FDA Clears Phase 2 Study of CAR T-Cell Therapy KYV-101 in Myasthenia Gravis

Aiden Haghikia, MD

Kyverna Therapeutics has announced that the FDA has cleared its investigational new drug (IND) application for KYV-101, a fully human CD19 chimeric antigen receptor (CAR) T-cell therapy, to be assessed in a phase 2 study of patients with myasthenia gravis (MG), an autoimmune disorder.¹

"We have seen firsthand the transformative effects of KYV-101 in MG patients treated with the investigational therapy in our clinic,” Aiden Haghikia, director of the department of neurology at Otto-von-Guericke University in Magdeburg, Germany, said in a statement.¹ "I welcome the FDA's decision and look forward to more clinical data to further our knowledge about CAR T-cell therapy in patients with severe neurological autoimmune diseases."

CAR T cells have been seen as a versatile new class of effective, molecularly precise therapy. Dubbed KYSA-6, the phase 2 study will continue to assess the efficacy and safety of KYV-101, an autologous agent, in patients with MG. In its release, Kyverna did not include much details on the design of the trial but that it expands on the current pipeline, which includes the ongoing US-based phase 1 KYSA-1 study and the phase 1/2 KYSA-3 trial in Germany, which feature patients with active lupus nephritis.

KYV-101 is designed to target, recognize, and remove CD19, a specific protein expressed on the surface of B cells in various autoimmune disorders. In addition to ongoing trials in lupus nephritis, the company is planning to assess KYV-101 in trials of systemic sclerosis and multiple sclerosis. The CAR in KYV-101 was designed by the National Institutes of Health to improve tolerability and was tested in a phase 1 trial (NCT02659943) in oncology with results published in Nature in 2020.²

The first-in-human study featured 20 patients with B cell lymphoma with the primary objective of assessing safety and feasibility and secondary objectives of blood levels, ant-lymphoma activity, second infusions, and immunogenicity. KYV-101, known as just a Hu19-CD828Z T cell therapy at the time, met all study objectives. Treated patients demonstrated lower levels of cytokines than those who received FMC63-28Z T cells, which investigators noted could have explained the lower level of neurologic toxicity associated with the agent.

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"We are grateful that the FDA's decision to clear the IND for our Phase 2 KYSA-6 trial will allow Kyverna to offer this potentially paradigm-shifting investigational treatment to patients that may benefit from a deep B cell depletion and possibly durable reset of their immune system," Peter Maag, PhD, chief executive officer at Kyverna, said in a statement.¹

Most recently, the company announced positive safety findings from a 28-day post infusion observation period in its phase 1 study assessing KYV-101 in patients with refractory lupus nephritis. In the open-label, dose-escalation, multicenter study, the Kyverna reported that the agent was well tolerated, with no cases of immune effector cell-associated neurotoxicity syndrome in a single patient treated with the agent.³

CAR T cell therapies, which have been successful in areas of cancer, are gaining more ground in the neurology field. A few months ago, data from the phase 1b/2 MG-001 trial (NCT04146051) published in Lancet Neurology was among the first to assess such therapy in patients with MG. Led by James F. Howard, MD, the study assessed Descartes-08, an autologous anti-B cell maturation antigen (BCMA) rCAR T therapy in adults with generalized MG who had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher.⁴

Comprised of 16 patients, the study showed that Descartes-08 was safe and well tolerated, with no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity observed. Infusions with the agent were followed by clinically meaningful decreases on MG severity scales at up to 9 months of follow-up, although the study authors noted that further investigation is needed to validate efficacy benefits.

REFERENCES
1. Kyverna Therapeutics announces FDA clearance of phase 2 IND for KYV-101, a fully human CD19 CAR T-cell therapy to treat myasthenia gravis. News release. Kyverna Therapeutics. November 13, 2023. Accessed November 13, 2023. https://www.prnewswire.com/news-releases/kyverna-therapeutics-announces-fda-clearance-of-phase-2-ind-for-kyv-101-a-fully-human-cd19-car-t-cell-therapy-to-treat-myasthenia-gravis-301986135.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. Kyverna Therapeutics announces achievement of 28-day post infusion milestone for first US patient dosed in phase 1 clinical trial of CD19 CAR T-cell therapy for Lupus Nephritis. News release. Kyverna Therapeutics. September 13, 2023. Accessed November 13, 2023. https://www.prnewswire.com/news-releases/kyverna-therapeutics-announces-achievement-of-28-day-post-infusion-milestone-for-first-us-patient-dosed-in-phase-1-clinical-trial-of-cd19-car-t-cell-therapy-for-lupus-nephritis-301925488.html
4. Granit V, Benatar M, Kurtoglu M, et al. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomized phase 1b/2a study. Lancet Neurol. 2023;22(7):578-590. doi:10.1016/S1474-4422(23)00194-1