Abstract
Knight EMP, Amin S, Bahi-Buisson N, Benke TA, Cross JH, Demarest ST, Olson HE, Specchio N, Fleming TR, Aimetti AA, Gasior M, Devinsky O. Lancet Neurol. 2022;21(5):417-427. doi:10.1016/S1474-4422(22)00077-1
CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n = 50) or placebo (n = 51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of −30.7% (IQR −49.5 to −1.9) in the ganaxolone group and of −6.9% (−24.1 to 39.7) in the placebo group (p = 0.0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was −27.1% (95% CI −47.9 to −9.6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial.Background:
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Commentary
The Cyclin-Dependent Kinase-Like 5 (CDKL5) protein has a critical role in brain development and function, regulating the proliferation, morphogenesis, and survival of neurons, in addition to synaptic function, structure, and plasticity. 1 Pathogenic loss-of-function gene variants (occurring most commonly de novo, but also due to other mechanisms) result in CDKL5 deficiency disorder (CDD). 2 CDKL5 deficiency disorder is an X-linked dominant disease that occurs in 1/40,000 to 1/60,000 live births with a strong (4:1 to 12:1) female preponderance. 2 CDKL5 deficiency disorder was once thought to be a variant of Rett syndrome (and was also known as early infantile epileptic encephalopathy type 2) but is now recognized as its own entity.
The phenotype of CDD encompasses intellectual disability, seizures, and impairments in speech, motor functions, vision, sleep, and gastrointestinal function. 1 -3 Seizures usually begin during the first 3 months of life and can appear in neonates. The most common types are generalized tonic–clonic convulsions, tonic seizures, and epileptic spasms. 4 Seizures occur multiple times daily in most people and are refractory to treatment with anti-seizure medications (ASMs). Most patients with CDD have severe intellectual delay with little or no language. The development of gross motor skills, such as sitting, standing, and walking, is delayed or not achieved, but about one-third of patients can walk independently. 1,3 Fine motor skills are also impaired; about half of affected individuals have purposeful use of their hands. Most people with CDD have cortical visual impairment. 1,2 Other common features are stereotypies like clapping, hand licking, and hand sucking; bruxism; disrupted sleep; feeding difficulties; and gastrointestinal problems including constipation and gastroesophageal reflux. Some patients have episodes of irregular breathing. Distinctive facial features can include a high, broad forehead, large, deep-set eyes, a well-defined philtrum, full lips, widely spaced teeth, and a high-arched palate. Other physical abnormalities include microcephaly, scoliosis, and tapered fingers. 1,3 The electroencephalographic and magnetic resonance imaging findings have been reviewed in a recent international consensus document. 2
There are a few reports on the effectiveness of ASMs in patients with CDD. 2 Studies of corticosteroids, vigabatrin, valproic acid, phenytoin, felbamate, carbamazepine, clonazepam, oxcarbazepine, and lacosamide reported not only initial seizure frequency reduction followed by loss of efficacy but also exacerbation of seizures in some cases. 2 The consensus document recommended no specific ASM in CDD, but indicated that alternatives could include ketogenic diet, vagus nerve stimulation, corpus callosotomy, pharmaceutical-grade cannabidiol, and ganaxolone. 2 The importance of successful treatment of CDD is suggested by a recent study that reported a slight improvement in subsequent development among patients who had better early seizure control. 5
Ganaxolone (3 hydroxy-3β-methyl-5δ-pregnane-20-one) belongs to a novel group of neuroactive steroids called epalons that act as positive allosteric modulators of synaptic and extrasynaptic GABAA receptors to enhance GABAergic inhibitory tone. 1,6 Neuroactive steroids are a class of molecules that are derived from the breakdown of progesterone or deoxycorticosterone and are enriched in the nervous system. Ganaxolone is a beta-methylated synthetic analog of allopregnanolone and is a neurosteroid exhibiting potent anti-seizure effects in several animal models of epilepsy. 7
Ganaxolone has undergone clinical trials involving persons with epilepsy. 1,7,8 A pilot study of the safety, dose range, and possible efficacy of ganaxolone was performed in children aged 5 to 15 years with refractory focal or generalized epilepsy. 7 Four of the 15 children exhibited at least a 50% reduction in seizure frequency. 7 In a subsequent Phase 2 randomized, double-blind, placebo-controlled trial (RCT) of 147 adults aged 18 to 69 years with focal-onset seizures, ganaxolone at 1500 mg/day demonstrated a mean percent seizure reduction of 17.6% compared to 2.0% with placebo (P = .0144), but responder rates were not significantly different (24% with ganaxolone vs 15% with placebo). 8 These early studies indicated mild clinical efficacy against seizures. They were followed by the 1042-0603 Phase 3 RCT of ganaxolone at 1200 mg and 1800 mg versus placebo in 405 adults with focal-onset seizures [NCT01963208]. 9 To this author’s knowledge, although the 1042-0603 study began in 2013 and was completed in 2016, its results have not yet been published. Intravenous ganaxolone was recently studied in a Phase 2 open-label trial for the treatment of refractory status epilepticus in 17 patients to prevent the need for anesthetizing ASMs. 10
Knight et al 1 recently published the results of a Phase 3 RCT in children and young adults aged 2 to 21 (median = 6) years with CDD. Subjects were required to have 16 “major motor seizures” per 28 days during an 8-week baseline. Subjects could be taking up to 4 ASMs at baseline but adrenocorticotropic hormone and corticosteroids were excluded. Hundred patients (79% female) were exposed to treatment and had at least one post-treatment seizure frequency measurement recorded. A significantly greater median percent reduction of major motor seizures/28 days occurred in the patients treated with ganaxolone than in those who received placebo. The 50% responder rates were 24% for ganaxolone and 10% for placebo (P = .0643). No subjects were seizure-free. Serious adverse effects and discontinuation rates were not significantly different between the groups. 1
This study led to the approval on March 18, 2022, by the US Food & Drug Administration (FDA) of ganaxolone for the treatment of seizures in patient aged 2 years and older with CDD. 11 The approved dose is a maximum of 21 mg/kg three times daily for patients weighing 28 kg or less, and 600 mg three times daily for patients >28 kg. The most common adverse effects (occurring in at least 5% of patients taking ganaxolone and at least twice the rate with placebo) were somnolence, pyrexia, salivary hypersecretion, and seasonal allergy. Use of concomitant drugs that are strong or moderate inducers of the hepatic isozyme CYP3A4 should be avoided. 11
A strength of the study 1 was that subjects were required to have a confirmed pathogenic variant of the CDKL5 gene. Study limitations included: only 50 subjects each were in the study drug and placebo groups, a second study for replication was not required for FDA approval, and adults above age 21 were excluded which limits generalizability. The importance of this study 1 is 2-fold. Firstly, it identified the first ASM that is proven to be effective in the treatment of CDD. Secondly, it is the first major study to show that a neuroactive steroid is effective for the treatment of seizures in any type of human epilepsy. It is crucial to remember that ganaxolone has not yet been shown in the currently published literature to be effective treatment for seizures in any other type of epilepsy.
Ganaxolone was approved under the United States Orphan Drug Act of 1983. Under this pathway to FDA approval, pharmaceutical companies are generally required to demonstrate efficacy and safety of an experimental ASM using only a single RCT and using a smaller number of subjects than are typically needed to obtain approval for more common types of seizures or epilepsy syndromes. Several companies have followed this pathway to achieve regulatory approval of their ASMs for Lennox-Gastaut syndrome, Dravet syndrome, and now CDD. Unfortunately, many of the ASMs approved for these rare (“orphan”) disorders are considerably more expensive than the ASMs approved for the more common seizure classes: focal and generalized. Such pricing has resulted in a concerningly high annual cost to government or private pharmaceutical insurance providers (and possibly to patients) for some of these ASMs.
