The positive allosteric modulator (PAM) of GABAA channels, CVL-865 (Cerevel, Boston, MA) has been shown in a phase 2 trial (NCT02564029) to have pronounced anticonvulsant activity in patients with photosensitive epilepsy, with efficacy similar to lorazepam (used as a positive control).
What sets CVL-865 apart as a GABAergic PAM is that it has minimal activity at channels containing the α1 subunit. Modulation of the α1 subunit has anticonvulsant effects but also causes the sedative and cognitive effects and addictive properties seen with non-selective GABAergics, such as benzodiazepines. Instead, CVL-865 acts at GABAA channels with α2, α3, and α5 subunits, known to have anticonvulsant (α2 only), analgesic, anxiolytic, and muscle-relaxing properties from GABAergic PAMs. It is hoped that CVL-865, by selectively modulating α2, α3, and α5 will enable higher receptor occupancy than can be achieved with non-selective benzodiazepines and achieve seizure suppression with greater tolerability owing to fewer sedative or cognitive effects. Further trials of CVL865 are expected to begin in the 4th quarter of 2019.
Data from these trials will be used to determine what populations of people with epilepsy can benefit most from CVL-865. Cerevel is prioritizing studies of CVL-865 for treatment of epilepsy, in which medically refractory seizures create great unmet need. They will also use the data from these studies to evaluate whether there might be potential benefits for people with other GABAergic responsive conditions (eg, pain, bipolar disorder, agitation) without sedative effects.
Raymond Sanchez, MD, chief medical officer of Cerevel said, “We are excited and encouraged by the specificity of CVL-865 because it has a wide range of possibilities to address unmet medical needs and add to the armamentarium of GABA modulators for a variety of conditions. The promise of CVL-865 is to give individuals with epilepsy, and eventually perhaps other conditions, better quality of life in terms of having a fruitful day-to-day existence without the inhibiting and detrimental effects of sedation.”
Yessar Hussain, MD; Krishna Pokala, MD; and Nancy Kuo, MS, MD
Stanley Jones P. Iyadurai, MD, PhD, FAAN