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by James O’Hanlon, Ph.D., Psychopharmacologist
The rise of cannabidiol (CBD) to prominence began on August 11, 2013 with a CNN documentary about Charlotte Figi, a 5-year-old born with a rare, single-gene mutation that causes a devastating type of epilepsy – Dravet syndrome. Her tonic-clonic (grand mal) seizures began at six months of age. By the age of three, she was having 300 per week, despite treatment with standard antiepileptic drugs (AEDs). Had this continued, she would have been physically and intellectually disabled and possibly died before reaching adulthood. On the advice of a friend, her parents tried an extract of marijuana that contained an unusually high concentration of CBD. Charlotte’s seizures declined after the first dose. When the original supply was almost exhausted, her parents contacted the Stanley brothers, respected “artisanal” cross-breeders of marijuana and hemp, who had developed an oily extract containing CBD as practically the only active component. On CBD, the girl’s seizure frequency stabilized at about four per month. The public reaction to CNN’s broadcast is hard to exaggerate. Parents whose children were afflicted with any type of intractable epilepsy clamored for access to the CBD-rich oil, and in States where that was then prohibited by Law, found means to circumvent the restriction. Other manufacturers rushed to produce their own artisanal CBD oil with variable and often dubious results since all are unregulated by FDA. Not to be outdone, the Stanley brothers changed the name of their product from “Hippies’ Disappointment” to “Charlotte’s Web” and went into high production.
Cannabidiol (CBD) is one of at least 113 cannabinoids synthesized by the plant, cannabis sativa. CBD and -tetrahydrocannabinol (THC) are the principal members of this family. THC possesses psychoactive properties owing to its strong affinity for a particular receptor type in the brain where its action mimics and in ways exceeds that of natural transmitters. CBD has little affinity for the same receptors and produces no subjective changes that gratify the user. But obviously CBD has some mechanism of action in the brain, perhaps several. Scientists were caught off guard by the antiepileptic efficacy of CBD and are now struggling to explain it. The number of relevant publications has jumped from 5 in 2013 to 36 in the first half of 2017. Various mechanisms have been proposed but none is generally accepted. About all that is certain is that the antiepileptic mechanism of CBD is unlike those of standard AEDs.
If scientists were slow to react to the CNN broadcast, BIG PHARMA was not. Before the end of 2013, GW Pharmaceuticals (GWP), a British corporation specializing in developing drugs from cannabis extracts, petitioned FDA to designate their own purified CBD oil (Epidiolex®) as an “orphan drug.” This allowed selected neurologists to prescribe Epidiolex to epileptic patients whose seizures resisted approved AEDs. GWP also began the process of filing for a permit (Investigational New Drug) from FDA for allowing the company to conduct clinical trials in the U.S. with Epidiolex as treatment for Dravet syndrome and other epilepsies that emerge in early childhood and resist standard AEDs. Now, four years later, the first results of GWP’s massive effort are emerging.
After preliminary Phase II trials to confirm efficacy, establish safety and define an optimum CBD dose, GWP initiated parallel Phase III trials with Epidiolex for treatment of Dravet and Lennox-Gastaut syndromes. Both trials followed essentially the same protocol. Children and adults were selected who met the diagnosis and whose seizures were poorly controlled by multiple AEDs. They continued to use these drugs during the trial. Approximately half of them received adjunctive Epidiolex and the others placebo, double-blind, for 14 weeks. Results of both trials are available from GWP and those from the Dravet trial have been published.1
In the Dravet trial, 61 participants received Epidiolex and 59, placebo. Respectively, 52 (85%) and 56 (95%) completed the trial. Prior to Epidiolex treatment, completers had a median frequency of 12.4 convulsive seizures per month. During treatment, their median frequency fell to 5.9. In contrast, median seizure frequency hardly changed among participants assigned to receive placebo; i.e., from 14.9 to 14.1 per month. Three (5%) Epidiolex but no placebo completers were seizure free by the end of the trial. Results of the Lennox-Gastaut trial were similar: 72 (84%) participants completed Epidiolex treatment and 84 (99%) completed placebo treatment. Prior to treatment, their respective median drop-seizure frequencies were 71/mo. and 75/mo. During treatment, median drop-seizure frequency fell by 44% among Epidiolex completers and 22% among placebo completers. Again, three (4%) Epidiolex but no placebo completers were drop-seizure free by the end of the trial.
GWP has submitted a New Drug Application to FDA for approval of Epidiolex marketing and prescription for seizure control in Dravet and Lennox-Gastaut syndromes. FDA’s decision is expected this year. GWP is not stopping there. Phase III trials of Epidiolex in Tuberous Sclerosis are underway and early results are promising. Phase II trials with Infantile Spasms have recently begun. The four epilepsies addressed by Epidiolex are very different with respect to etiology and clinical presentation. It would be surprising if the drug were shown to similarly effective in every trial. But even if GWP’s success in clinical trials continues there may be other hurdles ahead for the company. CBD is currently defined as a component of marijuana under Federal statutes. As such, CBD is a Schedule I substance under the Controlled Substance Act; i.e., with abuse potential but no accepted medical use. It is difficult to imagine how FDA could approve Epidiolex before CBD is rescheduled. There is also potential litigation pending that may delay the drug’s arrival on the market. Epidiolex has the status as an orphan drug. According to the Orphan Drug Act: “The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a 7-year exclusive marketing period in the U.S., for that product, for that indication.” Artisanal providers of CBD, like the Stanley brothers, can hardly be expected to stand aside while GWP acquires their market: they will challenge any such ruling in Court.