Ogsiveo (nirogacestat) / EMD Serono - LARVOL DELTA

Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial. (PubMed, J Clin Oncol) - P3 | "Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis."

Journal • Desmoid Tumors • Oncology • Sarcoma

AQbD-driven development of a green RP-HPLC method for nirogacestat with LC-MS structural elucidation. (PubMed, BMC Chem) - "The method's greenness was demonstrated using AGREE, AGSA, CACI, CaFRI, and a multi-assessment tool, with an overall whiteness index of 74%. Overall, this ethanol-based AQbD-optimized method offers a reliable, sustainable, and regulatory-compliant platform for impurity profiling and stability testing of NGT."

Journal • Desmoid Tumors • Oncology • Sarcoma

A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: Children's Oncology Group | Trial completion date: Mar 2026 ➔ Dec 2032

Trial completion date • Desmoid Tumors • Fibrosis • Sarcoma • Solid Tumor • CTNNB1

Regulatory Signaling Pathways in Ovarian Cancer Stem Cells: Their Role in Tumor Progression and Therapeutic Strategies. (PubMed, Iran Biomed J) - "Various therapeutic agents have been studied to target these pathways in OCSCs, including γ-secretase inhibitors (nirogacestat), smoothened inhibitors (vismodegib and sonidegib), and Wnt/β-catenin inhibitors (PRI-724 and ipafricept). To improve treatment outcomes, strategies involving combination approaches and personalized treatments need to be explored. This review aims to summarize current evidence on the role of Wnt/β-catenin, Notch, and Hedgehog signaling pathways in OCSCs and their therapeutic implications in ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Tumor volume and T2 hyperintensity changes from DeFi: A phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors. (ASCO 2023) - P3 | "In DeFi, nirogacestat demonstrated substantial reduction of tumor volume and T2 hyperintensity of the largest target tumors by MRI compared with placebo in adults with DT. These results are consistent with the significant improvement in ORR achieved with nirogacestat. These data suggest that volumetric MRI and T2 hyperintensity might provide additional information in the evaluation of treatment response in DT."

Clinical • P3 data • Desmoid Tumors • Oncology • Sarcoma

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors. (PubMed, N Engl J Med) - P3 | "Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.)."

Journal • Desmoid Tumors • Fatigue • Oncology • Pain • Renal Disease • Sarcoma • Solid Tumor

NIROGACESTAT TREATMENT IN ADULT PATIENTS WITH DESMOID TUMORS: LONG-TERM EFFICACY AND SAFETY FROM THE PHASE 3 DEFI TRIAL (CTOS 2024) - No abstract available

Clinical • P3 data • Desmoid Tumors • Oncology • Sarcoma

TECLISTAMAB (TEC) + NIROGACESTAT (NIRO) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): THE PHASE 1B MAJESTEC-2 STUDY (EHA 2023) - "The combination of tec + niro yielded response rates of 57–92% across 3 dose levels assessed. This initial experience with tec + niro provides insights on the combination of BCMA-directed therapies with a gamma secretase inhibitor. Phase I, Bispecific, Multiple myeloma, B-cell maturation antigen"

P1 data • Anemia • Cardiovascular • Dermatology • Fatigue • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Multiple Myeloma • Neutropenia • Novel Coronavirus Disease • Oncology • Septic Shock

EFFICACY OF NIROGACESTAT IN PATIENTS WITH DESMOID TUMORS AND POOR PROGNOSTIC FACTORS: PATIENT-REPORTED OUTCOMES, PROGRESSION-FREE SURVIVAL, AND OBJECTIVE RESPONSE RATE IN THE PHASE 3 DEFI TRIAL (CTOS 2024) - No abstract available

Biomarker • Clinical • P3 data • Patient reported outcomes • Desmoid Tumors • Oncology • Sarcoma

DEFI: A PHASE 3, RANDOMIZED, DOUBLE-BLIND TRIAL OF NIROGACESTAT VERSUS PLACEBO FOR PROGRESSING DESMOID TUMORS/AGGRESSIVE FIBROMATOSIS (CTOS 2022) - No abstract available

Clinical • P3 data • Desmoid Tumors • Fibrosis • Oncology • Sarcoma • Solid Tumor

DeFi: A phase III, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT) (ESMO 2022) - P3 | "Table: LBA2 Primary and secondary efficacy endpoints a - indicates improvement. b + indicates improvement."

Clinical • Late-breaking abstract • P3 data • Desmoid Tumors • Oncology • Sarcoma

The role of γ-secretase in familial hidradenitis suppurativa: Implications for pathogenesis and targeted therapy. (PubMed, JAAD Case Rep) - No abstract available

Journal • Dermatology • Hidradenitis Suppurativa • Immunology

Phase II clinical trial of nirogacestat in patients with relapsed ovarian granulosa cell tumours. (PubMed, Clin Transl Med) - P2 | "This Phase II clinical trial of a rare tumour achieved its enrolment target in under 1 year and completed primary analysis within 2 years. 87% (46 of 53 patients who received nirogacestat) had fresh or archival biopsies that were analysed by next-generation sequencing for mutational profiling. Of the 3 patients with activating NOTCH1 mutations, all achieved 6-month progression-free survival (PFS6); 8 other patients also achieved PFS6 but did not share a common mutation."

Journal • P2 data • Oncology • Ovarian Cancer • Solid Tumor • FOXL2 • NOTCH1 • NOTCH2 • NOTCH3

Androgenic hidradenitis suppurativa onset linked to gamma secretase inhibitor. (PubMed, JAAD Case Rep) - No abstract available

Journal • Dermatology • Desmoid Tumors • Hidradenitis Suppurativa • Immunology • Oncology • Sarcoma • Women's Health

306: Sarcoma Solutions? Advancements and Updates in Sarcoma Care (HOPA 2026) - "Then, new literature including doxorubicin + trabectedin followed by trabectedin maintenance for leiomyosarcoma and nirogacestat for desmoid tumors will be discussed...The session will conclude with practical pearls for administering sarcoma therapies, including high-dose methotrexate in the outpatient setting. Knowledge or Application Based: Application Learning Objectives: Describe recent clinical trial data supporting emerging therapies for select sarcoma subtypesApply practical management strategies for administering sarcoma therapies including high-dose methotrexate in the outpatient setting"

Desmoid Tumors • Leiomyosarcoma • Sarcoma • Solid Tumor

Nirogacestat hydrobromide approved to treat desmoid tumours (GOV.UK)

MHRA approval • Desmoid Tumors

NIR-OGT-201: Nirogacestat in Ovarian Granulosa Cell Tumors (clinicaltrials.gov) - P2 | N=53 | Completed | Sponsor: SpringWorks Therapeutics, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2027 ➔ Jul 2025 | Trial primary completion date: Jul 2026 ➔ Jul 2025

Trial completion • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor

Disproportionality Analysis of Dermatologic Adverse Events Associated with Nirogacestat: Insights from the FDA Adverse Event Reporting System (FAERS). (PubMed, J Am Acad Dermatol) - No abstract available

Adverse events • Journal

Belantamab mafodotin, nirogacestat, and pomalidomide in patients with relapsed/refractory multiple myeloma (ASH 2025) - P1 | "Median priorlines of therapy was 5; 100% were triple exposed (PI, IMiD, anti-CD38 monoclonal antibody), and 5patients had prior high dose melphalan with autologous stem cell transplant. Two patients had priorBCMA treatment; 1 patient had received a BCMA CAR T and a GPRC5D CAR T, and 1 patient had receiveda BCMA CAR T and a BCMA bispecific antibody.The overall response rate (ORR) was 66% including 3 with partial response (PR) and 3 with very goodpartial response (VGPR)...The rate of ocular AEs wassimilar to prior belantamab mafodotin trials and real-world studies. The significant increase inmembrane bound BCMA after starting nirogacestat indicates a possible therapeutic synergy betweenGSIs and BCMA targeted therapies."

Clinical • IO biomarker • Age-related Macular Degeneration • Infectious Disease • Macular Degeneration • Multiple Myeloma • Neutropenia • Ophthalmology • Renal Disease • Retinal Disorders • Thrombocytopenia

Safety and efficacy of elranatamab + nirogacestat in patients with relapsed or refractory multiple myeloma: Results from the Phase 1b MagnetisMM-4 study (ASH 2025) - P2 | "CRRs (95% CI) were 0.0% (0.0-84.2),33.3% (4.3-77.7), 40.0% (12.2-73.8), 30.0% (6.7-65.2), and 16.7% (0.4-64.1), respectively.ConclusionsAcross 5 evaluated dose levels, the combination of ELRA plus NIRO yielded response rates of 50.0% to70.0%. These initial results suggest careful evaluation is warranted when combining BCMA-targetedBsAbs with a GSI."

Clinical • P1 data • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Pneumonia • Respiratory Diseases • Thrombocytopenia

Quantitative clinical pharmacology analysis to support the dose escalation of elranatamab + nirogacestat in the MagnetisMM-4 study (ASH 2025) - P2 | "Patients with high baseline sBCMA are predicted to havethe greatest gain of efficacy with the ELRA plus NIRO combination vs ELRA monotherapy. If tolerable, theQSP model predicts that ELRA 76 mg QW plus NIRO 100 mg QD will achieve superior efficacy comparedwith ELRA 32 mg QW plus NIRO 100 mg QD in high sBCMA patients.ConclusionsThe pharmacokinetic, pharmacodynamic, dose-response analysis, and QSP modeling support NIRO 100mg QD to improve safety and further dose escalation of ELRA to 76 mg QW to maximize efficacy inpatients with high baseline disease burden/sBCMA."

Clinical • Hematological Malignancies • Multiple Myeloma

Case Report: Nirogacestat therapy induces rapid response in a patient with refractory, life-threatening desmoid tumor. (PubMed, Front Oncol) - "Following early relapse to surgery, the patient sequentially failed treatment with pegylated liposomal doxorubicin (PLD), sorafenib, and a combination of doxorubicin and dacarbazine. Albeit rarely lethal in general, DT can exert life-threatening danger by local infiltration into vital tissue, such as blood vessels. The presented case highlights the novel γ-secretase inhibitor nirogacestat as a highly effective therapy preventing infiltration of the right carotid artery by a remarkably refractory DT."

Journal • Desmoid Tumors • Oncology • Sarcoma • Solid Tumor

Rapid biocompatible solid phase microextraction: Nirogacestat protein binding in post dose human serum samples. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "The results show that BioSPME provides an accurate and reliable method for measuring protein binding in both in vitro and clinical samples. SIGNIFICANCE STATEMENT: BioSPME accurately measures the protein binding of nirogacestat in clinical serum samples and is an alternative to RED for measuring protein binding in vitro and in clinical samples."

Journal

To Determine the Effect of CYP Induction Following Administration of Nirogacestat in Healthy Adult Male Participants (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: SpringWorks Therapeutics, Inc.

New P1 trial

A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: Children's Oncology Group | Trial completion date: Dec 2025 ➔ Mar 2026 | Trial primary completion date: Dec 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Desmoid Tumors • Fibrosis • Sarcoma • Solid Tumor • CTNNB1