WALTHAM,
Mass., March 15, 2023 /PRNewswire/ -- Syndax
Pharmaceuticals, Inc. (Nasdaq: SNDX) today announced that data from
the Phase 1 portion of the ongoing Phase 1/2 AUGMENT-101 trial of
revumenib in patients with nucleophosmin mutant (mNPM1) and
KMT2A-rearranged (KMT2Ar) relapsed/refractory (R/R) acute leukemia
and an analysis describing MEN1 mutations observed in the study
have been published in the journal Nature. Revumenib is the
Company's highly selective, oral menin inhibitor.
The Phase 1 publication entitled "The menin inhibitor
revumenib in KMT2A-rearranged or NPM1-mutant leukaemia"
includes positive data from 68 patients with R/R acute
leukemia evaluable for safety, 60 patients of whom had mNPM1
or KMT2Ar acute leukemia and were evaluable for
efficacy. In these heavily pretreated patients with a median
of four prior therapies, 30% (18/60) experienced a CR/CRh with a
median duration of CR/CRh response of 9.1 months. Revumenib was
well-tolerated, and there were no discontinuations due to
treatment-related adverse events. The Phase 1 data were recently
featured in two oral presentations at the 64th American
Society of Hematology Annual Meeting.
"We are excited to have our Phase 1 AUGMENT-101 data published
in such a prominent peer-reviewed journal. As we continue to
deepen our understanding of the tumor biology driven by the
menin-KMT2A interaction, we gain more evidence to support the
potential of revumenib as a best-in-class treatment for both mNPM1
and KMT2Ar acute leukemias," said Michael A. Metzger, Chief
Executive Officer. "With the expectation of topline data from the
pivotal AUGMENT-101 trial beginning in the third quarter of
2023, followed by a potential New Drug Application filing by
the end of 2023, revumenib could become the first menin inhibitor
approved for patient use."
A separate companion article published in Nature entitled
"MEN1 mutations mediate clinical resistance to menin
inhibition" describes somatic mutations in MEN1 that confer
resistance to menin inhibitor treatment and further confirm the
dependency of mNPM1 and KMT2Ar acute leukemias on the menin-KMT2A
interaction. This represents the first report that menin inhibitors
exert sufficient selective pressure to drive evolution of escape
mutants that confer resistance to all first generation menin
inhibitors and impact both mNPM1 and KMT2Ar acute leukemia. These
data were highlighted in an oral presentation at the
64th American Society of Hematology Annual
Meeting.
"The robust clinical dataset from a heavily pretreated
relapsed/refractory patient population demonstrates that revumenib
monotherapy was associated with encouraging clinical benefit,
including deep molecular remissions and durable responses, with
minimal toxicities," said Ghayas C. Issa, M.D., Assistant
Professor, Department of Leukemia, Division of Cancer
Medicine, The University of Texas
MD Anderson Cancer Center and a corresponding author of the Phase 1
publication. "The identified resistance, a class effect among
first-generation menin inhibitors, further validates the
menin-KMT2A interaction as the key driver for both mNPM1 and KMT2Ar
leukemias. Future and ongoing trials may indicate whether treating
patients in earlier settings and in combination would provide
higher response rates in mNPM1 or KMT2Ar acute leukemia patients
who are less likely to have developed functional mutations."
Overview of Phase 1 Data
The Phase 1 publication in
Nature includes data from 68 patients evaluable for safety,
60 patients of whom were evaluable for efficacy, as of a
March 2022 data cutoff. Patients were
heavily pretreated with a median of four prior therapies, and 46%
(31/68) of the patients had at least one prior stem cell
transplant. Within the efficacy evaluable population, the
overall response rate was 53% (32/60) with a CR/CRh rate of 30%
(18/60), and 78% (14/18) of patients with CR/CRh attaining
measurable residual disease (MRD) negativity. The median time to
CR/CRh response in the trial was 1.9 months, and the median
duration of CR/CRh response was 9.1 months in the efficacy
evaluable population as of data cutoff. A total of 38%
(12/32) of responders proceeded to transplant, with nine in
remission at the time of the data cutoff, seven of whom have been
in remission for greater than six months and four who have been in
remission for greater than a year. Eleven (92%) patients who
underwent a transplant were MRD negative prior to transplant.
Revumenib was well-tolerated, and no new safety signals were
identified in the trial, including in patients who proceeded to
stem cell transplant. There were no discontinuations due to
treatment-related adverse events. The only dose limiting toxicity
was asymptomatic Grade 3 QT prolongation, observed in 10% of
patients treated at or below the RP2D and 13% of patients treated
at all doses tested. No ventricular arrythmias or other clinical
sequelae related to QTc prolongation were reported. Differentiation
syndrome occurred in 16% of patients, all which were Grade 2, and
patients responded to standard management of steroids with or
without hydroxyurea.
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 acute lymphoblastic leukemia (ALL) and acute myeloid
leukemia (AML), and NPM1-mutant AML. Revumenib is currently being
evaluated in several clinical trials, including the Company's
pivotal 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 FDA for the treatment of adult and pediatric patients with
R/R acute leukemias harboring a KMT2A rearrangement or NPM1
mutation. Revumenib was also granted Breakthrough Therapy
Designation by the FDA for the treatment of adult and pediatric
patients with R/R acute leukemia harboring a KMT2A
rearrangement.
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 is currently
underway. Patients will be enrolled across the following trial
populations: patients with NPM1-mutant AML, patients with KMT2Ar
AML, and patients with KMT2Ar ALL, each of which may serve as the
basis for regulatory filings. 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 will pool data from the AUGMENT-101 cohorts enrolling R/R
KMT2Ar AML and R/R KMT2Ar ALL to file a single NDA for the
treatment of adult and pediatric KMT2Ar acute leukemia. The primary
endpoint for each of the trials is efficacy as measured by complete
remission rate (CR + CRh), with key 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 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
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
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.
About Syndax Pharmaceuticals, Inc.
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, both currently in pivotal clinical trials. 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,"
"believe" and similar expressions (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 progress of regulatory submissions and approvals,
including the potential use of Syndax's 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; the
impact of macroeconomic conditions (such as COVID-19 pandemic,
the Russia-Ukraine war, inflation, among others) on
Syndax's business and that of the third parties on which Syndax
depends, including delaying or otherwise disrupting Syndax's
clinical trials and preclinical studies, manufacturing and supply
chain, or impairing employee productivity; 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.
Syndax Contact
Sharon Klahre
Syndax Pharmaceuticals, Inc.
sklahre@syndax.com
Tel 781.684.9827
SNDX-G
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SOURCE Syndax Pharmaceuticals, Inc.