On November 2, 2023 Syndax Pharmaceuticals (Nasdaq: SNDX), a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported that updated data from multiple trials across its clinical program for revumenib, the Company’s highly selective, oral menin inhibitor, will be featured in three poster presentations at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held December 9-12, 2023, in San Diego, California (Press release, Syndax, NOV 2, 2023, View Source [SID1234636797]). Copies of the abstracts are now available online via the ASH (Free ASH Whitepaper) website at www.hematology.org.
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"We look forward to sharing updated data, which we believe continue to underscore revumenib’s potential to serve as a first- and best-in-class treatment option for patients with KMT2Ar and mNPM1 acute leukemia across a variety of settings as monotherapy and in combination with standard of care agents," said Michael A. Metzger, Chief Executive Officer. "Following recently reported positive topline data from our pivotal AUGMENT-101 trial, and with an NDA filing on track for year-end, we are excited to finish what has thus far been a transformational year with several key data updates at ASH (Free ASH Whitepaper)."
Phase 1/2 AUGMENT-101 Trial
Pivotal Phase 2 Portion
The Company previously announced positive topline data from the protocol-defined pooled analysis of the pivotal Phase 2 portion of the AUGMENT-101 trial. The trial met its primary endpoint with a complete remission (CR) or a CR with partial hematological recovery (CRh) rate of 23% at the interim analysis of the pooled KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) cohorts (p-value = 0.0036). Based on the Independent Data Monitoring Committee (IDMC) recommendation, the Company stopped the trial to further accrual in the KMT2Ar cohorts. Syndax continues to expect to submit a New Drug Application (NDA) for revumenib for the treatment of relapsed/refractory (R/R) KMT2Ar acute leukemia to the U.S. Food and Drug Administration by year-end under the Real-Time Oncology Review (RTOR) program. Full data from the pivotal portion of the study will be reported at the meeting.
Abstract Number: 2907
Title: Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study
Presenter: Ibrahim Aldoss, M.D.
Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Session Date: Sunday, December 10, 2023
Presentation Time: 6:00 – 8:00 p.m. PT
Phase 1/2 SAVE Study
The Phase 1/2 SAVE study is an investigator-sponsored trial of the all-oral regimen of revumenib, venetoclax, and ASTX727 (fixed-dose combination of decitabine and cedazuridine) in children and adults with R/R AML and mixed phenotype acute leukemias. As of a data cutoff date of July 20, 2023, eight patients were enrolled, with 2.5 median prior lines of therapy.
Seven of eight patients were response-evaluable, and all seven attained a morphologic remission (overall response rate of 100%). Three patients transitioned to hematopoietic stem-cell transplantation (HSCT) following response. Two patients are in continued remission and have started maintenance treatment with revumenib. Enrollment in the study is ongoing, and updated data will be presented at the meeting.
The combination was well tolerated in this relapsed and refractory population. Grade ≥3 treatment related adverse events (TRAEs) were febrile neutropenia (63%), decreased platelets count (25%), and decreased neutrophil count (25%). There was one dose-limiting toxicity (DLT), Grade 4 prolonged thrombocytopenia and neutropenia. There were no deaths due to TRAEs and no Grade 3 or higher QTc prolongation occurred.
Abstract Number: 58
Title: Early Results of the Phase I/II Study Investigating the All-Oral Combination of the Menin Inhibitor Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax in Acute Myeloid Leukemia (SAVE)
Presenter: Ghayas Issa, M.D.
Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Upcoming Therapies in Newly Diagnosed and Relapsed/Refractory AML
Session Date: Saturday, December 9, 2023
Session Time: 9:30 – 11:00 a.m. PT
Presentation Time: 10:15 a.m. PT
Revumenib Maintenance Therapy Post-HSCT
The ASH (Free ASH Whitepaper) abstract #4950 describes data from AUGMENT-101 Phase 1 patients who received revumenib maintenance therapy, including some ongoing for more than one year after HSCT. Revumenib duration of treatment in the maintenance setting at the time of this analysis ranged from 23 to 588 days, with treatment ongoing for five of the nine patients. CRc (CR + CRh + CRp + CRi + MLFS) was maintained in six of nine patients after HSCT and maintenance revumenib. One patient with reported minimal residual disease (MRD) after HSCT converted to MRD negative status following initiation of revumenib maintenance therapy. MRD negative remissions were maintained in five patients as of the data cutoff. Three patients remain on revumenib maintenance therapy for more than one-year post-transplant. The presentation will include longer follow-up of these patients and data from the patients in the pivotal portion of the AUGMENT-101 trial.
Abstract Number: 4950
Title: Revumenib Maintenance Therapy Following Revumenib-Induced Remission and Transplant
Presenter: Andrius Žučenka, M.D.
Session Name: 723. Allogeneic Transplantation: Long-term Follow-up and Disease Recurrence: Poster III
Session Date: Monday, December 11, 2023
Presentation Time: 6:00 – 8:00 p.m. PT
About Revumenib
Revumenib is a potent, selective, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed for the treatment of KMT2A-rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including ALL and AML, and NPM1-mutant AML. Revumenib was granted Orphan Drug Designation by the FDA and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was granted BTD by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement. Syndax expects to complete an NDA submission for KMT2Ar acute leukemia under the Oncology Center of Excellence Review RTOR Program by year-end 2023.
About the AUGMENT-101 trial
AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of orally administered revumenib. The Phase 1 dose escalation portion of AUGMENT-101 included two cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. Arm A enrolled patients not receiving a strong CYP3A4 inhibitor, while Arm B enrolled patients receiving a strong CYP3A4 inhibitor. The Phase 2 pivotal portion of AUGMENT-101 has enrolled R/R patients across the following trial populations: patients with mNPM1 AML, patients with KMT2Ar AML, and patients with KMT2Ar ALL. Following the receipt of Breakthrough Therapy designation from the FDA for revumenib for the treatment of R/R acute leukemia harboring a KMT2A rearrangement, regardless of age or tumor type, and based on discussions with the FDA, the Company decided to pool data from the AUGMENT-101 cohorts enrolling R/R KMT2Ar AML and R/R KMT2Ar ALL. Based on the Independent Data Monitoring Committee (IDMC) recommendation at the protocol pre-specified interim analysis, the Company stopped the trial to further accrual in the KMT2A cohorts. The trial continues to enroll R/R patients with mNPM1 AML and expects to complete enrollment of this cohort by year-end. The primary endpoint for each of the cohorts is efficacy as measured by complete remission rate (CR + CRh) per protocol, with secondary endpoints including duration of response (DOR) and overall survival (OS).
About KMT2A (MLL) Rearranged Acute Leukemia
Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia that is known to have a poor prognosis, with less than 25% of adult patients surviving past five years. KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.
KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques. The median overall survival (OS) after standard of care first-line treatment, including intensive chemotherapy and transplant, is less than one year and the majority of patients suffer relapse within five years. Most R/R patients treated with second-line therapy relapse within the first year. With third line treatment or beyond, only a small percentage of patients achieve complete remission (CR), and the median OS is less than three months. There are currently no approved therapies indicated for KMT2A-rearranged acute leukemia.
About NPM1-Mutant Acute Myeloid Leukemia
NPM1-mutant AML, which is distinguished by mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%. Similar to KMT2A-rearranged acute leukemia, NPM1-mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-KMT2A interaction. NPM1-mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1-mutant AML.