Fenfluramine Shows Potential in CDKL5 Deficiency Disorder


No patient with CDKL5 Deficiency Disorder developed valvular heart disease or pulmonary arterial hypertension while being treated with fenfluramine.

Orrin Devinsky, MD

Preliminary results from a study evaluating fenfluramine (Fintepla; Zogenix) in patients with CDKL5 Deficiency Disorder (CDD) revealed the treatment is effective in controlling tonic-clonic seizures and has promise as an antiseizure medication for this patient population.1

The findings for the study were presented virtually at the American Epilepsy Society (AES) Annual Meeting, December 4–8, 2020, by Orrin Devinsky, MD, director, NYU Langone Comprehensive Epilepsy Center, professor of neurology, neurosurgery, and psychiatry, NYU Langone School of Medicine. Devinsky and colleagues found that fenfluramine treatment was associated with a median 90% reduction (range, 86–100) in 5 patients with tonic-clonic seizures. Additionally, there was a 50% to 60% reduction in the frequency of seizures in 2 patients with tonic seizures.

Subsequent addition of valproate reduced myoclonic seizure frequency in this patient, with no myoclonic seizures reported at the last study visit.

The study enrolled a total of 10 patients. At the time of the analysis, 6 patients were enrolled 6 patients with CDD with uncontrolled epilepsy whose seizures failed to be controlled with 5 to 12 antiseizure medications as well as with dietary and other therapies. Median age at enrollment was 6.5 years (range, 2–26), and patients were treated with fenfluramine for 2 to 9 months (mean, 5.3). Four of the 6 patients received the maximum dose of fenfluramine 0.7 mg/kg/day (absolute maximum of 26 mg/day) while the 2 other patients were maintained on 0.4 mg/kg/day.

READ MORE: Fenfluramine Demonstrates Efficacy in Lennox-Gastaut Syndrome in Phase 3 Results

The safety findings showed that 2 patients experienced adverse events (AEs). Lethargy was documented when valproate was started in the only patient who had a new medication added on to fenfluramine therapy. Decreased appetite and flatus were each reported in one patient.

The researchers found there was no development of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH). Fenfluramine, whose history began as a diet drug, was removed from the market in 1997 after evidence linked it to potentially serious heart valve problems.2 Since then, researchers have observed the cardiac side effects of fenfluramine in each of its studies.

CDD is an X-linked neurogenetic disorder resulting from mutations in the CDKL5 gene that codes for a kinase involved in neurodevelopment, including synaptic plasticity and glutamatergic signaling, and affects nearly 1 in 40,000 live births. It was designated a new, unique disease code and was added to the International Classification of Diseases (ICD) by the World Health Organization in January 2020.3

The effects of fenfluramine in patients with CDD have not been observed prior. The drug was approved to treat convulsive seizures in patients with Dravet syndrome (DS) in June and became available as an oral solution for patients age 2 and older. It included a boxed warning for risk of VHD and PAH and was distributed through the Fintepla Risk Evaluation and Mitigation Strategy (REMS) Program.4

Devinksy and colleagues noted that randomized controlled trials are needed to further understand the clinical use of fenfluramine in this patient population.

For more coverage of AES 2020, click here.

1. Devinsky O, King L, Price D. Fenfluramine to treat convulsive seizures in patients with CDKL5 Deficiency Disorder. Presented at AES 2020 Annual Meeting; December 4–8, 2020; Abstract 1060.
2. Cimons M. 2 Diet drugs tied to heart problems taken off market. Los Angeles Times. https://www.latimes.com/archives/la-xpm-1997-sep-16-mn-32755-story.html. Published September 16, 1997. Accessed December 7, 2020.
3. Rare disease CDKL5 deficiency disorder granted WHO disease classification. News release. LouLou Foundation. January 27, 2020. Accessed December 7, 2020.2020businesswire.com/news/home/20200127005604/en.
4. FDA approves Fintepla (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome. News release. Zogenix. June 25, 2020. Accessed December 6, 2020. https://www.globenewswire.com/news-release/2020/06/26/2053803/0/en/FDA-Approves-FINTEPLA-fenfluramine-for-the-Treatment-of-Seizures-Associated-with-Dravet-Syndrome.html
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