– Approval based on positive data from the
AUGMENT-101 clinical trial, in which Revuforj delivered robust and
durable rates of remission in R/R acute leukemia patients
with a KMT2A translocation –
– Syndax to host conference call today at
6:00 p.m. ET –
WALTHAM,
Mass., Nov. 15, 2024 /PRNewswire/ -- Syndax
Pharmaceuticals (Nasdaq: SNDX) today announced that the U.S. Food
and Drug Administration (FDA) has approved Revuforj®
(revumenib) as the first and only menin inhibitor for the treatment
of relapsed or refractory (R/R) acute leukemia with a lysine
methyltransferase 2A gene (KMT2A) translocation in adult and
pediatric patients one year and older. The FDA previously granted
Breakthrough Therapy and Fast Track designations as well as
Priority Review for Revuforj. The New Drug Application (NDA)
received approval through the FDA's Real Time Oncology Review
(RTOR) program.
"The approval of Revuforj is a remarkable achievement that
reflects the dedication and tenacity of everyone involved,
especially the patients and clinicians who participated in our
trial and our talented Syndax team," said Michael A. Metzger, Chief Executive Officer of
Syndax. "We are well-prepared to launch Revuforj this month and we
are committed to rapidly advancing the development of Revuforj
across the treatment continuum for KMT2A-rearranged acute leukemias
and mutant NPM1 AML."
The efficacy evaluation of Revuforj was based on an FDA analysis
of 104 patients with R/R acute leukemia with a KMT2A translocation
who were treated with Revuforj in the Phase 1/2 AUGMENT-101 trial.
In the efficacy population, the rate of complete remission (CR)
plus CR with partial hematological recovery (CRh) was 21% (22/104
pts; 95% CI: 13.8%, 30.3%). The median duration of CR+CRh was 6.4
months (95% CI: 2.7, not estimable) and the median time to CR or
CRh was 1.9 months (range: 0.9, 5.6 months). Twenty-three percent
(24/104 pts) of patients underwent hematopoietic stem cell
transplantation (HSCT) following treatment with Revuforj. Results
from the 104-patient efficacy analysis are consistent with the
previously reported, protocol-defined Phase 2 interim analysis of
patients with R/R KMT2Ar acute leukemia in the AUGMENT-101 trial
(n=57) which were published in the Journal of Clinical
Oncology1.
"The FDA approval of the first menin inhibitor is a major
breakthrough for patients with R/R acute leukemia with a KMT2A
translocation, a genetic alteration associated with a very poor
prognosis," said Ghayas C. Issa, M.D., Associate Professor of
Leukemia at The University of Texas MD
Anderson Cancer Center. "The significant clinical benefit and
robust efficacy seen with Revuforj represents a substantial
improvement over what has been historically observed in these
patients with previously available therapies and has the potential
to be an important new treatment option for patients."
The safety evaluation of Revuforj was based on an FDA analysis
of 135 patients with R/R acute leukemia with a KMT2A translocation
who were treated with Revuforj. The most common adverse reactions
(≥20%) including laboratory abnormalities were hemorrhage, nausea,
phosphate increased, musculoskeletal pain, infection, aspartate
aminotransferase increased, febrile neutropenia, alanine
aminotransferase increased, parathyroid hormone intact increased,
bacterial infection, diarrhea, differentiation syndrome,
electrocardiogram QT prolonged, phosphate decreased, triglycerides
increased, potassium decreased, decreased appetite, constipation,
edema, viral infection, fatigue, and alkaline phosphatase
increased. Adverse reactions leading to dose reduction or
permanent discontinuation were low at 10% and 12% of patients,
respectively.
Rearrangements of the KMT2A gene (KMT2Ar) give rise to an
aggressive form of acute leukemia that is associated with a very
poor prognosis and high relapse rates.2 It is
estimated that more than 95% of patients with KMT2Ar acute leukemia
have a KMT2A translocation, a type of rearrangement that occurs
when part of one chromosome breaks and fuses to a different
chromosome.3 More than half of patients with KMT2Ar
acute leukemia will relapse after receiving conventional frontline
therapies, with a median overall survival (OS) of less than one
year.4 With third line treatment or beyond, only 5% of
patients achieve complete remission, and the median OS is less than
three months.4
Syndax expects that the 110 and 160 mg tablets of Revuforj will
be available for order in the United
States through a network of specialty distributors and
specialty pharmacies in November. Syndax expects that the 25 mg
tablets, which may be used to treat patients who weigh less than 40
kg, will be commercially available in late first quarter or early
second quarter of 2025. Prior to commercial availability of the 25
mg tablets, an oral solution of revumenib will be available through
an expanded access program to allow for dosing of patients who
weigh less than 40 kg.
Syndax is committed to supporting patients and removing barriers
to access. As part of that commitment, Syndax has established
SyndAccess™, a robust program that offers personalized support and
resources to U.S. patients who are prescribed Revuforj, including
financial assistance for eligible patients. For more information,
visit SyndAccess.com or call 1-888-567-SYND (7963), Monday-Friday,
9:00 AM to 6:00 PM Eastern Time
(ET).
Conference Call and Webcast
Syndax will host a conference call and webcast to discuss the
FDA approval of Revuforj today, November
15, 2024, at 6:00 p.m. ET.
The live webcast 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: Syndax Conference Call 2
U.S. and Canada: (800)
590-8290
International: (240) 690-8800
Webcast URL:
https://www.veracast.com/webcasts/syndax/events/specialconf2.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 90 days
following the call.
About Revuforj® (revumenib)
Revuforj (revumenib) is an oral, first-in-class menin inhibitor
that is FDA approved for the treatment of relapsed or refractory
(R/R) acute leukemia with a lysine methyltransferase 2A gene
(KMT2A) translocation in adult and pediatric patients one year and
older.
Revumenib is in development for the treatment of R/R acute
myeloid leukemia (AML) with a nucleophosmin 1 mutation (mNPM1).
Positive pivotal data from the AUGMENT-101 trial in this population
with revumenib as a monotherapy were recently reported.
Additionally, multiple trials of revumenib in combination with
standard-of-care agents in mNPM1 AML or KMT2A-rearranged acute
leukemia are ongoing across the treatment landscape, including in
newly diagnosed patients.
Revumenib was previously granted Orphan Drug Designation for the
treatment of AML, ALL and acute leukemias of ambiguous lineage
(ALAL) by the U.S. FDA and for the treatment of AML by the European
Commission. The U.S. FDA also granted Fast Track designation to
revumenib for the treatment of adult and pediatric patients with
R/R acute leukemias harboring a KMT2A rearrangement or NPM1
mutation and Breakthrough Therapy Designation for the treatment of
adult and pediatric patients with R/R acute leukemia harboring a
KMT2A rearrangement.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME
Differentiation syndrome, which can be fatal, has occurred
with Revuforj. Signs and symptoms may include fever, dyspnea,
hypoxia, pulmonary infiltrates, pleural or pericardial effusions,
rapid weight gain or peripheral edema, hypotension, and renal
dysfunction. If differentiation syndrome is suspected, immediately
initiate corticosteroid therapy and hemodynamic monitoring until
symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation syndrome: Revuforj can cause fatal or
life-threatening differentiation syndrome (DS). Symptoms of
DS, including those seen in patients treated with Revuforj, include
fever, dyspnea, hypoxia, peripheral edema, pleuropericardial
effusion, acute renal failure, and/or hypotension. In clinical
trials, DS occurred in 39 (29%) of 135 patients treated with
Revuforj. DS was Grade 3 or 4 in 13% of patients and fatal in one.
The median time to onset was 10 days (range 3-41 days). Some
patients experienced more than 1 DS event. Treatment interruption
was required for 7% of patients, and treatment was withdrawn for
1%.
Reduce the white blood cell count to less than 25 Gi/L prior to
starting Revuforj. If DS is suspected, immediately initiate
treatment with systemic corticosteroids (e.g., dexamethasone 10-mg
IV every 12 hours in adults or dexamethasone 0.25-mg/kg/dose IV
every 12 hours in pediatric patients weighing less than 40 kg) for
a minimum of 3 days and until resolution of signs and symptoms.
Institute supportive measures and hemodynamic monitoring until
improvement. Interrupt Revuforj if severe signs and/or symptoms
persist for more than 48 hours after initiation of systemic
corticosteroids, or earlier if life-threatening symptoms occur such
as pulmonary symptoms requiring ventilator support. Restart
steroids promptly if DS recurs after tapering corticosteroids.
QTc interval prolongation: In the clinical trials, QTc
interval prolongation was reported as an adverse reaction in 39
(29%) of 135 patients treated with Revuforj. QTc interval
prolongation was Grade 3 in 12% of patients. The heart-rate
corrected QT interval (using Fridericia's method) (QTcF) was
greater than 500 msec in 8%, and the increase from baseline QTcF
was greater than 60 msec in 18%. Revuforj dose reduction was
required for 5% of patients due to QTc interval prolongation. QTc
prolongation occurred in 16% of the 31 patients less than 17 years
old, 33% of the 88 patients 17 years to less than 65 years old, and
in 50% of the 16 patients 65 years or older.
Correct electrolyte abnormalities, including hypokalemia and
hypomagnesemia, prior to treatment with Revuforj. Perform an
electrocardiogram (ECG) prior to initiation of Revuforj, and do not
initiate Revuforj in patients with QTcF >450 msec. Perform an
ECG at least once weekly for the first 4 weeks and at least monthly
thereafter. In patients with congenital long QTc syndrome,
congestive heart failure, electrolyte abnormalities, or those who
are taking medications known to prolong the QTc interval, more
frequent ECG monitoring may be necessary. Concomitant use with
drugs known to prolong the QTc interval may increase the risk of
QTc interval prolongation.
- Interrupt Revuforj if QTcF increases >480 msec and <500
msec, and restart Revuforj at the same dose twice daily after the
QTcF interval returns to ≤480 msec
- Interrupt Revuforj if QTcF increases >500 msec or by >60
msec from baseline, and restart Revuforj twice daily at the
lower-dose level after the QTcF interval returns to ≤480 msec
- Permanently discontinue Revuforj in patients with ventricular
arrhythmias and in those who develop QTc interval prolongation with
signs or symptoms of life-threatening arrhythmia.
Embryo-fetal toxicity: Revuforj can cause fetal harm when
administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
and males with female partners of reproductive potential to use
effective contraception during treatment with Revuforj and for 4
months after the last dose of Revuforj.
ADVERSE REACTIONS
Fatal adverse reactions occurred in 4 (3%) patients who received
Revuforj, including 2 with differentiation syndrome, 1 with
hemorrhage, and 1 with sudden death.
Serious adverse reactions were reported in 99 (73%) patients.
The most frequent serious adverse reactions (≥5%) were
infection (24%), febrile neutropenia (19%), bacterial infection
(17%), differentiation syndrome (12%), hemorrhage (9%), and
thrombosis (5%).
The most common adverse reactions (≥20%) including
laboratory abnormalities, were hemorrhage (53%), nausea (51%),
phosphate increased (50%), musculoskeletal pain (42%), infection
(41%), aspartate aminotransferase increased (37%), febrile
neutropenia (35%), alanine aminotransferase increased (33%),
parathyroid hormone intact increased (33%), bacterial infection
(31%), diarrhea (30%), differentiation syndrome (29%),
electrocardiogram QT prolonged (29%), phosphate decreased (25%),
triglycerides increased (25%), potassium decreased (24%), decreased
appetite (24%), constipation (23%), edema (23%), viral infection
(23%), fatigue (22%), and alkaline phosphatase increased (21%).
DRUG INTERACTIONS
Drug interactions can occur when
Revuforj is concomitantly used with:
- Strong CYP3A4 inhibitors: reduce Revuforj dose
- Strong or moderate CYP3A4 inducers: avoid concomitant use with
Revuforj
- QTc-prolonging drugs: avoid concomitant use with Revuforj. If
concomitant use is unavoidable, obtain ECGs when initiating, during
concomitant use, and as clinically indicated. Withhold Revuforj if
the QTc interval is >480 msec. Restart Revuforj after the QTc
interval returns to ≤480 msec.
SPECIFIC POPULATIONS
Lactation: advise
lactating women not to breastfeed during treatment with Revuforj
and for 1 week after the last dose.
Pregnancy and testing: Revuforj can cause fetal harm when
administered to a pregnant woman. Verify pregnancy status in
females of reproductive potential within 7 days prior to initiating
Revuforj.
Pediatric: monitor bone growth and development in
pediatric patients.
Geriatric: compared to younger patients, the incidences
of QTc prolongation and edema were higher in patients 65 years and
older.
Infertility: based on findings in animals, Revuforj may
impair fertility. The effects on fertility were reversible.
To report SUSPECTED ADVERSE REACTIONS, contact Syndax
Pharmaceuticals at 1-888-539-3REV or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
Please see Full Prescribing Information,
including BOXED WARNING.
About KMT2A-Rearranged Acute Leukemia
Rearrangements of the KMT2A gene (KMT2Ar) give rise to an
aggressive form of acute leukemia that is associated with a very
poor prognosis and high relapse rates.2 It is
estimated that more than 95% of patients with KMT2Ar acute leukemia
have a KMT2A translocation, a type of rearrangement that occurs
when part of one chromosome breaks and fuses to a different
chromosome.3
In KMT2Ar acute leukemias, binding of KMT2A fusion proteins with
the protein called menin drives the activation of a leukemogenic
transcriptional pathway. Inhibition of the menin-KMT2A interaction
has been shown to alter the transcription of multiple genes
including differentiation markers. KMT2Ar AML and ALL have a rapid
onset and quick progression that makes early identification of a
KMT2A rearrangement critical.4,5 It is routinely
diagnosed through currently available cytogenetic or molecular
diagnostic techniques.
About Syndax
Syndax Pharmaceuticals is a commercial-stage
biopharmaceutical company developing an innovative pipeline of
cancer therapies. Highlights of the Company's pipeline include
Revuforj® (revumenib), an FDA-approved menin inhibitor,
and Niktimvo™ (axatilimab-csfr), an FDA-approved monoclonal
antibody that blocks the colony stimulating factor 1 (CSF-1)
receptor. Fueled by our commitment to reimagining cancer care,
Syndax is working to unlock the full potential of its pipeline and
is conducting several clinical trials across the continuum of
treatment. For more information, please visit www.syndax.com/ or
follow the Company on X (formerly 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 "anticipate," "believe," "could," "estimate,"
"expects," "intend," "may," "plan," "potential," "predict,"
"project," "should," "will," "would" or the negative or plural of
those terms, 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 acceptance of Syndax and its partners' products in
the marketplace, sales, marketing, manufacturing and distribution
requirements, and the potential use of its 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 to Revuforj's commercial availability, 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
- Issa GC, et al. Menin Inhibition with Revumenib for
KMT2A-Rearranged Relapsed or Refractory Acute Leukemia
(AUGMENT-101). J Clin Oncol. Published online August 9, 2024. doi:10.1200/JCO.24.00826
- Issa, GC, et al. Therapeutic implications of menin inhibition
in acute leukemias. Leukemia 35, 2482–2495 (2021).
- Meyer, C, et al. The KMT2A recombinome of acute leukemias in
2023. Leukemia 37, 988–1005 (2023).
- Issa GC, et al. Predictors of outcomes in adults with acute
myeloid leukemia and KMT2A rearrangements. Blood Cancer J.
2021;11:162.
- Nguyen D, et al. Early mortality in acute myeloid leukemia with
KMT2A rearrangement is associated with high risk of bleeding and
disseminated intravascular coagulation. Cancer.
2023;129(12):1856-1865.
Investor Contact
Sharon
Klahre
Syndax Pharmaceuticals, Inc.
sklahre@syndax.com
Tel 781.684.9827
Media Contact
media@syndax.com
SNDX-G
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