Clinical Collaboration Underway for Nirogacestat/Teclistamab Combo in Myeloma

SpringWorks Therapeutics’ investigational gamma secretase inhibitor nirogacestat (PF-03084014) is slated to be evaluated in combination with Janssen Biotech, Inc’s BCMA- and CD3-targeted bispecific antibody teclistamab (JNJ-64007957) in a phase 1 study in patients with relapsed/refractory multiple myeloma.¹

The study, which will be sponsored by Janssen, will evaluate the safety, tolerability, and activity of the combination. SpringWorks Therapeutics will assume the costs of manufacturing for nirogacestat and spearhead the creation of a joint oversight committee with Janssen. The study is expected to begin by early 2021, pending regulatory discussions.

“We are delighted to enter into this collaboration with Janssen to study nirogacestat in combination with teclistamab,” said Saqib Islam, JD, chief executive officer of SpringWorks Therapeutics.¹ “We now have 3 collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate (ADC), an allogeneic CAR-T cell therapy, and now, a bispecific antibody.”

Nirogacestat is a potent, small molecule, selective, reversible, noncompetitive inhibitor of γ-secretase.² By inhibiting γ-secretase, myeloma cells can retain BCMA expression, which could enhance the activity of BCMA-directed therapies.

In a prior phase 1 study (NCT03145181), teclistamab was found to be safe and effective in patients with relapsed/refractory multiple myeloma. Among patients who had received a median of 6 prior therapies (range, 2-14), 67% experienced an objective response at a dose of 270 µg/kg (n = 12).³

“This collaboration is an important step in continuing to advance our goal of developing nirogacestat as a best-in-class BCMA potentiator,” said Islam.

Additional SpringWorks Therapeutics collaborations include the evaluation of nirogacestat in combination with GlaxoSmithKline’s BCMA ADC belantamab mafodotin-blmf (Blenrep) and Allogene’s allogeneic BCMA-directed CAR-T cell therapy ALLO-715.

Moreover, SpringWorks is sponsoring the global phase 3, double-blind, randomized, placebo-controlled DeFi trial (NCT03785964), which is evaluating nirogacestat in patients with progressive desmoid tumors.

In September 2019, the FDA granted a breakthrough therapy designation to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.⁴

The FDA had previously granted nirogacestat an orphan drug designation in June 2018 for the treatment of patients with desmoid tumors, and a fast track designation in November 2018 for the treatment of patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.

References

1. SpringWorks Therapeutics announces clinical collaboration with Janssen to evaluate nirogacestat in combination with teclistamab in patients with relapsed or refractory multiple myeloma. News release. SpringWorks Therapeutics. September 14, 2020. Accessed October 8, 2020. https://bit.ly/3nz0VaC
2. Nirogacestat for adults with desmoid tumor/aggressive fibromatosis (DT/AF) (DeFi). ClinicalTrials.gov. Updated September 22, 2020. Accessed October 8, 2020. https://clinicaltrials.gov/ct2/show/NCT03785964.
3. Usmani SZ, Mateos M, Nahi H, et. al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2020;38(suppl 15):100. doi:10.1200/JCO.2020.38.15_suppl.100
4. SpringWorks Therapeutics receives breakthrough therapy designation for nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors. News release. SpringWorks Therapeutics, Inc. August 29, 2019. Accessed October 9, 2020. https://bit.ly/30IV0Eb.