New Nirogacestat Combos to Enter Myeloma Trials, SpringWorks Says

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by David Melamed, PhD |

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SpringWorks Therapeutics announced new collaborations with two companies, Pfizer and Janssen, to investigate its oral therapy candidate nirogacestat in combination with BCMA-targeting agents to treat people with relapsed or refractory multiple myeloma.

The collaboration with Pfizer aims to test nirogacestat plus PF‐06863135 in a Phase 1b/2 trial, while SpringWorks and Janssen will launch a Phase 1 trial investigating the combination of nirogacestat and teclistamab.

Both these clinical trials are expected to launch in the first half of 2021.

Three other SpringWorks collaborations are testing similar combinations of nirogacestat. The BCMA-targeting agents investigated in these efforts are the antibody-drug conjugate Blenrep (belantamab mafodotin), and the CAR T-cell therapies PBCAR296A and ALLO-715.

The Blenrep trial (NCT04126200) reported dosing its first participant in July.

“We now have five collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities. We look forward to generating clinical data with our collaborators to further evaluate the ability of nirogacestat to improve outcomes for patients with multiple myeloma,” Saqib Islam, chief executive officer of SpringWorks Therapeutics, said in a press release.

The B-cell maturation antigen (BCMA) protein is expressed at high levels at the surface of most myeloma cells, and shows minimal levels in normal cells. This makes BCMA a promising target for myeloma.

A number of therapies targeting this protein have emerged in recent years; Blenrep was recently approved and at least one other is being reviewed by regulatory authorities for myeloma.

But research suggests that nirogacestat can increase the sensitivity of myeloma cells to BCMA agents, as it inhibits the activity of a protein — called gamma secretase — that works to break down BCMA in cells. By blocking gamma secretase, nirogacestat is expected to increase the amount of BCMA on the surface of cancer cells, and boost the effectiveness of BCMA-targeted therapies.

In agreement, preclinical data showed that myeloma cell death increased by 3,000 times when  nirogacestat was added to GlaxoSmithKline‘s Blenrep.

The most recent collaborations will test nirogacestat plus the bispecific antibodies PF‐06863135 and teclistamab. Both are antibodies that target two molecules, the BCMA protein on cancer cells and CD3, a protein found at the surface of immune T-cells.

Their mechanism of action is designed for the antibodies to draw immune cells into the proximity of cancer cells, so that the immune cells can attack and destroy the cancer cells.

“This collaboration is another important step in continuing to advance our goal of developing nirogacestat as a best-in-class BCMA potentiator, and we are pleased to work with Pfizer to study nirogacestat in combination with PF‐06863135, which has recently demonstrated promising monotherapy clinical data,” Islam said.

“We are delighted to enter into this collaboration with Janssen to study nirogacestat in combination with teclistamab,” Islam said in the separate press release announcing this collaboration.

Under each agreement, Pfizer and Janssen will be responsible for conducting the respective trials, and SpringWorks will form oversight committees with each company to ensure their proper conduct. SpringWorks will also cover the costs of nirogacestat manufacturing.

Nirogacestat has designated an orphan drug by the U.S. Food and Drug Administration (FDA) as a potential treatment of desmoid tumors, and by the European Commission for the treatment of soft tissue sarcoma.

The FDA also granted nirogacestat fast track and breakthrough therapy designations for progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.