SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage
biopharmaceutical company focused on severe rare diseases and
cancer, today announced that data from the Phase 2b ReNeu trial
evaluating mirdametinib, an investigational MEK inhibitor, in
pediatric and adult patients with neurofibromatosis type
1-associated plexiform neurofibromas (NF1-PN) will be presented in
an oral presentation at the 2024 American Society of Clinical
Oncology (ASCO) Annual Meeting, being held May 31 to June 4, 2024.
SpringWorks recently initiated a rolling submission of a New Drug
Application (NDA) to the U.S. Food and Drug Administration (FDA)
for mirdametinib in pediatric and adult patients with NF1-PN.
Additional data from the Phase 3 DeFi trial of OGSIVEO®
(nirogacestat) in adults with desmoid tumors were also accepted for
presentation at ASCO, including an abstract describing the onset
and resolution of ovarian toxicity for desmoid tumor patients
treated with nirogacestat, as well as two additional sub-group
analyses evaluating nirogacestat in desmoid tumor patients with
poor prognostic factors and in those with adenomatous polyposis
coli (APC) mutations.
“The Phase 2b ReNeu trial data are the cornerstone of our NDA
for mirdametinib in NF1-PN, and we are very pleased that these data
were accepted for an oral presentation at ASCO,” said Jim Cassidy,
M.D., Ph.D., Chief Medical Officer of SpringWorks. “We also look
forward to presenting additional data from our Phase 3 DeFi trial
and believe the results will further reinforce the robust safety
and efficacy profile of nirogacestat in adult patients with desmoid
tumors.”
Details of the presentations are as follows:
Presentation Title |
Presenter |
Presentation Details |
ReNeu: A pivotal phase 2b trial of mirdametinib in children and
adults with neurofibromatosis type 1 (NF1)-associated symptomatic
inoperable plexiform neurofibroma (PN) |
Christopher Moertel, M.D. |
Date and Time: June 3, 8:00 - 9:30 a.m.
CDTType: Rapid Oral
AbstractSession: Developmental Therapeutics:
Molecularly Targeted Agents and Tumor BiologyAbstract
#: 3016 |
Monitoring ovarian function in oncology studies: Results and
insights from the DeFi phase 3 study of nirogacestat in desmoid
tumor |
Elizabeth Loggers, M.D., Ph.D. |
Date and Time: May 31, 2:45 - 4:15 p.m.
CDTType: Rapid Oral
AbstractSession: SarcomaAbstract
#: 11520 |
Efficacy of nirogacestat in patients with poor prognostic factors
for desmoid tumors: Analyses from the randomized phase 3 DeFi
study |
Bruno Vincenzi, M.D., Ph.D. |
Date and Time: June 1, 1:30 - 4:30 p.m.
CDTType: PosterSession:
SarcomaAbstract #: 11556 |
Efficacy and safety of nirogacestat in patients with desmoid tumor
and adenomatous polyposis coli (APC) mutation: phase 3 DeFi
analyses |
Bernd Kasper, M.D., Ph.D. |
Date and Time: June 1, 1:30 - 4:30 p.m.
CDTType: PosterSession:
SarcomaAbstract #: 11558 |
About the ReNeu Trial
ReNeu (NCT03962543) is an ongoing, multi-center, open-label
Phase 2b trial evaluating the efficacy, safety, and tolerability of
mirdametinib in patients two years of age and older with an
inoperable NF1-associated PN causing significant morbidity. The
study enrolled 114 patients to receive mirdametinib at a dose of 2
mg/m2 twice daily (maximum dose of 4 mg twice daily) without
regard to food. Mirdametinib was administered orally in a 3-week
on, 1-week off dosing schedule and has a pediatric formulation
(dispersible tablet) for patients who cannot swallow a pill. The
primary endpoint of the ReNeu trial was confirmed objective
response rate defined as ≥ 20% reduction in target tumor volume as
measured by MRI and assessed by blinded independent central review.
Secondary endpoints included safety and tolerability, duration of
response, and changes from baseline in patient reported
outcomes.
About NF1-PN
Neurofibromatosis type 1 (NF1) is a rare genetic disorder that
arises from mutations in the NF1 gene, which encodes for
neurofibromin, a key suppressor of the MAPK pathway.1,2 NF1 is the
most common form of neurofibromatosis, with an estimated global
birth incidence of approximately 1 in 2,500 individuals, and
approximately 100,000 patients living with NF1 in the United
States.3,4 The clinical course of NF1 is heterogeneous and
manifests in a variety of symptoms across numerous organ systems,
including abnormal pigmentation, skeletal deformities, tumor growth
and neurological complications, such as cognitive impairment.5
Patients with NF1 have an eight to 15-year mean reduction in their
life expectancy compared to the general population.2
NF1 patients have approximately a 30-50% lifetime risk of
developing plexiform neurofibromas, or PN, which are tumors that
grow in an infiltrative pattern along the peripheral nerve sheath
and that can cause severe disfigurement, pain and functional
impairment; in rare cases, NF1-PN may be fatal.6,7 Patients with
NF1-PN can also experience additional manifestations, including
neurocognitive deficits and developmental delays. NF1-PNs are most
often diagnosed in the first two decades of life.6 These tumors can
be aggressive and are associated with clinically significant
morbidities; typically, they grow more rapidly during
childhood.8,9
Surgical removal of these tumors is challenging due to the
infiltrative tumor growth pattern along nerves and can lead to
permanent nerve damage and disfigurement.10 MEK inhibitors have
emerged as a validated class of treatment for NF1-PN.11
About Mirdametinib
Mirdametinib is a potent, oral, allosteric small molecule MEK
inhibitor in development as a monotherapy treatment for
neurofibromatosis type 1-associated plexiform neurofibromas
(NF1-PN) and low-grade glioma (LGG), and as a combination therapy
for the treatment of several subsets of biomarker-defined
metastatic solid tumors. Mirdametinib is an investigational drug
for which safety and efficacy have not been established.
Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy
pivotal positions in the MAPK pathway. The MAPK pathway is a key
signaling network that regulates cell growth and survival and that
plays a central role in multiple oncology and rare disease
indications when genetically altered.
The FDA and the European Commission have granted Orphan Drug
designation for mirdametinib for the treatment of NF1. The FDA has
also granted Fast Track designation for the treatment of patients ≥
2 years of age with NF1-PN that are progressing or causing
significant morbidity and Rare Pediatric Disease designation for
the treatment of NF1.
About the DeFi Trial
DeFi (NCT03785964) is a global, randomized (1:1), double-blind,
placebo-controlled Phase 3 trial evaluating the efficacy, safety
and tolerability of nirogacestat in adult patients with progressing
desmoid tumors. The double-blind phase of the study randomized 142
patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of
nirogacestat or placebo twice daily. Key eligibility criteria
included tumor progression by ≥20% as measured by Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months
prior to screening. The primary endpoint was progression-free
survival, as assessed by blinded independent central review, or
death by any cause. Secondary and exploratory endpoints include
safety and tolerability measures, objective response rate (ORR),
duration of response, changes in tumor volume assessed by magnetic
resonance imaging (MRI), and changes in patient-reported outcomes
(PROs). DeFi includes an open-label extension phase, which is
ongoing.
About Desmoid Tumors
Desmoid tumors (sometimes referred to as aggressive
fibromatosis, or desmoid fibromatosis) are rare, aggressive,
locally invasive tumors of the soft tissues that can be serious,
debilitating, and, in rare cases when vital structures are
impacted, life-threatening.12,13
Desmoid tumors are most commonly diagnosed in patients between
the ages of 20 and 44 years, with a two-to-three times higher
prevalence in females.14,15 It is estimated that there are
1,000-1,650 new cases diagnosed per year in the United
States.15,18,19
Although they do not metastasize, desmoid tumors are associated
with recurrence rates of up to 77% after surgical
resection.14,16,17 Desmoid tumor experts and treatment guidelines
now recommend systemic therapies as first-line intervention instead
of surgery for most tumor locations requiring treatment.17
About OGSIVEO® (nirogacestat)
OGSIVEO (nirogacestat) is an oral, selective, small molecule
gamma secretase inhibitor approved in the United States for the
treatment of adult patients with progressing desmoid tumors who
require systemic treatment.
OGSIVEO is not approved for the treatment of any other
indication in the United States, or for any indication in any other
jurisdiction by any other health authority.
SpringWorks is also evaluating nirogacestat as a potential
treatment for patients with ovarian granulosa cell tumors and for
patients with multiple myeloma as part of several B-cell maturation
agent (BCMA) combination therapy regimens in collaboration with
leaders in industry and academia.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
- Diarrhea: Diarrhea,
sometimes severe, can occur in patients treated with OGSIVEO.
Diarrhea occurred in 84% of patients treated with OGSIVEO, and
included Grade 3 events in 16% of patients. Median time to first
diarrhea event was 9 days (range: 2 to 434 days). Monitor patients
and manage using antidiarrheal medications. Modify dose as
recommended.
- Ovarian Toxicity:
Female reproductive function and fertility may be impaired in
patients treated with OGSIVEO. Impact on fertility may depend on
factors like duration of therapy and state of gonadal function at
time of treatment. Long-term effects of OGSIVEO on fertility have
not been established. Advise patients on the potential risks for
ovarian toxicity before initiating treatment. Monitor patients for
changes in menstrual cycle regularity or the development of
symptoms of estrogen deficiency, including hot flashes, night
sweats, and vaginal dryness.
- Hepatotoxicity: ALT
or AST elevations occurred in 30% and 33% of patients,
respectively. Grade 3 ALT or AST elevations (>5 × ULN) occurred
in 6% and 2.9% of patients. Monitor liver function tests regularly
and modify dose as recommended.
- Non-Melanoma Skin
Cancers: New cutaneous squamous cell carcinoma and basal
cell carcinoma occurred in 2.9% and 1.4% of patients, respectively.
Perform dermatologic evaluations prior to initiation of OGSIVEO and
routinely during treatment.
- Electrolyte
Abnormalities: Decreased phosphate (65%) and potassium
(22%) occurred in OGSIVEO-treated patients. Phosphate <2 mg/dL
occurred in 20% of patients. Grade 3 decreased potassium occurred
in 1.4% of patients. Monitor phosphate and potassium levels
regularly and supplement as necessary. Modify dose as
recommended.
- Embryo-Fetal
Toxicity: OGSIVEO can cause fetal harm when administered
to pregnant women. Oral administration of nirogacestat to pregnant
rats during the period of organogenesis resulted in embryo-fetal
toxicity and death at maternal exposures below human exposure at
the recommended dose of 150 mg twice daily. Advise pregnant women
of the potential risk to a fetus. Advise females and males of
reproductive potential to use effective contraception during
treatment with OGSIVEO and for 1 week after the last dose.
ADVERSE REACTIONS
- The most common (≥15%) adverse
reactions were diarrhea (84%), ovarian toxicity (75% in the 36
females of reproductive potential), rash (68%), nausea (54%),
fatigue (54%), stomatitis (39%), headache (30%), abdominal pain
(22%), cough (20%), alopecia (19%), upper respiratory tract
infection (17%), and dyspnea (16%).
- Serious adverse reactions occurred
in 20% of patients who received OGSIVEO. Serious adverse reactions
occurring in ≥2% of patients were ovarian toxicity (4%).
- The most common laboratory
abnormalities (≥15%) were decreased phosphate, increased urine
glucose, increased urine protein, increased AST, increased ALT, and
decreased potassium.
DRUG INTERACTIONS
- CYP3A Inhibitors and
Inducers: Avoid concomitant use with strong or moderate
CYP3A inhibitors (including grapefruit products, Seville oranges,
and starfruit) and strong or moderate CYP3A inducers.
- Gastric Acid Reducing
Agents: Avoid concomitant use with proton pump inhibitors
and H2 blockers. If concomitant use cannot be avoided, OGSIVEO can
be staggered with antacids (e.g., administer OGSIVEO 2 hours before
or 2 hours after antacid use).
- Consult the full Prescribing
Information prior to and during treatment for important drug
interactions.
USE IN SPECIFIC POPULATIONS
- Because of the potential for serious
adverse reactions in breastfed children, advise women not to
breastfeed during treatment with OGSIVEO and for 1 week after the
last dose.
To report suspected adverse reactions, contact SpringWorks
Therapeutics at 1-888-400-SWTX (1-888-400-7989) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full U.S. Prescribing Information for OGSIVEO for
more information.
About SpringWorks Therapeutics
SpringWorks is a commercial-stage biopharmaceutical company
applying a precision medicine approach to developing and delivering
life-changing medicines for people with severe rare diseases and
cancer. OGSIVEO® (nirogacestat), approved in the United States for
the treatment of adult patients with progressing desmoid tumors who
require systemic treatment, is the Company’s first FDA-approved
therapy. SpringWorks also has a diversified targeted therapy
pipeline spanning solid tumors and hematological cancers, with
programs ranging from preclinical development through advanced
clinical trials. In addition to its wholly owned programs,
SpringWorks has also entered into multiple collaborations with
innovators in industry and academia to unlock the full potential
for its portfolio and create more solutions for patients in
need.
For more information, visit www.springworkstx.com and
follow @SpringWorksTx on X (formerly
Twitter), LinkedIn, and YouTube.
SpringWorks Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, relating to our business, operations, and
financial conditions, including but not limited to current beliefs,
expectations and assumptions regarding the future of our business,
future plans and strategies, our development and commercialization
plans, our preclinical and clinical results, the potential for
mirdametinib to become an important new treatment for pediatric and
adult patients with NF1-PN, the potential for the results of the
Phase 2b ReNeu clinical trial to support an NDA submission, the
timing of our planned NDA submission for mirdametinib, our plans
for seeking regulatory approval for and making mirdametinib
available to NF1-PN patients, if approved, as well as relating to
other future conditions. Words such as, but not limited to, “look
forward to,” “believe,” “expect,” “anticipate,” “estimate,”
“intend,” “plan,” “would,” “should” and “could,” and similar
expressions or words, identify forward-looking statements. New
risks and uncertainties may emerge from time to time, and it is not
possible to predict all risks and uncertainties. Any
forward-looking statements in this presentation are based on
management’s current expectations and beliefs and are subject to a
number of risks, uncertainties and important factors that may cause
actual events or results to differ materially from those expressed
or implied by any forward-looking statements contained in this
presentation, including, without limitation, risks relating to: (i)
our expectations regarding the potential clinical benefit of
mirdametinib for patients with NF1-PN, (ii) estimates regarding the
global birth incidence of NF1-PN and the number of patients living
with NF1-PN in the United States and the potential market for
mirdametinib, (iii) the fact that topline or interim data from
clinical studies may not be predictive of the final or more
detailed results of such study or the results of other ongoing or
future studies, (iv) the timing of our planned regulatory
submissions and interactions, including the timing and outcome of
decisions made by the U.S. Food and Drug Administration (FDA),
European Medicines Agency (EMA), and other regulatory authorities,
investigational review boards at clinical trial sites and
publication review bodies, (v) whether FDA, EMA, or other
regulatory authorities will require additional information or
further studies, or may fail or refuse to approve or may delay
approval of our product candidates, including nirogacestat and
mirdametinib, (vi) our ability to obtain regulatory approval of any
of our product candidates or maintain regulatory approvals granted
for our products, (vii) our ability to maintain adequate patent
protection and successfully enforce patent claims against third
parties, and (viii) our ability to meet any specific milestones set
forth herein.
Except as required by applicable law, we do not plan to publicly
update or revise any forward-looking statements contained herein,
whether as a result of any new information, future events, changed
circumstances or otherwise. Although we believe the expectations
reflected in such forward-looking statements are reasonable, we can
give no assurance that such expectations will prove to be correct.
Accordingly, readers are cautioned not to place undue reliance on
these forward-looking statements.
For further information regarding the risks, uncertainties and
other factors that may cause differences between SpringWorks’
expectations and actual results, you should review the “Risk
Factors” in Item 1A of Part I of SpringWorks’ Annual Report on Form
10-K for the year ended December 31, 2023, as well as discussions
of potential risks, uncertainties and other important factors in
SpringWorks’ subsequent filings.
Contacts
Kim DiamondVice President, Communications and Investor
RelationsPhone: 203-561-1646 Email: kdiamond@springworkstx.com
Samantha Hilson SandlerSenior Director, Investor RelationsPhone:
203-461-5501Email: samantha.sandler@springworkstx.com
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