Nirogacesat (Gamma Secretase Inhibitor)

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Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor (GSI) in Phase 3 clinical development as a monotherapy for patients with desmoid tumors and is being evaluated in multiple studies as a potential cornerstone of BCMA combination therapy.

Nirogacestat (gamma secretase inhibitor)

Gamma secretase is a protease complex that cleaves multiple transmembrane proteins, including Notch, which, when dysregulated, can play a role in activating pathways that contribute to desmoid tumor growth.

Chart on the left titled "Low ADC binding and anti-BCMA activity" and a chart on the right titled "Increased ADC binding and enhanced anti-BCMA activity with MM cell death"

Gamma secretase has been shown to cause shedding of BCMA, a therapeutic target that is specifically expressed on multiple myeloma cells. We believe that by inhibiting gamma secretase with nirogacestat, membrane-bound BCMA can be preserved, thereby increasing target density while simultaneously reducing levels of soluble BCMA, which may interfere with BCMA-directed therapies. Combining nirogacestat with BCMA-targeted therapies may increase their activity and improve outcomes for multiple myeloma patients. SpringWorks is advancing nirogacestat as a potential cornerstone of multiple myeloma combination therapy in collaboration with industry-leading BCMA therapy developers.

Nirogacestat in desmoid tumors

Desmoid tumors are rare, aggressive soft-tissue tumors characterized by locally invasive growth, significant morbidity, and a high rate of recurrence. There are currently no FDA-approved therapies for the treatment of desmoid tumors.

Nirogacestat has been shown to be generally well tolerated in over 200 subjects and clinical activity has been observed in desmoid tumor patients enrolled in Phase 1 and Phase 2 trials. Importantly, this clinical activity was shown to be independent of the type and number of prior lines of therapy received as well as the specific underlying mutation driving desmoid tumor growth.

A Phase 1 study was conducted in 64 patients with advanced solid tumors, of which there were seven evaluable patients who had a diagnosis of desmoid tumor. Of these seven patients, five had an objective tumor response (defined as > 30% tumor reduction). Nirogacestat was generally well tolerated.
A Phase 2 open-label, investigator-initiated study sponsored by the National Cancer Institute (NCI) enrolled 17 desmoid tumor patients. Sixteen patients were evaluable for tumor response. Five patients had a confirmed partial response and 11 had stable disease. Symptomatic improvement was also reported in some patients. Nirogacestat was generally well tolerated; the most common adverse events were diarrhea, skin disorders and hypophosphatemia.

Nirogacestat in multiple myeloma

Multiple myeloma is the second most common hematologic malignancy in the U.S., accounting for approximately 10 percent of all hematologic cancers. There are approximately 130,000 patients in the U.S. living with multiple myeloma.

B-cell maturation antigen (BCMA) is a cell surface protein that is highly and specifically expressed on multiple myeloma cells. BCMA has emerged as a promising target in multiple myeloma across several therapeutic modalities. Gamma secretase directly cleaves membrane-bound BCMA.

We believe that by inhibiting gamma secretase with nirogacestat, membrane-bound BCMA can be preserved, thereby increasing target density while simultaneously reducing levels of soluble BCMA, which may interfere with BCMA-directed therapies. Together, these mechanisms combine to potentially enhance the activity of BCMA therapies and improve outcomes for multiple myeloma patients.

Nirogacestat’s ability to significantly enhance the activity of BCMA-directed therapies has been observed in several preclinical models of human multiple myeloma.

Nirogacestat is being developed as a cornerstone of combination in BCMA therapies

Six ongoing collaborations with industry-leading developers of BCMA-targeted therapies

A Phase 1b clinical trial is evaluating nirogacestat in combination with GSK’s BLENREP, an anti BCMA antibody-drug conjugate, in patients with relapsed or refractory multiple myeloma.
A Phase 1 clinical trial is evaluating nirogacestat in combination with Janssen’s teclistamab, an investigational bispecific antibody targeting BCMA and CD3, in patients with relapsed or refractory multiple myeloma.
A Phase 1b/2 clinical trial is planned to evaluate nirogacestat in combination with Pfizer’s elranatamab, an investigational BCMA CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma.
A Phase 1 clinical trial is evaluating nirogacestat in combination with Allogene’s ALLO-715, an investigational BCMA AlloCAR T therapy, in patients with relapsed or refractory multiple myeloma.
A Phase 1 clinical trial is evaluating nirogacestat in combination with Precision Biosciences’ PBCAR269A, an investigational BCMA allogeneic CAR T cell therapy, in patients with relapsed or refractory multiple myeloma.
A Phase 1 clinical trial is planned to evaluate nirogacestat in combination with Seagen’s SEA-BCMA, an investigational monoclonal antibody targeting BCMA, in patients with relapsed or refractory multiple myeloma.

Read more in these key publications

Desmoid Tumors

GSI + BCMA Combination Therapy