Blenrep-nirogacestat Combo Moves to Dose-testing Phase 2 of Trial

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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After promising early results, a sub-study of the DREAMM-5 platform trial is moving forward to its next phase to test a combination of Blenrep (belantamab mafodotin) with nirogacestat in adults with relapsed or refractory multiple myeloma.

In addition, two sub-studies will be added to the trial (NCT04126200), sponsored by Blenrep developer GlaxoSmithKline (GSK), to evaluate the combo with standard multiple myeloma therapies. DREAMM-5 is recruiting patients at sites in the U.S., Canada, Europe, Australia, and Korea.

“We continue to remain intensely focused on advancing nirogacestat as a potential best-in-class cornerstone of BCMA combination therapy for patients with multiple myeloma and are pleased with the progress that has been made with our collaborator GSK,” Saqib Islam, CEO of SpringWorks Therapeutics, which is developing nirogacestat, said in a press release.

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The B-cell maturation antigen (BCMA) is a protein found at high levels on the surface of myeloma cells and at minimal levels in healthy cells, making it an ideal target for myeloma. Administered directly into the bloodstream, Blenrep is a BCMA-targeting therapy approved in the U.S. and Europe for heavily pretreated adults with relapsed or refractory multiple myeloma.

The treatment is an antibody-drug conjugate, comprising a BCMA-targeting antibody bound to a cancer-killing agent called auristatin F. Once the antibody binds to BCMA, auristatin F is released into the cancer cells, promoting their death.

Nirogacestat is an orally available small molecule that works by blocking gamma secretase, an enzyme that cleaves BCMA from the surface of myeloma cells, releasing it in a soluble form.

By suppressing the enzyme’s activity, the experimental therapy is expected to increase the amount of BCMA on the cells’ surface, while reducing the levels of soluble BCMA, which may work as decoy targets for BCMA-targeted agents. Together, these effects are thought to boost the effectiveness of BCMA-targeting therapies.

Preclinical data have shown that myeloma cell death increased by 3,000 times when nirogacestat was added to Blenrep.

“We believe in the emerging role of nirogacestat as a BCMA potentiator and we look forward to working with GSK to advance the expanded program,” Islam said.

The international DREAMM-5 platform trial is assessing the safety and effectiveness of Blenrep, in combination with other anti-cancer therapies — with each combo as a sub-study — in up to 464 adults with relapsed or refractory multiple myeloma.

In each sub-study’s dose-exploration portion, an optimal dose of the combination therapy will be determined to move to its expansion phase, which will test the combo against Blenrep alone (at its approved dose of 2.5 mg/kg once every three weeks) in additional myeloma patients.

The Phase 1b portion of the Blenrep-nirogacestat portion is evaluating the safety, tolerability, and preliminary efficacy of several doses and schedules of the combo.

Based on encouraging preliminary data from the first combination dose (0.95 mg/kg of Blenrep every three weeks plus nirogacestat), additional patients are being recruited for its Phase 2 expansion portion, meant to confirm the combo’s benefits.

In addition, two new sub-studies will evaluate the Blenrep-nirogacestat combo with standard therapy: Pomalyst (pomalidomide) plus dexamethasone or Revlimid (lenalidomide) plus dexamethasone. Results from these sub-studies may prompt the launch of future trials testing these combos as earlier lines of treatment.

DREAMM-5 is the result of a global collaboration agreement in 2019 between SpringWorks and GSK, and was recently amended to allow additional sub-studies to be conducted.

According to the agreement, GSK is sponsoring and conducting the trial, and responsible for all its costs, except expenses related to nirogacestat’s manufacturing and intellectual property rights. The companies have formed a joint development committee to help manage and oversee the trial.

SpringWorks is also collaborating with five other industry partners to evaluate nirogacestat in combination with distinct BCMA-directed therapies.

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Research collaborations were established with the Fred Hutchinson Cancer Research Center and the Dana-Farber Cancer Institute to further characterize nirogacestat’s ability to modulate BCMA and potentiate BCMA-directed therapies using several preclinical models of multiple myeloma.

SpringWorks is also evaluating nirogacestat potentially for desmoid tumors — rare, aggressive, abnormal growths that arise from soft tissue and for which there are no approved therapies. Its potential benefits in this context are thought to be linked to its ability to block Notch signaling, a pathway known to play a key role in cancer.