–
82% ORR (27 of 33 pts) and 48%
CR/CRh (16 of 33 pts) in SAVE trial studying revumenib in
combination with venetoclax and decitabine/cedazuridine in R/R
AML –
–
64% ORR (62 of 97 pts) and 23%
CR/CRh (22 of 97 pts) with high rates of MRD negativity and ability
to proceed to HSCT in expanded dataset of Ph 2 R/R KMT2Ar acute
leukemia patients in AUGMENT-101 –
–
Responses were rapid, durable and observed across all
major subgroups in expanded dataset of
Ph 2 R/R KMT2Ar acute leukemia patients in AUGMENT-101 –
–
Latest data highlight the compelling clinical profile of
revumenib and support advancement into combination trials in the
frontline setting –
WALTHAM,
Mass., Dec. 7, 2024 /PRNewswire/ -- Syndax
Pharmaceuticals (Nasdaq: SNDX), a commercial-stage
biopharmaceutical company developing an innovative pipeline of
cancer therapies, today presented positive data from multiple
trials of Revuforj® (revumenib) as a single-agent and in
combination with standard of care agents in patients with acute
leukemias in oral sessions at the 66th American Society
of Hematology (ASH) Annual Meeting being held in San Diego, December
7-10, 2024. 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.
"On the heels of the recent approval of Revuforj for R/R acute
leukemia with a KMT2A translocation, we are excited to present
clinical data highlighting the consistent efficacy and favorable
tolerability of this first-in-class therapy, as both a single-agent
and in combination with standard of care, in patients with mNPM1
and KMT2Ar acute leukemia," said Michael A.
Metzger, Chief Executive Officer. "We are thrilled that our
U.S. launch of Revuforj is firmly underway, and we look forward to
building on this momentum as we continue to advance our clinical
development program which we believe will position us to pursue
meaningful label expansion opportunities."
Overview of Revumenib Data Presented in Oral Sessions at
66th ASH Annual Meeting
Results from Phase 1/2 SAVE Trial of Revumenib in Combination
with Venetoclax and Decitabine/Cedazuridine in R/R AML
The Phase 1/2 SAVE trial is an investigator-sponsored trial
testing an all-oral regimen of revumenib, venetoclax and the
hypomethylating agent (HMA) ASTX727 (decitabine/cedazuridine) in
pediatric and adult patients with R/R acute myeloid leukemia (AML)
or mixed-lineage acute leukemia (MPAL) harboring either KMT2Ar,
NUP98r or mNPM1 alterations. In the previously announced ASH
abstract, data from 26 patients in the SAVE trial were reported
(data cutoff [DCO]: July 2024).
During the oral session at the ASH meeting, data from 33
patients were presented (DCO: November
2024). The median age of patients enrolled in the trial was
35 (range 12-81), and 16 patients (49%) had KMT2Ar, 12 patients
(36%) had mNPM1, and five patients (15%) had NUP98r. Patients had
received a median of three (range: 1-5) prior lines of therapy; 58%
had prior venetoclax, 36% had prior hematopoietic stem cell
transplantation (HSCT), and 6% had received a prior menin
inhibitor.
The all-oral combination resulted in high rates of remission in
patients with KMT2Ar, mNPM1, and NUP98r with an overall response
rate (ORR)1 of 82%
(27/33) and a CR/CRh rate of 48% (16/33). In patients with minimal
residual disease (MRD) status available, 65% (17/26) who achieved a
response were MRD negative, and among patients who achieved a
CR/CRh response, 88% (14/16) were MRD negative. 39% (13/33) of
patients proceeded to HSCT following this combination, with 54%
(7/13) of patients resuming revumenib post-HSCT.
With a median follow-up of 9.3 months (N=33), the 6-month
overall survival (OS) was 68% (95% CI: 47%, 80%); median OS was not
reached. The median duration of CR/CRh response was also not
reached.
The combination was generally well tolerated in this population.
The most common (>20%) Grade 3 or higher treatment-emergent
adverse events (TEAEs) were febrile neutropenia (33%) and lung
infection (33%). Grade 3 treatment-emergent differentiation
syndrome (DS) was observed in one patient (3%), with no Grade 4 or
Grade 5 events. Grade 3 treatment-emergent QTc prolongation was
observed in two patients (6%) and Grade 4 was observed in one
patient (3%) with no Grade 5 events.
"The latest SAVE data show high efficacy and the ability to
combine revumenib with venetoclax and hypomethylating agents, which
highlights the potential for this combination to become a treatment
for patients with acute leukemias that are susceptible to menin
inhibition," said Ghayas C. Issa,
M.D., Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center. "In
particular, the high rates of overall response, MRD negativity, and
HSCT in the R/R cohort are very encouraging, as well as the initial
duration of response and overall survival data. These promising
data underpin our excitement to expand the SAVE trial to evaluate
the combination in newly diagnosed AML patients who are older or
unfit for intensive chemotherapy."
Data from Phase 2 Portion of the AUGMENT-101 Trial of
Revumenib in R/R KMT2Ar Acute Leukemia
A larger data set with longer follow-up data (DCO: February 2024) from the pivotal Phase 2 portion
of the AUGMENT-101 trial of revumenib in R/R KMT2A-rearranged
(KMT2Ar) acute leukemia were presented at the 66th ASH
Annual Meeting. This larger efficacy population is comprised of 97
patients, including the 57 patients from the previously
reported Phase 2 protocol-defined interim efficacy analysis
(DCO: July 2023).
As described in the previously announced ASH abstract, the
CR+CRh rate was 23% (22/97), CRc was 42% (41/97), and ORR was 64% (62/97) among the 97 efficacy
evaluable patients. In patients with MRD results available, 61%
(11/18) of CR/CRh responders and 58% (21/36) of CRc responders
achieved MRD negativity. Of the 62 patients who achieved
ORR, 34% (21/62) proceeded to HSCT
and nine resumed revumenib post-HSCT.
During the oral session at the ASH meeting, the Company
presented additional data from this larger data set showing that
responses were observed across all major subgroups, including
heavily pretreated patients, patients with prior venetoclax
exposure, and patients of all ages. The updated analyses also show
that of the 21 responders who proceeded to HSCT, 67% (14/21) went
to transplant in CRc [38% (8/21) in CR/CRh and 29% (6/21) in
CRp/CRi] and 33% (7/21) went to transplant in MLFS. Of the patients
who proceeded to transplant in CRc and had MRD results available,
82% (9/11) were MRD negative.
Time to response was rapid with a median time to ORR of 1.0 months (range: 0.9-3.1) and median
time to CR/CRh of 2.0 months (range: 0.9-4.6). As previously
reported, the median duration of CR/CRh was 6.4 months among the 22
CR/CRh responders. Of note, with seven months of additional
follow-up, the median duration of CR/CRh extended to 13 months
among the 13 CR/CRh responders included in the interim analysis
presented at the ASH Annual Meeting in 2023.
In this larger data set, which includes 116 patients in the
safety population, revumenib was generally well tolerated and the
safety profile was consistent with the Company's previously
reported data. Treatment-related adverse events (TRAEs) and
treatment-emergent adverse events (TEAEs) leading to treatment
discontinuation were low at 5% (6/116) and 14% (16/116),
respectively. The most common Grade 3 or higher TEAEs were
consistent with previously reported data. Grade 3
treatment-emergent DS was observed in 14% (16/116) of patients and
one patient (1%) experienced a Grade 4 DS. Grade 3
treatment-emergent QTc prolongation was observed in 13% (15/116) of
patients, with no Grade 4 or Grade 5 events. No patients
discontinued treatment due to differentiation syndrome, QTc
prolongation, or cytopenias.
Initial Results from INTERCEPT Platform Trial of Revumenib as
Pre-Emptive Therapy for MRD Positive AML
INTERCEPT is an investigator-sponsored platform trial evaluating
the use of novel therapies, including revumenib, to target MRD and
early relapse in AML. This proof-of-concept trial is exploring
whether targeting MRD in patients with AML may be an effective
approach to maintaining patients in first or second
remission.
As of the latest data cutoff, 14 patients with MRD relapse (13
with mNPM1 and one with KMT2Ar) were enrolled in the safety cohort
and received revumenib. The median age was 56 years; 12 were in
first remission and two were in second remission. Prior to starting
revumenib treatment, two patients received venetoclax-based
treatment and 12 received prior intensive chemotherapy-based
treatment as their frontline therapy. In the safety cohort (N=14),
the most common (>10%) Grade 3 or higher TEAEs were neutropenia,
thrombocytopenia, and QTc interval prolongation. There were no
reports of DS, and no Grade 5 events.
Among the 11 efficacy evaluable mNPM1 patients who received
revumenib, 54% (6/11) patients had MRD reduction at any time,
including 36% (4/11) who achieved MRD negativity. These initial
data support the further evaluation of revumenib as a novel
approach to targeting MRD relapse.
Copies of the ASH presentations are available in
the Publications and Meeting Presentations section of
Syndax's website.
Syndax Corporate Event
Data presented by the Company at the 66th ASH Annual
Meeting from 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 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. 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.
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. It is routinely diagnosed through
currently available cytogenetic or molecular diagnostic
techniques.
About Mutant NPM1 (mNPM1) Acute Myeloid Leukemia
(AML)
Mutations in the NPM1 gene are the most common genetic
alteration in adult AML and are observed in approximately 30% of
cases. Patients with relapsed or refractory mNPM1 AML have a poor
prognosis and high unmet need. Similar to KMT2A-rearranged acute
leukemia, mNPM1 AML is highly dependent on the expression of
specific developmental genes shown to be negatively impacted by
inhibitors of the menin-KMT2A interaction. mNPM1 AML is routinely
diagnosed through currently available screening techniques. There
are currently no approved targeted therapies for mNPM1 AML.
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
Syndax Contact
Sharon Klahre
Syndax Pharmaceuticals, Inc.
sklahre@syndax.com
Tel 781.684.9827
SNDX-G
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