– Subgroup analyses from Ph 2 protocol-defined
R/R mNPM1 AML efficacy population (N=64) show responses across
all major subgroups, including heavily pretreated patients
–
– 26% CR+CRh (20/77) and 48% ORR (37/77) in
all enrolled patients who met the efficacy evaluable
criteria in Ph 2 R/R mNPM1 AML cohort –
– 100% ORR (37/37) and 95% CRc (35/37) in BEAT
AML trial exploring revumenib in combination with
venetoclax/azacitidine in newly diagnosed mNPM1 or KMT2Ar AML
–
– BEAT AML data highlight the potential for
revumenib to advance the current standard of care –
WALTHAM,
Mass., Dec. 9, 2024 /PRNewswire/ -- Syndax
Pharmaceuticals (Nasdaq: SNDX), a commercial-stage
biopharmaceutical company developing an innovative pipeline of
cancer therapies, today announced additional positive data from the
AUGMENT-101 trial of Revuforj® (revumenib) in relapsed or
refractory (R/R) mutant NPM1 (mNPM1) acute myeloid leukemia (AML)
and the BEAT AML trial of revumenib in combination with venetoclax
and azacitidine in newly diagnosed AML patients. Revuforj is the
Company's 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.
"These new data continue to highlight the exciting potential for
Revuforj as both a monotherapy and in combination with other
therapies," said Michael A. Metzger,
Chief Executive Officer of Syndax. "The recent approval of Revuforj
for R/R acute leukemia with a KMT2A translocation, coupled with the
consistency of the results we have reported across KMT2Ar and mNPM1
within the different trials and populations, continues to bolster
our confidence in its practice-changing and blockbuster
potential."
Additional Results from R/R mNPM1 AML Patients in Pivotal
Phase 2 Portion of AUGMENT-101
Syndax recently announced that the primary endpoint was met
with a complete remission (CR) plus CR with partial hematological
recovery (CRh) rate of 23% (15/64; 95% confidence interval [CI]:
14%, 36%; one-sided p-value =0.0014) in the protocol-defined
efficacy population of 64 adults with R/R mNPM1 AML in the Phase 2
cohort of the AUGMENT-101 trial of revumenib (DCO: September 2024). The median duration of CR/CRh
responses was 4.7 months at the time of the data cutoff with three
patients remaining in response. Minimal residual disease (MRD)
status was assessed in 14 of 15 patients who achieved CR/CRh, 64%
(9/14) of whom were MRD negative. The overall response rate
(ORR)1 was 47% (30/64). The safety profile observed with
revumenib in the 84 patients enrolled in the cohort was consistent
with previously reported data.
Syndax announced today additional results from the Phase 2
cohort of R/R mNPM1 AML patients in the AUGMENT-101 trial,
including data generated from the protocol-defined efficacy
population of 64 adults and a post-hoc efficacy analysis based on
all patients who met the efficacy evaluable criteria.
Subgroup analyses from the Phase 2 protocol-defined R/R mNPM1
efficacy population (N=64) show that CR/CRh responses were observed
across all major subgroups, including patients with multiple prior
lines of therapy and prior venetoclax exposure, although the trial
was not powered to evaluate differences among subgroups. The CR+CRh
rate was 25% (4/16) among patients with 1 prior line of therapy,
20% (5/25) among patients with 2 prior lines of therapy, and 26%
(6/23) among patients who had received three or more prior lines of
therapy. The CR+CRh rate was 44% (7/16) among patients without
prior venetoclax exposure and 17% (8/48) among patients with prior
venetoclax exposure. Historically, AML patients who have failed
prior treatment with venetoclax are unlikely to respond to
subsequent therapy, with a CR rate of 6% reported for other
targeted therapies after prior venetoclax therapy.2
Syndax also shared results from an expanded analysis of the R/R
mNPM1 AML patients who enrolled into the Phase 2 cohort of
AUGMENT-101. Among the 84 patients enrolled in the cohort, 77 met
the efficacy evaluable criteria requiring patients to have blast
counts >5% measured within 28 days prior to treatment and a
centrally confirmed NPM1 mutation. In this expanded post-hoc
efficacy analysis, 48% (37/77; 95% CI: 37%, 60%) achieved an
overall response, and 26% (20/77; 95% CI: 17%, 37%) achieved a
CR/CRh. The median duration of CR/CRh response was 4.7 months as of
the September 2024 DCO. Minimal
residual disease (MRD) status was assessed in 19 of 20 patients who
achieved CR/CRh, 63% (12/19) of whom were MRD
negative.
Updated Data from BEAT-AML Trial of Revumenib in Combination
with Venetoclax and Azacitidine in Newly Diagnosed AML
Patients
Today the company announced an update from the Phase 1 BEAT-AML
trial evaluating the combination of revumenib with venetoclax and
azacitidine in newly diagnosed mNPM1 or KMT2A-rearranged (KMT2Ar)
AML patients aged 60 years or older. The trial is being conducted
as part of the Leukemia & Lymphoma Society's Beat AML® Master
Clinical Trial. Today's update builds on the BEAT AML data that was
presented in June at the European Hematology Association (EHA)
2024 Congress from 24 efficacy evaluable patients showing a
composite complete remission (CRc) rate of 96% (23/24) as of a
May 2024 data cutoff.
As of a November 2024 data cutoff,
46 newly diagnosed mNPM1 (n=37) or KMT2Ar (n=9) patients have been
enrolled in BEAT AML across two dose levels of revumenib (113 mg
q12 or 163 mg q12h with azoles) in combination with venetoclax and
azacitidine. The median age of patients enrolled was 71 years
(range: 60-92).
The efficacy evaluable population includes 37 patients across
both dose levels with an ORR1 of 100% (37/37) and CRc
rate of 95% (35/37). The rate of MRD negativity was 95% (35/37).
27% (10/37) of patients proceeded to hematopoietic stem cell
transplant (HSCT).
Revumenib was generally well tolerated at both the 113 mg and
163 mg q12h dose in combination with venetoclax and azacitidine. In
the safety population (N=46), 15% (7/46) of patients experienced
differentiation syndrome with two (4%) Grade 3 or greater events.
43% (20/46) of patients experienced QTc prolongation with five
(11%) Grade 3 or greater events. DS and QTc prolongations were
self-limiting and did not cause any discontinuations. Analysis of
the onset and extent of hematologic toxicities suggest a similar
experience to what has been reported for the venetoclax/azacitidine
doublet alone. Overall, there were no new or increased safety
signals observed when revumenib was included in this triplet
combination.
"These are very exciting data that highlight the potential for
revumenib to enhance the responses typically observed with
venetoclax/azacitidine in newly diagnosed patients with mNPM1 or
KMT2Ar who are unfit to receive intensive chemotherapy," said
Joshua F. Zeidner, M.D., Chief,
Leukemia Research at the University of North
Carolina, Lineberger Comprehensive Cancer Center. "These new
data continue to show that revumenib has a safety profile that
could enable it to be combined with venetoclax/azacitidine and,
importantly, we are observing high rates of response and MRD
negativity that underscore the potential for revumenib to become an
integral component of frontline treatment for KMT2Ar and mNPM1 AML
patients."
Enrollment in the expansion cohort is ongoing at both dose
levels. The Company plans to initiate a pivotal trial with this
combination in front-line newly diagnosed patients by year-end
2024.
Syndax Corporate Event
The new data described above, along with other data presented
through today at the 66th ASH Annual Meeting being held in
San Diego, CA for both the
Revuforj (revumenib) and Niktimvo (axatilimab-csfr) clinical
programs, will be highlighted at the Company's investor event on
Monday, December 9, 2024 at
7:00 a.m. PT/10:00 a.m. ET. The live audio webcast and
accompanying slides for the event may be accessed through the
Events & Presentations page in the Investors section of
the Company's website or directly through the meeting link
here.
For those unable to participate in the conference call or
webcast for the event, a replay will be available on the Investors
section of the Company's website at www.syndax.com for a limited
time.
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. The Company
expects to file a supplemental NDA filing for revumenib in R/R
mNPM1 AML in the first half of 2025. 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 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
1. Overall response rate (ORR) 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
2. Bewersdorf JP, Shallis RM, Derkach A, et al. Efficacy
of FLT3 and IDH1/2 inhibitors in patients with acute myeloid
leukemia previously treated with venetoclax. Leuk Res. 2022;122:106942.
doi:10.1016/j.leukres.2022.106942
Contact
Sharon
Klahre
Syndax Pharmaceuticals, Inc.
sklahre@syndax.com
Tel 781.684.9827
SNDX-G
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SOURCE Syndax Pharmaceuticals, Inc.