Despite the continual epilepsy treatment landscape growth, there are only a few if any approved therapies for rare developmental and epileptic encephalopathies.
Epilepsy is a chronic neurologic disorder resulting in unpredictable, unprovoked, recurrent seizures that affect mental and physical functions. Antiepileptic drug therapy aims to eliminate or reduce seizure frequency, minimize adverse effects during long- term treatment, and help patients maintain a normal lifestyle.1 Existing antiepileptic drugs function by decreasing the electrical activity of the brain, either by preventing neuronal depolarization via modulation of ion channels, inhibiting excitation mediated by the neurotransmitter glutamate, or promoting inhibition mediated by γ-aminobutyric acid.2 Selecting the appropriate drug therapy for epilepsy management necessitates an understanding of the disorder’s natural history and treatment response profile.1
Despite the availability of antiepileptic drugs, there are few if any approved therapies for rare developmental and epileptic encephalopathies (DEEs), which are associated with severe cognitive and developmental impairment in addition to frequent treatment-refractory seizures. For example, patients with Dravet syndrome typically present with seizures before 18 months of age that are often refractory to treatment, while those with Lennox-Gastaut syndrome experience up to hundreds of intractable seizures per day of various subtypes, often the result of hypoxic brain injury, cerebral dysgenesis, or neurocutaneous disorders, among other etiologies.2,3 Patients with CDKL5 deficiency disorder have reduced or altered CDKL5 protein in neurons, resulting in treatment-resistant tonic-clonic or tonic seizures that begin in infancy.2 Given the significant morbidity associated with these syndromes,2 novel therapies are necessary to address comorbidities while altering the course of the disease.
Cholesterol 24-hydroxylase, a central nervous system–specific enzyme encoded by the CYP46A1 gene and expressed in cell bodies and dendrites of neurons,4 is a promising target for treatment of brain disorders, including epilepsy. Cholesterol is particularly enriched in mammalian brains, indicating that this sterol is essential for proper brain development and function. Indeed, cholesterol is a neurosteroid precursor and key component of eukary-otic membranes, with 70% found in myelin sheaths of white matter and 30% in glial cells and subcellular membranes of neurons of gray matter.5,6 Due to the impermeability of the blood-brain barrier to lipoproteins, brain cholesterol is derived almost exclusively from in situ biosynthesis. Excess cholesterol is then extruded from the brain after hydroxylation by cholesterol 24-hydroxylase7 to yield the rapidly diffusible 24(S)-hydroxycholesterol (FIGURE).5,8,9 24(S)-hydroxycholesterol has a direct impact on synaptic plasticity by modulating N-methyl-D-aspartic acid (NMDA) receptors, implicating cholesterol 24-hydroxylase in memory and learning.10 This maintenance is crucial for neuronal cholesterol homeostasis, with abnormalities implicated in neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and Huntington disease.11,12
Both inhibition and activation of cholesterol 24-hydroxylase exhibit therapeutic potential.13,14 Increasing cholesterol 24-hydroxylase expression in a mouse model of Huntington disease reduced the number and size of intranuclear protein aggregates by activating autophagy, improving motor impairment.13 Downregulation of the enzyme in the adult mouse hippocampus via RNA interference conversely led to increased neuronal cholesterol concentration due to reduced efflux, although cholesterol biosynthesis was unaffected.11 Several types of phospholipids, such as structural glycerophospholipids and sphingolipids, were also increased in the brains of these mice.12 However, knockout mice lacking cholesterol 24-hydroxylase from birth maintained normal levels of cholesterol in the brain despite decreased efflux by reducing cholesterol synthesis.15 A reduction in cholesterol 24-hydroxylase levels modulates brain NMDA receptors to reduce downstream glutamate signaling pathway activity, consequently reducing the number and severity of seizures. Cholesterol 24-hydroxylase inhibition may therefore be useful for treatment of patients with rare DEEs.5
Soticlestat (TAK-935/OV935; Takeda Pharmaceuticals, Ovid Therapeutics) is a potent, highly selective, first-in-class inhibitor of cholesterol 24-hydroxylase that is currently in phase 2 studies for treatment of rare DEEs. Results from the phase 2, multicenter, open- label ARCADE study (NCT03694275) and the phase 2, prospective, interventional, open-label, multicenter extension ENDYMION study (NCT03635073) in patients with CDKL5 deficiency disorder (CDD) and Dup15q syndrome were recently announced,16 showing seizure reduction over time. In patients with CDD (n = 12), median motor seizure frequency was reduced by 24% during the 12-week maintenance treatment period in ARCADE, which increased to a 50% reduction in ENDYMION in the 5 patients who completed 9 months of continuous treatment. Notably, patients with Dup15q syndrome (n = 8) recorded an increase in median motor seizure frequency during the ARCADE study; however, after 9 months of continuous treatment through the ENDYMION study (n = 4), a 74% reduction in median motor seizure frequency was recorded. Notably, all patients who completed the ARCADE study elected to roll over into ENDYMION, with a consistent safety and tolerability profile observed throughout both studies.16
In addition, topline results from the phase 2, multicenter, randomized, double-blind, placebo-controlled ELEKTRA clinical trial (NCT03650452), which assessed soticlestat treatment
in patients age 2 to 17 with Dravet syndrome or Lennox-Gastaut syndrome, showed that the study met its primary end point, demonstrating a statistically significant reduction in seizures from baseline compared with placebo (P = .0007) in Dravet syndrome and numeric, but not statistically significant reductions in patients with Lennox-Gastaut syndrome.17 Specifically, a 27.8% median reduction from baseline in convulsive and drop seizure frequency compared with a 3.1% median increase in the placebo group was recorded during the 12-week maintenance period, with a 29.8% reduction recorded for the full 20-week treatment period. Results in the Dravet syndrome cohort, which showed a 33.8% median reduction in convulsive seizures compared with a 7.0% median increase in the placebo group, have propelled Ovid to pursue initiation of a phase 3 registrational program for the drug in this patient population.17 Incidence of treatment-emergent adverse events was similar between the treatment and placebo groups, with lethargy and constipation reported most frequently in those treated with the study drug. Notably, all patients who completed ELEKTRA elected to roll over to the ENDYMION extension study, early results from which indicate that treatment effect in patients originally randomized to receive soticlestat have been maintained over 6 months, with similar seizure frequency reductions observed in those originally assigned to placebo.17
Based on these results, cholesterol 24-hydroxylase inhibition as epilepsy treatment appears promising, so long as preci- sion dosing and efficacy duration are well understood. The results of the ENDYMION study will reveal the tolerability of soticlestat and its effects on seizure frequency reduction after long-term use. Meanwhile, other classes of epilepsy drugs, including cannabidiol (Epidiolex; GW Pharmaceuticals), have already been approved for treatment of severe DEEs.18 Going forward, an assessment of the implication of cholesterol accumulation resulting from cholesterol 24-hydroxylase inhibition, in terms of neuronal death in humans, is also warranted due to observations that inhibiting this enzyme resulted in epileptic behavior, including seizures, paralleled by neuronal loss in the mouse hippocampus.19 Overall, cholesterol 24-hydroxylase remains justified as a therapeutic target, so long as investigators are cognizant of the full effects of cholesterol 24-hydroxylase inhibition on brain cholesterol metabolism in cell types, specific brain regions, and the whole brain.