FDA Drug Approvals: Neurology — Year in Review 2018

Mary L Windle, PharmD

Disclosures

January 15, 2019

New Drugs for Seizures

Diacomit (stiripentol)

Stiripentol is indicated for seizures associated with Dravet syndrome in patients aged 2 years or older who are taking clobazam. Stiripentol belongs to the group of aromatic allylic alcohols and is unrelated to other anticonvulsants. The precise mechanism of action is unknown, but it is thought to include direct effects mediated through the GABA-A receptor. It may also elicit indirect effects involving inhibition of cytochrome P450 activity, with a resulting increase in blood levels of clobazam and its active metabolite.

Stiripentol approval was based on two multicenter, placebo-controlled, double-blind, randomized studies conducted according to similar protocols. To be enrolled in either study, patients were required to be aged 3 years to younger than 18 years, to have Dravet syndrome (International League Against Epilepsy classification of epilepsy, 1989), and to be inadequately controlled on clobazam and valproate, with at least four generalized clonic or tonic-clonic seizures per month despite optimized therapy. In study 1 (n=41), 71% of stiripentol-treated patients were responders versus 5% in the placebo group (P<.0001), while in study 2 (n=23), 67% of stiripentol-treated patients were responders versus 9.1% in the placebo arm (P<.0094). Treatment with stiripentol was also superior to placebo for the reduction in mean frequency of generalized clonic or tonic-clonic seizures. (Diacomit [stiripentol] prescribing information )

Epidiolex (cannabidiol)

Cannabidiol (CBD) is indicated for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients aged 2 years or older. It is a purified CBD that has been engineered to reduce the hallucinogenic properties and physical dependence generally associated with delta-9-tetrahydrocannabinol (THC).

The exact mechanism by which CBD produces its anticonvulsant effects is unknown. CBD is a structurally novel anticonvulsant. It does not appear to exert its anticonvulsant effects through CB1 receptors or through voltage-gated sodium channels. CBD may exert a cumulative anticonvulsant effect, modulating a number of endogenous systems, including, but not limited to, neuronal inhibition (synaptic and extrasynaptic GABA channels), modulation of intracellular calcium (TRPV, VDAC, GPR55), and possible anti-inflammatory effects (adenosine).

Because CBD is associated with hepatocellular injury, assess ALT, AST, and total bilirubin before initiating therapy and as recommended during therapy.

CBD approval was based on results from several studies that compared adding CBD to conventional antiepileptic drugs (AEDs) and adding it to placebo, by observing the incidence of drop seizures from baseline. An international study of 225 patients with LGS (mean patient age, 15 years) were randomized to receive CBD 20 mg/kg/day, CBD 10 mg/kg/day, or placebo over 14 weeks. During the 4-week baseline period, the median number of drop seizures was 85 in all groups combined. The median reduction from baseline in drop-seizure frequency per 28 days during the treatment period was 41.9% in the 20-mg CBD group, 37.2% in the 10-mg CBD group, and 17.2% in the placebo group. During treatment, 30 patients (39%) in the 20-mg group, 26 (36%) in the 10-mg group, and 11 (14%) in the placebo group had at least a 50% reduction from baseline in drop-seizure frequency. The odds ratio (OR) for 20 mg versus placebo was 3.85 (95% CI, 1.75-8.47; P<.001), and the OR for 10 mg versus placebo was 3.27 (95% CI, 1.47-7.26; P=.003). (N Engl J Med. 2018 May 17;378(20):1888-1897)

A study (n=171) conducted in 24 clinical sites in the United States, the Netherlands, and Poland showed the median percentage reduction in monthly drop-seizure frequency from baseline was 43.9% (interquartile range, -69.6 to -1.9) in the CBD group and 21.8% (interquartile range, -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was -17.21 (P=.0135) during the 14-week treatment period. (Lancet. 2018 Mar 17;391(10125):1085-1096)

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