Phase II Trial of SGS-742 in Succinic Semialdehyde Dehydrogenase Deficiency

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DESCRIPTION (provided by applicant): Succinic semialdehyde dehydrogenase (SSADH) deficiency remains the most prevalent and untreatable disorder of GABA (4-aminobutyrate) metabolism. A placebo-controlled phase II trial of SGS742 (GABA(B) receptor antagonist) in SSADH-deficient patients is proposed, based upon preclinical efficacy findings in the corresponding murine model, which will evaluate safety, tolerability, and change in relevant indicators of SSADH severity in treatment vs. placebo groups. A crossover design will be employed where patients are randomized into an initial six month trial of SGS742 versus placebo. Our project's innovation resides in implementing the first placebo-controlled, blinded trial in this disorder using a rational intervention based upon preclinical efficacy studies in aldh5a1-/- mice. Our single formal hypothesis is that SSADH-deficient patients will have lengthening toward normal values of the cortical silent period (CSP), and return of long interval intracortical inhibition (LICI), during SGS742 intervention as quantified by transcranial magnetic stimulation. Secondary, exploratory outcomes include metabolic biomarkers in cerebrospinal fluid (GABA, GHB), neuropsychological evaluation, and safety. Aim 1 will compare the effect of SGS742 v. PBO on TMS levels as the primary outcome, relying both on the magnitude of the difference in TMS between the SGS742 and PBO group, as well as the equivalent of a paired t-test to assess the statistical significance level. The same procedure is employed in Aim 2 which evaluates SGS742 effects on biomarker levels, including GABA and GHB, as well as scores on neuropsychological assessments on vs. off SGS742. In Aim 3, we shift to the evaluation of safety. When we evaluate the frequency of adverse or toxic events, our analysis framework will comprise multiple logistic regression models to compare the odds of discrete occurrences such as reported adverse and serious adverse events in those on SGS742 relative to PBO. Appropriate biomarker outcomes, an investigative team with experience in a similar trial of taurine in this patient cohort, a proven, practical trial design, and a broad cohort of recruitable subjects are features that underscore our potential for success. In the short term, we will formulate a "go/no-go" decision regarding further clinical development of SGS742. The project's long term significance centers on identification of effective treatment for SSADH deficiency and related disorders in which neurocognitive dysfunction correlates with GABAergic systems.