Abstracts

Rationale: Stiripentol (STP) is indicated for the treatment of seizures associated with Dravet syndrome (DS) in patients taking clobazam (CLB). Since STP has a different mechanism of action from CLB, showing that STP and CLB act concomitantly, but also that due to pharmacokinetic interactions STP increase the plasma concentrations of CLB and its active metabolite norclobazam (norCLB), this analysis evaluates the intrinsic activity of STP.

Methods: This analysis summarizes non-clinical pharmacological activities and clinical response of STP, alone and synergistic effects when combined with CLB. Information was extracted from the literature, from Biocodex internal reports, and from clinical trials. Also, a covariate adjusted analysis was performed to evaluate the contribution of increased plasma concentrations of CLB and NCLB to the antiepileptic efficacy of STP.

Results: STP alone, in clinically relevant doses, is effective in mice, rats, rabbits, and primates in models of the main seizure types observed in Dravet syndrome (tonic-clonic; petit mal; partial complex). In addition, STP was found to be active in a model that can be viewed as predictive of seizure spread (MES), suggesting efficacy in preventing status epilepticus, and this was confirmed in a rat model of status epilepticus. Results of several independent studies of the mechanism of action of STP show that it potentiates phasic and tonic GABAergic currents by acting postsynaptically at a modulatory site associated with the GABA receptor, but unique to STP. When effective concentrations of STP and diazepam were applied together, the drugs act additively to further increase channel activity. These results were later extended to CLB, NCLB, and clonazepam. In addition, STP increases GABA and glutamate release by acting presynaptically through a mechanism that has not yet been identified. 
_x000D_ In pivotal clinical trials in Dravet syndrome, a covariate adjusted analysis showed that the plasma concentrations of CLB and NCLB in the STP group significantly increased from baseline but results demonstrated that there is no statistically significant contribution of the increase in CLB and NCLB plasma concentrations on response to STP treatment. Thus, the effect of STP-associated increase in plasma concentrations of CLB and NCLB on treatment response was marginal (if any), that is, the observed treatment effect is mainly from STP.
_x000D_ Two studies in Dravet syndrome who titrated up to maximal tolerated or maximally effective dose of CLB showed that these patients still experienced seizures, showed there was no difference between response rate in patients who received STP+CLB and in those who received STP alone (without CLB).

Conclusions: The supra-additive synergy activity of STP and CLB administered together has widely been described and supports the concomitant use of these two drugs. However, this analysis also confirms the per se antiepileptic activity of STP alone.

Funding: Biocodex