AAN 2026 | Findings from a Phase III trial of fenfluramine in patients with CDKL5 deficiency disorder

The abstract on fenfluramine in CDD, CDKL5 deficiency disorder, was recently released and results of the clinical trial have been published in an abstract way just recently. Just wanted to summarize mainly the major results, but starting on what is CDD, which is characterized by early onset drug-resistant epilepsy. And in this situation, seizure freedom is quite rare. Most patients experience daily seizures and there is a very strong unmet need related to the non-seizure symptoms. So the trial was done, this was a Phase III randomized double-blind placebo-controlled trial. The key features were the following, I mean patients enrolled were aged between 1 and 35 years, and they should have had at least four countable motor seizures per week. All patients were randomized to fenfluramine, 0.7 milligram per kilogram per day, or placebo, and the duration of trial was around 14 weeks. So, two weeks titration and 12 weeks maintenance phase. So regarding the population results, so going to the core of the data of results, so 87 patients were randomized and importantly to notice, this was a really highly refractory population of patients with most patients tried multiple anti-seizure medications. And in fact, also many of them, they were actually on polytherapy with a baseline seizure burden, which was more than 40 seizures per month. Regarding the data of efficacy, so definitely what I can summarize is that the study met its primary endpoint with highly statistical significance and fenfluramine achieved around more than 50% greater reduction in seizure frequency versus placebo. And this difference was really highly significant. And the magnitude of this effect is really particularly meaningful in patients with CDD. Regarding another point which it’s very interesting to summarize is the responder rate and secondary outcome which was again very interesting. So more than 50% seizure reduction was seen in about 45% of patients on fenfluramine compared with only 5% with placebo. And 75% seizure reduction, which is actually much more, even more interesting, was seen in 25% of patients on fenfluramine versus 2% of patients on placebo. And lastly, what I would like to mention is the global functioning. This was evaluated with the administration of the global clinical improvement scales, which was definitely rated by caregivers around 38% versus 7%. I mean, fenfluramine versus placebo. And it was rated from caregivers at 52% versus 2%. Safety and tolerability and conclusion is the following. I mean, adverse events were quite similar to placebo. Of course, some of patients on treatment branch had a little bit more somnolence and there were no cases definitely of valvular heart disease or pulmonary hypertension. No deaths reported. And overall, the fenfluramine documented in this trial quite a robust seizure reduction in this population of patients which is highly refractory and with clinically meaningful responder rate and an improvement also on global function.

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