Stiff Person Syndrome Patients Regain Mobility After Single-Dose Cell Therapy

A single dose of mivocabtagene autoleucel (miv-cel), an autologous CD19 chimeric antigen receptor (CAR)-T cell therapy, showed benefit in people with stiff person syndrome (SPS) in the pivotal phase II KYSA-8 trial.

The 26-person study met the primary efficacy endpoint of improvement in the timed 25-foot walk at week 16 with a median improvement of 46% (P=0.0003), said Amanda Piquet, MD, of the University of Colorado Anschutz in Aurora, in a late-breaking science session at the American Academy of Neurology (AAN) annual meeting.

Most participants (81%) achieved clinically meaningful improvement, defined as at least 20% improvement from baseline. Nearly a third of all participants (31%) walked at the speed of healthy adults by week 16, completing the timed 25-foot walk in under 5 seconds. Of 12 patients who needed a walking aid at baseline, 67% no longer needed walking assistance at week 16.

All 26 patients remained free of immunomodulatory therapies at week 16 and through the last follow-up. At the time of the primary analysis, median follow-up was 6.5 months.

“Results showed that miv-cel delivered a rapid, statistically significant, and clinically meaningful improvement across all primary and secondary endpoints at week 16, with the majority of patients regaining neurologic function,” Piquet said during an AAN press conference.

“From a clinical perspective, the magnitude and consistency of functional improvement observed is unprecedented,” she stated.

Stiff person syndrome is a rare, progressive autoimmune disease affecting the central nervous system, with muscle stiffness and painful spasms that lead to loss of mobility. Patients often have antibodies to glutamic acid decarboxylase 65 (GAD65) or the glycine receptor (GlyR). The disorder drew worldwide attention when singer Celine Dion announced her diagnosis in 2022.

There are no approved treatments for stiff person syndrome. Existing approaches focus on managing symptoms or using immunotherapies like intravenous immunoglobulin, rituximab, and plasmapheresis.

“Most patients have inadequate or no response to these treatments,” Piquet said. “In fact, 80% of patients ultimately need some type of walking assistance or even a wheelchair, resulting in poor quality of life.”

Miv-cel is a fully human, autologous CD19 CAR-T therapy incorporating CD28 co-stimulation, Piquet noted. “It works by eliminating B cells, which in turn, helps reset the immune system,” she said.

KYSA-8 is a single-arm, registrational phase II trial that enrolled 26 adults with stiff person syndrome. Participants had seropositivity for high-titer GAD65 or GlyR antibodies either historically or at screening, an inadequate response to one or more immunomodulatory therapies, and a stiffness index of at least 2.

Participants received lymphodepletion with low-dose cyclophosphamide and fludarabine followed by a single infusion of miv-cel at a target dose of 1×10⁸ CAR T cells. The trial’s two primary endpoints were the change from baseline to week 16 in the timed 25-foot walk and safety.

“Overall, miv-cel showed a consistent, well-tolerated, and manageable safety profile,” Piquet reported. The most common treatment-related adverse events were low-grade cytokine release syndrome (92%; 38% were grade 1 and 54% were grade 2), fatigue (54%), diarrhea (38%), and headache (31%). There were three grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) events (12%).

No severe cases of cytokine release syndrome or ICANS were reported. Grade 3/4 neutropenia occurred in four patients (15%) and was manageable with no associated serious infection. Three patients (12%) experienced serious treatment-related adverse events that resolved fully without sequelae.

Secondary endpoints included scores on the modified Rankin Scale of disability, the heightened sensitivity scale, the distribution of stiffness index, and the Hauser ambulation index. Miv-cel showed mean improvements from baseline in all four outcomes (P<0.0001).

Nearly all — 25 of 26 patients — had improvement in at least one primary or secondary efficacy endpoint, Piquet noted.

Developer Kyverna Therapeutics said it plans to submit miv-cel for FDA approval to treat stiff person syndrome this year. The company also is evaluating miv-cel in a phase II/III trial of myasthenia gravis.

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