Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder

Abstract

CDKL5 deficiency disorder (CDD) is an X-linked disorder resulting from mutations in the CDKL5 gene, which encodes a kinase involved in synaptic plasticity, glutaminergic signaling, and dendrite formation. 1,2 Girls are ~4-fold more often affected, but boys are more severely affected. The incidence is ~1 per 50 000 births. 1 CDD typically presents in the first 3 months of life with treatment-resistant epilepsy (TRE) and hypotonia followed by global developmental delays and cortical visual impairment. 1,2 Infantile spasms and other generalized or mixed generalized/focal epilepsies may be the initial seizure type, with evolution to multiple seizure types that often straddle or fail to conform to standard classifications. Seizures often respond initially but recur, and most children have daily seizures despite multiple antiseizure medication (ASM) regimens. 1,2 Fenfluramine (FFA) enhances serotonin release, positively modulates sigma-1 receptors, 3 and has potent, durable efficacy in treating convulsive seizures in Dravet syndrome and

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany

“…Of note, FFA has also shown efficacy in reducing seizures in other drugresistant epilepsy syndromes including Lennox-Gastaut syndrome and CDKL5 deficiency disorder. 21,22 As well as reductions in total seizures and GTCSs, we found a statistically significant reduction in seizure days, in line with data from the pivotal RCTs that have reported increases in seizure-free days and statistically significant increases in seizure-free intervals. 6,7 In addition, FFA was associated with improvements in overall condition (physician-rated CGIC).…”

“…Furthermore, the ultimate treatment goal of seizure freedom or near freedom from seizures has been observed in a notable proportion of patients in our study (29.5% with ≤1 seizure per month) and others, 6,7,16 with Nabbout et al 7 reporting a statistically significant difference in the proportion of patients having ≤1 convulsive seizure during the 14‐week treatment period with FFA compared to placebo (Table ). Of note, FFA has also shown efficacy in reducing seizures in other drug‐resistant epilepsy syndromes including Lennox–Gastaut syndrome and CDKL5 deficiency disorder 21,22 …”

Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder

“…Fenfluramine acts on multiple receptors and is involved in the modulation of glutamate as well as increasing serotonin release and inhibiting reuptake [40]. Fenfluramine showed 90% reduction of generalized tonic clonic seizures in this small open label study, while ataluren did not show efficacy [41,42].…”

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

“…Additionally, longer-term seizure control was observed in a recently published phase 2 study [79]. Investigator-initiated studies have demonstrated clinical efficacy of fenfluramine in controlling seizures in other DEEs as well, including CDKL5-associated disorder (CDD) and Sunflower syndrome [15][16][17]. It is important to note that fenfluramine shows evidence of improvement in executive function-a non-seizure-related outcome-after administration over 14 weeks (short term) in Lennox-Gastaut syndrome and Dravet syndrome, and over 1 year (long term) in Dravet syndrome [7,14].…”

“…Patients with DEEs also present with developmental delay; profound cognitive impairment; impairments in motor function, speech, and language; and growth abnormalities [1][2][3]. The drug fenfluramine, originally described only in terms of serotonin (5-hydroxytryptamine, 5-HT) pharmacology [4][5][6], recently has demonstrated efficacy in treating DEEs in multiple phase 3 trials [7][8][9][10] (Supplemental Table S1 [7][8][9][10][11][12][13][14][15][16][17]). The profound effects of fenfluramine on seizures as demonstrated in clinical trials cannot be explained by serotonergic activity alone, as other serotonergic drugs have only marginal or inconsistent effects on seizure frequency [18][19][20][21].…”