The FDA's approval of GW Pharma plc's liquid Epidiolex – the first pharmaceutical formulation of purified, plant-based cannabidiol (CBD) to reach the market – in Dravet syndrome (DS) and Lennox-Gastaut syndromes (LGS) opens the door to a new therapeutic and regulatory world.

Epidiolex won the marketing nod from U.S. regulators for patients 2 or older, and GW said the product will be available when it's rescheduled by the Drug Enforcement Agency (DEA), which should happen within 90 days.

For one, GW's win likely will put an end to the "hysteria" and "cannabinoid immigration" of parents with suffering children who travel to states with access to what they need, said George Anastassov, CEO of Axim Biotechnologies Inc., which is also at work in the field. Instead of counseling the caretakers of sick kids to "try the Charlotte's Web [hemp extract CBD] oil from Colorado," doctors can prescribe Epidiolex, an active, standardized drug. "I would like to see the patients receiving something which is tightly regulated and consistent," he said.

LGS and DS, which bring high rates of early mortality, are tough-to-treat childhood epilepsies that often require multiple seizure medications, and the majority of patients are resistant to approved therapies. Epidiolex will be marketed in the U.S. by Greenwich Biosciences Inc., of Carlsbad, Calif., a subsidiary of Cambridge, U.K.-based GW. The drug currently bears schedule I status from the DEA, but once the schedule level is changed, access should resemble that of other antiepileptic drugs (AEDs).

Epidiolex's clinical development program included three randomized, controlled phase III trials and an open-label extension study. In the phase III experiments, published in The New England Journal of Medicine and The Lancet, the compound when added to other AEDs significantly reduced the frequency of seizures in patients with LGS and DS. The most common adverse reactions on drug included somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise and asthenia; rash; insomnia, sleep disorder and poor quality sleep; and infections. (See BioWorld Today, Jan. 4, 2016.)

CBD, a cannabinoid that does not bring the high associated with marijuana, represents the first in a new category of AEDs. GW has more in the cannabinoid hopper, too: In December 2017, two years after a failed effort to develop Sativex (delta-9-tetrahydrocannabinol and CBD) as a therapy for cancer pain in the U.S., the company and Tokyo-based Otsuka Pharmaceutical Co. Ltd. ended their pact, which began more than a decade previously. GW regained full rights to develop and commercialize Sativex in the U.S., though it's been upstaged by Epidiolex, an extract containing 99 percent CBD, with only trace amounts of other cannabinoids. Sativex is cleared in 30 other countries. (See BioWorld, Dec. 14, 2017.)

Researchers working with drug-grade cannabinoids have had to overcome the notion that medical marijuana, with its woefully short half-life, can work just as well. Epidiolex seems to have slam-dunked the argument. Axim's Anastassov, for his part, said "there is no such thing as medical marijuana. There is adult use, or nutraceutical, if you will, but it's not medical" without going through gatekeeper channels. GW and Insys Therapeutics Inc., of Phoenix, which threaded the regulatory needle with its generic dronabinol to treat chemotherapy-induced nausea and vomiting, have been lauded for their efforts. "GW is definitely the leader of the pack," he said. "I wouldn't put Insys there, because they have invented nothing new." The major players – though more are lining up – at this point are GW, Insys, Tel Aviv-based Therapix Biosciences Ltd. and Zynerba Pharmaceuticals Inc., of Devon, Pa.

No future for growers?

DEA scheduling is the number-one hurdle for companies in the space, Anastassov said; schedule I classification means the drug is "not only useless but harmful and addictive," as with heroin. Also, "there is very little knowledge about these particular compounds because they've been isolated not that long ago, and we have 70-plus years of prohibition."

Confounding research is "the fact that there are more than 140 cannabinoids [other than well-known tetrahydrocannabinol (THC)]. That's a different problem, because little is known about the effects of the other compounds, and about the interactions" between them, he said. Each bears a different mechanism of action. THC and CBD, for instance, are "extremely similar as far as their molecular structure, but they have totally opposite effects. While THC can cause paranoia and the so-called high," CBD acts nothing like it. Then, too, cannabis contains "antioxidants and all kinds of molecules within the plant, which all interact with each other" as well, in an isolated way as well as in concert, to create the "entourage effect." Knowledge is "increasing, of course," he said. "If you look 20 years back, maybe there were only two or three or four compounds known."

Another problem is the plant itself, since "there are no two plants alike." In the U.S., one legal producer of cannabis exists by way of the University of Mississippi, funded by the National Institute on Drug Abuse. But the output is "very poor quality," Anastassov said, with disparities in cannabinoids between batches, which means "truly a lack of good material with which to conduct studies," he told BioWorld. Even in GW's case, the company "does not have a [current good manufacturing practices (cGMP)] plant, so the process of procurement of their materials, whether it's THC or CBD, is cGMP, but the plant itself is not." He called the situation "peculiar," and noted that GW has "spelled [out] in their filings to the SEC that it's a concern because their plant is not cGMP."

In its annual report for the period ending September 2017, GW said the company has a site "at which we can grow the specific cannabinoid plants which produce the CBD used in Epidiolex, a second site at which we can extract CBD from botanical raw material and a second site at which we can crystallize the purified CBD from the liquid plant extract, but we are currently reliant on a single manufacturing facility, and no back-up facilities are yet in place, for the other steps in the Epidiolex production process."

Anastassov pointed to the "one company in the world which actually has a cGMP plant: Bedrocan BV, of Veendam, the Netherlands, overseen by the Dutch Ministry of Health. "It took them 30 years to get the designation," he said. "Why is that? Because, again, the plants have to be absolutely consistent between the batches, and it's extremely difficult." Axim sources its product from Bedrocan, and is pursuing drug delivery by chewing gum of therapies for such indications as irritable bowel syndrome, multiple sclerosis/pain spasticity, and nausea/vomiting/loss of appetite.

The cannabis landscape has begun to change, Anastassov said, and will change more. "Irrational exuberance is rotating mostly around so-called medical marijuana – growing and so on," especially in Canada, he said. "I don't think there is a great future there, because like [with] any other commodity, the market will be saturated. Canada is not such a large country to produce hundreds of pounds of plant," and the plant is "very difficult to export elsewhere," although some have been able to do business with Germany and Australia, he said. "The prices will correct, and also the prices of equity in these companies."

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