Allogene Therapeutics (ALLO), SpringWorks Therapeutics (SWTX) Report First Patient Dosing in Phase 1 Study Evaluating ALLO-715 in Combination with Nirogacestat in Patients with R/R Multiple Myeloma

Allogene Therapeutics, Inc. (NASDAQ: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic chimeric antigen receptor T cell (AlloCAR T™) therapies for cancer, and SpringWorks Therapeutics, Inc. (NASDAQ: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced that the first patient has been dosed in a Phase 1 trial evaluating ALLO-715, Allogene’s investigational anti-B-cell maturation antigen (BCMA) AlloCAR T therapy, in combination with nirogacestat, SpringWorks’ investigational gamma secretase inhibitor (GSI), in patients with relapsed or refractory multiple myeloma.

“We are pleased to have initiated this portion of the UNIVERSAL trial and look forward to investigating ALLO-715 in combination with nirogacestat as part of our comprehensive anti-BCMA strategy aimed at bringing an off-the-shelf cell therapy to patients with relapsed or refractory multiple myeloma,” said David Chang, M.D., Ph.D., President, CEO and Co-Founder of Allogene Therapeutics.

Gamma secretase inhibition prevents the cleavage and shedding of BCMA from the surface of multiple myeloma cells. In preclinical models, nirogacestat has been shown to increase the cell surface density of BCMA and reduce levels of soluble BCMA, which may enhance the activity of BCMA-targeted therapies.1 In addition, emerging clinical data suggest that a GSI may increase antitumor efficacy of BCMA-targeted autologous CAR T therapy in patients with relapsed and refractory multiple myeloma.2,3

“Multiple myeloma is incurable for the overwhelming majority of patients diagnosed with this cancer and those who have relapsed or are refractory to current treatments have very limited therapeutic options available to them,” said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. “SpringWorks is advancing nirogacestat as a cornerstone of BCMA combination therapy across modalities, with the goal of potentiating BCMA therapies to provide better outcomes for patients. This study represents the first clinical trial combining nirogacestat with a CAR T therapy and we are delighted that the milestone of dosing the first patient has been achieved.”

The Phase 1 trial (NCT04093596), which is part of the ongoing UNIVERSAL trial being conducted by Allogene, is an open-label study evaluating the safety, tolerability and preliminary efficacy of ALLO-715 in combination with nirogacestat in patients with relapsed or refractory multiple myeloma. The trial is being advanced pursuant to a clinical trial collaboration agreement between Allogene and SpringWorks. Under the terms of the agreement, Allogene is sponsoring and conducting the Phase 1 study. Allogene and SpringWorks have formed a joint development committee to oversee this portion of the clinical study.

About ALLO-715ALLO-715, an AlloCAR T therapy targeting B-cell maturation antigen (BCMA), is a potential novel treatment for multiple myeloma and other BCMA-positive malignancies. Multiple myeloma originates in the bone marrow and it is characterized by abnormalities in plasma cells that reproduce uncontrollably in the bone marrow and other disease sites.4 Multiple myeloma is incurable for most patients, as relapses occur despite most treatments available.5 Initial results from the Phase 1 UNIVERSAL study of ALLO-715 in relapsed/refractory multiple myeloma were presented at an oral session of the American Society of Hematology (ASH) annual meeting in December 2020. This study also uses ALLO-647, Allogene's anti-CD52 monoclonal antibody (mAb), as a part of its differentiated lymphodepletion regimen.

ALLO-715 utilizes the TALEN® gene-editing technology pioneered and owned by Cellectis. Allogene has an exclusive license to the Cellectis technology for allogeneic products directed at the BCMA target. Allogene holds the global development and commercial rights for this investigational candidate.

About NirogacestatNirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.

In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has five collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies and two bispecific antibodies. In addition, SpringWorks and Fred Hutchinson Cancer Research Center have entered into a sponsored research agreement to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA directed therapies using a variety of preclinical and patient-derived multiple myeloma models developed by researchers at Fred Hutch.

Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.

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