A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DELAYED-START TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF L-SERINE IN SUBJECTS WITH HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE 1 (HSAN1) (S45.001)

Objective: To evaluate the safety and efficacy of L-serine in patients with HSAN1. Background: HSAN1 is an autosomal dominant disorder caused by mutations to serine palmitoyl-CoA transferase. Mutations induce a permanent shift in the substrate preference from serine to alanine thereby forming a class of neurotoxic 1-deoxysphingolipids (1-deoxySL). We report a two-year, delayed-start placebo-controlled clinical trial to evaluate safety and efficacy of oral L-serine (400 mg/kg/d) in HSAN1. Design/Methods: Eighteen HSAN1 patients with prominent sensory loss, foot ulcers or shooting pains were enrolled. Subjects were equally randomized to L-serine or placebo for 1 year. At 48-weeks, the placebo group crossed-over and all participants took open-label L-serine for one additional year. Results: Sixteen subjects completed their 96-week visit. There were no serious adverse events related to L-serine. Participants randomized to L-serine experienced a significant decline in the CMTNS over 1 year relative to placebo (−1.8 units, 95% CI −3.3 to −0.3, p = 0.02). Both groups improved in the second year of the study, with a diminished difference in the CMTNS at 96 weeks. (−1.45 units, 95% CI −3.7 to 0.81, p=0.20). Mean reports of sharp pain improved by 1.2 units on a 0–10 scale over 96 weeks in the L-serine group but did not differ significantly from placebo (p=0.70). 1-deoxySL levels declined significantly among subjects on L-serine vs. those on placebo after one year of treatment (59% decrease in deoxysphinganine vs. 11% increase on placebo, p Conclusions: L-serine is a safe and potentially efficacious treatment for HSAN1. Disclosure: Dr. Fridman has nothing to disclose. Dr. Novak has nothing to disclose. Dr. David has nothing to disclose. Dr. Macklin has received personal compensation for activities with Acorda Therapeutics, Lantheus Medical Imaging, and Shire Human Genetic Therapies. Dr. Macklin has received research support from Biotie Therapies, ALSA, ALSTDI, ALS Therapy Alliance, MJ Fox Foundation, A Coors Foundation, Autism Speaks, NIH, and HRSA. Dr. McKenna-Yasek has nothing to disclose. Dr. Walsh has nothing to disclose. Dr. Oaklander has nothing to disclose. Dr. Brown has received personal compensation for activities with Voyager and Mitobridge as a consultant. Dr. Hornemann has nothing to disclose. Dr. Eichler has received research support from Bluebird Bio and Vertex Pharmaceuticals.