On April 24, 2024 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported 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) (Free ASCO Whitepaper) Annual Meeting, being held May 31 to June 4, 2024 (Press release, SpringWorks Therapeutics, APR 24, 2024, View Source [SID1234642297]). 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.
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Additional data from the Phase 3 DeFi trial of OGSIVEO (nirogacestat) in adults with desmoid tumors were also accepted for presentation at ASCO (Free ASCO Whitepaper), 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 (Free ASCO Whitepaper)," 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. CDT
Type: Rapid Oral Abstract
Session: Developmental Therapeutics: Molecularly Targeted Agents and Tumor Biology
Abstract #: 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. CDT
Type: Rapid Oral Abstract
Session: Sarcoma
Abstract #: 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. CDT
Type: Poster
Session: Sarcoma
Abstract #: 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. CDT
Type: Poster
Session: Sarcoma
Abstract #: 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.