 2025 and nominate a next-generation menin-inhibitor development candidate targeting diabetes in early 2025. For our farnesyl transferase inhibitor programs, identify the maximum tolerated dose for KO2806 as a monotherapy in the second half of 2024, complete enrollment of two expansion cohorts in current HM, and identify the optimal biologically active dose of tipifanib and alpelesib by the end of 2024, and present data from the current HM trial of tipifanib in combination with alpelesib in PI With that ending, we're now ready for questions.
Speaker Change: Initiate a proof of concept study evaluating system ended and Imatinib in patients with advanced Gist in the first half of 2025 and nominated a next generation Menin inhibitor development candidate targeting diabetes in early 2025.
Speaker Change: For our final cell transfer inhibitor programs identify the maximum tolerated dose for <unk> 2008 of <unk> as a monotherapy in the second half of 2024 complete enrollment of two expansion cohorts in current HN and identify the optimal biologically active dose of <unk> by the end of 2024.
Tom Doyle: We're going to lay out our anticipated upcoming milestones. For our men in the Higgative Program, present updated data from the Comet 007 trial of systematic in combination with Venetia and 743 medical meeting in the fourth quarter of 2024. The fourth top-line data from Comet 001 registration directed trial of systematic in NCM1 meeting will ask the faculty AML in early 25. Present preclinical data supporting the opportunity for GIFs, possess a method in GIFs, excuse me, at a scientific meeting in the second half of 2024.
Speaker Change: And present data from the current HN trial of <unk> in combination with <unk> and <unk> dependent head and neck squamous cell carcinoma in the first half of 2025.
Operator: Thank you. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been answered and you would like to withdraw your question, please press star then two. Our first question comes from Li Watsek at Cancer Fitzgerald.
Chuck: With that Andrew we're now ready for questions.
Speaker Change: Thank you to ask a question you May Press Star then one on your telephone keypad.
Tom Doyle: Initiate a proof-of-concept study evaluating GIFs and the maintenance in patients with advanced GIFs in the first half of 2025 and nominate a next-generation men in the inhibitor development candidate targeting diabetes in early 2025. For our financial transcripts in Higgative Program, identify the maximum tolerated dose for care of 28 or 6 as a model therapy in the second half of 2024. Complete enrollment of two expansion cohorts in current HM and identify the optimal biologically active dose to be funded by the end of 2024 and present data from the current HM. Trial is to be funded in combination with all pellets, in picture, see the kind that had an exclaimable carcinoma in the first half of 2025.
Speaker Change: Are you using a speakerphone please pick up your handset before pressing the keys.
Speaker Change: If at any time. Your question has been addressed and you would like to withdraw your question. Please press Star then two.
Speaker Change: Our first question.
Speaker Change: Comes from.
Whit Cantor: What ticket Cantor Fitzgerald.
Whit Cantor: Okay, great congrats on the progress.
Li Watsek: Okay, great. Congratulations on the progress. Maybe just first on the update in Q4, Troy, can you tell us a little bit about, you know, in terms of patient distribution, being the expansion cohort among, I believe there are a hundred patients, and so we're looking at multiple cohorts at different doses. So maybe a little bit of information there will be helpful. And then the second question is on GIST. I thought that was very interesting, biology.
Speaker Change: Maybe just first on the.
Speaker Change: The uptake in Q4.
Troy: Troy can you how I felt bad about you know in terms of patient distribution.
Whit Cantor: In the expansion cohort.
Troy: I believe there are 100 patients now we're looking at multiple cohorts at different analysis itself, maybe a little better.
Speaker Change: Information that will be helpful.
Operator: With that ending, we're now ready for questions. Thank you. To ask a question, request dogs and one on your telephone keypad. If you're using a speaker phone, please pick up your handset before requesting the keys. If at any time your question has been addressed and you would like to enjoy your question, please press 12 and 2.
Speaker Change: And then the second question is on <unk> chest.
Speaker Change: That was very interesting biology.
Speaker Change: So just wondering what are the gating steps are before you're moving to proof of concept study in first half of next year and what would be the bar for success.
Li Watsek: So just wondering what the gating steps are before you move into a proof of concept study in the first half of next year, and what the bar for success would be? Thank you.
Li Watsek: Our first question comes from Lee Wattsick, a cancer-fetched Gerald. Okay, great congrats on the progress. Maybe just first on the update in Q4.
Speaker Change: Yeah.
Speaker Change: Sure. Thanks for the questions so on the.
Troy Wilson: Thanks for the questions. So, on the update for 007, as we said, we've dosed more than 100 patients at this point in the ongoing 007 study. Just to remind everyone, we need to dose at least 72 patients across the four different genetically-driven cohorts at each of 200, 400, and 600 milligrams. So that's, you know, four genotypes times three doses times at least six patients per dose.
Speaker Change: The update for 007.
Speaker Change: As we said, we we've dosed at this point more than 100 patients in the in the ongoing over seven study.
Troy Wilson: Troy, can you tell us a little bit about, you know, in terms of patient distribution in the expansion cohort? I believe there are a hundred patients and so we're looking at multiple cohorts at different doses. So maybe a little bit of information there will be helpful. And then the second question is on just, I thought that was very interesting biology. So just wondering what are the gateings that are before you're moving to proof-of-concept study in first half of next year?
Speaker Change: To remind everyone.
Speaker Change: We need to do is to minimum of 72 patients across the four different genetically.
Speaker Change: Driven cohorts each of 200, 400, 600 milligrams, so thats for genotype three doses at least six patients per dose.
Troy Wilson: The reason we've enrolled more than 72 patients is, we think, due to investigator and patient enthusiasm to get access to Zika Medev, as well as the fact that we leave these cohorts open for enrollment while we're moving to the next dose level, so patients that are in screening are eligible to go into that cohort if the next cohort hasn't yet opened. So, we've actually seen, I believe, over enrollment in nearly every cohort at every dose.
Speaker Change: The reason we have enrolled more than the 72 is we think due to investigator and patient enthusiasm to get access to <unk> as well as the fact that we leave these cohorts opened for enrollment while aware.
Speaker Change: Moving to the next dose level. So patients that are in screening are eligible to go into that cohort.
Troy Wilson: And what would be the bar for success? Thank you. Sure. Thanks for the questions. So on the update for 007, as we said, we'd go to this point more than a hundred patients in the ongoing over seven study. Just to remind everyone, we need to go to minimum of 72 patients across the four different genetically driven cohorts at each of 200, 400 and 600 milligrams. So that's four genotypes, times three doses, times at least six patients per dose.
Speaker Change: The next cohort.
Speaker Change: Well it hasnt yet opened so we've actually seen I believe over enrollment in nearly every cohort at every dose.
Troy Wilson: Lee, what we're encouraged by is the fact that safety and tolerability continue to be very consistent with what you saw in our January update. I think enrollment has been robust, and we would expect, once we get into these expansion cohorts, enrollment should continue to be robust because, in the case of 7 plus 3, we're moving the restrictions on adverse risk.
Speaker Change: What we're encouraged by is the fact that.
Speaker Change: The safety and Tolerability continue to be very consistent with what you saw in our January update I think enrollment has been robust and we would expect once we get into these expansion cohorts enrollment should continue to be robust because we are in the case of seven plus three.
Troy Wilson: The reason we've enrolled more than the 72 is we think due to investigator and patients' enthusiasm to get access to the recommended as well as the fact that we leave these cohorts open for enrollment while we're moving to the next dose level. So patients that are in screening are eligible to go into that cohort if the next cohort stop hasn't yet opened. So we've actually seen, I believe, over enrollment in nearly every cohort at every dose, we were encouraged by the fact that the safety and tolerability continue to be very consistent with what you saw in our January update.
Speaker Change: We're moving the restrictions on adverse risk I'll, just remind everyone the escalation using the adverse risk population.
Troy Wilson: I'll just remind everyone, you know, the escalation is in the adverse risk population, and in the case of Veneza, we will move from the relapsed refractory setting to expand in both the frontline setting, as well as in the relapsed refractory setting. So, by the time we get to the end of the year, Lee, we'll – that's why I say, I don't think we know exactly today what the update will be, but it's going to be a meaningful update with a lot of patients, a lot of data, you know, good durability across the cohorts.
Speaker Change: And in the case of <unk>, we will move from the relapsed refractory setting to expand in both the frontline and then Asia as well as two to expand in the relapsed refractory setting.
Speaker Change: So by the time, we get to the end of the year Leigh will that's why I say I don't think we know exactly today, what's the update will be completely but it's going to be a meaningful update with a lot of patients a lot of data.
Leigh: Good good durability across the cohorts, obviously, the 200 milligram cohorts having been on the longest.
Troy Wilson: Obviously, the 200 milligram cohorts have been on the longest, so we're looking forward to sharing that update at a later date. In terms of GIST, you asked about the gating steps for the trial. At this point, the study is in study startup, so, you know, we'll do this with relatively few U.S. sites initially.
Speaker Change: We're looking forward to sharing the update in time comes.
Troy Wilson: I think enrollment has been robust and we would expect once we get into these expansion cohorts enrollment should continue to be robust. Because we are in the case of seven plus three, we're moving the restrictions on adverse risk of us remind everyone, you know, the escalation is in the adverse risk population. And in the case of venesa, we will move from the real after factory setting to expand in both the frontline venesa as well as to expand in the real after factory setting.
Speaker Change: In terms of just you asked about the gating steps for the trial at this point that the study is in study startup. So we'll do this with relatively few U S sites. Initially the now that we have an open IND.
Troy Wilson: Now that we have an open IND, we can move as quickly as possible through the site initiation and contracting phase. You know, things have changed quite a bit from when I started in this industry. We used to be able to do this in a couple of months.
Speaker Change: We can move as quickly as possible through the site initiation and contracting phase.
Speaker Change: Things have changed quite a bit from when I started in this industry used to used to be able to do this in a couple of months, it's been longer now to get up and running we do think first half next year.
Troy Wilson: It's a bit longer now to get up and running. We do think, you know, first half next year is a reasonable guide for the first patient in. We used, we worked with multiple leading KOLs in GIST, both to evaluate the data and to help design the study. You asked what the success looked like. That really came from those KOLs.
Troy Wilson: So by the time we get to the end of the yearly rule, that's why I say, I don't think we know exactly today what the update will be completely, but it's going to be a meaningful update with a lot of patients, a lot of data. You know, good durability across the cohorts, obviously the 200 milligram cohorts having been on the longest.
Speaker Change: As a reasonable guide for first patient in.
Speaker Change: We use we worked with multiple leading kols and Jess both to evaluate the data and two to help design the study.
Speaker Change: What does success look like that really came from those kols. So we're going to deliberately b in the population that is progressing or has just failed imatinib. So what you are looking to do is to reverse that again.
Troy Wilson: We're looking forward to sharing that update in time comes. In terms of chance, you asked about the dating steps to the trial. At this point, the study is in study startup. So, you know, we'll do this with relatively few US sites initially. The now that we have an open I and B, we can we can move as quickly as possible through the, you know, the site initiation and contracting phase. You know, things have changed quite a bit from when I started in this industry used to be able to do this in a couple of months.
Troy Wilson: So, we're going to deliberately be in the population that is progressing or has just failed a matinee. So, what you're looking to do is to reverse that. Again, you'll see that the non-clinical data goes quite a bit beyond what Dr. Armstrong and his colleagues presented in their paper. But if you can, you know, either, if you can drive responses, right, durable responses, that would be the gold standard. That's really what we're looking for, and we are going to do some amount of dose optimization to ensure that we meet the requirements of the FDA's Project Optimist Initiative, right? That continues as you move through the combos.
Speaker Change: Again, youll see that in the non clinical data it goes quite a bit beyond what doctor Armstrong and his colleagues presented in their paper, but if you can.
Speaker Change: If you could drive responses right durable responses that would be that would be the gold standard.
Speaker Change: That's really what we're looking for and we are going to do some amount of dose optimization to ensure that we meet the requirements of the FDA project optimists initiatives like that that.
Troy Wilson: It's a bit longer now to get up and running. We do think, you know, first half next year is a reasonable guide for first patient in. We use, we worked with multiple leading KOLs and just both to evaluate the data and to help design the study. You asked what the success looked like. That really came from those KOLs. So, we're going to deliberately be in the population that is progressing or has just failed.
Speaker Change: As that continues as we move through these combos. So we'll talk more about Lee kind of once we once we show you. The non clinical data, we can talk a little bit more about what to expect obviously, if we get if we get a good signal our goal would be to go straight into the frontline because this combination is so powerful and <unk>.
Troy Wilson: So, we'll talk more about, Lee, kind of once we show you the non-clinical data, we can talk a little bit more about what to expect. Obviously, if we get the, you know, if we get a good signal, our goal would be to go straight into the front line. Because this combination is so powerful and so orthogonal to how people have treated GIST, we think it could really be transformational for those patients and really help, you know, drive durable responses. The next question comes from Jonathan Chang at Learing Partners. Hi guys. Thanks for attending. The first question with a face.
Speaker Change: So orthogonal to how people are treated yes, we think it really could be transformational for those patients.
Troy Wilson: So, what you're looking to do is to reverse that. Again, you'll see that the non clinical data goes quite a bit beyond what Dr. Armstrong and his colleagues presented in their paper. But if you can, you know, either if you can drive responses, right, durable responses, that would be that would be the gold standard. That's really what we're looking for. And we are going to do some amount of ghost optimization to ensure that the needs of requirements of the FDA project out from this initiative.
Speaker Change: And really help drive durable responses, but let's take it one step at a time.
Speaker Change: The next question comes from Jonathan Chang at Leerink partners.
Speaker Change: Yeah.
Jonathan Chang: Hi, guys. Thanks for taking my questions.
Jonathan Chang: The next question comes from Jonathan Chang at Learing Partners. Hi guys, thanks for taking my questions.
Jonathan Chang: First question with a phase III registration directed comment there is there a one study fully enrolled as you look ahead to interactions with regulators. How are you thinking about what you can do to minimize any potential hiccups along the regulatory process.
Troy Wilson: That continues as you move through these combos. So, we'll talk more about the kind of once we've once we show you the non clinical data, we can talk a little bit more about what to expect. Obviously, if we get the group, you know, if we get a good signal or goal would be to go straight into the front line because this combination is so powerful and so orthogonal to how people have treated. You know, we think it really could be transformational for those patients and really help drive durable responses.
Troy Wilson: But let's take it one step.
Jonathan Chang: And second question on comments 007.
Speaker Change: Can you provide any color around your experience what the different dose.
Speaker Change: Dose levels and growing with the 600 mixed dose in the expansion combination cohorts. Thank you.
Jonathan Chang: Sure Jonathan Thank you for the questions.
Troy Wilson: Thank you, Jonathan. Thank you for the questions. So, with respect to 001, we said consistently that we were looking to secure, if possible, breakthrough therapy designation ahead of engagement with FDA. This is where it becomes really important, right?
Jonathan Chang: No.
Jonathan Chang: With respect to 001.
Jonathan Chang: We've said consistently that we were looking to secure its possible to secure breakthrough therapy designation.
Jonathan Chang: Ahead of engagement with FDA. This is where it becomes really important right as you interact regularly with the FDA.
Jonathan Chang: The next question comes from Jonathan Chang at Learing Partners. Hi guys, thanks for taking my questions. First question, with a Phase 2 registration directed comment, there's a one study fully enrolled.
Troy Wilson: As you interact regularly with the FDA, we are actively doing that. We are preparing the modules for the ultimate NDA submission. Obviously, the long pole in that tent is the clinical data, but you have to do CM&C and ClinPharm and all the various modules of the NDA.
Speaker Change: We are actively doing that we are preparing the modules for the ultimate NDA submission obviously the long pole in that 10% is the clinical data, but you have to do CMC and <unk> farm and all the various modules of the NDA.
Troy Wilson: As you look ahead to interactions with regulators, how are you thinking about what you can do to minimize any potential hiccups along the regulatory process?
Troy Wilson: We are, as we've done with, we're going to talk about O7 in a second, we've, I think, been steady in how we've managed things and guided them. We've done a lot of work around dose optimization, a lot of work around safety, extensive characterization of the ClinPharm and the dose. But we're not, Jonathan, planning on taking advantage of RTOR.
Jonathan Chang: We are as we've done with <unk>.
Jonathan Chang: Talk about almost 7% in the second.
Troy Wilson: And second question, on comment 007, can you provide any color around your experience with a different lift of mental dose levels, and going with a 600-mic dose in the expansion combination boards? Thank you. Sure, Jonathan. Thank you for the questions. So with respect to 001, we said consistently that we were looking to secure, if possible, to secure breakthrough therapy designation ahead of engagement with FDA. This is where it becomes really important, right?
Jonathan Chang: We've I think been steady and how we've how.
Jonathan Chang: How we manage things and guided the things we've done a lot of work around dose optimization lot of work around safety.
Jonathan Chang: Extensive characterization of the <unk> farm in the dose.
Speaker Change: We're not Jonathan planning on taking advantage of <unk>, we're planning on pursuing just the normal pass through us leveraging the interactions through BTB.
Troy Wilson: We're planning on pursuing just the normal path through, leveraging the interactions through BTD. We look forward to continuing to have a pretty engaged interaction with FDA. We meet with them regularly, and I think we are very much on track to where we want to be. There are obviously no guarantees, but I think we're doing everything we can. We've got an expert team, both internally and through various outside experts, to help us guide that. On your second question relating to 007, So you've seen a couple of things.
Speaker Change: We will look forward to continuing to have a pretty engaged interaction with FDA. We are meeting with them regularly and I think very much on track to where we want to be there obviously.
Troy Wilson: As you interact regularly with the FDA, we are actively doing that. We are preparing the modules for the ultimate NDA submission. Obviously, the long poll in that tent is the clinical data, but you have to do CM&C and clean farm and all the various modules of the NDA. We are, as we've done with, we're going to talk about 007 in a second. We've, I think, been steady in how we've managed things and guided the things.
Speaker Change: There are obviously no guarantees.
Speaker Change: But I think we're doing everything we can we've got an expert team both internally and through various outside experts to help us guide that.
Speaker Change: On your second question relating to 007.
Speaker Change: Okay.
Speaker Change: So you've seen a couple of things you've seen the data from the monotherapy.
Troy Wilson: You've seen the data from the monotherapy at the 200, 400, and 600 doses, and you've seen the initial combination data from 200 in our January update. What we can tell you is, as with the monotherapy, the safety and tolerability are consistent as you go up in dose. We don't see drug-drug interactions, and we don't see dose-limiting toxicities. We don't see any kind of, you know, any kind of safety signals that aren't attributable to either the backbone or the disease.
Troy Wilson: We've done a lot of work around dose optimization, lot of work around safety, extensive characterization of the clean farm and the dose. We're not, Jonathan, planning on taking advantage of RTOR. We're planning on pursuing just the normal path through leveraging the interactions through BTB. We look forward to continuing to have a pretty engaged interaction with FDA. We are meeting with them regularly, and I think very much on track to where we want to be.
Speaker Change: At the 204 hundred 600 doses and you've seen the initial combination data from 200 and our January update what we can tell you is as with the monotherapy the safety and Tolerability as consistent as you go up in dose, we don't see drug drug interactions, we don't see dose limiting toxicities, we don't.
Speaker Change: See any kind of.
Speaker Change: Any kind of safety signals that arent attributable to either the backbone or the disease. So you might say well why do you choose the higher dose versus one of our lower doses, particularly as the dose cohorts are are still maturing and what I would tell you here is the monotherapy data sets.
Troy Wilson: So you might say, well, you know, why do you choose the higher dose versus one of the lower doses, particularly as those cohorts are still maturing? And what I would tell you here is that the monotherapy data says very clearly there is enhanced activity at 600 relative to 200. If the safety is equivalent, and the safety, you know, augurs in favor of the higher dose, you're going to go with that higher dose. But let me go one step further.
Troy Wilson: There are obviously no guarantees, but I think we're doing everything we can. We've got an expert team both internally and through various outside experts to help us guide that. On your second question relating to 007, so you've seen a couple of things. You've seen the data from the monotherapy at the 200 and 400 and 600 doses, and you've seen the initial combination data from 200 in our January update. What we can tell you is, as with the monotherapy, the safety and tolerability is consistent as you go up and dose.
Speaker Change: Clearly there is enhanced activity at 600 relative to 200, if the safety is equivalent and the safety augers in favor of the higher dose you are going to go with that higher dose, but let me go one step further one of the advantages we think that <unk> has over potential competitors.
Troy Wilson: One of the advantages we think that ZipTheMenib has over potential competitors is its very high tissue penetrance, its whole body exposure. On the downside, this is ultimately what led to a higher incidence of DS as a monotherapy in the KMT2A rearranged population. But now that we've mitigated that, it's what we think will ultimately drive long-term whole-body exposure, potentially delay, you know, micrometastases or extramedullary disease, and ultimately, we hope, lead to better outcomes.
Speaker Change: Is it is very high tissue penetrates its whole body exposure.
Speaker Change: On the downside. This is ultimately what what led to a higher incidence of DFS as a monotherapy in the Kmt <unk> rearranged population, but now that we've mitigated that.
Troy Wilson: We don't see drug interactions. We don't see dose limiting toxicities. We don't see any kind of safety signals that aren't attributable to either the backbone or the disease. You might say, well, why do you choose the higher dose versus one of the lower doses, particularly as those cohorts are still maturing? What I would say data says very clearly, there is enhanced activity at 600 relative to 200. If the safety is equivalent and the safety, you know, augers in favor of the higher dose, you're going to go with that higher dose.
Speaker Change: What we think will ultimately drive long term whole body exposure potentially delay.
Speaker Change: Micro metastases or extra medullary disease, and ultimately we hope lead to better outcomes. So all things being equal Jonathan if if the data supports it we'll go with the higher dose.
Troy Wilson: So all things being equal, Jonathan, if the data supports it, we'll go with the higher dose. The Safety Monitoring Committee accepted the team's recommendation in the first two cohorts. I have every expectation that will be the case here imminently in the remaining two cohorts, and then we'll be expanding at 600. We think that's going to give you the best benefit-risk balance in these combination populations.
Speaker Change: The safety monitoring committee accepted the team's recommendation on the first two cohorts I have every expectation that will be the case here imminently on that on the remaining two cohorts and then we will be expanding at 600, we think thats going to give you the best benefit risk in these combination populations.
Troy Wilson: But let me go one step further. One of the advantages we think that Zip the Meneb has over potential competitors is it's very high tissue penetrance, its whole body exposure. On the downside, this is ultimately what led to a higher incidence of DS as a monotherapy and the KMT2A rearranged population, but now that we've mitigated that, it's what we think will ultimately drive long-term, whole-body exposure, potentially delay, you know, micrometastases or extramedulary disease, and ultimately we hope lead to better outcomes.
Speaker Change: Understood. Thanks for taking the questions.
Speaker Change: Our pleasure thank you.
Speaker Change: The next question is from Jason Umansky at Bank of America.
Jason Zemansky: The next question is from Jason Zemansky at Bank of America.
Speaker Change: Hey, Jim This is Cameron on for Jason Congrats on the quarter and thanks for taking our question.
Cameron: Hey team, this is Cameron on behalf of Jason. Congratulations on the quarter and thanks for taking our question. I'm curious how we should be benchmarking success for activity in the expansion cohorts. I mean, how do you expect the goalposts to shift once you enter 7 plus 3 and non-adverse risk AML? And then what about for the first line, Van Aza combo, and then a follow-up, if I may?
Cameron: I'm curious, how we should be benchmarking success for activity in the expansion cohorts I guess, how do you expect to Coke Hershey shift once you enter seven plus three in non adverse Chris came out and then what about for the first time Vanessa.
Troy Wilson: So all things being equal, Jonathan, if the data supports it, we'll go with the higher dose. The Safety Monitoring Committee accepted the team's recommendation on the first two cohorts. I have every expectation that will be the case here, imminently, on the remaining two cohorts, and then we'll be expanding at 600. We think that's going to give you the best benefit risk in these combination populations. Understood. Thanks for taking the questions.
Speaker Change: And then a follow up if I may.
Troy Wilson: Yeah, so it's a good question Cameron. I won't give you specific numbers, but there are references there, things like the Viali study, for example, in Veneza. Clearly, you do expect higher response rates, better outcomes as you go to these frontline populations. By the same token, you know, in general, you're dealing with healthier patients. I mean, they're relatively healthy, right?
Speaker Change: Yeah. So so it's a good question Cameron.
Troy Wilson: Pleasure, thank you.
Speaker Change: I won't give you specific numbers I mean today there are references there things like that the Ali study for example in Venezuela.
Speaker Change: Clearly you do expect higher response rates better outcomes as you go to these frontline populations.
Speaker Change: By the same token in general Youre dealing with healthier patients I mean, they are healthy relatively speaking right. They still have life threatening AML, but all things being equal they are healthier than than patients with adverse risk or relapsed refractory so given the outstanding safety and.
Cameron: The next question is from Jason Zimanski at Bank of America. 18, this is Cameron on for Jason. Congrats on the quarter, and thanks for taking our question. I'm curious how we should be benchmarking success for activity in the expansion cohorts. I guess, how do you expect the goalpost to shift once you enter some plus three and non-adverse risk ammo? And then what about for the first sign, Van Aza combo, and then a follow-up of my name? Yeah, so it's a good question, Cameron.
Troy Wilson: They still have life-threatening AML, but all things being equal, they're healthier than patients with adverse risk or relapsed refractory. So given the outstanding safety and tolerability that we're seeing, given the encouraging activity, you saw the 200 milligram dose in January; you will see When the abstracts come out in November, expect to see 200 and 400 milligram data. The 200 is the most mature; the 400, you know, a little less mature.
Speaker Change: Our ability that we're seeing given the encouraging activity you saw the 200 milligram dose in January you will see.
Speaker Change: When when the abstracts come out in November and expect to see 200 400 milligram data. The 200 is the most mature of the 400.
Troy Wilson: I won't give you specific numbers. I mean, today there are references there, things like the Dioli study, for example, in Van Aza. Clearly, you do expect higher response rates, better outcomes as you go to these frontline populations. By the same token, in general, you're dealing with healthier patients. I mean, they're healthy, relatively speaking, right? They still have life-threatening AML, but all things being equal, they're healthier than patients with adverse risk or relapse refractory.
Speaker Change: Little less mature the 600 at that stage given that was as of the June data cut relatively less mature when you because that'll we submitted the abstracts in in August.
Troy Wilson: The 600 at that stage, given that it was as of a June data cut, relatively less mature when you – because that'll – you know, we submitted the abstracts in August. You will see – you'll see them in November. I think by the time we get to the end of the year at the medical meeting, you'll have a much more mature sort of comprehensive picture of how to think about that combination data. And then you had a – Cameron, you had a second follow-up question as well.
Speaker Change: You will see you will see them in November I think by the time, we get to the end of the year at the medical meeting you'll have you'll have a much more.
Speaker Change: Mature sort of comprehensive picture of how to think about that combination data.
Speaker Change: And then you had a you Kevin you had a second follow up question as well.
Troy Wilson: So given the outstanding safety and tolerability that we're seeing, given the encouraging activity, you saw the 200 milligram dose in January. You will see, you know, when the abstracts come out in November, expect to see 200 and 400 milligram data. The 200 is the most mature, the 400, you know, a little less mature. The 600 at that stage, given that was as of a June data cut, relatively less mature because that'll, you know, we submitted the abstracts in August. You will see them in November.
Cameron: Yeah, I'm just curious if you look towards additional updates, maybe what would be encouraging in terms of duration of response in these cohorts, as well as maybe MRD positivity rates, what's differentiating, and what are physicians ultimately likely to focus on here?
Kevin: Yeah I'm just curious as you look towards additional updates maybe what would be encouraging in terms of duration of response in these cohorts is wrong, maybe MRI deeming it to be right.
Kevin: What's differentiating in and what are physicians ultimately likely to focus on here.
Speaker Change: Yeah. So.
Troy Wilson: That's a really good question, and Pete and I talk regularly. I think we will spend much of the second half of the year probably in an expectation-setting exercise. There are a few things here, Cameron.
Speaker Change: That's a really good question and I.
Speaker Change: Pete and I talk regularly I think we will spend much of the second half of the year, probably in an expectation setting exercise theres a few things here Cameron ideally you want to so.
Troy Wilson: Ideally, you want to – so the real benefit of menin inhibitors and Zyfta-Menib in particular, once these patients come off of standard of care – and let's just take the simple example of 7 plus 3, that's 7 days. You want to keep them on a menin inhibitor for as long as they're responding to clinical benefit. Whether or not they go to transplant, that's really where Zyfta-Menib has an advantage, I think.
Speaker Change: The real benefit of Menin inhibitors, and <unk> in particular.
Troy Wilson: I think by the time we get to the end of the year at the medical meeting, you'll have a much more mature, sort of comprehensive picture of how to think about that combination data. And then you had a, Kevin, you had a second follow-up question as well. Yeah, I'm just curious if you look towards additional updates, maybe what would be encouraging in terms of duration response in these cohorts, as well as maybe MRD negative rebates, what's differentiating and what are physicians ultimately likely to focus on?
Speaker Change: Once these patients come off of standard of care and let's just take a simple example of seven plus three that seven days.
Speaker Change: You want to keep them on our Menin inhibitor for as long as as they are in response receiving clinical benefit.
Speaker Change: Are there or not they go to transplant, that's really I think where <unk> has an advantage in advantage we offer the potential for physicians to take their patients to transplant, but at least in the NPM one setting they don't need to.
Troy Wilson: We offer the potential for physicians to take their patients for transplant, but at least in the NPM1 setting, they don't need to. As you know, transplants are more common in KMT2A patients. They're quite common in the relapsed refractory with KMT2A, but with the much larger – I mean NPM1 is 10 times larger than KMT2A. In that population, you're going to look at the depth of response, the durability of response, do they go to transplant, essentially how long can we keep them in response.
Speaker Change: As you know transplants are more common in the <unk> patients.
Troy Wilson: Yeah, so that's a really good question, and Pete and I talk regularly, I think we will spend much of the second half of the year probably in an expectation setting exercise. There's a few things here, Cameron, ideally you want to, so the real benefit of men and inhibitors and Ziffmann have been particular. Once these patients come off of standard of care, and let's just take the simple example of seven plus three, that's seven days.
Speaker Change: We're quite common in the relapsed refractory <unk>, but with the much larger I mean, NPM. One is 10 times larger than Kmt to way in that population.
Speaker Change: Youre going to look at the depth of response durability of response do they go to transplant.
Speaker Change: Essentially how long can we keep keep them in our response and I think the safety and Tolerability that we've seen from Ziff Doe is looking very attractive relative to other targeted therapies that people might use its benchmarks again, we can talk about that more offline, but thats sort of how we think about it and I think how.
Troy Wilson: I think the safety and tolerability that we've seen from Zyfto is looking very attractive relative to other targeted therapies that people might use as benchmarks. Again, we can talk about that more offline, but that's sort of how we think about it, and I think, you know, at a high level, how the physician community is going to look at it as well.
Troy Wilson: You want to keep them on a men and inhibitor for as long as their in response receiving clinical benefit. Whether or not they go to transplant, that's really I think where Ziffmann has an advantage. We offer the potential for physicians to take their patients to transplant, but at least in the NPM1 setting, they don't need to. As you know, transplants are more common in the KMT2A patients. They're quite common in the relapse refractory, the KMT2A, but with the much larger, NPM1 is ten times larger than KMT2A.
Speaker Change: At a high level, how the physician community is going to look at it as well.
Speaker Change: Thank you so much.
Speaker Change: Sure.
Speaker Change: The next question is from Roger song with Jefferies.
Roger Song: The next question is from Roger Song at Jeffreys.
Speaker Change: Okay.
Roger Song: British, um, localities. Thank you very much. Questions? Thank you for taking our questions. So maybe we are looking ahead for your cohort in 2007. How should we think about the data release versus the potential pivotal for those standard of care combinations, given you will potentially have the label for monotherapy soon, and then how should we think about a combo into the label? Roger, can I, I'm sorry, can you, can you repeat that question?
Speaker Change: Great.
Roger Song: Bright spot for the progression. Thank you for taking my question. So maybe we are looking ahead.
Speaker Change: Your expansion cohort for <unk>.
Speaker Change: Seven.
Troy Wilson: In that population, you're going to look at the depth of response, the durability of response, do they go to transplant? Essentially, how long can we keep them in a response? And I think the safety and tolerability that we've seen from Ziffdo is looking very attractive relative to other targeted therapies that people might use as benchmarks.
Speaker Change: How should we think about the data ready.
Speaker Change: Versus the potential pivotal for those standard of care combination.
Speaker Change: And then you will potentially have the label for monotherapy soon and then how should we think about our commvault.
Speaker Change: They're in April thank you.
Roger Song: Roger can I I'm, sorry can you can you repeat that question Im not sure I understand the interplay between the expansions in the monotherapy.
Roger Song: I'm not sure I understand the interplay between the expansions and the monotherapy, and I want to make sure I answer the question you're asking. Can you just run that by me one more time?
Troy Wilson: Again, we can talk about that more offline, but that's sort of how we think about it, and I think how at a high level how the physician community is going to look at it as well.
Speaker Change: And I want to make sure I answer the question you're asking can you can you just run that by me one more time.
Troy Wilson: Thank you so much.
Roger Song: Yeah, sure. So the expansion cohort is curious about the data timing versus the potential pivotal plan for the and then, you know, the monotherapy, you're gonna have, here about how we should think about the combination pivotal time. Thank you.
Speaker Change: Yeah sure. So the expansion cohort just curious about the data timing versus the potential pivotal plan for that combination.
Roger Song: Sure. The next question is from Roger Song and Jeffrey. Great.
Troy Wilson: Congrats for the progression. Thank you for taking on the question. So maybe we're looking ahead for your expansion cohort for 07. How should we think about the data-ready versus the potential pivotal for those standard care combination, given you will potentially have the label for monotherapy soon, and then how should we think about the combo into the label? Thank you. Roger, I'm sorry. Can you repeat that question? I'm not sure I understand the interplay between the expansions and the monotherapy.
Speaker Change: And then the monotherapy.
Speaker Change: Going to have the data next year, but how we should think about that combination pivotal time. Thank you.
Troy Wilson: Thank you. Thank you, Roger. I appreciate that.
Speaker Change: Okay. Thank you. Thank you Roger I appreciate that.
Speaker Change: So.
Speaker Change: I can tell you this.
Troy Wilson: I can tell you this: we are preparing at risk for Combination Pivotals and exactly how we prosecute them, the tactics by which we do it. Let's set that to the side for now. Everything that we're seeing gives us increasing confidence that there are meaningful opportunities both for patients and for shareholders to move into the fit, the unfit, and, I'm optimistic, the flip three population as well. Our goal is really, you know, we talk about potentially being applicable to up to 50% of AML patients.
Speaker Change: We are preparing at risk.
Speaker Change: For combination pivotal.
Speaker Change: And exactly how we prosecute them the tactics by which we do it let's let's set that to the side for now.
Speaker Change: Everything that we're seeing gives us.
Speaker Change: Increasing confidence that there are.
Speaker Change: Meaningful opportunities both for patients and for shareholders to move into the fit the unsaid and I'm optimistic the flip <unk> population as well our goal is really.
Troy Wilson: And I want to make sure I answer the question you're asking. Can you run that by me one more time? Yeah, sure. So the expansion cohort is curious about the data timing versus the potential pivotal plan for the combination, and then the monotherapy, you're going to have the data next year. But how would you think about the combination pivotal plan? Thank you. Oh, okay. Thank you, Roger. I appreciate that. So I can tell you this.
Speaker Change: We talk about potentially being applicable to up to 50% of AML patients.
Speaker Change: Everything we're seeing suggests that thats the right aspirational goal.
Troy Wilson: Everything we're seeing suggests that that's the right aspirational goal. We will – what the agencies or the health authorities, Roger, care about from the standpoint of the pivotal is safety and tolerability, and have you defined your dose. We will have that information, you know, in time to inform those discussions with health authorities and start the pivotal, you know, I think in the first half of next year. So we're on track to do that.
Speaker Change: We will.
Speaker Change: What the agencies or the health authorities Roger care about from the standpoint of the pivotal is safety and Tolerability and have you defined your dose we will have that information.
Troy Wilson: We are preparing at risk for combination pivotals, and exactly how we prosecute them, the tactics by which we do it. Let's set that to the side for now. Everything that we're seeing gives us increasing confidence that there are meaningful opportunities both for patients and for shareholders to move into the fit, the unfit, and I'm optimistic the flip three population as well. Our goal is really, you know, we talk about potentially being applicable to up to 50% of AML patients.
Speaker Change: In time to inform those discussions with health authorities and start the pivotal.
Speaker Change: I think in the first half of next year. So we're on track to do that the question of activity.
Troy Wilson: The question of activity, we are already moving at risk, again based on what we're seeing, believing that we can design a trial or trials that will potentially support a marketing application in the combination. So we're not necessarily, in other words, waiting for the efficacy data to read out in the expansions. I think we're optimistic that it will be as good as, if not better, than what we've seen in the escal
Speaker Change: We are already moving at risk again based on what we're seeing.
Speaker Change: Believing that we can design a trial or trials that will potentially support a marketing application in the combinations. So we're not we're not necessarily in other words waiting for the efficacy data to readout. Many expansions I think we're optimistic it will be as good as if not better.
Troy Wilson: Everything we're seeing suggests that that's the right aspirational goal. We will, what the agencies or the health authorities, Roger, care about from the standpoint of the pivotal is safety and tolerability, and have you defined your dose. We will have that information, you know, in time to inform those discussions with health authorities and start the pivotal, you know, I think in the first half of next year. So we're on track to do that.
Speaker Change: Then what we've seen in the Escalations and what we've seen is encouraging given again, where an adverse risk in the seven plus three escalation where in relapsed refractory in the case of then Asia, but we look at our own data we look at data from our competitors and I think we feel pretty good as far as.
Troy Wilson: And what we've seen is encouraging, given, again, we're in adverse risk in the seven plus three escalation, and we're in relapse refractory in the case of Venasa, but we look at our own data, we look at data from our competitors, and I think we feel pretty good. As far as the monotherapy, again, we've said top-line data, early 25. I think we're looking likely at an NDA submission sometime next year. I don't think we've guided specifically, but we're gonna move as quickly as we can. We wanna do the right thing and get it in there as smoothly as possible.
Speaker Change: The monotherapy again, we've said topline data early 25, I think we're looking likely at an NDA submission sometime next year I don't think we've guided specifically, but we're going to move as quickly as we can.
Troy Wilson: The question of activity, we are already moving at risk again based on what we're seeing, believing that we can design trial or trials that will potentially support a marketing application in the combinations. So we're not, we're not necessarily, in other words, waiting for the efficacy data to read out in the expansions. I think we're optimistic. It will be as good as if not better than what we've seen in the escalations and what we've seen is encouraging.
Speaker Change: We want to do the right thing.
Speaker Change: And.
Speaker Change: Get it in there as smoothly as possible.
Speaker Change: I.
Troy Wilson: Whether physicians use these drugs in combination in the real world, Roger, I think that's partly what's driving the incredible interest in the combinations. We'll, of course, promote ZyftaMedib initially within that monotherapy label. But that's why, and we're not alone here, everybody wants to get to these frontline populations as quickly as we can, because that will make it, that will be best for patients.
Speaker Change: Whether physicians use these drugs in combination in the real World. Roger I think that is partly what's driving the incredible interest in the combinations will of course promote.
Speaker Change: Promote zipped amended initially in that month within that monotherapy label, but that's why and we're not alone here everybody wants to get to these frontline populations as quickly as we can because that will make it that will be the best for patients. It will also for that for the two or three leaders.
Troy Wilson: Given, again, we're in adverse risk in the 7 plus 3 escalation, we're in relapse for factory in the case of Venesa, but we look at our own data, we look at data from our competitors, and I think we feel pretty good. As far as the monotherapy, again, we've said top-line data early 25 I think we're looking likely at an NDA submission sometime next year. I don't think we've guided specifically, but we're going to move as quickly as we can.
Troy Wilson: It will also, for the two or three leaders in the field, make it that much more difficult for anyone to come behind us because the chance of dosing a menin-naive patient will go down dramatically when you have two or, potentially, three sponsors running frontline studies. So there's a lot going on, Roger, and we're gonna try to do as much as we can in a staged way to both impact patients and drive value for shareholders. Excellent Thank you.
Speaker Change: In the field it will make it that much more difficult for anyone to come behind us because the the chance of dosing a man and naive patient will go down dramatically. When you have two or potentially three sponsors running frontline studies. So theres a lot going on Roger and we're going to try to do as much as we can and.
Troy Wilson: We want to do the right thing and get it in there as smoothly as possible. Whether physicians use these drugs in combination in the real world Roger, I think that is partly what's driving the incredible interest in the combinations. We'll, of course, promote, you know, we'll promote ZIFT and then initially within that monotherapy label. But that's why, and you know, we're not alone here. Everybody wants to get to these frontline populations as quickly as we can, because that will make it, you know, that will be the best for patients.
Speaker Change: A staged way to both impact patients and drive value for shareholders.
Roger Song: Excellent. Thank you and thank you for the guidance regarding the.
Roger Song: Thank you for the guidance and the Tumbo Pivotal early next year. Okay, maybe just a follow-up, and the NextGen Manin Inhibitor, which I think you mentioned, Type 1 and Type 2.
Speaker Change: Commvault pivotal next year early next year, Okay, maybe just a follow up question related to the Nextgen met inhibitor. I think you mentioned, mostly focused on the diabetes type one type two just curious would you be also considering.
Roger Song: Just curious, would you be also considering next-gen management and other therapeutic areas, including oncology, solid tumor, etc. Thank you. Yeah, um... So there are two answers to that question, Roger. The first answer is:
Speaker Change: Nextgen, many better in other therapeutic areas, including the oncology solid tumor et cetera. Thank you.
Troy Wilson: It will also, for the two or three leaders in the field, it will make it that much more difficult for anyone to come behind us, because the chance of dosing a men and naive patient will go down dramatically when you have two or potentially three sponsors running frontline studies. So there's a lot going on, Roger, and we're going to try to do as much as we can in a staged way to both impact patients and drive value for sure.
Roger Song: Yeah.
Roger Song: <unk>.
Roger Song: So theres two answers to that question Roger the first answer is.
Troy Wilson: And again, you'll see this when we show you the non-clinical data for JIT. All menin inhibitors are likely to be active in this setting, but there's something very special about the drug-like properties of ZIF-DIF. Those properties that give you high tissue penetrance and a very high volume of distribution are ultimately what you want, whether you're treating disseminated AML or solid tumors. One moment, please. Sorry Amy.
Roger Song: And Youll again, you'll see this when we show you the non clinical data for <unk>.
Roger Song: All men and inhibitors are likely to be active in this setting, but there is something very special about the drug like properties of <unk>.
Speaker Change: Those properties that give you high tissue penetrates a very high volume of distribution are ultimately what you want whether you're treating disseminated AML or solid tumor gentleman. Please so.
Troy Wilson: Thank you. Thank you for the guidance regarding the combo pivotal next year, early next year. Okay, maybe just a follow-up question to the next year, many inhibitor. Do I think mention mostly folks on the diabetes type 1 type 2. Just curious, would you be also considering next year, many inhibitor in other therapeutic areas, including the oncology Thank you. Thank you. Yeah, so there's two answers to that question, Roger. The first answer is, and you'll, again, you'll see this when we show you the nonclinical data for gist.
Roger Song: Sorry, I mean.
Speaker Change: Oh, okay. So.
Troy Wilson: Okay. So, we think ZIFTO-MENIB is ideal from the standpoint of both liquid and solid tumors. Is there a reason for a follow-on compound?
Speaker Change: Your your we think <unk> is ideal from the standpoint of both liquid and solid tumors is there a reason for a follow on compound potentially but at the moment I think youre seeing us put the focus on on.
Troy Wilson: Potentially, but at the moment, I think you're seeing us put the focus on ZIFTO in that setting. And we're talking right now just about leukemia and GIST. We have other things that Francis Burroughs and his team are working on. If and when the time is right, we'll share additional opportunities with you. I think we've been very deliberate, very measured in how we bring you this data for you. Shifting gears to diabetes, it's safety, safety, safety.
Roger Song: On <unk> in that setting and were talking right now just about leukemia and just.
Francis Boroughs: We have other things that Francis boroughs and his team are working on if and when the time is right. We will share additional opportunities with you I think we've been very deliberate very measured in how we bring out this data for Ya shifting gears to diabetes, there Hugh Hugh It's safety safety.
Troy Wilson: All men in inhibitors are likely to be active in this setting, but there's something very special about the drug-like properties of Zift-O. Those properties that give you high tissue penetrating a very high volume of distribution are ultimately what you want, whether you're treating disseminated AML or solid tumor. So, sorry, Amy. Okay. So, you're, you're, we think Zift-O-Menib is ideal from the standpoint of both liquid and solid tumors. Is there a reason for a follow-on compound potentially, but at the moment, I think you're seeing us put the focus on Zift-O in that setting.
Speaker Change: Safety, if you look at the preclinical data for <unk> in our view and the view of many experts. It says one should move forward and and evaluate a menin inhibitor a reversible <unk> inhibitor in diabetes, we will we intend to do that.
Troy Wilson: If you look at the preclinical data for ZIFTO, in our view and in the view of many experts, it says one should move forward and evaluate a menin inhibitor, a reversible menin inhibitor, in diabetes. We intend to do that. We have a number of different molecules that we are advancing. There's really a premium, at the risk of stating the obvious, there's really a premium on safety in that
Roger Song: A number of different molecules that we are advancing theres really a premium at the risk of stating the obvious there's really a premium on safety in that indication. So we are being very I think deliberate very measured again and moving those compounds forward.
Troy Wilson: We are being very, I think, deliberate, very measured again in moving those compounds forward. I think we're going to find that menin continues to show us new sides and new opportunities. There's a lot of really interesting emerging biology. At AACR, there was some interesting biology with Cat6.
Troy Wilson: And we're talking right now just about leukemia and gist. We have other things that Francis Burrows and his team are working on. If and when the time is right, we'll share additional opportunities with you. I think we've been very deliberate, very measured in how we bring out this data for you. Shifting gears to diabetes. There, you, you know, it's safety, safety, safety. If you look at the preclinical data for Zift-O in our view and in the view of many experts, it says one should move forward and evaluate a men and inhibitor, a reversible men and inhibitor in diabetes.
Speaker Change: I think we're going to find that men continues to show us new sites and new opportunities. There's a lot of really interesting emerging biology.
Speaker Change: At ACR, there was some interesting biology with cat six.
Troy Wilson: I would say stay tuned. Menin has more to teach us. Roger, that's how we think about it. ZIFTO on the oncology side, NextGen on the diabetes side. Let's move those forward as quickly as we can. Thank you so much, Troy.
Roger Song: I would say stay tuned Menon has more to teach us, but Roger that's how we think about it zip still on the oncology side Nextgen on the diabetes side and let's let's move those forward as quickly as we can.
Troy: So much Troy.
Troy Wilson: We will, we intend to do that. We have a number of different molecules that we are advancing. There's really a premium at the risk of stating the obvious. There's really a premium on safety in that indication. So we are being very, I think, deliberate, very measured again in moving those compounds forward. I think we're going to find that men and continues to show us new sides and new opportunities. There's a lot of really interesting emerging biology.
Troy: My pleasure.
Troy: And our next question today will come from Brad <unk> of Stifel. Please go ahead.
Brad: Hi, Thank you and impressive enrollment here.
Bradley Canino: Hi, thank you, and an impressive enrollment here. I wanted to ask about what we saw from J&J's menin combos at EHA.
Brad: I wanted to ask about what we saw from J&J as men and combos at EI.
Bradley Canino: Last year at 23, they reported monotherapy DS rates around 12 percent, but they had one grade 5 event. And then recently at EHA 24, they showed the combo work where they did the scheme where they pre-dosed with Venn to reduce blast burden, which is very similar to what you're doing. And the combo did cut rates down to about 3 percent in 60 patients, which I think is very validating for your approach.
Speaker Change: Last year in 'twenty three they reported the monotherapy.
Speaker Change: Rates from 12%, but I had one grade five events and then recently at <unk> 24. This showed the combo work, where they did the scheme, where they pre dose would have been to reduce blast burden, which is very similar to what youre doing in the combo did cut rates down to about 3% and 60 patients which is very validating for euro approach, but when.
Troy Wilson: You know, at AACR, there was some interesting biology with CAT-6. You know, I would say stay tuned. Men and has more to teach us. But Roger, that's how we think about it. Zift-O on the oncology side, next gen on the diabetes side, and let's, let's move those forward as quickly as we can.
Bradley Canino: But when they had DS, it was again a grade 5. So, first, I want to know if it's unfair to draw parallels here to ZIFTO. But under that assumption, I'm wondering what the level of assurance that you can have for a menin inhibitor with a heightened monotherapy DS signal when it comes to the ability to completely avoid grade 5, even in combos. Thank you.
Brad: They had DFS was again a great five.
Speaker Change: So first I wanted to know do you think it's unfair to draw parallels here to Zip, though but under that assumption I'm wondering how you think about the level of assurance that you can have for menin inhibitor with a heightened monotherapy signal when it comes to the ability to completely avoid grade five.
Troy Wilson: So much, tonight. My pleasure.
Bradley Canino: And our, our next question today will come from Brad Canino of Steeple. Please go ahead. Hi, thank you, and impressive enrollment here. I wanted to ask about what we saw from J&J's men and combos at EHAH. Last year in 23, they reported the Monotherapy DS rates around 12%, but they had one grade five event, and then recently at EHAH 24, they showed the combo work where they did the schema, where they pre-dose with the vent to reduce blast burden, which is very similar to what you're doing, and the combo did cut rates down to about 3% and 60 patients, which is very validating for your approach, but when they had DS, it was again a grade five.
Speaker Change: Even in combos. Thank you.
Speaker Change: Yes, Brett it's a good question.
Troy Wilson: Yeah, Brad, it's a good question. I don't, do you know, Brad, I don't off the top of my head, do you know whether that second grade 5 event or that combo grade 5 event was in a KMT2A rearranged patient?
Speaker Change: Yeah.
Speaker Change: I don't do you know Brad I don't off the top of my head do you know whether that second grade five events or that combo grade five event was in a Kmt <unk> rearranged patient.
Speaker Change: I don't believe it's disclosed in the deck okay.
Bradley Canino: I don't believe it's disclosed in the Okay, in our experience.
Troy Wilson: Okay. In our experience, again, I said in January, I said two things. With respect to the hundred percent CR rate on the front line 7 plus 3, I said don't get emotionally attached to it. And I said don't get emotionally attached to zero as far as DS is concerned.
Speaker Change: Our experience again I said on in January.
Speaker Change: So two things with respect to 100% CR rate in the frontline seven plus three I said don't get emotionally attached to a 100% and I said don't get emotionally attached to zero as far as BS you are going to see some measure of DFS.
Bradley Canino: So first I want to know, do you think it's unfair to draw parallels here to ZIFDO, but under that assumption, I'm wondering how you think about the level of assurance that you can have for a men and inhibitor with a heightened monotherapy DS signal when it comes to the ability to completely avoid grade five even in combos. Thank you.
Troy Wilson: You are going to see, you know, some measure of DS. And just for everyone on the call, for these relapsed refractory patients, many of them are hospitalized. If you're hospitalized, you are, you know, by definition, grade 3. You want it to be, ideally, sufficiently mild that you can treat it with steroids.
Speaker Change: And just for everyone on the call for.
Speaker Change: These relapsed refractory patients many of them are hospitalized if you're hospitalized you are.
Speaker Change: By definition grade three.
Speaker Change: One it should be ideally sufficiently mild that you can treat it with steroids you don't have to withdraw the menin inhibitor and the patient essentially right through it.
Troy Wilson: Yeah, Brad, it's a good question. I don't, do you know, Brad, I don't top the top of my head. Do you know whether that second grade five event or that combo grade five event was in a KMT2A rearranged patient? I don't believe it's disclosed in the deck. Okay.
Troy Wilson: You don't have to withdraw the menin inhibitor, and the patient essentially rides through it. I will say, Brad, you know, there is a learning curve on these compounds. And we've seen that both in monotherapy and in combos. The physicians who've treated a handful of patients have a much better time. They just know what to look for versus physicians who, perhaps, this is their first experience with a menin inhibitor. And, you know, you will see, for example, if you do a time course, it may look like the patient still has blasts.
Speaker Change: I will say, Brad there is a learning curve on these compounds and we've seen that both in the monotherapy and the compounds the physicians who have treated a handful of patients have a much better time. They just know what to look for versus physicians who've. Perhaps this is their first experience with the Menin inhibitor.
Troy Wilson: In our experience, again, I said in January, I said two things, which respect to 100% CR8 in the front line 7 plus 3. I said don't get emotionally attached to 100% and I said don't get emotionally attached to zero as far as DS. You are going to see, you know, some measure of DS and just for everyone on the call. For these wheel-outs, the factory patients, many of them are hospitalized. If you're hospitalized, you are, you know, by definition grade three.
Speaker Change: <unk> and.
Speaker Change: You will see for example.
Speaker Change: If you're if you do a time course, it may look like the patient still has blass those glass or actually in the process of differentiating if you give them a week or two in the patient comes back the patient may be clear.
Troy Wilson: Those blasts are actually in the process of differentiating. If you give them a week or two and the patient comes back, the patient may be clear. There is a learning curve, Brad. I don't know that we're ever going to reduce it to zero.
Speaker Change: There is a learning curve, Brad I don't know that we're ever going to reduce it to zero.
Brad: We've been fortunate to this point that the DFS debt.
Troy Wilson: We've been fortunate to this point that, you know, the DS that we've observed has been mild and very manageable. But I do think there is that off chance that, you know, you get a patient who's unlucky, a complicated medical history, the physician who, you know, maybe there are, you know, some confounding factors. I don't think we can rule it out. But that's not unlike veneto
Troy Wilson: You want it to be ideally sufficiently mild that you can treat it with steroids. You don't have to withdraw the men and inhibitor and the patient essentially rides through it. I will say, Brad, you know, there is a learning curve on these compounds and we've seen that both in the monotherapy and the combos. The physicians who've treated, you know, a handful of patients have a much better time. They just know what to look for versus physicians who, perhaps this is their first experience with a men and inhibitor.
Ben: We've observed as Ben has been mild and very manageable, but I do think there is that off of chance that you get a patient who is unlucky a complicated medical history, the physician who.
Troy Wilson: And, you know, you will see, for example, if you do a time course, it may look like the patient still has blasts. Those blasts are actually in the process of differentiating. If you give them a week or two and the patient comes back, the patient may be clear. There is a learning curve, Brad. I don't know where ever going to reduce it to zero. We've been fortunate to this point that, you know, the DS that we've observed has been mild and during manageable.
Speaker Change: Maybe there is some confounding factors I don't think we can rule it out, but that's not unlike venetic clacks with Tls.
Troy Wilson: It's not unlike CRS, you know, and some of the other therapies. It is definitely a measure of activity. And we are making real efforts toward education and just informing physicians, as I'm sure our competitors are as well. The entire field is learning as we go. And I think we're all benefiting from one another's experience, so it's not something we're overly concerned about, but I do think you have to be watching.
Speaker Change: It's not unlike Crs and some of the other therapies. It is and it is definitely a measure of activity in and we are making real efforts towards education, and just informing physicians as I'm sure. Our competitors are as well the entire field is learning as we go and and I think.
Speaker Change: All of these physicians are benefiting from one another's experience. So it's not something we're overly concerned about but I do think you have to be watchful.
Tarek: Thanks Tarek.
Tarek: My pleasure.
Tarek: The next question is from Phil Nadeau from TD Cowen.
Philip Nadeau: The next question is from Philip Nadeau of TD Cowen.
Troy Wilson: But I do think there is that off chance that, you know, you get a patient who's unlucky, a complicated medical history, the physician who, you know, maybe there's, you know, some confounding factors. I don't think we can rule it out. But that's not unlike Vanetta Clax with TLS. It's not unlike CRS, you know, in some of the other therapies. It is definitely a measure of activity. And we are making real efforts toward education and just informing physicians as I'm sure our competitors are as well.
Phil Nadeau: Thanks for taking our questions a couple on the combo data and then one on just in terms of the.
Philip Nadeau: Thanks for taking our questions. A couple on the combo data and then one on just in terms of the combo data for ZIFTO. You're not calling the 600 milligram dose yet the recommended phase two dose, at least it doesn't sound like it is. We're curious why that is.
Phil Nadeau: The combo data for <unk>.
Phil Nadeau: Youre not calling the 600 milligram dose at the recommended phase II dose. So it doesn't sound like it is we're curious why that is is it just a question of semantics or is there another step that's necessary before 600 milligrams the formal phase two dose for combo therapies.
Troy Wilson: Is it just a question of semantics, or is there another step that's necessary before 600 milligrams, the formal phase two dose for combo therapies? And second, on the combos, do you anticipate providing overall survival data from the combos when you report them, presumably at ASH? And then our gist, our understanding is that the vast majority of patients who are resistant to imatinib have secondary mutations, so we're kind of curious as to the mechanism by which ZIFTO can resensitize. We don't want to steal the thunder of the upcoming medical presentation, but we're curious if you could give any details.
Speaker Change: And second on the combos do you anticipate providing overall survival data from the combos. When you reported presumably at Ash and is there an overall survival profile you need to see before moving into pivotal studies.
Troy Wilson: The entire field is learning as we go. And I think we're, you know, all of these physicians are benefiting from one another's experience. So it's not something we're overly concerned about, but I do think you have to be watchful. Thanks, Troy.
Speaker Change: And then not just our understanding is that the vast majority of patients who are resistant to imatinib, perhaps secondary mutation. So.
Speaker Change: Kind of curious as to the mechanism by which <unk>.
Speaker Change: To re sensitize, you don't want to steal the Thunder of the upcoming medical presentation, but were curious if you can give any details.
Phil Nadeau: The next question is from Phil Nadeau from TD Cowling. Thanks for taking our questions. A couple on the combo data and then one on just in terms of the combo data for Zift O, you're not calling the 600 milligram dose yet the recommended phase two dose, at least it doesn't sound like it is. I'm curious why that is, is it just a question of semantics or is there another step that's necessary before 600 milligrams, the formal phase two dose for combo therapies?
Philip Nadeau: Yeah, yeah, three good questions, Bill. Brad, you had a good question, too. Sorry, I didn't mean to say you didn't. But three good questions, Phil.
Tarek: Yeah, Yeah, three three good questions Bill.
Tarek: Brad you had a good question two sorry, I didn't mean to say you didn't see for three good questions. Phil So, let's let's <unk>.
Troy Wilson: So let's—on the RP2D, I think it's doing a disservice to the process and to the agency to call it semantics. We've identified the recommended phase 2 dose. We made a recommendation to the Safety Monitoring Committee, and they gave the go-ahead to move into the expansion.
Speaker Change: Think it's doing a disservice to the process into the agency to call. It semantics. We've identified the recommended phase II dose, we made a recommendation to the safety monitoring committee.
Speaker Change: They gave the go ahead to move into the expansion.
Phil Nadeau: And second, on the combos, do you anticipate providing overall survival data from the combos when you report it at Presumably Dash, and is there an overall survival profile you need to see before moving into pivotal studies? And then our gist, our understanding is that the vast majority of patients who are resistant to a matineeb have secondary mutations, so we're kind of curious as to the mechanism by which Zift O can resensitize.
Troy Wilson: Where this becomes relevant is that it doesn't really get tested until you take your next design, in this case, a combination pivotal, to the appropriate health authority and say, This is the study we're going to run at this dose, and this is the data supporting that dose. And that's where, you know, we're calling it—we're saying we identified it. I wouldn't want to beat our chest and say this is it, because ultimately that is the decision of a health authority.
Speaker Change: This becomes relevant is it doesn't really get tested until you take your next design in this case, a combination pivotal to the appropriate health authority and say this is the study we're going to run at this dose and this is the data supporting that dose and that's where we're calling it.
Speaker Change: We identified it I wouldn't want to beat our chest and say this is it because ultimately that is a decision of a health authority, but the agency was very clear and when when we designed the 007 study we did not need to go back to them and share data after the escalation before we moved into.
Phil Nadeau: We don't want to steal the thunder of the upcoming medical presentation, but we're curious if you give any details. Yeah, three good questions, Phil. Brad, you had a good question too. Sorry, I didn't mean to say you didn't, but three good questions, Phil. So on the RP2D, I think it's doing a disservice to the process and to the agency to call it semantics. We've identified the recommended phase two dose. We made a recommendation to the Safety Monitoring Committee.
Troy Wilson: But the agency was very clear that when, you know, when we designed the 007 study, we did not need to go back to them and share data after the escalation before we moved into the expansion. They felt comfortable that Kura, as sponsor, in collaboration with the Safety Monitoring Committee and the IDMC, made that determination as to what was the right dose to move into the expansions.
Speaker Change: The expansion they felt comfortable that occur as sponsor in.
Speaker Change: In collaboration with the safety monitoring committee and the IMC and make that determination as to what is the right dose to move into the expansions. So for all intents and purposes still that is the.
Phil Nadeau: They gave the go ahead to move into the expansion. Where this becomes relevant is it doesn't really get tested until you take your next design, in this case, a combination pivotal to the appropriate health authority and say, this is the study we're going to run at this dose and this is the data supporting that dose. And that's where we're calling it, we're saying we identified it. I wouldn't want to beat our chest and say this is it because ultimately that is a decision of a health authority.
Troy Wilson: So for all intents and purposes, still, that is the identified RP2D. Let's just, you know, as with everything relating to the ultimate combination pivotal, it is something that will ultimately be reviewed by the health authorities. I hope that makes it clear.
Speaker Change: We identified <unk>, let's just as with everything relating to the ultimate combination pivotal it is something that will ultimately be reviewed by the health authorities I hope that makes it clear more than semantics, but.
Speaker Change: Not not a whole lot more.
Troy Wilson: On your question around survival, I wouldn't call it survival. Survival is, you know, that's something more appropriate for kind of a randomized study. You will see durability, you will see both time on the study and, I suspect, time on therapy, and that will be instructive. Again, what we can tell you is that we started this study in July of last year, and we have patients who are coming on a year now.
Speaker Change: I mean your question around survival I wouldn't call. It survival survival is something more appropriate for kind of a randomized study.
Speaker Change: We'll see durability, you will see both time on study and I suspect time on therapy and that is instructive.
Phil Nadeau: But the agency was very clear in when we designed the 007 study, we did not need to go back to them and share data after the escalation before we moved into the expansion. They felt comfortable that Kura as sponsor in collaboration with the Safety Monitoring Committee and the IDMC make that determination as to what is the right dose to move into the expansions. So for all intents and purposes, Phil, that is the identified RP2D.
Speaker Change: Again, what we can tell you. So we've had we started dosing the study in.
Speaker Change: In July of last year.
Speaker Change: We have patients who are coming on a year now I think we're feeling good about what we're seeing in terms of safety tolerability ability too to drive clinical activity Youll see that I would characterize it Philip Morris durability duration of response rather than survival.
Troy Wilson: I think we're feeling good about what we're seeing in terms of safety, tolerability, you know, ability to drive clinical activity. You'll see that. I would characterize it more as durability, duration of response rather than survival, but we're going to show you the patients, and of course, the 200 milligram will be longer than the four will be longer than the six. But I think it's, as I say, it was a bit understated on Pete's part when we were putting the written comments together. It'll be a meaningful update. You know, we're looking forward to sharing it.
Phil Nadeau: Let's just, you know, as with everything relating to the ultimate combination pivotal, it is something that will ultimately be reviewed by the health authorities. I hope that makes it clear, more than semantics, but, you know, not a whole lot more. On your question around survival, I wouldn't call it survival. Survival is, you know, that's something more appropriate for kind of a randomized study. You will see durability. You will see both time on study and I suspect time on therapy and that is instructive.
Speaker Change: But we're going to show you the patients and of course, the 200 milligram will be longer than the four will be longer than six but.
Speaker Change: I think it's as I say.
Speaker Change: It was a bit understated on pizza part when we were putting the comp the written comments together, it's it'll be a meaningful uptick.
Speaker Change: We're looking forward to sharing it on your third question around the secondary mutations, yes, that's our understanding as well I.
Philip Nadeau: On your third question about secondary mutations, yes, that's our understanding as well. I did say something in my prepared remarks that's important. So, with the exception, there is a mutation in GIST that prevents the binding of imatinib. So, you do need imatinib to be able to bind. If a matinib is able to bind, then that synergy will occur. In our experience, there's really only one mutant that actually blocks matinib. The other mutations that people are going after, as long as the matinib is still active, the combination is, this may be, you know, Francis might slap me upside the head, but it's synthetic lethal at this point.
Speaker Change: I did say something in the prepared remarks thats important.
Phil Nadeau: Again, what we can tell you, so we've had, you know, we started dosing the study in July of last year. We have, you know, patients who are coming on a year now. I think we're feeling good about what we're seeing in terms of safety, tolerability, you know, ability to drive clinical activity. You'll see that. I would characterize it, Phil, more as durability, duration of response rather than survival, but we're going to show you the patients and, of course, the 200 milligram will be longer than the four will be longer than the six, but I think it's, as I say, it was a bit understated on Pete's part when we were putting the written comments together.
Speaker Change: With the exception there is a mutation ingest that prevents the binding of Imatinib. So you do need a mat nib to be able to bind.
Speaker Change: If if a Matt <unk> is able to bind.
Speaker Change: Then you can.
Speaker Change: Then that synergy will occur in our experience Theres really only one one mutant they'd actually blocks, Matt nib. The other mutations that people are going after as long as Imatinib is still active.
Speaker Change: The combination is.
Speaker Change: This may be Francis might slapped upside the head but.
Speaker Change: Its synthetic lethal at this point so the interesting opportunity here is you don't need potentially you don't need a companion diagnostics potentially you don't have to slice and dice. The population. If you can go on top of generic imatinib in the frontline or let's say the one one lb setting.
Philip Nadeau: So the interesting opportunity here is that you don't need, potentially, you don't need a companion diagnostic. Additionally, you don't have to slice and dice the population. If you can go on top of generic matinib in the frontline, or let's say, you know, the 1LB setting, you know, you're going to come ahead of everybody else, and that's the target population that we're going to be shooting for. You will see, you'll see that non-clinical data when we show it to you later this year.
Phil Nadeau: It'll be a meaningful update. You know, we're looking forward to sharing it. On your third question around the secondary mutations, yes, that's our understanding as well. I did say something in the prepared remarks that's important. So with the exception, there is a mutation in gist that prevents the binding of a If a matineebe is able to bind, then that synergy will occur. In our experience, there's really only one mutant that actually blocks a matineebe.
Speaker Change: Youre going to come ahead of everybody else and that's the target population that we're going to be shooting for you will see youll see that non clinical data when we show. It to you later this year, that's the manner in which the study is designed I will say this mechanism works equally well with the other kit inhibitors that are used in.
Philip Nadeau: That's the manner in which the study is designed. I will say, this mechanism works equally well with the other kit inhibitors that are used in GIST. The reason we're going with matinib is that it's, you know, obviously go after the largest part of the funnel and make it as simple as possible for both physicians and patients. So that's the rationale. That makes a lot of sense. Thanks for taking our questions.
Speaker Change: Ingest the reason, we're going with Imatinib as that's up obviously go after the the largest part of the funnel.
Phil Nadeau: The other mutations that people are going after, as long as a matineebe is still active, the combination is, this maybe Francis might slap me upside the head, but it's synthetic lethal at this point. So the interesting opportunity here is, you don't need potentially, you don't need a companion diagnostic. Potentially, you don't have to slice and dice the population. If you can go on top of generic a matineebe in the front line, or let's say, you know, the one LB setting, you know, you're going to come ahead of everybody else, and that's the target population that we're going to be shooting for.
Speaker Change: And make it as simple as possible for both physicians and patients. So that's the rationale that makes a lot sense. Thanks for taking our questions.
Speaker Change: Our pleasure.
Speaker Change: Okay.
Speaker Change: The next question comes from Peter Watson at Barclays.
Peter Lawson: The next question comes from Peter Lawson at BART.
Alex: Hey, good afternoon. It's Alex on for Peter.
Peter Watson: Hey, good afternoon.
Speaker Change: Alex on for Peter Thanks for taking the question.
Speaker Change: Of the one seven in the update later this year.
Speaker Change: Specifically on the phase one dose escalation with southern plus three.
Troy Wilson: Thanks for taking the question. Another one on OS7 and the update later this year, specifically on phase 1, the dose escalation with 7 plus 3 in the adverse risk population. Just maybe remind us the benchmark there, how we should think about, you know, CR, CRH, and durability in that specific group of patients.
Speaker Change: Adverse risk population, just maybe remind us the benchmark there how we should think about CR CRH and durability.
Phil Nadeau: You will see that nonclinical data when we show it to you later this year. That's the manner in which the study is designed. I will say, this mechanism works equally well with the other kit inhibitors that are used in gist. The reason we're going with a matineebe is that's obviously go after the largest part of the funnel and make it as simple as possible for both physicians and patients. So that's the rationale. That makes a lot sense. Thanks for taking our questions. From pleasure.
Speaker Change: In that specific group of patients.
Alex: Yep, yeah, Alex, good question. The reference that we've cited previously is the control arm of the registrational study that was conducted with Vixio. That showed, I think it's approximately a 35% CR-CRH rate, you know, that's about, and just to remind everybody, adverse risk here, the KMT2A is an adverse risk by definition, the other, the NPM1 are an adverse risk if they are over age 60, if they have a treatment-related AML, or if they have the ELN criteria that make them an adverse risk.
Alex: Yes, Alex good question.
Speaker Change: The the referenced that we've cited previously is the control arm to the Registrational study that was conducted with vaccines that showed I think it's approximately a 35% CR CRH rate.
Speaker Change: <unk>.
Speaker Change: That's about it and just to remind everybody adverse risk here that <unk> are adverse risk by definition.
Troy Wilson: The next question comes from Peter Lawson at Barclays. Hey, good afternoon. It's Alex on for Peter. Thanks for taking the question. Another one on 0-7 and the update later this year, specifically on the phase one, the dose escalation with 7 plus 3 in the adverse risk population. Just maybe remind us the benchmark there how we should think about, you know, CRCH and durability in that specific group of patients. Yeah. Yeah, Alex, good question.
Alex: The other the NPM, one or adverse risk if they are over age 60, if they have a treatment related AML or if they have the el N criteria that make them adverse risk its one or more of those three categories. So Alex to the best of our understanding.
Alex: It's one or more of those three categories. So, Alex, to the best of our understanding, that's kind of the benchmark of what you would expect for 7 plus 3 in this adverse risk population. In terms of durability, I'll be honest with you, Alex. I don't have that number right off the top of my head. You can look it up in the Vixios reference. I'm sure it's there.
Alex: That's kind of the benchmark of what you would expect for seven plus three in this adverse risk population in terms of durability.
Alex: I'll be honest with you Alex I don't have that number right off the top of my head you can look it up in the <unk> referenced.
Troy Wilson: The reference that we've cited previously is the control arm to the registration of study that was conducted with VIXIOs. That showed, I think it's approximately a 35% CRCH rate. You know, it's, that's about it. And just to remind everybody, adverse risk here, the AMP2A are adverse risk by definition. The other, the NPM1 are adverse risk if they are over age 60, if they have a treatment related AML or if they have the ELN criteria that make them adverse risk.
Alex: I'm sure I'm sure it's there.
Alex: Okay. Thank you and then just maybe a quick question on the come.
Troy Wilson: Okay, thank you. And then maybe a quick question on the COMET-08 study. I'm wondering if you could make any comments on enrollment dynamics here, and I'm guessing the initial data from this is probably 2025.
Speaker Change: Oh eight study.
Speaker Change: Wondering if you could make any comments on enrollment dynamics here and then I'm guessing initial data from this is probably in 2025. Thank you.
Troy Wilson: Yeah, right, so there are two parts to your question. So, 007 is being conducted at presently at approximately 30 U.S. sites. We've not taken the study internationally yet. The 008 study, Alex, is being conducted at even fewer sites at this point. And that was done deliberately so that the enrollment in 008 didn't cannibalize patients from 007 or 001. So the team, our clinical operations team, and our development colleagues were very deliberate in how they did it.
Alex: Thank you. Yeah, right. So
Speaker Change: Yeah, right. So two parts to your question so.
Speaker Change: So <unk> seven is being conducted at presently at approximately 30 U S sites.
Speaker Change: We have not taken the study internationally.
Troy Wilson: It's one or more of those three categories. So Alex, to the best of our understanding, that's kind of the benchmark of what you would expect for 7 plus 3 in this adverse risk population. In terms of durability, I'll be honest with you Alex, I don't have that number right off the top of my head. You can look it up in the VIXIOs reference. I'm sure it's there.
Speaker Change: Yet.
Alex: The <unk> eight study Alex is being conducted at even fewer sites at this point and that was done deliberately so that the enrollment in OE didnt cannibalize patients from <unk> seven or <unk>. One. So we showed the team our clinical operations team and our development colleagues were very deliberate in how.
Speaker Change: They did it but we will await the enrollment is now beginning to tick up because there is oh, seven crests and moves into the expansion now you put <unk> into the next slot.
Troy Wilson: The enrollment is now beginning to tick up because as 007 crests and moves into the expansion, now you put 008 into the next slot. And so we're beginning to see a pick-up across all three arms there, GILT, RIT-NIB, FLAG-IDA, and LDAC. We haven't guided Alex yet to timing for data. There is a lot of interest in that GILT combo because, again, half of the NPM1 patients are believed to have co-occurring FLT3 mutations. So that's a combination. I mean, you know, all combinations are—we do them for a reason, but that one's of particularly high interest.
Troy Wilson: Okay, thank you. And then just maybe a quick question on the comment. 08 study. I'm wondering if you could make any comments on the enrollment dynamics here. And then I'm guessing of initial data from this is probably in 2025. Thank you. Yeah, right. So two parts to your question. So, OO-7 is being conducted at approximately at approximately 30 U.S, sites. We've not taken the study internationally. Yet, the OO-8 study, Alex, is being conducted at even fewer sites at this point.
Gil: And so we're beginning to see a pick up across all three arms there Gil to written flag Ida and Outback I would we haven't guided Alex yet to timing for data. There is a lot of interest in that guilt combo.
Speaker Change: Cause again half of the NPM one patients.
Speaker Change: Are believed to have co occurring flip three mutations so that's a combination.
Speaker Change: All combinations are we do them for a reason, but that one is a particularly high interest. So I would say stay tuned and when we have more visibility as to when Youll expect data, we'll provide that in a future a future update.
Troy Wilson: And that was done deliberately so that the enrollment in OO-8 didn't cannibalize patients from OO-7 or OO-1. So the team, our clinical operations team and our development colleagues, we're very deliberate in how they did it. OO-8, the enrollment is now beginning to take up because as OO-7 crests and moves into the expansion, now you put OO-8 into the next slot. And so we're beginning to see a pickup across all three arms there, guilt-ridden nib, flag-IDA, and LDAC, we haven't guided Alex yet to timing for data.
Troy Wilson: So I would say stay tuned, and when we have more visibility as to when you'll expect data, we'll provide that in a future update. Great, thank you. The next question comes from Justin Zelin at BTIG. Thanks for taking the question and congratulations on the progress.
Speaker Change: Great. Thank you.
Speaker Change: Sure.
Joseph <unk>: The next question comes from Joseph <unk> with BTG.
Troy Wilson: Yeah, Justin, it's a good question. So, again, I think you have to be... Mollie, who's not on the call, has taught me to be precise in my language.
Justin Zelin: The next question comes from Justin Zelin at BTIG.
Joseph <unk>: Thanks for taking the question and congrats on the progress.
Speaker Change: You made a comment earlier about patients on Ziff don't may not have to go on to transplant they might be able to stay on drug here, but just wanted to hear your latest thoughts about use in the maintenance setting and.
Speaker Change: Do you expect the usage of <unk> in the maintenance setting after you get your first approval here. Thanks.
Troy Wilson: There is a lot of interest in that guilt combo because, again, half of the NPM-1 patients are believed to have co-occurring flip three mutations. So that's a combination, I mean, you know, all combinations are, we do them for a reason, but that one's a particularly high interest. So I would say stay tuned. And when we have more visibility as to when you'll expect data, we'll provide that in a few days. Thank you for your, a future update.
Joseph <unk>: Yes, Justin it's a good question.
Joseph <unk>: Yeah.
Joseph <unk>: So again I think it is I think we ought to be.
Alexandre Bouilloux: Okay, thank you.
Joseph <unk>: Molly who is not on the call has taught me to be to be precise in my in my language.
Speaker Change: In the Kmt too in the frontline and in the relapsed refractory for KMT two way those patients are typically younger you want to get them to transplant as quickly as you can.
Troy Wilson: In KMT2, in the front line, and in the relapsed refractory for KMT2A, those patients are typically younger. You want to get them to transplant as quickly as you can, in general. Not always, but in general, that's true. In the case of NPM1, those patients are often older, and so there may not be as much of a desire to move them to transplant. What we're seeing, Justin, is quite interesting, and that is, they seem to do well in either case.
Speaker Change: In general not always but in general Thats true in the case of NPM. One those patients are often older us and so.
Troy Wilson: The next question comes from Justin Zellan at BTIG. Thanks for taking the question and congrats on the progress. So Troy, you made a comment earlier about patients on ZIFDO may not have to go on to transplant. They might be able to stay on drug care, but just wanted to hear your latest response about using in the maintenance setting. And, you know, do you expect the usage of ZIFDO in the maintenance setting after you get your first approval here?
Speaker Change: And there may not be as much of a.
Joseph <unk>: Have a desire to move them to transplant what we're.
Joseph <unk>: We're seeing just in is quite interesting in that is.
Joseph <unk>: They seem to do well in either case this is.
Troy Wilson: This is, you know, focused more on NPM1 than KMT2A because your question's about transplant. But I think we give physicians the option. If they want, if they believe it's in a patient's best interest to go to transplant, they have that option, and then they can put them back on zyftomenib. All of our protocols allow that.
Speaker Change: Focus more on the NPM, one Kmt each way because your questions about transplant, but I think we give physicians the option if they want if they believe it's in the patient's best interest to go to transplant. They have that option and then they can put them back on just a minute all of our protocols allow that allow the physician or the patient to go back.
Troy Wilson: Thanks. Yeah, Justin, it's a good question. So again, I think it's, I think you have to be, you know, Molly who's not on the call has taught me to be, to be precise in my, in my language. In the KMT2, in the frontline and in the relapse refractory for KMT2A, those patients are typically younger. You want to get them to transplant as quickly as you can in general, not always, but in general.
Troy Wilson: Allow the physician or the patient to go back on zyfto post-transplant. If, on the other hand, they feel that perhaps they'd want to save that transplant, delay that transplant, then they can do that. And they seem to get, you know, very good, very good benefit. You might say, well, why would they save that transplant? And the reasons are, we forget.
Joseph <unk>: On Ziff deal post transplant.
Joseph <unk>: If on the other hand, they feel that perhaps they want to save that transplant delay that transplant.
Joseph <unk>: Then they can do that and they seem to get.
Joseph <unk>: Very good very good benefit you might say well why would they safe transplant and the reasons are we forget I mean it is in.
Troy Wilson: That's true. In the case of NPM1, those patients are often older and so there may not be as much of a desire to move them to transplant. What we're seeing Justin is quite interesting and that is they seem to do well in either case. This is, you know, focus more on the NPM1 than the KMT2A because your question is about transplant. But I think we give physicians the option if they want, if they believe it's in a patient's best interest to go to transplant, they have that option.
Troy Wilson: I mean, it's, in many cases, still the best option for a cure, but it is not cost-free. There is a 20 to 25% risk of mortality. You typically have graft versus host disease. You're on lifelong immunosuppressants.
Joseph <unk>: In many cases still the best option for cure, but it is not cost free there is a 20% to 25% risk of mortality.
Joseph <unk>: Typically have graft versus host disease youre on lifelong immunosuppressants.
Troy Wilson: There are a lot of complications associated with transplant. So in that older population, particularly NPM1, Justin, you may actually, if you're able to drive a durable CR, you may greatly delay the time to transplant and really save that. The final thing I'll say, Justin, is that we are also pursuing a formal post-transplant maintenance study. That's the 012 protocol.
Justin: There are a lot of complications associated with transplant. So in that older population, particularly NPM one Justin you may actually if youre able to drive a durable CR you made greatly delay the time to transplant and really say to that.
Speaker Change: The final thing I'll say just in as we are also pursuing a formal post transplant maintenance study. That's the 012 protocol that is currently in a safety run in phase as part of an ISP that would ideally allow any patient who fits the genotype to come on post.
Troy Wilson: And then they can put them back on ZIF to minute. All of our protocols allow that. Allow the physician or the patient to go back on ZIFDO post transplant. If on the other hand they feel that perhaps they want to save that transplant, delay that transplant, then they can do that. And they seem to get, you know, very good, very good benefit. You might say, well, why would they save transplant? And the reasons are, we forget.
Troy Wilson: This is currently in a safety run-in phase as part of an IST. This would ideally allow any patient who fits the genotype to come on post-transplant. Whether that patient comes from ZIFTO, from a FLIP3 inhibitor, or from another menin inhibitor, they would be eligible to go on that. Let's break that out separately. We're basically, Jason, going to do it all. And I think the beauty of it is, again, because of the safety, the tolerability, and the activity of ZIFTO, giving physicians this optionality. They can take patients for transplant or not.
Joseph <unk>: Whether that patients come from ZIP go from a <unk> three inhibitor from another menin inhibitor. They would be eligible to go to that let's let's break that out separately.
Troy Wilson: I mean, it is, in many cases, still the best option for a cure, but it is not cost free. There is a 20 to 25% risk of mortality. You typically have graft versus host disease. You're on lifelong immunosuppressants. There are a lot of complications associated with transplant. So in that overpopulation, particularly in PM1 Justin, you may actually, if you're able to drive a durable CR, you may greatly delay the time to transplant and really save that.
Speaker Change: Basically Jason going to do it all.
Speaker Change: I think the beauty of it is is again because of the safety the tolerability of the activity of Ziff Doe Youre, giving physicians. This optionality they can take patients to transplant or not and we're looking forward to sharing this data with you at the end of the year I think it will become clearer as we walk you through through the data.
Troy Wilson: And we're looking forward to sharing this data with you at the end of the year. I think it'll become clearer as we walk you through the data that has been generated in the 007 protocol so far. Great, that's helpful. Thanks for taking the time. My pleasure. The next question comes from George Farmer at Scotiabank.
Joseph <unk>: That has been generated in India or seven protocol to date.
Troy Wilson: The final thing I'll say Justin is we are also pursuing a formal post transplant maintenance study. That's the 01-2 protocol. That is currently in a safety run-in phase as part of an IST. That would ideally allow any patient who fits the genotype to come on post transplant. Whether that patient's come from ZIFDO, from a flip three inhibitor, from another men in inhibitor, they would be eligible to go to that.
Speaker Change: Great. That's helpful. Thanks for taking my question.
Speaker Change: Our pleasure.
Speaker Change: The next question comes from George Farmer with Scotiabank.
George Farmer: Hi, Good afternoon. Thanks for taking my question Troy I was wondering if you could elaborate a little bit more on your diabetes data.
George Farmer: Hi, good afternoon.
George Farmer: You know other than safety, how do you think because if Doe compares and maybe one of your follow on compounds compares to.
Justin Zelin: Let's break that out separately. Well, basically, Jason is going to do it all. And I think the beauty of it is, again, because of the safety, the tolerability, the activity of ZIFDO, giving physicians this optionality. They can take patients to transplant or not. And we're looking forward to sharing this data with you at the end of the year. I think it will become clearer as we walk you through the data that has been generated in the 01-7 protocol today. Great, that's helpful.
Speaker Change: Existing menin inhibitor data that's out there.
Troy Wilson: Thanks for taking my question.
Speaker Change: And how does this program differentiate itself from others.
Troy Wilson: Yeah, George, it's a great question. Thank you for the question. So what you saw on the ADA poster was Zifta-Menib in, you know, the various assays, the rodent assays, as well as the in sphero assay. We have run the competitor compounds against those same assays, but that data remains unpublished.
Speaker Change: Yeah, George It's a great question. Thank you for the question. So what you saw in the 88 poster was.
Speaker Change: Just a minute.
Speaker Change: And in the various assays.
Speaker Change: And in the road and assays as well as in the DN Spiro assay, we have run the competitor compounds.
Speaker Change: Against those same assets that data remains on publish I will tell you the safety tolerability the activity look different.
George Farmer: That's a question from George Farmer. It's Gosha Bank.
Troy Wilson: I will tell you, the safety, the tolerability, and the activity look different. And what is clear, I think an open question was, at least preclinically, George, could you drive the activity with a reversible menin inhibitor? And I think the answer is unequivocally yes.
Troy Wilson: Good afternoon. Thanks for taking my question. Troy, I was wondering if you could elaborate a little bit more on your diabetes data. Other than safety, how do you think Zipto compares, and maybe one of your follow-on compounds, compares to existing minute inhibitor data that's out there in the clinic, and how does this program differentiate itself from others? Yeah, George, it's a great question. Thank you for the question. So, what you saw in the 88 poster was Zipto Meneb in the various assays in the rodent assays as well as in the in-spiral assays.
Speaker Change: And in a.
George Farmer: What is clear I think an open question was at least pre clinically George could you drive the activity with a reversible <unk> inhibitor.
George Farmer: And I think the answer is unequivocally yes.
Troy Wilson: And again, having, you know, my team pioneered the KRAS covalent inhibitors, I've had my fair share of experience with irreversible inhibitors; those electrophiles are not to be underestimated. What's important is that, with a compound that has the safety and tolerability of ZIFTO or even better, potentially with a next-gen compound, you can get all of that activity that you see in the ADA So we are planning on moving it forward for many reasons. We think it makes more sense to pursue the oncology applications with ZIFTO and the diabetes applications with one or more additional compounds.
George Farmer: And again, having my team pioneered the K Ras covalent inhibitors.
Speaker Change: I've had my fair share of experience with irreversible inhibitors.
Speaker Change: That is that that those electric files are not to be underestimated. What's important as you can with a compound that has the safety and tolerability of <unk> or even better potentially with the next gen compound you can get all of that activity that you see in the 88 presentation. So we are.
Troy Wilson: We have run the competitor compounds against those same assays. That data remains unpublished. I will tell you the safety, the tolerability, the activity look different. And what is clear, I think an open question was at least preclinically, George, could you drive the activity with a reversible men in inhibitor? And I think the answer is unequivocally yes. And again, having my team pioneered the K-RAS covalent inhibitors. I've had my fair share of experience with irreversible inhibitors.
Speaker Change: Planning on moving it forward FERC for many reasons, we think it makes more sense to prosecute the oncology applications with Cisco the diabetes.
Speaker Change: Diabetes applications with one or more additional compounds that that's our approach rather than trying to do it all in one we will have more to say about that.
Troy Wilson: That's our approach, rather than trying to do it all in one. We'll have more to say about that as this year progresses and we get into next year. Okay, great. That's it. Our pleasure. Thank you.
George Farmer: As this year progresses, and we get into next year.
Speaker Change: Okay, Great that's very helpful. Troy. Thanks.
Troy: Our pleasure thank you.
Speaker Change: There are no further questions at this time.
Troy Wilson: There are no further questions at this time, and that concludes our question and answer session. I would like to turn the conference back over to Troy Wilson for any closing remarks.
Speaker Change: A question and answer session I would like to turn the conference back over to Troy Wilson for any closing remarks.
Troy Wilson: Those electrophiles are not to be underestimated. What's important is you can, you know, with a compound that has the safety and tolerability of Zipto, or even better potentially with the next gen compound, you can get all of that activity that you see in the 88 presentation. So we are planning on moving it forward for many reasons. We think it makes more sense to prosecute the oncology applications with Zipto, the diabetes applications with one or more additional compound. That's our approach rather than trying to do it all in one. We'll have more to say about that, you know, as this year progresses and we get into next year.
Troy Wilson: Thank you Amy Thank you all once again for joining the call today, we're going to be participating in a series of upcoming healthcare conferences, and we look forward to seeing many of you. There in the meantime, if you have any additional questions you know how to reach US. Please feel free to contact Pete Tom or me. Thank you again and have a good evening everyone.
Troy Wilson: Thank you, Amy. Thank you all once again for joining the call today. We're going to be participating in a series of upcoming healthcare conferences, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, you know how to reach us. Please feel free to contact Pete, Tom, or me. Thank you again, and have a good evening, everyone.
Operator: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
Speaker Change: Okay.
Speaker Change: The conference has now concluded. Thank you for attending today's presentation you may now disconnect.
Speaker Change: Okay.
Operator: [music] Thanks for watching!
Speaker Change: [music].
Troy Wilson: Okay, great. That's very helpful, Troy. Thanks. Our pleasure. Thank you.
Operator: There are no further questions at this time. And it concludes our question and answer session.
Troy Wilson: Would like to turn the conference back over to Troy Wilson for any closing remarks. Thank you, Amy. Thank you all once again for joining the call today. We're going to be participating in a series of upcoming healthcare conferences, and we look forward to seeing many of you there. In the meantime, if you have any additional questions, you know how to reach us. Please feel free to contact Pete, Tom, or me. Thank you again and have a good evening everyone.
Operator: The conference is now concluded. Thank you for attending today's presentation. You may not.
Speaker Change: Okay.
Speaker Change: Yes.