Pharmacodynamic Effects of Nirogacestat, a Gamma Secretase Inhibitor, on B-Cell Maturation Antigen in Healthy Participants

Purpose: B-cell maturation antigen (BCMA) is expressed on the cell membrane of normal plasma cells (PCs) and multiple myeloma (MM) cells and is the target of several investigational agents and approved products for the treatment of MM. Low BCMA receptor density may be associated with lower response rates, less durable responses, or resistance to BCMA therapies. Mechanistically, BCMA is cleaved from the cell surface by the enzyme gamma secretase (GS), which results in reduced levels of membrane bound BCMA (mbBCMA) and generation of soluble BCMA (sBCMA). GS inhibitors (GSIs) have been shown to increase mbBCMA, and potentiation of the activity of several BCMA-targeted therapies has been demonstrated in vitro and in clinical studies in combination with GSIs. While the effect of GS inhibition on mbBCMA has been reproducibly characterized in vitro, the effect on BCMA dynamics has yet to be adequately characterized in humans. Therefore, this study sought to evaluate the pharmacodynamics of the GSI nirogacestat on mbBCMA on PCs in healthy participants.

Methods: An adaptive design clinical study in healthy participants used quantitative flow cytometry to evaluate mbBCMA receptor density on PCs collected from bone marrow (BM) and whole blood (WB) following administration of nirogacestat. In the first cohort, 9 participants received a single dose of nirogacestat 150 mg, and mbBCMA density on PCs isolated from BM and WB was measured at baseline and 4, 8, 24, or 48 hours post-dose. Changes in the percentage of mbBCMA+ PCs, serum concentrations of sBCMA, and serum concentrations of nirogacestat were also determined. Based on the results of the first cohort, participants were enrolled in a second cohort in which different dose levels, treatment schedules, and post-dose collection time points were included to refine the exposure-response relationship and to better understand the dynamics of mbBCMA.

Results: Nirogacestat dosing in healthy participants resulted in a rapid increase in mbBCMA density on PCs isolated from BM and WB. Maximal increases in mbBCMA (8- to 12-fold) were observed from 4 to 8 hours post-dose and returned to baseline levels by 24 to 48 hours. These changes in mbBCMA density correlated with serum concentrations of nirogacestat. The responses in BM and WB were generally similar, but there were some differences in mbBCMA dynamics. The serum nirogacestat concentrations and mbBCMA density values were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes mbBCMA dynamics relative to GSI concentrations, including receptor density on PCs in both BM and WB. Results of the final PK/PD model will be presented.

Conclusions: Administration of a single dose of nirogacestat in healthy participants resulted in a robust but temporary increase in mbBCMA receptor density on PCs in both BM and WB that correlated with nirogacestat serum concentrations, indicating that the turnover of mbBCMA on PCs is rapid and its abundance on the cell surface is directly regulated by GS activity. PK/PD modeling showed that sustained serum concentrations of nirogacestat are necessary for maintaining elevated levels of mbBCMA receptor density, thereby suggesting that the schedule of nirogacestat dosing may have direct implications on the potentiation of BCMA-targeting therapies. This PK/PD study supports the use of nirogacestat to increase mbBCMA levels on myeloma cells in patients receiving BCMA-directed therapy. Ongoing and planned studies are evaluating mbBCMA dynamics with nirogacestat combined with BCMA-targeted treatments in patients with MM.

Shearer:SpringWorks Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties: 63/263,635. Williams:SpringWorks Therapeutics: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Minor unrelated stock positions in PFE, VTRS, MBIO, RIGL, SNDL, SRNE, and various mutual funds, Patents & Royalties: USPTO Application 63/263,635 (Compositions and Treatments with Nirogacestat ) -- Assigned to SpringWorks. Johnson:Precision BioSciences: Current equity holder in private company, Ended employment in the past 24 months, Patents & Royalties: Patents. Cendrowicz:ICON plc.: Current Employment. Leonowens:SpringWorks Therapeutics: Consultancy. Smith:SpringWorks Therapeutics: Current Employment, Current equity holder in publicly-traded company. Baughman:SpringWorks Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Breitbach:SpringWorks Therapeutics: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Smith:SpringWorks Therapeutics: Current Employment, Current equity holder in publicly-traded company. Burgess:SpringWorks Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cheng:SpringWorks Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: treatments with nirogacestat and combinations.