Stiripentol in Dravet syndrome

Wirrell EC, Laux L, Franz DN, Sullivan J, Saneto RP, Morse RP, Devinsky O, Chugani H, Hernandez A, Hamiwka L, Mikati MA, Valencia I, Le Guern ME, Chancharme L, de Menezes MS. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia. 2013 Sep;54(9):1595-604.

Abstract

PURPOSE:

To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome.

METHODS:

U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded.

KEY FINDINGS:

Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy.

SIGNIFICANCE:

Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome. 

Kossoff E. Stiripentol for Dravet syndrome: is it worth it? Epilepsy Curr.2014 Jan;14(1):22-3. (a comment on the Wirrell, et al. paper)

Why exactly was this study performed? It was funded by Biocodex, the French company that owns and produces stiripentol. Two of the authors are company employees. One has to suspect that Biocodex may be considering either expanding its market to the United States or selling stiripentol to a U.S.-based pharmaceutical company for distribution. Perhaps this study is to test the waters of efficacy and interest here prior to a large scale FDA-mandated prospective clinical trial.

Regardless of the reasons for this study, the results were promising. The authors chose to group patients with sufficient data into those receiving stiripentol alone (n = 6), those on stiripentol with clobazam (n = 35), stiripentol with valproate (n = 14), and stiripentol with both clobazam and valproate (n = 48). One presumes some children were counted twice if they tried stiripentol in different combinations. Overall, 66% (68/103) had a reduction in seizures, with approximately half of those being a “marked” reduction. Most dramatically, every single one of the 35 children with prolonged seizures (and sufficient data to assess response) had improvement, with approximately 80% markedly improved. The best combination identified was stiripentol with clobazam, followed by all three AEDs together. Stiripentol was tolerated well, with sedation seen in 18% and decreased appetite in 8.5%. Quality of life improved in 88%, according to their physicians.

How should we interpret this information? On one hand, it confirms previous reports that stiripentol is helpful for children with Dravet syndrome, especially for those with very prolonged seizures. The value is significant in preventing emergency department visits, need for rescue medications, status epilepticus, and death due to prolonged seizures. On the other hand, the value of stiripentol may at least partially be due to raised clobazam levels. Perhaps it would be more cost-effective to increase the daily clobazam dose to a maximum, and only then consider stiripentol when that approach has failed?

Inspired when in response to my posting in another forum my personal best with a clobazam level of  860 and a desmthylclobazam level  of  19659 in a 14 year old female receiving clobazam at a 30/40 mg dosage and not taking cannibidiol,  A correspondent asked regarding stiripentol.  The patient does not take stiripentol but does receive felbamate and zonisamide.