The Efficacy of Efgartigimod PH20 SC (VYVGART Hytrulo ) in Patients With Stiff Person Syndrome (SPS): A Double-blind, Placebo-controlled, Cross-over Trial

Summary

Stiff Person Syndrome (SPS) is a rare autoimmune disorder, characterized by: a) incapacitating diffuse muscle stiffness prominent in the axial, abdominal and thoracolumbar paraspinal muscles leading to hyperlordosis, difficulty turning and bending; b) painful muscle spasms precipitated by external stimuli with difficulty performing routine daily activities; and c) slow freezing gait with frequent falls and need for walking aids leading to disability. SPS is due to impaired inhibitory GABAergic neurotransmission associated with high-titer IgG antibodies against Glutamic Acid Decarboxylase (GAD), the rate-limiting enzyme for the synthesis of the inhibitory gammaaminobutyric acid (GABA). Although SPS patients respond to IVIg based on the PI's controlled study (NEJM 2001), several patients do not improve, or their response is modest and declines over time, as documented in a longitudinal study of 36 patients followed in our Jefferson clinic; because another controlled study we performed with Rituximab was negative and SPS is a progressive disease, new therapies are needed. Efgartigimod is an FcRn inhibitor that enhances the catabolism of circulating IgG; its subcutaneous, self-administered form, HYTRULO, has been effective and FDA-approved in patients with myasthenia gravis or CIDP poorly responding to IVIg. There is evidence that patients with myasthenia who also had SPS, Hytrulo not only helped their myasthenia but the SPS also impressively improved. The present study is an investigator- initiated, double-blind, placebo controlled, cross-over, trial in 26 GAD-positive SPS patients poorly responding to available therapies. Patients will be recruited from the large number of patients seen and referred to the PI who is known for his work in SPS and has conducted the 2 previous controlled trials. Although Hytrulo is approved as selfadministered subcutaneous drug with pre-refilled syringes, in this study will be given by a contracted home infusion company once a week to ensure convenience, safety and validity. Patients will be randomized by the Jefferson Pharmacy to receiving Hytrulo or identical hyaluronidase-containing placebo for 3 months; then they will be crossed-over to placebo/Hytrulo for another 3 months. Efficacy will be based on one primary endpoint, the stiffness index, previously validated by the PI, and on two also validated secondary endpoints of time to walk and excitability index. This design provides the statistical power to objectively assess a 25-50% or greater change and objectively determine if Hytrulo offers meaningful benefits in reducing stiffness and spasms, improving gait and increasing quality of life in SPS patients poorly responding to current therapies.