ziftomenib (KO-539)

P1, N=22, Not yet recruiting, M.D. Anderson Cancer Center

To date, this new class of drugs has been tested in phase I and II clinical trials, both alone and in combination with synergistic drugs showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this brief review, we summarize the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data on the treatment of acute myeloid leukemia with this promising new class of agents, particularly revumenib and ziftomenib.

P1, N=20, Not yet recruiting, LLS PedAL Initiative, LLC

Recent phase 1/2 clinical trials confirmed the efficacy of SNDX-5613 (revumenib) and KO-539 (ziftomenib) and their acceptable tolerability. Several small molecule menin inhibitors are currently being evaluated as a combination therapy with standard of care treatments. The current paper reviews the recent progress in exploring the inhibitors of menin-KMT2A interactions and their application prospects in the treatment of acute leukemias.

P1/2, N=90, Recruiting, Tanja Andrea Gruber | Not yet recruiting --> Recruiting

P1, N=171, Recruiting, Kura Oncology, Inc. | Not yet recruiting --> Recruiting

P1, N=212, Recruiting, Kura Oncology, Inc.

Data suggest durable remissions as the DoR continues to mature with 5 of 8 pts with CRc ongoing at cutoff. A single-arm registration-directed Ph 2 study is currently accruing to further evaluate ziftomenib monotherapy in R/R NPM1-m AML.

These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and nuclear export is a viable strategy for the treatment of MLL-r AML. Ongoing experiments with functional proteomic analysis will be presented at the ASH meeting.

In this study, bortezomib and vorinostat were incorporated into an ALL chemotherapy backbone containing dexamethasone, mitoxantrone, and pegasparaginase during induction and reinduction chemotherapy cycles...Following induction intensification with cyclophosphamide, cytarabine, and mercaptopurine, 77% and 66% of all patients and KMT2Ar patients respectively were MRD negative at the time of count recovery...Although the study was not powered to evaluate outcomes, EFS and OS in KMT2Ar patients suggest a clinical signal worth pursuing given the low proportion of patients transplanted in first remission. The successor study, TINI 2 (NCT05848687), will build upon the bortezomib/vorinostat backbone by incorporating 2 cycles of blinatumomab and the menin inhibitor ziftomenib in combination with chemotherapy during reinduction.

Preclinical data have demonstrated ziftomenib's ability to target multiple types of menin-dependent AML clones, and that the antitumor activity of ziftomenib and other menin inhibitors in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of KMT2A-r and NPM1-m AML is enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib. Secondary endpoints include preliminary efficacy (including MRD-negative responses and number of patients able to receive stem cell transplant) and pharmacokinetics. Exploratory end points include biomarkers for efficacy and resistance and pharmacodynamic biomarkers potentially related to the activity of ziftomenib when combined with SOC treatments in adults with R/R AML with NPM1-m or KMT2A-r.

P1/2, N=90, Not yet recruiting, Stanford University | Initiation date: Jul 2023 --> Nov 2023

The phase Ib portion will also evaluate zifto/ven/aza in newly diagnosed AML (NPM1m and KMT2Ar) and zifto/ven in R/R AML (NPM1m only). Setting: United States and Europe

Ziftomenib demonstrates significant clinical activity in heavily pretreated and co-mutated R/R NPM1m AML patients where 35% of patients achieved CR with a manageable safety profile. Remissions are durable, with MRD clearance of NPM1 and key co-mutations. Resistance mutations develop infrequently and ziftomenib remains effective against a common gatekeeper mutation.

P1, N=171, Not yet recruiting, Kura Oncology, Inc.

P1, N=212, Recruiting, Kura Oncology, Inc. | Not yet recruiting --> Recruiting

Ziftomenib continues to demonstrate significant clinical activity in heavily pretreated and co-mutated R/R NPM1mAML pts where 35% of pts achieved CR. The safety profile remains consistent, and episodes of DS are clinicallymanageable. Data reveal that remissions are durable, with MRD clearance of NPM1 and key co-mutations.Resistance mutations develop infrequently, and ziftomenib remains effective against a common menin gatekeepermutation.

During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts ( NPM1- m and KMT2A- r) using a rule-based approach (n=6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. KOMET-007 will determine the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy and intensive chemotherapy in newly diagnosed or R/R patients with NPM1- m and KMT2A- r AML. AML, Venetoclax, Induction chemotherapy, relapsed/refractory

Venetoclax combined with azacitidine leads to high response rates (~60%) in elderly de novo AML patients at least partially through targeting of LSCs. In conclusion, our data show that in some patient specimens venetoclax resistance can be overcome with ziftomenib as a single agent. These findings suggest that ziftomenib-mediated targeting of AML cell populations, including LSCs, may be an effective strategy for preventing disease progression in patients who are refractory or relapse in response to initial ven/aza treatment. Combination of ziftomenib and venetoclax needs to be further studied but may also represent a viable strategy in the presence of known characteristics corresponding tovenetoclax resistance.

Like described in most reported adult patients with KMT2A::ARHGEF12 fusion, complete remission could not be achieve by Daunorubicine and Cytarabine , neither with Azacytidine and Venetoclax. The patient is at present included in a clinical trial testing a KMT2A inhibitor, the Ziftomenib... We herein report a first case of AML with rare KMT2A::ARHGEF12 fusion transcript with a rare germline DDX41 variant. We highlight both the importance of multiple methods, including RNA high throughput sequencing, to discover rare KMT2A rearrangements as well as systematic research of DDX41 mutation in myeloid neoplasm. Reporting unusual and rare genetic aberrations is important in order to improve knowledge of their prognosis and treatments modalities including new clinical trials.

Median number of prior therapies was 2.5 (r: 1 to 8), including 15% with ≥1 prior stem cell transplant (SCT) and 60% with prior venetoclax. Ziftomenib continues to demonstrate significant clinical activity in heavily pretreated and co-mutated R/R NPM1 m AML pts. The safety profile remains consistent and the on-target effect of DS continues to be manageable. Data suggest durable remissions as the DoR continues to mature with 5 of 8 pts with CRc ongoing at the cutoff.

P1/2, N=90, Not yet recruiting, Stanford University

To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

Not available.

Both KO-539 and SNDX-5613 show notable changes in binding in M327I vs WT menin. The Janssen chemotype shows a novel binding mode. Although it has 30-fold lower affinity for M327I, it shows little change in its bound position to M327I menin.Given the clinical validation of menin inhibition in AML, the design of next generation compounds that block MLL1 binding while avoiding acquired MEN1 mutations may be a strategy to overcome acquired resistance to first generation menin inhibitors.

Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.

P1, N=212, Not yet recruiting, Kura Oncology, Inc.

P1/2, N=199, Recruiting, Kura Oncology, Inc. | N=60 --> 199 | Trial completion date: Dec 2022 --> Sep 2025 | Trial primary completion date: Jun 2022 --> Sep 2024

These preclinical findings demonstrate that simultaneous inhibition of the menin-KMT2A interaction and nuclear export could be a viable strategy for the treatment of MLL-r AML. Ongoing experiments with CDX and PDX using MLL-r models and functional analysis using total transcriptome sequencing and proteomics will be presented at the ASH meeting.

As we have demonstrated with other menin-i, ziftomenib induced transcriptional downregulation of FLT3 in the FLT3-mutant AML setting and also exhibited synergistic activity with the FLT3 inhibitor gilteritinib. In summary, we demonstrated that ziftomenib has significant activity against MLL-r and NPM1mut AML and synergizes with certain agents targeting chromatin regulation and apoptosis. The combination of ziftomenib with venetoclax is particularly synergistic and already available for clinical trial assessment.

Our data demonstrate in vitro target inhibition and remarkable in vivo activity of the menin inhibitor ziftomenib against infant, pediatric, and young adult KMT2A-R ALL. Ziftomenib monotherapy activity was further augmented in most models when combined with conventional chemotherapy drugs vincristine or dexamethasone, which were well-tolerated in PDX mice. Based upon early clinical safety/tolerability data for ziftomenib in adult patients with acute leukemias and our pediatric-specific data described herein, a phase 1 clinical trial of ziftomenib in combination with multi-agent chemotherapy for children with relapsed/refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemias is planned.

Clinical benefit with disease control (eg, decreasing blast counts [BC] or hydroxyurea requirement) occurred across dose levels. P1b results suggest that with appropriate DS management, ziftomenib is well tolerated. Additionally, the 600 mg dose demonstrates meaningful signs of efficacy in heavily pretreated R/R AML pts, warranting further investigation of ziftomenib as a monotherapy and in combination with rational therapeutic partners.

No abstract available

Menin-MLL interaction inhibitors have therapeutic potential in the treatment of acute leukemia, such as AML and ALL. SNDX-5613 and KO-539 have been granted orphan drug designation by the FDA for treatment of refractory/relapsed leukemia and AML, respectively. In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.

P1/2, N=60, Recruiting, Kura Oncology, Inc. | N=90 --> 60 | Trial completion date: Aug 2022 --> Dec 2022 | Trial primary completion date: Feb 2022 --> Jun 2022

KO-539-mediated Menin depletion was associated with polyubiquitylation and proteasomal degradation of Menin protein, given that protein levels were restored by co-treatment with the proteasome inhibitor carfilzomib. Notably, co-treatment (in vitro) with KO-539 in combination with venetoclax, OTX015 (pan-BET inhibitor) or abemaciclib (CDK6 inhibitor) for 72 to 96 hours induced synergistic loss of viability in cultured cell lines and PD AML cells from both MLL-r and NPM1c AML but not normal CD34+ progenitor cells or AML cells lacking MLL-FP or NPM1c, as determined by the SynergyFinder algorithm. Findings of ongoing in vivo studies determining effects of treatment with KO-539 and/or venetoclax or OTX015, versus vehicle control in PDX models will be presented at the meeting. These preclinical findings highlight the molecular correlates of anti-AML efficacy of KO-539 and demonstrate potentially synergistic KO-539-based combinations with inhibitors of BCL2, BET proteins and CDK6 against MLL-r or NPM1 mutant AML.

This will be followed by the Ph2 expansion portion in genetically defined populations once a RP2D is determined. Results N/A (trial in progress) Conclusion N/A (trial in progress)

The DOT1L inhibitor pinometostat in KMT2A-rearranged AML, the menin inhibitors KO-539 and SYNDX-5613 in KMT2Ar and NPM1-mutated AML, and the mutant TP53 inhibitor APR-246 are examples of novel agents targeting specific mutations in AML. AML remains in incurable disease for many patients but advances in genomics, epigenetics, and drug discovery have led to the development of many potential novel therapeutic agents, many of which are being investigated in ongoing clinical trials. Additional studies will be necessary to determine how best to incorporate these novel agents into routine clinical treatment of AML.

The 50 mg pt with a KMT2A-r and the 200 mg pt with a p53 mutation and PICALM-AF10 fusion exhibited evidence of tumor lysis syndrome and markedly decreased hydroxyurea requirements with blood count stabilization, respectively. In conclusion, the early biologic activity of KO-539 in relapsed AML is encouraging, and its unique PK characteristics may be advantageous for clinical benefit. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the conference.