– Pivotal AUGMENT-101 trial met its primary
endpoint at interim analysis of the pooled KMT2Ar AML and ALL
cohorts (p-value = 0.0036); CR/CRh rate consistent across adult and
pediatric patients –
– 63% overall response rate; responses
observed across all major subgroups –
– Median overall survival at time of
data cutoff of 8.0 months –
– Favorable safety and tolerability profile;
treatment discontinuations were low at 6% with none due to
differentiation syndrome or QTc prolongation –
– Supportive results from the AUGMENT-101
trial, including post-transplant maintenance data, continues to
demonstrate consistent clinically meaningful responses across
subgroups –
WALTHAM,
Mass., Dec. 12, 2023 /PRNewswire/ -- Syndax
Pharmaceuticals (Nasdaq: SNDX), a clinical stage biopharmaceutical
company developing an innovative pipeline of cancer therapies,
today presented positive data from the protocol-defined pooled
analysis of the pivotal AUGMENT-101 trial of revumenib, a
first-in-class menin inhibitor, in adult and pediatric patients
with relapsed/refractory (R/R) KMT2A-rearranged (KMT2Ar) acute
myeloid leukemia (AML) and acute lymphoid leukemia (ALL) at the
65th American Society of Hematology (ASH) Annual Meeting
being held December 9-12, 2023 in
San Diego, California. The pivotal
results were featured in a late-breaking oral presentation titled
"Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar
Acute Leukemia: Topline Efficacy and Safety Results from the
Pivotal AUGMENT-101 Phase 2 Study."
Additional supportive results from the AUGMENT-101 trial,
including data from patients in the Phase 1 portion and patients
who received revumenib maintenance therapy after hematopoietic stem
cell transplant (HSCT), were also featured in two poster
presentations at the meeting, titled "Revumenib Monotherapy in
Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Efficacy
and Safety Results from the AUGMENT-101 Phase 1/2 Study" and
"Revumenib Maintenance Therapy Following Revumenib-Induced
Remission and Transplant."
"We are thrilled to present additional detail on the positive
results for revumenib in KMT2Ar acute leukemia that continue to
demonstrate its consistently impressive clinical profile as a
potential monotherapy for these patients," said Michael A.
Metzger, Chief Executive Officer of Syndax. "We look forward to
delivering on several important, near-term milestones across our
pipeline, including submitting a New Drug Application to the U.S.
Food and Drug Administration for revumenib for the treatment of R/R
KMT2Ar acute leukemia at year-end."
Pivotal Phase 2 Portion of AUGMENT-101 Trial
The AUGMENT-101 trial met its primary endpoint at the
protocol-defined interim analysis with a complete remission (CR) or
a CR with partial hematological recovery (CRh) rate of 23% (13/57;
95% confidence interval [CI]: [12.7, 35.8, one-sided p-value =
0.0036]) among the 57 efficacy evaluable patients in the pooled
KMT2Ar acute leukemia population. The CR/CRh rate was 23% (10/44;
95% CI: 11.5, 37.8) in adult patients and 23% in pediatric patients
(3/13; 95% CI: 5.0, 53.8), with a median time to CR/CRh of 1.9
months (95% CI: 0.9, 4.5). The CR/CRh responses in both the overall
population and the AML subset were durable with a 6.4-month (95%
CI: 3.4, NR) median duration as of the July
24, 2023 data cutoff, with 46% (6/13) remaining in response.
Minimal residual disease (MRD) status was assessed in 10 of the 13
patients who achieved a CR/CRh, 70% (7/10) of whom were MRD
negative. In patients who achieved a CRc (CR+CRh+CRp+Cri), 68%
(15/22) achieved MRD negative status.
In the efficacy-evaluable patients, the overall response
rate1 was 63% (36/57; 95% CI: [49.3, 75.6]), and the
composite response rate (CRc) was 44% (25/57). Minimal residual
disease (MRD) status was assessed in 22 of the 25 patients who
achieved a CRc, 68% (15/22) of whom were MRD negative.
Responses were observed in all major subgroups, including across
the number of prior treatments and prior stem cell transplant. A
total of 14 (39%) patients who achieved an overall response
underwent HSCT, eight of whom did not achieve a CR or CRh prior to
transplant. Half (7/14) of the patients who had an HSCT received
post-transplant maintenance with revumenib and three additional
patients (3/14; 21%) were in follow-up and are eligible to restart
revumenib as post-transplant maintenance. Median overall survival
at the time of data cutoff was 8.0 months (95% CI: 4.1, 10.9).
"I am pleased that this pivotal dataset of revumenib as a
monotherapy in heavily pretreated R/R patients continues to support
its profile as a potential best- and first-in-class therapy,"
said Ibrahim Aldoss, M.D., Attending Physician and Associate
Professor, Division of Leukemia, Department of Hematology &
Hematopoietic Cell Transplantation at City of Hope, and Principal
Investigator in the AUGMENT-101 trial. "Of particular note,
the data presented today demonstrate rapid responses with
revumenib, with a median time to CR/CRh of 1.9 months, which is
particularly impressive in this patient population. Responses were
also observed across all major subgroups, with a similar CR/CRh
rate across adult and pediatric patients, which speaks to the wide
clinical utility of revumenib across this underserved patient
population."
AUGMENT-101 enrolled a total of 94 acute leukemia patients in
the KMT2Ar cohorts of the pivotal trial as of the July 2023 data cutoff, 57 of whom had central
confirmation of their KMT2Ar status, sufficient follow-up and were
in the efficacy-evaluable population. The majority of patients
included in the efficacy-evaluable population (56%; 32/57) relapsed
following treatment with at least one salvage regimen (refractory
relapse patients) prior to enrollment, including nearly half (46%;
26/57) having undergone prior stem cell transplant. Seventy-two
percent (41/57) of patients were previously treated with
venetoclax.
Revumenib was well tolerated and the safety profile was
consistent with the Company's previously reported data.
Treatment-related adverse events (TRAEs) leading to dose reductions
and treatment discontinuation were low at 9% (8/94) and 6% (6/94),
respectively. TRAEs of any grade in greater than 20% of patients
included nausea (28%), differentiation syndrome (DS) (27%), and QTc
prolongation (23%). Grade 3 DS was observed in 15% (14/94) of
patients while one patient (1%) experienced Grade 4 DS and no
patients experienced a Grade 5. Grade 3 QTc prolongation was
observed in 14% (13/94) of patients, with no Grade 4 or 5
events. There were no discontinuations related to DS,
cytopenias or QTc prolongation on the trial.
Revumenib Maintenance Therapy Post-HSCT
Data featured in a poster presentation from AUGMENT-101 Phase 1
patients who received revumenib maintenance therapy, including some
ongoing for more than one year after HSCT, demonstrated revumenib
duration of treatment in the maintenance setting at the time of
this analysis ranged from 1 to 701 days, with treatment ongoing for
nine of the 16 patients. CRc was maintained in 12 patients after
HSCT and maintenance revumenib. MRD negative remissions were
maintained in six patients as of the data cutoff with one patient
converting from an MRD+ to MRD- response. Three patients remain on
revumenib maintenance therapy for more than one-year
post-transplant.
Phase 1 Portion of AUGMENT-101 Trial
In the Phase 1 portion of the study, patients were assigned to
one of six dose-escalation cohorts designed to identify a
recommended phase 2 dose (RP2D) for concomitant administration with
a strong CYP3A4 inhibitor and without a strong CYP3A4 inhibitor. As
of the July 2023 data cutoff, 77
patients with R/R KMT2Ar acute leukemia were enrolled in the Phase
1 study and were included in the overall population. Most
patients were female (60%), and 34% of patients had ≥4 prior lines
of therapy and 47% had prior HSCT.
Updated follow-up on Phase 1 data presented at the meeting
continues to demonstrate clinically meaningful response, high
percentage of responders proceeding to transplant, consistency of
response across subgroups, and a manageable safety profile in
heavily pretreated patients with R/R KMT2Ar acute leukemia. Phase 1
KMT2Ar patients demonstrated a CR/CRh rate of 31.2%, and ORR of
64.9%, with 38% proceeding to HSCT. In adults with AML (n=51), the
CR/CRh rate was 37.3% and ORR was 68.6%, with 40% of responders
proceeding to HSCT. Pediatric patients (n=15) demonstrated
consistent response rates, with a CR/CRh rate of 20.0% and an ORR
of 66.7%, with 40% of responders proceeding to transplant.
Copies of the ASH presentations are available in
the Publications and Meeting Presentations section of
Syndax's website.
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 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 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 in late 1Q24 or early 2Q24. 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. 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. With third line treatment or
beyond, less than 5% 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 Syndax
Syndax Pharmaceuticals is a clinical stage
biopharmaceutical company developing an innovative pipeline of
cancer therapies. Highlights of the Company's pipeline include
revumenib, a highly selective inhibitor of the menin–KMT2A binding
interaction, and axatilimab, a monoclonal antibody that blocks the
colony stimulating factor 1 (CSF-1) receptor. For more information,
please visit www.syndax.com or follow the Company
on Twitter and LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995. Words such as "may," "will," "expect," "plan," "anticipate,"
"estimate," "intend," "could," "believe" and similar expressions
such as "look forward" (as well as other words or expressions
referencing future events, conditions or circumstances) are
intended to identify forward-looking statements. These
forward-looking statements are based on Syndax's expectations and
assumptions as of the date of this press release. Each of these
forward-looking statements involves risks and uncertainties. Actual
results may differ materially from these forward-looking
statements. Forward-looking statements contained in this press
release include, but are not limited to, statements about the
progress, timing, clinical development and scope of clinical
trials, the reporting of clinical data for Syndax's product
candidates, the potential submission of an NDA by year-end, and the
potential use of our product candidates to treat various cancer
indications and fibrotic diseases. Many factors may cause
differences between current expectations and actual results,
including: unexpected safety or efficacy data observed during
preclinical or clinical trials; clinical trial site activation or
enrollment rates that are lower than expected; changes in expected
or existing competition; changes in the regulatory environment;
failure of Syndax's collaborators to support or advance
collaborations or product candidates; and unexpected litigation or
other disputes. Other factors that may cause Syndax's actual
results to differ from those expressed or implied in the
forward-looking statements in this press release are discussed in
Syndax's filings with the U.S. Securities and Exchange
Commission, including the "Risk Factors" sections contained
therein. Except as required by law, Syndax assumes no obligation to
update any forward-looking statements contained herein to reflect
any change in expectations, even as new information becomes
available.
References
1 Overall response rate includes CR, CRh, CRp,
CRi, MLFS, and PR; Composite complete remission (CRc) includes CR,
CRh, CRp, and CRi
CR = Complete remission
CRh = Complete remission with partial hematologic recovery
CRp = Complete remission with incomplete platelet recovery
CRi = Complete remission with incomplete count recovery
MLFS = Morphologic leukemia-free state
PR = Partial response
Syndax Contact
Sharon Klahre
Syndax Pharmaceuticals, Inc.
sklahre@syndax.com
Tel 781.684.9827
SNDX-G
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