For medical cannabis, the winds of change are blowing. And while some parties are shoring up walls, others are building windmills. The walls, of course, are the laws prohibiting cannabis. In the United States, they’re crumbling here and there, allowing cannabis to be used medically and, in a few places, even recreationally. As the winds sweep over increasingly free expanses, the stigma hanging over cannabis begins to dissipate, and legitimate operations pop up to commercialize cannabis-derived products.
These operations, like windmills on the prairie, are signs of progress. Among the most promising operations are pharmaceutical companies specializing drugs that interact with the endocannabinoid system. Most of these drugs are derived from phytocannabinoids (cannabinoids produced by plants) or synthetic compounds.
Ten years ago, the endocannabinoid system was an inaccessible frontier. Now, however, it is being surveyed by pharmaceutical companies that look forward to exploiting promising targets, starting with the endocannabinoid system’s main components: the two G-protein-coupled receptors known as cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R), and their natural ligands anandamide and 2-arachidonoylglycerol. In the coming decade, the endocannabinoid system’s richness will attract many pioneering drug developers. Eventually, they’ll build a distinct industry segment and churn out therapeutics for a broad range of diseases.
Cannabinoids from plant extracts
The best-known phytocannabinoid is ∆9-tetrahydrocannabinol (THC), a biologically active compound responsible for cannabis’ psychoactive effects. Almost as prominent is cannabidiol (CBD), which is nonintoxicating. In fact, it can counter the psychoactive effects of THC. CBD’s potential benefits include pain relief. Besides THC and CBD, there are over 100 biologically active phytocannabinoids, many of which have therapeutic potential in areas like inflammation, cancer, epilepsy, and addiction.
Phytocannabinoids are being developed by several companies. One such company is GW Pharmaceuticals. It has two approved, marketed phytocannabinoid products: Sativex and Epidiolex.
Sativex is a full-spectrum, cannabis-derived treatment for spasticity in multiple sclerosis. The drug is currently approved and marketed in Europe and Canada, and it is coming to the United States as well. Sativex is an oromucosal spray and a botanical drug product that is a mixture of THC and CBD extracts and that also contains minor constituents including related cannabinoid and non-cannabinoid plant components such as terpenes, sterols, and triglycerides.
Epidiolex is a pharmaceutical formulation of highly purified CBD approved by the U.S. FDA and the European Commission for seizures associated with two treatment-resistant epilepsy syndromes: Dravet syndrome and Lennox-Gastaut syndrome. GW is also expecting to file a supplemental new drug application with the FDA for Epdiolex in the treatment of seizures associated with tuberous sclerosis complex in the first quarter of 2020. The company is planning to file in Europe as well.
Founded in the United Kingdom in 1998, GW is one of the oldest companies developing cannabis-based medicines. While many companies are working exclusively with synthetic derivatives, GW has staked out a position working with plant extracts.
In its work with natural phytocannabinoids, GW has invested in plant breeding to get the specific chemical compositions needed for its medicines. The company also ensures that its development work follows established clinical regulatory pathways.
“The regulatory pathway is the proper approach to develop and commercialize cannabis-based medicines,” says Stephen D. Schultz, vice president of investor relations at GW. The company’s pipeline includes programs for autism spectrum disorders, Rett syndrome, glioma, neonatal hypoxic-ischemic encephalopathy, and schizophrenia.
The controlled substance status of cannabis in the United States has been a hurdle for GW and many other companies in the space, even those working with completely synthetic compounds that lack psychoactive effects. Yet GW is managing to deal with the legal issues. “I think we’ve proved you can effectively study a schedule 1 drug,” Schultz says. “It does take a very specific core set of understandings and expertise to be able to work with the government agencies to get that done.”
From a pharmaceutical perspective, using extracts from the cannabis plant can have some disadvantages. One is that even with highly purified extracts, there will still be some traces of unwanted compounds in the plant, particularly THC. That has led a few biotech companies working on the endocannabinoid system to create synthetic analogues of biologically active phytocannabinoids. Emerald Health Pharmaceuticals (EHP) is one such company. It is developing synthetic derivatives of CBD and cannabigerol (CBG).
The company’s lead candidate, EHP-101, has completed a Phase I clinical trial and is entering Phase II. “We should have our first patient in the first indication, systemic sclerosis, a severe form of scleroderma, within the next few weeks,” says Jimmy DeMesa, MD, EHP’s CEO. Initial data from that trial is expected by the end of the year. The company also plans to start a Phase II trial of EHP-101 in multiple sclerosis in 2020. Its other candidate, EHP-102, is in preclinical development for Parkinson’s disease and Huntington’s disease.
DeMesa confides that the company’s strategy is to pair large market opportunities with rare disease opportunities for each drug candidate. For EHP-101, the large market opportunity is multiple sclerosis, and the rare disease opportunity is scleroderma, which has orphan disease designation in the United States and Europe. Similarly, for EHP-102, Parkinson’s disease is the large market indication and Huntington’s has orphan designation.
Working with synthetic cannabinoids allows the company to quickly produce the many kilograms of material needed for clinical trials, and to do so while following good manufacturing practice (GMP) guidelines. “The whole extraction side of things for CBD and other cannabinoids was still evolving at the time of our decision,” DeMesa notes, “and as a pharmaceutical [developer], we needed large quantities of pure CBD with strict specifications as our starting material.” He adds that the company also wanted to ensure there were no residual components. “Our novel molecules,” DeMesa asserts, “are derived from nearly 100% pure synthetic CBD.”
Because unmodified THC and CBD molecules are not patentable, companies developing them as drugs are building their patent portfolios around unique formulations. That’s the case with Zynerba Pharmaceuticals, which is developing a transdermal formulation of synthetic CBD called Zygel for fragile X syndrome, autism spectrum disorder (ASD), developmental and epileptic encephalopathies, and 22q11.2 deletion syndrome.
Results from three of Zynerba’s clinical studies are due in the second quarter of 2020, and enrollment has been completed in its Phase II in autism spectrum disorder. Enrollment is near completion in a pivotal Phase III trial for fragile X syndrome, with topline results expected near the end of the second quarter of 2020.
According to Armando Anido, Zynerba’s CEO, CBD inhibits metabolism of the cannabinoid receptor ligands anandamide and 2-arachidonoylglycerol, thereby increasing the levels of these endocannabinoids in the body. “2-Arachidonoylglycerol and anandamide are very important for signaling in the brain, and they affect socialization behaviors,” says Anido. CBD can also modulate hyperexcitability in the brain, which is responsible for seizures in people with those disorders.
Hemp-derived CBD is now legal nationwide, and various CBD preparations are widely available. Anido asserts that Zygel has a couple of important advantages over those nonpharmaceutical products in its dosage and its proprietary penetration enhancers. “In our fragile X study, we’re administering 500 mg daily of CBD,” says Anido, comparing that to a typical salve that might have 50 mg of CBD in the entire container.
Anido notes that controlled substance restrictions have delayed Zygel’s development by about six months, but despite those initial delays, he expects to release the results of the pivotal trial in fragile X late in the second quarter of this year. At this point, Anido expects that Zygel will be designated schedule 5 or unscheduled, and that going forward, the company’s development timeline will not be affected by changes in the DEA’s approach. Still, Anido says that Zygel has pushed back on the DEA’s approach to CBD. “We have tried to challenge the DEA on its scheduling on multiple occasions—unfortunately to no avail yet,” Anido complains. “If it’s a purified CBD, it has no THC in it, and there’s no reason it should be a scheduled drug.”
Corbus Pharmaceuticals is a clinical-stage pharmaceutical company focusing on novel therapies targeting the endocannabinoid system. Its pipeline of rationally designed synthetic drugs contains candidates for systemic sclerosis, cystic fibrosis, dermatomyositis, and systemic lupus erythematosus. Corbus’s CEO, Yuval Cohen, PhD, points out that the endocannabinoid system plays an important role in mediating between the central nervous system and the immune system.
“This is a system designed to help us recover from trauma,” says Cohen. “Say you’re a cave-dwelling human 30,000 years ago and you just got bit. You’re injured, you’re bleeding, you’re going into shock. That’s where the endocannabinoid system kicks in.”
In addition to providing pain relief, stimulating appetite, and preventing shock and convulsions, the endocannabinoid system, Cohen says, reduces inflammation and mediates the innate immune system. That’s the activity Corbus is attempting to exploit with its lead compound lenabasum. Lenabasum is designed to target cannabinoid receptor 2 to generate an anti-inflammatory and antifibrotic response without crossing the blood-brain barrier. It’s in Phase III trials for systemic sclerosis and dermatomyositis, and in Phase II for systemic lupus erythematosus and cystic fibrosis.
“In cystic fibrosis, we have received the support of the Cystic Fibrosis Foundation, to the tune of $30 million dollars,” says Cohen. A Phase II study is due to read out in the summer of 2020. If approved in any of its indications, lenabasum could be the first synthetic cannabinoid approved for inflammatory disease.
Other endocannabinoid-targeted drugs in Corbus’s pipeline include CRB-4001, which binds to cannabinoid receptor 1 in the liver and has potential against treat nonalcoholic steatohepatitis. Also, the company has more than 700 discovery-stage compounds in its library.
A botanical medicine like any other
Emerald Bioscience is developing two cannabinoid molecules—a prodrug of THC and an analogue of CBD. Both drugs are synthetic compounds that have the amino acid valine and a hemisuccinate moiety attached through an ester linkage.
The THC prodrug, THC-valine-hemisuccinate (THC-VHS), is in development for glaucoma. Emerald Bioscience has shown in validated rabbit models of the disease that THC-VHS lowers intraocular pressure in a superior manner comparable to the leading competitor drugs on the market.
Emerald Bioscience CEO Brian Murphy, MD, assert that the chemical modifications to the THC prodrug make it much better for dosing into the eye. “If you isolate THC, and make it into an eye drop, it almost looks like a drop of cooking oil, it’s so viscous,” he says. “But by virtue of attaching these groups, the molecule is more water soluble, and it’s able to get into the eye much more efficiently.”
Emerald Bioscience is also developing a CBD drug, CBD-valine-hemisuccinate (CBD-VHS), for ocular indications, pain management, and fibrotic diseases, including nonalcoholic steatohepatitis. The drug has performed well in an animal model of chemotherapy-induced peripheral neuropathy.
“What we were able to show in this animal model is that CBD-VHS had analgesic capability comparable to morphine, which is very profound,” Murphy says. The company also has animal data showing that CBD-VHS is effective for addiction to oxycontin.
The DEA has ruled that CBD-VHS is not a controlled substance, so it is not scheduled. Murphy says that while THC-VHS is currently a scheduled substance during the development process, many of the roadblocks to cannabinoid medicine development are being removed.
Murphy suggests that cannabinoids shouldn’t be associated with the stigma cannabis has carried ever since it was declared a controlled substance in the 1930s. “From a scientific perspective, these are just plant-derived pharmaceuticals, like Taxol for breast cancer, or theophylline for asthma—even aspirin is a botanical medicine,” he argues. “If you take the politics and stigma and social pressures out of the equation, cannabinoids are just like every other drug derived from plants.”