FDA Clears Phase 2 KYSA-7 Study of CAR T-Cell Therapy in Refractory Progressive Multiple Sclerosis

Bruce Cree, MD, PhD, MAS

According to an announcement, the FDA has cleared Kyverna Therapeutics’ investigational new drug application (IND) to test KYV-101, a CAR T-cell therapy, in patients with refractory progressive multiple sclerosis (MS), a disease for which there are limited available therapies. The approved phase 2 open-label trial will target a large patient demographic to evaluate the effectiveness and safety of the agent in this patient population.¹

"This approval is a critically necessary step that paves the way to enroll patients with treatment-refractory progressive MS for whom there are no currently available treatment options in the KYSA-7 trial," Bruce Cree, MD, PhD, MAS, clinical research director and professor of clinical neurology at the University of California, San Francisco, said in a statement.¹ "This study offers participants a new hope for arresting relentless disability worsening and a potentially durable, treatment-free remission."

The IND clearance is the 7th for KYV-101, which is also currently being assessed in patients with lupus nephritis and soon to be evaluated in trials of systemic sclerosis and myasthenia gravis. The autologous, fully human CD19 CAR T-cell product candidate was previously assessed in a phase 1 trial (NCT02659943) in oncology, using patients with B cell lymphoma. Published in Nature in 2020, that small-scale study of 20 individuals met its primary objective of safety and feasibility.²

Previous research has suggested that progressive MS may be in part result from ongoing central nervous system (CNS) damage associated with meningeal ectopic lymphoid follicles. A 2023 mouse model study showed that the use of anti-CD19 CAR-T cells ameliorated experimental autoimmune encephalitis and depleted B cells in peripheral tissues and in the CNS. Investigators concluded that the ability of CAR-T cells to penetrate the CNS more readily may offer a therapeutic benefit over existing monoclonal antibody therapies that only deplete B cells in the periphery.³

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"This very important study will answer whether CAR T-cell therapy offers a new treatment option for patients living with MS. This therapy holds the promise to alter the treatment paradigm of MS by fundamentally readjusting the immune system," Manuel Friese, MD, professor of neurology and director of the Institute of Neuroimmunolgoy and Multiple Sclerosis at the University Medical Center-Hamburg-Eppendorf, Hamburg, Germany, said in a statement.¹

There are more than 20 FDA-approved disease-modifying therapies for MS in the US; however, most of these are indicated for relapsing disease, with the exception of ocrelizumab (Ocrevus; Genentech), which is approved for primary progressive MS. Currently, there are no approved treatments for patients with non-relapsing progressive MS that is worsening, treatment refractory, and non-active as defined operationally by absence of relapse of MRI evidence of inflammatory disease within the preceding 2 years.

"As a patient-centered organization, we are thrilled to see KYV-101 being cleared for a large patient demographic as part of our KYSA-7 trial,” Peter Maag, PhD, chief executive officer, Kyverna, said in a statement.¹ "This is a clear paradigm shift for autoimmune diseases, and a testament to our commitment to expand potentially life-changing therapeutic benefits to multiple indications."

REFERENCES
1. Kyverna’s KYV-101 receives US FDA clearance for treatment of patients with refractory, progressive multiple sclerosis in the KYSA-7 phase 2 trial. News release. January 3, 2024. Accessed January 4, 2024. https://www.prnewswire.com/news-releases/kyvernas-kyv-101-receives-us-fda-clearance-for-treatment-of-patients-with-refractory-progressive-multiple-sclerosis-in-the-kysa-7-phase-2-trial-302025646.html
2. Bruno JN, Lam N, Vanasse D, et al. Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Nature. 2020;26:270-280. doi:10.1038/s41591-019-0737-3
3. Gupta S, Simic M, Sagan SA, et al. CAR-T cell-mediated B-cell depletion in central nervous system autoimmunity. Neurology. 2023;10(2). doi:10.1212/NXI.0000000000200080