Design of KYSA-8, A Phase 2, Open-Label, Multicenter Study of KYV-101, an Autologous Fully Human Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Treatment-Refractory Stiff-Person Syndrome
Amanda L Piquet1, Anastasia Zekeridou2, Esther H. Nie3, Dominic Borie3, James Chung3, Marinos C. Dalakas4
1Department of Neurology, University of Colorado, 2Department of Neurology, Laboratory Medicine and Pathology and Center for MS and Autoimmune Neurology, Mayo Clinic, 3Kyverna Therapeutics, Inc, 4Department of Neurology, Thomas Jefferson University
Objective:
To evaluate the safety and efficacy of KYV-101 in patients with refractory stiff-person syndrome (SPS).
Background:
SPS is a progressive neuroinflammatory disease in which autoreactive B cells play a pathogenic role, resulting in disability due to impaired mobility. KYV-101 is a first-in-class, fully human autologous anti-CD19 CAR T-cell therapy with a promising clinical safety profile. KYV-101 demonstrated acceptable tolerability and promising clinical benefits, including marked improvement of stiffness, walking speed, and reduction of symptomatic medications in a patient with SPS (Faissner S, et al. PNAS 2024;121:e2403227121). KYV-101 is being investigated in KYSA-8 (NCT06588491), a phase 2 open-label, single-arm multicenter study of KYV-101 in refractory SPS. KYV-101 received FDA Regenerative Medicine Advanced Therapy (RMAT) designation for SPS.
Design/Methods:
Twenty-five patients 18-75 years old, with active seropositive SPS and inadequate response to at least 1 immunomodulatory therapy (IVIG, rituximab, or plasmapheresis), and stiffness index ≥2, are eligible. Patients bedridden >3 months or with a history of stem cell transplant will be excluded. Following lymphodepletion (fludarabine 30 mg/m2/day, cyclophosphamide 300 mg/m2/day; 3 days), patients will receive a single infusion of KYV-101 at the target dose of 1×108 CAR T cells. The primary endpoints are change in the timed 25-foot walk from baseline to week 16 and safety events. Secondary endpoints include other evaluations of SPS-related clinical outcomes and disease-related biomarkers, including modified Rankin scale, distribution-of-stiffness index, heightened sensitivity scores, and quality of life.
Results:
KYSA-8 is actively enrolling patients in the US.
Conclusions:
KYSA-8 is the first phase 2 study of anti-CD19 CAR T-cell therapy in refractory SPS. KYV-101 may potentially change the immunotherapy paradigm through deep B-cell depletion and immune reset in autoimmune diseases like SPS.
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