A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency

Abstract

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 (P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://ichgcp.net/clinical-trials-registry/NCT02019667.

Keywords: cognition; efficacy; epilepsy; inborn errors of metabolism; neurodevelopment; treatment.

Conflict of interest statement

DECLARATION OF CONFLICTING INTERESTS

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.

Randomized, double-blinded crossover study design.

Figure 2.

CONSORT flow diagram detailing recruitment and handling of subjects.

Figure 3.

General adaptive composite standardized scores on the Adaptive Behavior Assessment System, Third Edition (ABAS-3) for each subject in each condition.

Figure 4a-c.

Results of transcranial magnetic stimulation. 4a. Motor threshold, expressed as a percentage of maximal stimulator output for each patient in each condition. 4b. Conditioned motor evoked potentials (MEP) for paired-pulse stimuli including intra-cortical facilitation (ICF), long interval intra-cortical inhibition (LICI), and short interval intra-cortical inhibition (SICI). Values are expressed as a percentage of the mean MEP compared to the baseline (conditioning) MEP in each patient for each study condition.4c. Recruitment curves for each subject across each condition, expressed as absolute mean motor evoked potential amplitude in millivolts at increasing stimulus intensities (expressed as a percentage of the motor threshold).