TG Therapeutics Receives Clearance from FDA for Phase 1 Trial in Multiple Sclerosis for Allogeneic CAR-T Azer-Cel

The FDA has cleared an investigational new drug (IND) application submitted by TG Therapeutics for azercabtagene zapreleucel (azer-cel), an investigational allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, for a phase 1 clinical trial in patients with progressive multiple sclerosis (MS).¹

Azer-cel was originally developed by Precision BioSciences, but licensed to TG Therapeutics for further development for the potential treatment of autoimmune diseases and other noncancer indications. In light of the IND clearance, TG Therapeutics now intends to initiate a phase 1 clinical trial before the end of the year.

“We would like to congratulate TG Therapeutics on receiving IND clearance for azer-cel in patients with progressive MS,” Michael Amoroso, MBA, the chief executive officer of Precision BioSciences, said in a statement.¹ “We believe the expansion of allogeneic CAR-T into autoimmune diseases holds the potential to unlock new therapies for patients living with chronic disease. We look forward to TG Therapeutics initiating a clinical trial for azer-cel in autoimmune disease as we focus on the advancement of our own wholly owned in vivo gene editing pipeline, including our planned IND and/or clinical trial application submission for PBGENE-HBV for hepatitis B this year.”

Precision garnered an upfront payment and potential near-term economics valued at $17.5 million for the licensing of azer-cel to TG Therapeutics. In addition, the deal includes potential for up to $288 million in further milestone payment, as well as the potential for royalties.

Azer-cel is not the only cell therapy currently in development for the treatment of MS. Just earlier this month, the FDA cleared Indapta Therapeutics’ IND application to evaluate its g-natural killer (g-NK) cell therapy IDP-023 in participants with progressive multiple sclerosis (MS).² IDP-023 is a universal, allogeneic NK cell therapy designed to have highly robust antibody-dependent cell mediated cytotoxicity, inherent antiviral activity, and an NKG2C receptor that targets HLA-E expressing cells. It consists of naturally occurring g minus NK cells, which arise from epigenetic changes resulting from exposure to cytomegalovirus.

Another trial assessing a novel therapy for MS is IASO Bio’s recently cleared phase 1/2 trial of itsCAR) T-cell therapy equecabtagene autoleucel (eque-cel), which received IND clearance in July 2024.³ Eque-cel is a fully human anti-BCMA CAR T-cell therapy initially investigated for treating multiple myeloma and also being explored for treating other forms of central nervous system autoimmunity, including neuromyelitis optica spectrum disorder, myasthenia gravis, immune-mediated necrotizing myopathy, and generalized myasthenia gravis.

Kyverna Therapeutics is also exploring the potential of bringing its CAR-T therapy KYV-101 to MS.⁴ It showed a manageable safety profile and demonstrated expansion-dependent effects of CAR-T cells on CD19+ target cells in the central nervous system of patients with MS treated by researchers from the University Medical Center Hamburg. KYV-101 is an autologous, fully human CD19 CAR T-cell therapy being investigated for treating B cell-driven autoimmune diseases.

Precision BioSciences is directing its own efforts towards the advancement of in vivo gene therapy products based on its ARCUS platform. CGTLive® previously spoke with Gary Owens, MS, the associate director for gene therapy discovery at Precision Biosciences, about the potential of the ARCUS platform in Duchenne muscular dystrophy (DMD) at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16 to 20, in Los Angeles.⁵ Owens discussed the preclinical findings he presented at the conference and the main implications of the research for the healthcare community. He highlighted that the DMD model mice treated with the ARCUS approach achieved a maximum force output (MFO) in the gastrocnemius muscle that reached 86% of levels seen in healthy control mice, a significant improvement over the MFO seen in untreated DMD model mice.

REFERENCES
1. Precision BioSciences announces investigational new drug clearance by partner TG Therapeutics for investigation of azer-cel for multiple sclerosis. News release. Precision BioSciences, Inc. August 9, 2024. Accessed August 14, 2024. https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-announces-investigational-new-drug
2. Indapta Therapeutics Announces FDA Clearance of IND for Phase 1 Trial of IDP-023 for Progressive Multiple Sclerosis. News release. Indapta Therapeutics. August 6, 2024. https://www.businesswire.com/news/home/20240806112913/en/Indapta-Therapeutics-Announces-FDA-Clearance-of-IND-for-Phase-1-Trial-of-IDP-023-for-Progressive-Multiple-Sclerosis
3. IASO Bio Receives U.S. FDA Approval of Investigational New Drug Application for EquecabtageneAutoleucel for Multiple Sclerosis. News release. IASO Bio. July 23, 2024. https://www.prnewswire.com/news-releases/iaso-bio-receives-us-fda-approval-of-investigational-new-drug-application-for-equecabtagene-autoleucel-for-multiple-sclerosis-302204711.html
4. Fischbach F, Richter J, Pfeffer LK, et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis. Med. Published online March 29, 2024. doi: 10.1016/j.medj.2024.03.002
5. Lewis W, Owens G, Jordan-Steele M, et al. ARCUS-mediated excision of the “hot spot” region of the human dystrophin gene for the treatment of Duchenne muscular dystrophy (DMD). Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA.