Rationale:
Lennox-Gastaut Syndrome (LGS) is a Developmental and Epileptic Encephalopathy (DEE) starting in early childhood, characterized by polymorphous epileptic seizures: atypical absences, axial tonic and atonic seizures with EEG patterns consisting of diffuse slow spikes and waves, burst of fast rhythm during sleep and cognitive impairment. Despite many available treatment options, management of LGS remains problematic due to intractable seizures. Thus, some physicians use stiripentol (STP), a FDA-approved drug for Dravet Syndrome, as an alternative. This work aimed at reviewing the use of STP in LGS.
Methods:
A Literature search was done (May 2023) in Cochrane Library and PubMed using the terms "stiripentol AND Lennox," as well as in the abstract books from relevant meetings (from 2007 onwards) searching firstly "stiripentol" and then "Lennox." Eligibility criteria was the presence of data on STP related to LGS treatment. Additionally, results of an unpublished exploratory multicenter, single-blind Phase II trial conducted in the early 90’s in four French centers in patients (2-20 years) with inadequately controlled (≥1 seizure/week) LGS and were reviewed.
Results:
The Literature search found 29 references, of which only five were eligible (three observational studies [one meeting abstract], one clinical trial, and one review). Despite scarce, the data reported that STP can be an effective and well-tolerated therapeutic option in LGS treatment. This finding is also supported by some real-world evidence (RWE) which confirmed stiripentol efficacy in Lennox Gastaut patients.
In the phase II trial, further a one-month placebo period, stiripentol was added to the ongoing treatments for two months, at a daily dose between 2,000 and 3,000 mg according to patients’ age. A total of 16 LGS patients were included and stiripentol treatment was interrupted in one due to adverse events. Compared to baseline, a significant decrease in the overall seizure frequency was reported in the 15 LGS patients assessable (p=0.02), notably tonic-clonic seizures (p=0.01). A decrease in seizures was observed in 80% of these patients, of whom five were seizure-free and four were responders (defined as a ≥ 50% reduction in seizures). Additionally, maximal time interval between seizures increased in 13 patients as compared to the baseline period (p=0.01). Regarding safety, one patient discarded the study due to side effects (nausea, vomiting, somnolence). The most frequently reported adverse events were anorexia, nausea, vomiting, constipation, and somnolence, in line with the stiripentol safety profile.
Conclusions:
The evidence published so far together with the results the phase II study suggest a good efficacy and tolerability of STP in treating LGS when used in combination with the current drugs indicated for this syndrome. According to these preliminary data, stiripentol might be a relevant therapeutic option for patients with drug-resistant epilepsy in LGS. However, this needs to be confirmed in a well-conducted phase III study.
Funding: This phase II study has been financially supported by Biocodex.