ziftomenib (KO-539) / Kura Oncology, University of Michigan, Kyowa Kirin - LARVOL DELTA

Ziftomenib in relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML): Phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT04067336 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NPM1

Phase 1a/1b study of the safety, pharmacokinetics, and antitumor activity of ziftomenib in combination with imatinib in patients with advanced gastrointestinal stromal tumors (GIST) after imatinib failure. (ASCO 2025) - P1 | "Enrollment opens Feb 2025. The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Combination therapy • Metastases • P1 data • PK/PD data • Stroma • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Kura Oncology Reports First Quarter 2025 Financial Results (GlobeNewswire) - "Forecasted Milestones: (i) Present data from the KOMET-001 Phase 1b/2 registration-directed trial in R/R NPM1-m AML at ASCO and EHA in the second quarter of 2025; (ii) Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with intensive chemotherapy (7+3) in the frontline setting at EHA in the second quarter of 2025; (iii) Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with venetoclax and azacitidine in the frontline setting at a medical meeting in the second half of 2025; (iv) Initiate two independent Phase 3 registration-enabling trials in 1L intensive (KOMET-017-IC) and non-intensive (KOMET-017-NIC) AML in the second half of 2025."

Clinical data • New P3 trial • Acute Myelogenous Leukemia

RGT-61159, best-in-class oral small molecule inhibitor of MYB via selective RNASplicing alteration, synergistic anti-tumor aActivity when combined with standards of care in leukemia disease models harboring AML common genetic lesions and with NOTCH inhibitors in ACC disease models (AACR 2025) - P1 | "The data revealed synergistic cell killing activity when RGT-61159 was combined with Flt3 inhibitors (e.g. gilteritinib and midostaurin) in MOLM-13 and MV4.11 cell lines harboring Flt3 IDT mutation, and with menin inhibitors (e.g. KO-539, revemenib) in AML cell lines with NPM1 mutant) or MLL-fusion. Finally, RGT-61159 combination with a Bcl2 inhibitor (venetoclax) resulted in synergistic cell killing activity in AML cell lines carrying NPM1 mutations or AML-1-ETO fusion protein. These studies provide compelling supportive evidence for combining RGT-61159 with standards-of-care for AML treatment in the relevant population of patients with AML. ."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NPM1

Kura Oncology Announces First Patients Dosed in Phase 1 Combination Trial of Ziftomenib for the Treatment of Advanced GIST (GlobeNewswire) - "Kura Oncology, Inc...today announced that the first patients have been dosed in KOMET-015, a Phase 1 clinical trial of ziftomenib, the Company’s potent and selective, oral investigational menin inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST) after imatinib failure."

Trial status • Gastrointestinal Stromal Tumor

KMT2A rearranged acute myeloid leukemia is vulnerable to the combinatorial inhibition of menin and MYC protein degradation (AACR 2025) - "This interaction has been targeted by menin inhibitors revunemib and ziftomenib with promising results in clinical trials (Aldoss & Issa, 2023; Erba, 2022), and revumenib is now FDA-approved...We have investigated GT19715, the first-in-class MYC/GSPT1 degrader in MYC-driven hematological malignancies (Nishida, ASH 2022, 2023, 2024)... Combinatorial approach of menin inhibition and MYC degradation results in a profound synergistic reduction of KMT2Ar AML cells in vitro and in vivo, validating the underlying premise. Further mechanistic studies and efficacy in PDX models are ongoing."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • GSPT1 • KMT2A • MYC • TP53

RCZY-711, a novel, highly potent, and orally bioavailable menin-MLL inhibitor with superior efficacy in preclinical acute leukemia models (AACR 2025) - "The FDA-approved menin inhibitor SNDX-5613 treats relapsed/refractory acute leukemia with MLL translocations, while ongoing trials explore its use in KRAS-mutant solid tumors and Wnt-driven cancers. Another menin inhibitor, KO-539, is being tested in advanced gastrointestinal stromal tumors...The observed superior in vivo efficacy may be attributed to its high cellular potency and improved half-life (mouse: T1/2 = 2.0 h). In conclusion, RCZY-711 is a novel, highly potent and orally bioavailable menin-MLL inhibitor with best-in-class clinical potential for treating MLL-rearranged and NPM1-mutant acute leukemias."

Preclinical • Acute Myelogenous Leukemia • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hematological Malignancies • Leukemia • Oncology • Sarcoma • Solid Tumor • KMT2A • KRAS • MEIS1 • MEN1 • NPM1

Lintuzumab-Ac225 has potent mutation agnostic antileukemic activity in preclinical models of AML (AACR 2025) - "In clinical trials, lintuzumab-Ac225 had positive responses when combined with CLAG-M chemotherapy in relapsed/refractory AML patients, including those with high-risk features like venetoclax resistance and TP53 mutations...FLT3 inhibitors (gilteritinib, quizartinib), KMT2A inhibitors (revumenib, ziftomenib) and azacitidine were evaluated as single agents and in combination with Lintuzumab-Ac225... Lintuzumab-Ac225 shows broad anti-leukemic activity in AML cell lines, in a mutation (FLT3, KMT2A, NPM1, TP53) agnostic manner. It improves AML control in high-risk cases and enhances response durability when combined with standard of care treatments. These findings support its potential as a backbone therapy for relapsed/refractory AML, warranting further clinical evaluation."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • CDKN1A • FLT3 • KMT2A • NPM1 • TP53

KOMET-001: First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=199 | Recruiting | Sponsor: Kura Oncology, Inc. | Trial completion date: Sep 2025 ➔ Oct 2028 | Trial primary completion date: Sep 2024 ➔ Oct 2028

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A • NPM1

KO-MEN-015: A Study of Ziftomenib, an Oral Menin Inhibitor, in Combination With Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors (GIST) (clinicaltrials.gov) - P1 | N=157 | Recruiting | Sponsor: Kura Oncology, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

Ziftomenib for the Treatment of Patients With NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia Not Eligible for Standard Therapy (clinicaltrials.gov) - P2 | N=70 | Not yet recruiting | Sponsor: Uma Borate

New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Kura Oncology and Kyowa Kirin Announce Submission of New Drug Application for Ziftomenib to FDA (GlobeNewswire) - "Kura Oncology, Inc...and Kyowa Kirin Co., Ltd...announced Kura submitted a New Drug Application (NDA) for ziftomenib, a highly selective, once-daily, oral, investigational menin inhibitor, for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM 1) mutation to the U.S. Food and Drug Administration (FDA) on March 31, 2025....Kura expects to receive notification from the FDA on this preliminary evaluation in the second quarter of 2025."

FDA filing • Acute Myelogenous Leukemia

A Phase I Study Investigating the Combination of the Menin Inhibitor Ziftomenib With Venetoclax and Gemtuzumab in Pediatric Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=22 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

KO-MEN-015: A Study of Ziftomenib, an Oral Menin Inhibitor, in Combination With Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors (GIST) (clinicaltrials.gov) - P1 | N=157 | Not yet recruiting | Sponsor: Kura Oncology, Inc. | Initiation date: Jan 2025 ➔ Apr 2025

Trial initiation date • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

Ziftomenib in Combination With Chemotherapy for Children With Relapsed/Refractory Acute Leukemia (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: LLS PedAL Initiative, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Leukemia • Oncology

Kura Oncology Reports Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Forecasted Milestones: Submit an NDA for ziftomenib in R/R NPM1-m AML in the second quarter of 2025; Present topline data from KOMET-001 Phase 2 registration-directed trial in R/R NPM1-m AML in the second quarter of 2025; Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with intensive chemotherapy (7+3) at a medical meeting in the second quarter of 2025."

FDA filing • P1 data • P2 data • Acute Myelogenous Leukemia

Kura Oncology Reports Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Forecasted Milestones: Initiate the KOMET-015 trial evaluating ziftomenib and imatinib in patients with advanced GIST in the first half of 2025; Initiate two independent Phase 3 registration-enabling trials in 1L intensive (KOMET-017-IC) and non-intensive (KOMET-017-NIC) AML in the second half of 2025; Topline MRD-negative CR results from KOMET-017-IC Phase 3 trial anticipated in 2028; Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with venetoclax and azacitidine at a medical meeting in the second half of 2025."

New P3 trial • P1 data • P3 data: top line • Trial status • Acute Myelogenous Leukemia • Gastrointestinal Stromal Tumor

A Phase I Study Investigating the Combination of the Menin Inhibitor Ziftomenib With Venetoclax and Gemtuzumab in Pediatric Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | Initiation date: Nov 2024 ➔ May 2025

Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

Pharmacokinetics and ADME Characterization After Oral and Intravenous Administration of [14C]-Ziftomenib in Healthy Male Participants. (PubMed, Clin Transl Sci) - "Ziftomenib was well tolerated with no new safety concerns in healthy men. Considering the pharmacokinetic profile and manageable safety outcomes, these findings support further clinical investigation of ziftomenib as treatment for AML."

Journal • PK/PD data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • NPM1

Positive FDA Feedback for Upcoming Frontline Combination Trial Designs (GlobeNewswire) - "Following successful End-of-Phase 1 meetings with the FDA, the companies announced they will proceed with plans to initiate the KOMET-017 trial, comprising of two independent, global, randomized, double-blind, placebo-controlled Phase 3 trials to evaluate ziftomenib in combination with both intensive and non-intensive combination regimens in patients with newly diagnosed NPM1-m and/or KMT2A-r AML.....The registrational KOMET-017-IC (Intensive Combination) trial will evaluate the combination of ziftomenib with induction chemotherapy (7+3) in newly diagnosed NPM1-m and KMT2A-r AML patients...and is anticipated to be initiated in the second half of 2025....The registrational KOMET-017-NIC (Non-Intensive Combination) trial will evaluate the combination of ziftomenib with venetoclax plus azacitidine in newly diagnosed NPM1-m patients unfit to receive intensive chemotherapy....The KOMET-017-NIC trial is anticipated to be initiated in the second half of 2025."

FDA event • New P3 trial • Acute Myelogenous Leukemia

2025 Anticipated Clinical Data Highlights (GlobeNewswire) - "KOMET-007 Phase 1b data of ziftomenib in combination with 7+3 in newly diagnosed NPM1-m AML and KMT2A-r AML (2Q 2025)....KOMET-007 Phase 1b data of ziftomenib in combination with venetoclax / azacitidine in NPM1-m AML (2H 2025)."

P1 data • Acute Myelogenous Leukemia

Positive KOMET-001 Ziftomenib Monotherapy Trial in R/R NPM1-m AML (GlobeNewswire) - "The KOMET-001 trial achieved its primary endpoint of CR plus CR with partial hematological recovery (CRh) and the primary endpoint was statistically significant. The benefit-risk profile for ziftomenib is highly encouraging, and safety and tolerability were consistent with previous reports....Full results from the KOMET-001 trial will be presented at a future medical meeting in the second quarter of 2025....Kura announced that it is on track to submit an NDA to the FDA for ziftomenib for the treatment of patients with R/R NPM1-mutant AML in the second quarter of 2025."

FDA filing • P1/2 data • Acute Myelogenous Leukemia

Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions. (PubMed, Int J Cancer) - "Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A-rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A-complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors."

Journal • Review • Acute Myelogenous Leukemia • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • AFF1 • KMT2A • MLLT10 • MLLT3 • NPM1 • NUP98

Ziftomenib in Combination With Chemotherapy for Children With Relapsed/Refractory Acute Leukemia (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: LLS PedAL Initiative, LLC | Trial completion date: Oct 2026 ➔ Jan 2027 | Initiation date: Nov 2024 ➔ Feb 2025 | Trial primary completion date: Oct 2026 ➔ Jan 2027

Trial completion date • Trial initiation date • Trial primary completion date • Hematological Malignancies • Leukemia • Oncology

Menin Inhibitors: New Targeted Therapies for Specific Genetic Subtypes of Difficult-to-Treat Acute Leukemias. (PubMed, Cancers (Basel)) - "MEN1 inhibitors (MIs), such as revumenib, ziftomenib, and other active small molecules, represent a promising new class of therapies currently under clinical development. It illustrates data from clinical trials and discusses the emergence of resistance mechanisms. In addition, we outline future directions for the use of MIs and emphasize the need for further research to fully realize the potential of these novel compounds, especially in the context of specific genetic subtypes of challenging AL."

Journal • Review • Acute Myelogenous Leukemia • Developmental Disorders • Hematological Malignancies • Leukemia • Oncology • KMT2A • MEN1 • NPM1