4-Phenylbutyrate for SLC6A1-Meaningful Outcomes and Access : A case for repurposing Phenylbutyrate (ATX-018) to include use in the treatment of SLC6A1 and additional rare indications

IntroductionThe clinical picture of SLC6A1 gene mutations is characterised by a mild-to-moderate intellectual disability, speech difficulties, behavioural problems, epilepsy characterizing a myoclonic-atonic epilepsy (MAE), and neurological signs (1).

Backgroundo J. Kang has shown that 4-phenylbutyrate improves the function and trafficking of GAT-1 (2)o Glyceryl Phenylbutyrate (Ravicti®) is a prodrug and approved for use ONLY in treating children with urea cycle disorder.o Ravicti ® currently costs around $793,632 for a year of treatment in the US (3)

SLC6A1connect has financially supported the following research:• Study of 4-phenylbutyrate (PBA) rescue of SLC6A1 mutation-mediated disorders in patient derived cell and mouse models (4)• Open Label Trial,in SLC6A1 and STXBP1 patients for which the fully analysed published results are pending (5)• Preliminary results showed SLC6A1 patients that had seizures all saw a significant response in seizure activity with reductions from 50% (n=1) to 90% (n=4), to seizure freedom (n=1), at 10 weeks from baseline (as did STXBP1).

DiscussionThe impact on quality of life is its real meaningful outcome. As numbers on Ravicti® increase, families report significant improvements in sleep, mood, behaviour, aggression, cognition, articulation, focus and of course seizure burden.

What next?

Full analysis of the trial to be published

Obtain new sources of phenylbutyrate - Aayam Therapeutics has identified an alternate patentable drug – ATX-018. SLC6A1 and Aayam are raising investment through sources that would also allow this to be affordable for patients globally.

Support in the repurposing of Phenylbutyrate (ATX-018) to include use in the treatment of SLC6A1, and access for families