On September 21, 2020 Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS genome editing platform, 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, reported they have entered into a clinical trial collaboration agreement. Per the agreement, PBCAR269A, Precision BioSciences’ wholly-owned investigational allogeneic chimeric antigen receptor (CAR) T cell therapy candidate targeting B-cell maturation antigen (BCMA), will be evaluated in combination with nirogacestat, SpringWorks’ investigational gamma secretase inhibitor (GSI), in patients with relapsed or refractory multiple myeloma (Press release, Precision Biosciences, SEP 21, 2020, View Source [SID1234565414]).
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"Based on recent clinical data using GSIs in combination with BCMA-targeted therapies, it is exciting to combine these agents in patients who have a need for better therapies," said Nina Shah, M.D., study Principal Investigator and Associate Professor in the Department of Medicine at the University of California, San Francisco. "I look forward to the data generated from this investigational study to see if PBCAR269A plus nirogacestat improves clinical outcomes in patients with multiple myeloma."
Gamma secretase inhibition has been shown preclinically to enhance the activity of BCMA-targeted therapies by preventing the cleavage and shedding of BCMA from the surface of myeloma cells, which increases the cell surface density of BCMA and reduces levels of soluble BCMA. Via this mechanism, nirogacestat may enhance the activity of BCMA-targeted therapies.1 Emerging clinical data also suggest that a GSI may increase antitumor efficacy of BCMA-targeted autologous CAR T therapy in patients with relapsed or refractory multiple myeloma.2,3
"In June, we initiated our Phase 1/2a clinical trial of PBCAR269A, which targets BCMA for the treatment of relapsed or refractory multiple myeloma and has demonstrated anti-tumor activity in preclinical disease models," said Chris Heery, M.D., Chief Medical Officer at Precision BioSciences. "Preclinical data from our own program as well as others have suggested the importance of gamma secretase inhibition to unlock the full potential of BCMA targeted therapies. We look forward to further evaluating this in the clinic."
Under the terms of the agreement, Precision BioSciences will assume all development costs of the expanded Phase 1/2a study of PBCAR269A to include nirogacestat and evaluate the safety and preliminary clinical activity of the combination therapy. Precision BioSciences and SpringWorks will form a joint development committee to oversee the clinical study, which is expected to commence in the first half of 2021, pending discussions with regulators.
Exhibit 99.1
"Patients with multiple myeloma are in great need of treatment advances," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "We continue to believe that nirogacestat has the potential to become a cornerstone of BCMA combination therapy for these patients and are pleased to work with Precision BioSciences and their leading group of scientific advisors and clinical investigators to evaluate the combination of our gamma secretase inhibitor with their ‘off-the-shelf’ CAR T therapy."
About PBCAR269A
PBCAR269A is an allogeneic BCMA-targeted CAR T cell therapy candidate being evaluated for the safety and preliminary clinical activity in a Phase 1/2a multicenter, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study of adults with relapsed or refractory multiple myeloma. The starting dose of PBCAR269A is 6 x 105 CAR T cells/kg body weight with subsequent cohorts receiving escalating doses to a maximum dose of 6 x 106 CAR T cells/kg body weight.
PBCAR269A is the company’s third CAR T candidate to advance to the clinic and is part of a pipeline of cell-phenotype optimized allogeneic CAR T therapies derived from healthy donors and then modified via a simultaneous TCR knock-out and CAR T knock-in step with the Company’s proprietary ARCUS genome editing technology. Precision BioSciences optimizes its CAR T therapy candidates for immune cell expansion in the body by maintaining a high proportion of naïve and central memory CAR T cells.
The U.S. Food and Drug Administration (FDA) recently granted Fast Track Designation to PBCAR269A for the treatment of relapsed or refractory multiple myeloma for which the FDA previously granted Orphan Drug Designation. The PBCAR269A clinical trial will be conducted at multiple U.S. sites. For more information, visit www.clinicaltrials.gov, study identifier number NCT04171843.
About Nirogacestat
Nirogacestat 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 four 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 a bispecific antibody. 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 (June 2018) and from the European Commission for the treatment of soft tissue sarcoma (September 2019). 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 (November 2018 and August 2019).