Damian Green from the University of Washington is the Principal Investigator for a new research project in multiple myeloma. This project is thanks to a research agreement between the Fred Hutch Cancer Research Center and SpringWorks Therapeutics.

Nirogacestat

This project is investigating a gamma secretase inhibitor (GSI) called Nirogacestat. It is a small oral molecule. They believe this therapy could help to control BCMA and increase the likelihood of the successful development of BCMA targeted therapies like radioimmunotherapies.

The therapy works to disrupt the BCMA that is on the surface of multiple myeloma cells. Preclinical studies have shown that it was able to increase the surface density of the BCMA on the cancerous cells. At the same time, it enhanced the activity of therapies targeting BCMA.

GS cleaves Notch, which is a protein complex that plays a vital role in activating the pathways that allow tumors to grow. By cleaving to BCMA, it allows the extracellular domain (ECD) to be released. When GS is inhibited, the BCMA can be preserved. This increases the density of the target and reduces levels of soluble BCMA ECD.

By combining GSI with a BCMA-targeted therapy like CAR T cell therapy, outcomes may be improved for patients. Clinical data has shown this combination’s efficacy in relapsed and refractory multiple myeloma.

Nirogacestat has already received FDA Fast Track Designation and Breakthrough Therapy Designation for refractory desmoid tumors, as well as deep fibromatosis. Additionally, it has Orphan Drug Designation for desmoid tumors. The therapy is still in a Phase 3 clinical trial for this type of tumor. The European Commission has granted its use as a therapy for soft tissue sarcoma.

You can read more about this investigative therapy here.