Study Details of Phase 2 KYSA-6 Trial of CAR-T Therapy in Myasthenia Gravis Presented

Author(s):

Key Takeaways

KYSA-6 will assess KYV-101's efficacy and safety in refractory generalized myasthenia gravis, focusing on MG-ADL changes as the primary endpoint.
Inclusion criteria require MG diagnosis with specific autoantibodies, MGFA Class IIB-IV, and prior treatment failure, while excluding those with cardiac impairments or uncontrolled conditions.
Secondary outcomes include changes in QMG scores, disease-related antibodies, and patient-reported outcomes, alongside pharmacodynamic assessments.
FDA clearance allows KYSA-6 to proceed, with KYV-101 also being investigated for refractory progressive multiple sclerosis and other autoimmune disorders.

The multicenter, 24-week study will feature 20 patients with MG, testing changes on MG-ADL as well as several other secondary outcomes, including patient-reported assessments.

Ralf Gold, MD

New details have emerged regarding a multicenter, open-label, phase 2 study, dubbed KYSA-6 (NCT06193889) that will investigate the efficacy and safety of KYV-101 (Kyverna Therapeutics), an investigational fully human anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory generalized myasthenia gravis (gMG). The trial will feature 20 patients with the disease, using change in Myasthenia Gravis-Activities of Daily Living (MG-ADL) as the primary efficacy end point.¹

These details were released in a poster presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held October 15-18, in Savannah, Georgia, by senior author Ralf Gold, MD, chair of the department of neurology at the University of Bochum at St. Joself-Spital. The study will last approximately 24 weeks and will test safety, through adverse events (AEs), and efficacy through MG-ADL. After lymphodepletion (fludarabine 30 mg/m²/day, cyclophosphamide 300 mg/m²/day; 3 days), patients will receive a single infusion of 1×10⁸ CAR T cells.

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.

Inclusion criteria for the study include a diagnosis of MG with acetylcholine (AChR) or muscle-specific kinase (MuSK) autoantibodies, MGFA Class IIB-IV (or III-IV in Germany), and an MG-ADL score ≥6. Participants must have failed 1-2 years of prior treatments, including immunotherapies, monoclonal antibodies, IVIG, or plasmapheresis, depending on the site. They must also be on stable doses of immunotherapies or acetylcholinesterase inhibitors before screening, with no recent IVIG or plasma exchange.

Exclusion criteria include impaired cardiac function, such as recent myocardial infarction, severe arrhythmias, cardiomyopathy, or an LVEF <45%. Patients with uncontrolled medical conditions, including active infections, dementia, recent thromboembolic events, or those on unsafe anticoagulants for procedures, are also excluded.

Secondary outcome objectives of the study include observing change in Quantitative Myasthenia Gravis (QMG) score, Myasthenia Grvais Composite score, disease-related antibodies, and other patient-reported outcomes such as Myasthenia Gravis Quality of Life-15, MGFA Post-Intervention Status, Neuro-QOL, and EQ-5D. Investigators will also characterize the pharmacodynamics of CAR-positive T cell counts, B-cell counts, systemic cytokine concentrations, and the immunogenicity response of KYV-101.

In November 2023, the FDA cleared the investigational new drug application for KYSA-6, allowing the study to proceed. Months later, the agency also cleared the company’s investigational new drug application to study KYV-101 in patients with refractory progressive multiple sclerosis (MS), a disease for which there are limited available therapies. Kyverna did not release many details behind that study, noting that it will target a large patient demographic to appropriate evaluate the efficacy and safety of KYV-101 in that patient population.²

Earlier this year, Kyverna published the first report of individual treatment with KYV-101 in 2 patients with progressive MS. Overall, results showed that the therapy was tolerable over a short-term period, with CAR-T cell expansion observed in cerebrospinal fluid (CSF) without neurotoxicity. Intrathecal antibody production also decreased after CAR-T cell infusion in 1 patient. Despite both patients receiving ocrelizumab before the trial, circulating B cells were only detectable in the peripheral blood of patient 1 but not patient 2. This residual B cell population of patient 1 was depleted by day 2 post-infusion and did not reconstitute as of day 100. Notably, patient 1 saw a decrease in the number of oligoclonal bands from 13 to 6 on day 64, sustained through day 64, whereas patient 2 had no changes in the number of OCBs nor intrathecal immunoglobulin levels.³

REFERENCE
1. Haghikia A, Borie D, Chung J, Gold R. Design of KYSA-6, a phase 2, open-label, multicenter study of KYV-101, a novel fully human anti-CD19 chimeric antigen receptor T-cell therapy in refractory generalized myasthenia gravis. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA. ABSTRACT 183
2. 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 November 21, 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
3. Fischbach F, Richter J, Pfeffer LK, et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis. Cell Press. Published March 29, 2024. doi:10.1016/j.medj.2024.03.002.