On November 27, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that the U.S. Food and Drug Administration (FDA) has approved OGSIVEO (nirogacestat), an oral gamma secretase inhibitor, for the treatment of adult patients with progressing desmoid tumors who require systemic treatment (Press release, SpringWorks Therapeutics, NOV 27, 2023, View Source [SID1234637977]). The FDA previously granted breakthrough therapy, fast track and orphan drug designations to nirogacestat for the treatment of desmoid tumors.
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"Our team is honored to deliver the first FDA-approved therapy for patients with desmoid tumors. This community has been waiting for an effective treatment that not only shrinks their tumors but also significantly improves pain, which is the most debilitating symptom reported by people living with desmoid tumors," said Saqib Islam, Chief Executive Officer of SpringWorks. "We are pleased with the broad label, which includes all progressing adult patients and specifically references improvement in pain, and believe OGSIVEO has the potential to become the new standard of care for people living with these devastating tumors. This is a watershed moment for the desmoid tumor community and we would like to extend our gratitude to the patients, families, investigators, and advocacy groups involved in the journey to making OGSIVEO available in the U.S."
Desmoid tumors are locally aggressive and invasive soft-tissue tumors that can lead to substantial morbidity.2,3 In addition, when vital structures are impacted, desmoid tumors can be life-threatening.3 Although they do not metastasize, desmoid tumors are often refractory to existing off-label systemic therapies and associated with recurrence rates of up to 77% following surgical resection.4-6 Desmoid tumor experts and treatment guidelines now recommend systemic therapies as first-line intervention instead of surgery for most tumor locations requiring treatment.6
"Desmoid tumors can have a significant impact on people’s lives and are difficult to manage due to their invasive nature and high rates of recurrence. OGSIVEO is a highly innovative therapy with efficacy data demonstrating both meaningful antitumor activity and a significant improvement in desmoid tumor symptoms," said Mrinal M. Gounder, M.D., sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York City and an investigator in the Phase 3 DeFi trial. "As a treating physician, it was encouraging to see in the DeFi trial that OGSIVEO achieved statistically significant and clinically meaningful improvements across the primary and all key secondary endpoints, while also having a manageable safety profile. This approval represents an important therapeutic advance for patients."
The FDA approval of OGSIVEO is based on the results from the Phase 3 DeFi trial, which were published in the March 9, 2023 edition of the New England Journal of Medicine.7 OGSIVEO met the primary endpoint of improving progression-free survival (PFS), demonstrating a statistically significant improvement over placebo with a 71% reduction in the risk of disease progression (hazard ratio (HR) = 0.29 (95% CI: 0.15, 0.55); p< 0.001). Median PFS was not reached in the OGSIVEO arm and was 15.1 months in the placebo arm. Confirmed objective response rate (ORR) based on RECIST v1.1 was 41% with OGSIVEO versus 8% with placebo (p<0.001); the complete response rate was 7% in the OGSIVEO arm and 0% in the placebo arm. The median time to first response was 5.6 months with OGSIVEO and 11.1 months with placebo.7 PFS and ORR improvements were in favor of OGSIVEO regardless of baseline characteristics including sex, tumor location, tumor focality, treatment status, previous treatments, mutational status, and history of familial adenomatous polyposis.7,8 OGSIVEO also demonstrated early and sustained improvements in patient-reported outcomes (PROs), including pain (p<0.001), desmoid tumor-specific symptoms (p<0.001), physical/role functioning (p<0.001), and overall health-related quality of life (p≤0.01).7
OGSIVEO exhibited a manageable safety and tolerability profile. The most common adverse events (>15%) reported in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea. Please see Important Safety Information below, including Warnings & Precautions relating to diarrhea, ovarian toxicity, hepatotoxicity, non-melanoma skin cancers, electrolyte abnormalities, and embryo-fetal toxicity.1
"Today is an extraordinary day for the desmoid tumor community. This approval is the culmination of a collaborative effort between the patient community, academia and the biopharmaceutical industry, who worked together with tenacity and persistence to advance promising science," said Jeanne Whiting, Executive Director Emeritus and Co-Founder of the Desmoid Tumor Research Foundation. "Our hope is that patients and their families will benefit from greater awareness of desmoid tumors, faster diagnoses, and better outcomes now that there is an approved and effective treatment."
SpringWorks is dedicated to helping patients with desmoid tumors access OGSIVEO and to providing support throughout their treatment journey. As part of this commitment, the Company is introducing SpringWorks CareConnections, a comprehensive patient support program that offers personalized services to eligible OGSIVEO patients, including insurance coverage information and access support, financial assistance and personalized educational and emotional support. Physicians and patients can contact 1-844-CARES-55 (1-844-227-3755) or visit www.springworkstxcares.com for more information.
OGSIVEO will be available to order through a specialty pharmacy and specialty distributor network in the United States within five to ten business days. SpringWorks expects to file a Marketing Authorisation Application for OGSIVEO in desmoid tumors with the European Medicines Agency in the first half of 2024.
Conference Call and Webcast Information
SpringWorks will host a conference call and webcast to discuss the FDA approval of OGSIVEO on Tuesday, November 28, 2023, at 8:00 a.m. ET. To join the live webcast and view the corresponding slides, please click here. To access the live call by phone, please pre-register for the call here. Once registration is complete, participants will be provided with a dial-in number and conference code to access the call. A replay of the webcast will be available for a limited time following the event on the Investors and Media section of the Company’s website at View Source
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 occurred in 84% of patients treated with OGSIVEO. Grade 3 events occurred in 16% of patients. 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 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: Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity 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, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.
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.
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 Prescribing Information for OGSIVEO for more information.
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.2,3
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.4,9 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.9-11
Although they do not metastasize, desmoid tumors are associated with recurrence rates of up to 77% after surgical resection.4-6 Desmoid tumor experts and treatment guidelines now recommend systemic therapies as first-line intervention instead of surgery for most tumor locations requiring treatment.