In push to use pot for pain, synthetics hold upper hand
Amid the national opioid addiction crisis, one of the oldest known compounds believed to ease pain is getting a second look from a small group of drugmakers and developers.
While some studies suggest medical benefits from cannabis, most fall short of the gold standard of randomized clinical trials. The plant's classification as a controlled substance and the spotty patchwork of state laws governing legality have limited the scope of the studies.
"There is an unmet need for a cannabis-based medicine that has the hallmarks of a modern medicine: one that does not vary every time the patient takes it, [one where we have] a full understanding of its safety and efficacy against placebo, one that is fully characterized, [where the] interactions it may have with other drugs that patients are taking [are known]," said Stephen Schultz, VP of investor relations at GW Pharmaceuticals plc.
The company is currently working on bringing the first whole-plant-derived medication to the U.S. market and faces an FDA advisory panel in April.
As regulators crack down on overzealous use of opioids, physicians are searching for new ways to effectively serve patients in pain without worrying they are fueling addiction in the process.
At the same time, use of legacy opioid products are declining, as much of the $6 billion market goes generic.
Cowen & Co. analysts identified cannabis as a big opportunity in a 2017 report, citing data that suggested 64% of medical cannabis patients use the drug to alleviate pain.
"This could be potentially disruptive for both the ~$5 billion opioid market, and the $2 billion [over-the-counter] market," the analysts wrote.
With the National Academy of Sciences (NAS) finding no studies linking cannabis as a direct cause of overdose death, the drug could be a viable alternative to narcotic-based painkillers.
Two medications based on cannabis have been approved by the Food and Drug Administration — Marinol/Syndros (dronabinal) and Cesamet (nabilone). They represent synthetic forms of the chemicals that naturally occur in the marijuana plant. Both approved in 1985, neither are meant to treat pain and are used sparsely because one has psychoactive effects and the other is challenging to dose, according to University of Colorado pharmacists Jacci Bainbridge and Matthew Makelky.
A scheduling problem
A major reason for the dearth of studies of the whole plant and its derivatives is due to the classification of cannabis by the Drug Enforcement Administration (DEA).
By federal law, marijuana is illegal and has "no currently accepted medical use and a high potential for abuse." As a result, it has a Schedule 1 classification, grouped with drugs like heroin and psilocybin.
The NAS report called into question the scheduling of synthetic, pharmaceutical-grade cannabinoids as Schedule 3 while assigning the botanical as Schedule 1.
"That THC, which is the principal active ingredient in cannabis, in its pure form is listed in Schedule 3 indicates that the placement of botanical or whole cannabis in Schedule 1 may be driven by the lack of recognition of medical use for the whole plant," wrote the authors of the report.
Marinol in particular was approved as a Schedule 1, but DEA reclassified it in 1986 to Schedule 2, and to Schedule 3 in 1998.
Still, pharma is cautiously eyeing the space — and is doing some of the research on extractions and synthetics. But work on the properties of the whole plant, like studies in Colorado of cannabis to treat chronic back pain, won't likely be of interest to big pharma, at least not yet.
"The pharma industry will ignore this and similar studies," said Ethan Russo, former medical director of Phytecs Inc., a company doing preclinical work on the endocannabinoid system. "Only large Phase 2 or 3 randomized controlled trials with a viable pharmaceutical preparation garner any notice [from the industry]."
Ari Greis, a physician specializing in non-operative treatment of spinal and musculoskeletal disorders at the Rothman Institute, argues synthetic extracts may not be as effective as the whole plant.
"A lot of serious cannabis researchers feel pretty strongly that whole-plant extractions are most beneficial from a therapeutic standpoint," he said.
The 113 known cannabinoids in the natural plant are synergistic with its other substances, such as terpenoids and flavonoids; subtract one or more components from that equation, and the resulting compound may not be as safe or effective as the whole plant, Greis said.
Additionally, when the components are separated they can be even more potent. An example is Marinol, which is a synthetic THC.
In 2015, there were approximately 28 trials studying cannabis for indications other than nausea and vomiting associated with chemotherapy and appetite stimulation in wasting illnesses (which represent indications for which there were already synthetic cannabinoid products available), according to a JAMA study.
Now, there appear to be approximately 120 trials looking specifically at cannabis for pain on the federal database cinicaltrials.gov, about 67 of which appear to be be complete. These encompass all forms of cannabis, including whole plant, plant extracts and synthetic options.
Due to the classification, supply for research purposes is controlled by the National Institute on Drug Abuse, which at one point only procured the plant from one location: The University of Mississippi. But in 2016, NIDA anticipated a large increase in demand and expanded the number of entities registered under the Controlled Substances Act to grow cannabis.
"The major barriers [to bringing a plant-based drug to market] are the restrictions in the U.S. to use only unstandardized NIDA cannabis, particularly in smoked form. All the studies done in this manner domestically have been too short, [conducted] in too few patients, and [are] poorly controlled," said Russo.
An FDA advisory panel to watch
Running clinical trials with a Schedule 1 substance, although complex, is not impossible, Schultz said.
GW's anti-seizure candidate for two epilepsy types, called Epidiolex (cannabidiol), will be reviewed in an FDA advisory committee meeting on April 19. It has a user fee action date of June 27.
Though not meant for pain, an Epidiolex approval could push the DEA to address cannabis' status as a Schedule 1 drug (and its potential rescheduling).
Such an approval and potential reassessment could swing the door to the cannabis market wide open.
Another cannabis-based compound in GW's pipline is Sativex (nabiximols).
In 2015, the company announced it missed its primary endpoint in Phase 3 trials, after failing to prove it adequately quelled pain. Schultz chalked up the failure to problems associated with measuring patient pain. "Pain can be a challenging area to study, as the measures are generally subjective."
Despite this setback, Sativex is currently mentioned in a whopping 605 clinical trials (after eliminating studies listed as withdrawn, suspended or terminated).
Sativex was first indicated in Canada in 2005 to treat neuropathic pain in multiple sclerosis and then was approved in Canada for cancer pain in 2007. It is also OK'd for both of these pain indications in Israel.
The drug will be investigated for the indication of spasticity in multiple sclerosis, and if approved, Sativex could officially reach the market in the U.S. — although still not for pain.
"GW is now evaluating the optimal route to submit a NDA in the MS spasticity indication, which we believe may require an additional single pivotal trial. During 2018, GW plans on consulting with the FDA regarding this development plan," Schultz said.
A Sativex approval in the U.S., coupled with a rescheduling of cannabis, could spur off-label prescriptions to patients experiencing pain.
"If it was Schedule 2 or higher and approved for use, it could be used off-label," Greis said.
Though hypothetical in the U.S., in Canada, where there are some medical cannabis products already approved, drugs like Sativex are available at the pharmacy level.
The largest chain pharmacy in Canada, Shoppers' Drug Mart, recently applied for a Health Canada license to dispense medical marijuana. And Tilray Canada Ltd. announced in mid-March that it will partner with Novartis AG's Sandoz Canada unit to develop drugs in preclinical stages.
All said, the path to FDA approval of botanical marijuana for pain is a rocky one rife with many challenges.
As recently as July 2016, the DEA denied a petition to reschedule cannabis to Schedule 2, reasoning (again) the substance has no currently accepted medical use in treatment in the U.S.
GW does not plan to totally abandon pain as a target for its products. "We remain interested in the pain space — you just don't see that at this time in our pipeline," added Schultz.
Editor's note: Ethan Russo's title has been corrected.
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