On November 3, 2022 Syndax Pharmaceuticals, Inc. (Nasdaq: SNDX), a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported updated positive data from the Phase 1 portion of the ongoing Phase 1/2 AUGMENT-101 trial of revumenib in patients with nucleophosmin (NPM1) mutant and mixed lineage leukemia rearranged (MLLr) relapsed/refractory (R/R) acute leukemias (Press release, Syndax, NOV 3, 2022, View Source [SID1234622864]). Revumenib is the Company’s highly selective, oral menin inhibitor. Updated data from the Phase 1 portion of the trial will be featured during two oral sessions at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on Saturday, December 10, 2022 at 10:00 a.m. CT and 4:45 p.m. CT. Copies of the abstracts are available on the ASH (Free ASH Whitepaper) website at www.hematology.org.
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"These data continue to showcase revumenib’s potential as a best-in-class treatment option for patients with mNPM1 or MLLr acute leukemia. We are highly encouraged by the updated data including the percentage of patients achieving a CR/CRh, which improved to 30%," said Michael A. Metzger, Chief Executive Officer. "We expect to report top-line data for at least one of the cohorts from the pivotal Phase 2 portion of the AUGMENT-101 trial beginning in the third quarter of 2023, followed by an expected New Drug Application filing by the end of 2023. In addition to the R/R setting, we are committed to unlocking the full potential of revumenib by testing combinations to enable the expansion into newly diagnosed and maintenance settings in mNPM1 and MLLr acute leukemias, as well as into colorectal cancer, our first assessment of revumenib in solid tumors."
The ASH (Free ASH Whitepaper) abstract #63 describes updated results from the Phase 1 portion of the AUGMENT-101 trial. As of the March 2022 data cutoff date, sixty patients with R/R mutant NPM1 or MLLr (KMT2Ar) acute leukemia were efficacy evaluable, an increase of nine patients from the 51 evaluable for efficacy at the 2021 ASH (Free ASH Whitepaper) Annual Meeting. The overall response rate (ORR) was 53% (32/60) with a CR/CRh rate of 30% (18/60). There were no discontinuations due to treatment-related adverse events, and the median duration of response in the trial was 9.1 months as of data cutoff.
Additional results included:
Best Response
Efficacy Population (N=60)
Response
Overall response rate1, n, (%)
32 (53 %)
CR/CRh
18 (30 %)
CR
12 (20 %)
CRh
6 (10 %)
CRp
5 (8 %)
MLFS
9 (15 %)
MRDneg
CRc MRDneg rate2
18/60 (30%)
within CR/CRh MRDneg, n, (%)
14/18 (78%)
within CR/CRh/CRp MRDneg, n, (%)
18/23 (78%)
MLLr (KMT2Ar)
Overall response rate1, n, (%)
27/46 (59%)
CR/CRh
15/46 (33%)
mNPM1
Overall response rate1, n, (%)
5/14 (36%)
CR/CRh
3/14 (21%)
1. Overall Response Rate = CR+CRh+CRp+MLFS; 2. CR+CRh+CRp; MRD status assessed locally by PCR or MCF
Revumenib was well-tolerated, and no new safety signals were identified in the trial, including in patients who proceeded to stem cell transplant. The only dose limiting toxicity observed was asymptomatic Grade 3 QT prolongation. No ventricular arrythmias or other clinical sequelae related to QTc prolongation were reported. All cases of differentiation syndrome were Grade 2, and readily managed with standard therapies.
The ASH (Free ASH Whitepaper) abstract #376 describes outcomes after transplant in patients achieving remissions in the Phase 1 portion of the AUGMENT-101 trial. Across evaluable patients with mNPM1 (n=14) or MLLr (n=46) acute leukemia who received revumenib, 12 (20%) patients proceeded to stem cell transplant, ten (83%) of whom were minimal residual disease-negative. Nine of the 12 patients (75%) who received a stem cell transplant remained in remission as of the data cutoff date, with a median follow-up of 12.3 months, and four patients experienced remission for longer than one year. Three patients were treated in the compassionate use setting with revumenib maintenance following stem cell transplant or non-myeloablative stem cell boost, two (67%) of whom remained in remission as of the data cutoff date for over one year.
Details for the presentations are as follows:
Abstract Number: 63
Title: The Menin Inhibitor SNDX-5613 (revumenib) Leads to Durable Responses in Patients (Pts) with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase (Ph) 1 Study
Presenter: Ghayas Issa, M.D.
Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Relapsed/Refractory AML
Session Date: Saturday, December 10, 2022
Session Time: 9:30 a.m. – 11:00 a.m. CT
Presentation Time: 10:00 a.m. CT
Abstract Number: 376
Title: Outcomes after Transplant in Relapsed/Refractory KMT2Ar (MLLr) and mNPM1 (NPM1c) leukemia Patients Achieving Remissions after Menin Inhibition: SNDX-5613 (revumenib) Ph1 Experience
Presenter: Ghayas Issa, M.D.
Session Name: 723. Allogeneic Transplantation: Long-term Follow-up and Disease Recurrence II
Session Date: Saturday, December 10, 2022
Session Time: 4:00 p.m. – 5:30 p.m. CT
Presentation Time: 4:45 p.m. CT
Conference Call and Webcast
The Company also announced today that it will host a conference call and webcast to discuss the ASH (Free ASH Whitepaper) data update on Sunday, December 11, 2022 at 8:00 a.m. CT/ 9:00 a.m. ET. Joining the call will be members of the Syndax management team as well as principal investigators in the AUGMENT-101 trial.
The live audio webcast and accompanying slides may be accessed through the Events & Presentations page in the Investors section of the Company’s website. Alternatively, the conference call may be accessed through the following:
Conference ID: SYNDAX12
Domestic Dial-in Number: 800-225-9448
International Dial-in Number: 203-518-9708
Live webcast: https://www.veracast.com/webcasts/OpenEx/General/p08Np3.cfm
For those unable to participate in the conference call or webcast, a replay will be available on the Investors section of the Company’s website at www.syndax.com approximately 24 hours after the conference call and will be available for a limited time.
About AUGMENT-101
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 was separated into 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 portion of AUGMENT-101 is currently underway. A total of 64 adult and up to ten pediatric patients will be enrolled across each of the following three distinct trial populations: patients with NPM1 mutant AML, patients with MLLr (KMT2A) AML, and patients with MLLr (KMT2A) ALL. Discussions with the FDA have confirmed that AUGMENT-101 may potentially serve as the basis for regulatory filings in each of the three distinct trials. The primary endpoint for each of the three trials will be efficacy as measured by complete remission rate (CR + CRh), with key secondary endpoints including DOR and overall survival.
About Mixed Lineage Leukemia (MLL a.k.a. KMT2A) Rearranged Acute Leukemias
Rearrangements of the MLL (KMT2A) gene give rise to mixed lineage leukemia rearranged (MLLr) acute leukemias known to have a poor prognosis, with less than 25% of adult patients surviving past five years. MLL rearrangements produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-MLLr interaction has been shown to halt the growth of MLLr leukemic cells. MLLr leukemias, which are routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques, occur in approximately 80% of infant acute leukemias and up to 10% of all acute leukemias. There are currently no approved therapies indicated for MLLr leukemias.
About NPM1 Mutant Acute Myeloid Leukemia
NPM1 mutant acute myeloid leukemia (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 mixed lineage leukemia rearranged (MLLr) leukemias, NPM1 mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-MLL interaction. NPM1 mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1 mutant AML.
About Revumenib
Revumenib is a potent, selective, small molecule inhibitor of the menin-MLL binding interaction that is being developed for the treatment of mixed lineage leukemia rearranged (MLLr) acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1 mutant AML. Revumenib is currently being evaluated in the Company’s AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Robust clinical activity with durable responses have been reported in the Phase 1 portion of AUGMENT-101. Revumenib was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Commission for the treatment of patients with AML, and Fast Track designation by the U.S. FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a mixed lineage leukemia rearranged MLLr or NPM1 mutation.