NEJM paper buoys GW Pharma as it eyes FDA filing for cannabis drug Epidiolex

Lead author and epilepsy specialist Orrin Devinsky, M.D.

GW Pharma's cannabis-based epilepsy treatment Epidiolex is firmly on track for a filing in the U.S. after new data published in the New England Journal of Medicine showed impressive effects on seizure rates.

Preliminary results from the phase 3 trial in Dravet syndrome—a rare and malignant form of childhood epilepsy that is highly resistant to current therapies—were reported last year, prompting suggestions that the drug could bring in blockbuster sales.

Now, the NEJM paper brings the findings up to date. All told, 43% of children on GW Pharma's drug saw a 50% reduction or better on seizure frequency, compared to 17% with placebo, and a handful (5%) of patients became entirely seizure-free with Epidiolex. In real terms, the median number of seizures dropped from over 12 per month to less than six with placebo, and this was accompanied by a significant improvement on quality-of-life scores.

An editorial accompanying the paper by Samuel Berkovic, M.D., of the Epilepsy Research Centre of the University of Melbourne at Austin Health in Australia, welcomes what it describes as the first "real data" showing the benefits of medical cannabinoids in the treatment of epilepsy.

"Future trials may answer further questions about the applicability of cannabinoids to the many other syndromes of childhood epilepsy and to treatment in adults," he writes.

Dravet syndrome is estimated to affect about 5,500 patients in the U.S., with another 6,000 to 7,000 in Europe, and usually appears in the first year of life. Due to the severity of the condition, between 10% and 14% of patients die by the time they are 6 or 7 years old, and all suffer severe learning difficulties.

The syndrome "is one of the most difficult types of epilepsy to treat and many of the children in this study were experiencing dozens, even hundreds, of seizures per month despite taking multiple concurrent anti-epileptic medications," said Orrin Devinsky, M.D., the lead author of the NEJM paper and director of the NYU Langone Medical Center's Comprehensive Epilepsy Center.

"These results suggest that Epidiolex can provide clinically meaningful benefits and I look forward to the prospect of an appropriately standardized and tested pharmaceutical formulation of cannabidiol available as a treatment option for these patients."

Armed with this trial in Dravet syndrome and two positive phase 3 trials in another rare and severe form of epilepsy—Lennox-Gastaut syndrome (LGS)—GW Pharma says it plans to submit Epidiolex to the FDA for both indications in the middle of 2017. An application in Europe is expected to follow shortly afterward.

Analysts at Edison say the consistent effects of Epidiolex across the three trials means regulatory risk appears low, and they are predicting a launch in mid-2018, with peak sales of about $800 million assuming approval in both Dravet and LGS.

There are a few possible stumbling blocks, however, according to Edison. One is that Epidiolex seems to have a drug interaction with clobazam, a widely used epilepsy drug, leading to increased blood levels, although they suggest that the dose of clobazam can be cut without reducing efficacy.  

Data also suggest elevations in liver enzymes that could suggest liver toxicity, but they note it seems these have generally occurred in patients already receiving valproate, another epilepsy drug known to have the potential to damage the liver.

For its part, GW Pharma has put together an integrated safety analysis of data from 1,500 patients treated with Epidiolex that will form a key part of its regulatory submission to the FDA and includes around 400 individuals who have received the drug for a year or more.

Analysts at Leerink also note that investors have some reservations about clobazam, but for a slightly different reason. Some are suggesting that clobazam "may have been a major contributor to Epidiolex's efficacy, and that this could ultimately prove to be important to or problematic for FDA," they write in a research note.

On this topic, "seizure reduction sub-group analyses remain of interest," they continue, adding that GW Pharma has suggested these analyses could be presented before a potential FDA advisory committee.