Ogsiveo (nirogacestat) / EMD Serono - LARVOL DELTA

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

A PHASE 1/2 TRIAL OF FOG-001, A FIRST-IN-CLASS DIRECT β-CATENIN:TCF4 INHIBITOR: SAFETY AND PRELIMINARY ANTITUMOR ACTIVITY IN PATIENTS WITH DESMOID TUMORS (DT) (CTOS 2025) - "Preliminary data show that FOG-001 has acceptable tolerability in pts with DT. Tumor reductions were seen in all pts, including multiple PRs in pts who progressed on nirogacestat. Dose expansion in a DT-specific cohort is currently ongoing."

Clinical • P1/2 data • Desmoid Tumors • Oncology • Sarcoma • Solid Tumor • APC • CTNNB1 • TCF4

TRENDS IN SURGICAL MANAGEMENT OF DESMOID TUMOR IN THE VETERANS AFFAIRS (VA) NATIONAL DATABASE (CTOS 2025) - "An evolving understanding of the natural history of DT has resulted in a shift to active surveillance for asymptomatic or minimally symptomatic, non-morbid or non-progressive DTs, while systemic treatment options, such as nirogacestat, should be considered first-line if treatment is warranted.The purpose of this study was to characterize the utilization and timing s of surgical management for DT following initial diagnosis, using the national VA database. Surgical pathology notes from 2003 to 2024 were searched to identify histopathologic diagnoses of DT and the earliest date of the core needle or excisional biopsy was used as the date of DT diagnosis... The majority of patients who received surgery were operated on within three months of initial diagnosis. The early surgery suggests there may be a gap between guideline recommended active surveillance and real-world practice within the VA. Further analyses will focus on understanding how surgical practices may have..."

Desmoid Tumors • Oncology • Sarcoma

MRI VOLUMETRIC AND MODIFIED CHOI-BASED ASSESSMENT OF TREATMENT RESPONSE IN EXTREMITY DESMOID TUMORS TREATED WITH NIROGACESTAT OR SORAFENIB (CTOS 2025) - "Patients treated with nirogacestat displayed larger magnitude of volumetric and mChoi changes across treatment, with the fastest positive response (highest slope) and similar period of sustained positive treatment effects compared to patients treated with sorafenib, indicating the potential advantage of nirogacestat as an effective treatment in desmoid tumors."

Desmoid Tumors • Oncology • Sarcoma • Solid Tumor

GERMLINE RECQL4 VARIANT IN A PEDIATRIC PATIENT WITH EWING SARCOMA AND DESMOID FIBROMATOSIS (CTOS 2025) - "A hotspot missense variant in CNNTB1 was observed in the DF sample, consistent with the histopathologic diagnosis.Due to recurrence of DF 2 years post-resection, the gamma secretase inhibitor Nirogacestat was initiated with radiograph remission. Biallelic pathogenic RECQL4 alterations are associated increased risk for malignancy. Biallelic pathogenic RECQL4 alterations are associated increased risk for malignancy. However, the relationship between heterozygous RECQL4 carriers and malignancy risk is understudied. Currently, there is no known association between RECQL4 and risk for ES or DF; however, this case underscores the value of comprehensive genetic testing for pediatric solid tumors in uncovering potential germline predisposition and enhancing patient care."

Clinical • Desmoid Tumors • Ewing Sarcoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CTNNB1 • EWSR1 • FLI1 • RECQL4

TRIAL IN PROGRESS: A SINGLE-ARM, OPEN-LABEL PHASE 4 TRIAL OF NIROGACESTAT IN ADULT PREMENOPAUSAL FEMALES WITH DESMOID TUMORS (CTOS 2025) - "N/A"

Clinical • P4 data • Desmoid Tumors • Oncology • Sarcoma

ASSESSMENT OF PAIN DIAGNOSIS AND PAIN MEDICATION USE IN ADULTS TREATED WITH NIROGACESTAT: A UNITED STATES REAL-WORLD ANALYSIS (CTOS 2025) - "This analysis showed a clinically relevant reduction in pain dx for patients during 3 months of niro treatment. These results are consistent with the significant and clinically meaningful benefit of pain reduction associated with niro in DeFi. The reduction in opioid Rx and dose during 3 months of niro treatment may help reduce the risk of chronic opioid use."

Clinical • Real-world • Real-world evidence • Desmoid Tumors • Oncology • Sarcoma

MECHANISTIC AND TRANSCRIPTOMIC ANALYSES REVEAL MUTATION-SPECIFIC THERAPEUTIC RESPONSES IN DESMOID TUMOR CELLS TREATED WITH SORAFENIB AND NIROGACESTAT (CTOS 2025) - "To our knowledge this is the first study investigating nirogacestat and sorafenib treatment response in these novel preclinical models of desmoid tumor biology. The transcriptomic signatures identified represent promising targets for further translational strategies to overcome treatment resistance, specifically NOTCH, β-catenin and KRAS signaling. Moreover, this study demonstrates mutation-specific therapeutic vulnerabilities in desmoid tumors with potential implications for personalized treatment approaches in desmoid tumor management."

Tumor cell • Desmoid Tumors • Oncology • Sarcoma • ABL1 • HES1 • HEY1 • KRAS • NOTCH1

EFFICACY OF NIROGACESTAT IN PATIENTS WITH DESMOID TUMORS AND PRESENCE OR ABSENCE OF POOR PROGNOSTIC FACTORS: POST HOC ANALYSES OF THE PHASE 3 DEFI TRIAL (CTOS 2025) - P3 | "Niro was associated with consistent improvement in PFS, ORR, and PROs vs pbo regardless of the presence or absence of DT poor prognostic factors."

Biomarker • Clinical • P3 data • Retrospective data • Desmoid Tumors • Oncology • Sarcoma • CTNNB1

Belantamab Mafodotin, nirogacestat and Pomalidomide for Patients with Relapsed/Refractory Multiple Myeloma (ASH 2024) - P1 | "Within the belamaf 1.4 mg/kg and 1.9 mg/kg dose cohorts, 4/6 patients achieved PR or better with the two remaining patients still being evaluated. Updated safety and efficacy data as well as translational BCMA studies will be presented at the conference."

Clinical • IO biomarker • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology • Ophthalmology

DREAMM 5: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P2 | N=208 | Active, not recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Feb 2029 ➔ Mar 2027 | Trial primary completion date: Feb 2029 ➔ Apr 2025

Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) Analysis of Nirogacestat in Patients With Desmoid Tumors (ISPOR-EU 2025) - "Nirogacestat significantly improved Q-TWiST versus placebo. Q-TWiST gains with nirogacestat were primarily driven by time in the "good" health state (TWiST), which resulted from long-term PFS benefits and lower differences in Grade ≥3 TRAEs versus placebo. Sensitivity analyses show benefits of nirogacestat are maintained with longer follow-up."

Clinical • Desmoid Tumors • Oncology • Sarcoma

UNMASKING AN ATYPICAL CULPRIT: MALIGNANT GLOMUS TUMOR OF PULMONARY ORIGIN (CHEST 2025) - "Gamma-secretase inhibitors, such as nirogacestat target this pathway and represent a promising therapeutic option. With rapidly progressing disease, pazopanib, can be initiated as a temporizing agent... This case highlights the diagnostic and therapeutic challenges of malignant pulmonary glomus tumors. Integrating advanced imaging, multidisciplinary care and timely access to emerging treatments is vital for improving patient outcomes. Further research is needed to establish surveillance protocols and expand therapeutic options for such rare malignancies."

Diabetes • Gastrointestinal Disorder • Genetic Disorders • Lung Cancer • Metabolic Disorders • Obesity • Obstructive Sleep Apnea • Oncology • Palliative care • Pulmonary Disease • Respiratory Diseases • Sarcoma • Sleep Apnea • Sleep Disorder • Soft Tissue Sarcoma • Solid Tumor • Type 2 Diabetes Mellitus • BCL2 • CD99 • MIR143 • NOTCH2

A phase I/II trial of FOG-001, a first-in-class direct β-catenin:TCF4 inhibitor - Safety and preliminary antitumor activity in patients with desmoid tumors (ESMO 2025) - P1/2 | "Clinical trial identification NCT05919264. Tumor reductions were seen in all pts, including a PR in a pt who progressed on prior nirogacestat. Dose expansion in a desmoid-specific cohort is currently ongoing."

Clinical • P1/2 data • Colorectal Cancer • Desmoid Tumors • Oncology • Sarcoma • APC • CTNNB1 • TCF4

Functional NOTCH4 Variants Drive Vasculopathy and Fibrosis in Systemic Sclerosis. (ACR Convergence 2025) - "Inhibition of NOTCH4 using genetic knockdown, blocking antibody, or the FDA-approved drug Nirogacestat restored angiogenesis (Fig... Functional variants in NOTCH4 gene are associated with SSc pathogenesis and vasculopathy and may explain the higher disease burden of SSc in AAs. Blocking NOTCH4 signaling restored angiogenesis and EndoMT, highlighting its potential as a therapeutic target in restoring angiogenesis in SSc and connective tissue diseases."

Cardiovascular • Fibrosis • Immunology • Pulmonary Arterial Hypertension • Respiratory Diseases • Rheumatology • Scleroderma • Systemic Sclerosis • ACTA2 • HES1 • NOTCH4

SpringWorks reports long-term efficacy data for desmoid tumor drug (Investing.com) - "According to the company’s press release, the objective response rate improved from 34.3% in the first year to 45.7% in patients who received the drug for up to four years. The median best reduction in tumor size deepened from -32.3% at year one to -75.8% for patients completing at least four years of treatment."

Desmoid Tumors

NIROGACESTAT-INDUCED HYPOPHOSPHATEMIA LEADING TO HYPERCAPNIC RESPIRATORY FAILURE (CHEST 2025) - "Nirogacestat-induced hypophosphatemia can precipitate acute respiratory failure in susceptible individuals. This emphasizes the need for vigilant monitoring of serum phosphate in patients on nirogacestat therapy and suggests that early phosphate repletion should be considered when serum levels approach the lower threshold of 2.5 mg/dL."

Colon Cancer • Colorectal Cancer • Desmoid Tumors • Metabolic Disorders • Pulmonary Disease • Renal Disease • Respiratory Diseases • Sarcoma • Short Bowel Syndrome • Solid Tumor

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: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Sep 2025 ➔ Dec 2025

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

Efficacy of nirogacestat in patients with desmoid tumors and presence or absence of poor prognostic factors: Post hoc analyses of the phase III DeFi trial (ESMO 2025) - P3 | "PRO improvements were observed early and sustained on treatment with niro vs pbo. Conclusions In conclusion, niro was associated with consistent improvement in PFS, ORR, and PROs vs pbo regardless of the presence or absence of DT poor prognostic factors."

Biomarker • Clinical • P3 data • Retrospective data • Desmoid Tumors • Oncology • Sarcoma • CTNNB1