Miv-cel CD19 CAR T-Cell Therapy Shows Efficacy and Safety in Stiff Person Syndrome in a Pivotal, Multicenter, Phase 2 Study (KYSA-8)
Amanda L Piquet1, Anastasia Zekeridou2, Usama Gergis3, Jonathan Gutman4, Saad S Kenderian5, Mallory Lowe1, Sadie Eggmann1, Andrew McKeon2, Sean J Pittock2, Goran Rakocevic6, Jessica J Yi6, Scott D Newsome7, Justin Chou8, Tom Van Blarcom8, Xue Han8, John Sun8, Shouvonik Sengupta8, Ryan Tooker8, Aditi Mehta8, Dena Grayson8, Naji Gehchan8, Marinos C Dalakas6
1Department of Neurology, University of Colorado Anschutz, Aurora, CO, USA, 2Departments of Neurology and Laboratory Medicine and Pathology, and Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA, 3Department of Oncology, Jefferson Health, Philadelphia, PA, USA, 4Department of Oncology, University of Colorado Anschutz, Aurora, CO, USA, 5Division of Hematology, Department of Immunology, and Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA, 6Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA, 7Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 8Kyverna Therapeutics, Inc., Emeryville, CA, USA
Objective:
To evaluate the efficacy and safety of miv-cel (mivocabtagene autoleucel; formerly KYV-101) in patients with stiff person syndrome (SPS) in the pivotal, multicenter, phase 2 study, KYSA-8 (NCT06588491).
Background:
SPS is a progressive, autoimmune neurologic disease characterized by muscle stiffness and painful spasms, leading to substantial disability. Miv-cel is a fully human, autologous CD19 CAR T-cell therapy with CD28 co-stimulation that showed durable clinical benefit on a named-patient basis in SPS and other autoimmune diseases.
Design/Methods:
Adults with SPS with inadequate response to immunomodulatory therapies received lymphodepletion (fludarabine 30 mg/m2/day, cyclophosphamide 300 mg/m2/day; 3 days) followed by a single infusion of miv-cel (target dose, 1×108 CAR T cells). Primary endpoints were the change from baseline to week 16 in the timed 25-foot walk (T25FW) and safety. Secondary endpoints were modified Rankin scale, stiffness index, heightened sensitivity scale, and Hauser ambulation index. Exploratory endpoints included pharmacokinetics/pharmacodynamics, and biomarkers.
Results:
Twenty-six patients were treated. Median follow-up was 6.5 months (range, 4.4–12.2). The primary efficacy endpoint was met, with significant improvement (p=0.0003) in T25FW of median -4.8 seconds (IQR, -11.9, -2.5; 45.6% median improvement) at week 16. At week 24, improvement was sustained (median 44.4%) among 16 patients who reached the timepoint. All secondary efficacy endpoints showed significant week 16 improvements (p<0.0001). The most common Grade 3/4 related adverse event was neutropenia (15.4%). Low-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 92.3% (38.5% Grade 1; 53.8% Grade 2) and 11.5% (Grade 1) of patients, respectively; all resolved without sequalae. Deep B-cell depletion was observed, associated with immune reset. At last follow-up, all patients remained free of immunomodulatory therapies for SPS.
Conclusions:
A single dose of miv-cel resulted in immunotherapy-free remissions with a consistent, well-tolerated safety profile, demonstrating a highly effective therapy with the potential for durable remissions in SPS. Long-term follow-up is ongoing.
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