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://clinicaltrials.gov/ct2/show/NCT02019667

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine

“…Importantly, these treatment strategies produced appreciable therapeutic outcomes in aldh5a1 −/− mice including seizure suppression, phenotypic reversal and extended lifespan. These promising preclinical results also formed the scientific basis for clinical drug trials, including taurine [ 37 , 38 ] and a recently completed study of GABA B R antagonist SGS-742 [ 39 ]. Yet, while these drugs were well-tolerated in patients, their therapeutic effects were rather limited.…”

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency

“…109 Current treatment options for SSADHD are symptomatic with limited efficacy. 110 Gene replacement therapy is a potential disease-modifying treatment for SSADHD but is currently unavailable. 111,112 The broad expression profile of ALDH5A1 in the brain suggests that a brainwide-targeted approach is likely necessary.…”

“…An SSADHD natural history study is ongoing, and thus far revealed a 15% incidence of sudden unexpected death in epilepsy in this patient population among other developmental and behavioral morbidities 109 . Current treatment options for SSADHD are symptomatic with limited efficacy 110 . Gene replacement therapy is a potential disease‐modifying treatment for SSADHD but is currently unavailable 111,112 .…”

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

“…For example, the only phase II clinical trial to date, which tested the GABA B receptor antagonist SGS-742, neither showed any improvement of cognition nor of cortical excitability. 7 A more detailed understanding of the pathophysiology of the disease, beyond the accumulation of GABA and GHB, may support novel therapy development for SSADHD. Whereas the deficiency directly affects GABA metabolism, it is possible that related metabolic pathways are affected as well.…”

“…Some clinical trials (phase I or II) have been performed, but without beneficial outcomes. For example, the only phase II clinical trial to date, which tested the GABA B receptor antagonist SGS‐742, neither showed any improvement of cognition nor of cortical excitability 7 …”