GW Pharmaceuticals Changes Its Focus To Rare Diseases

By Suzanne Elvidge, Contributing Writer
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Building a pharmaceutical company based on cannabis may have seemed like an ”out there” idea back in the 1990s, but in 2016, with a listing on NASDAQ and AIM (the London Stock Exchange’s international market for smaller growing companies) and a lead drug, Sativex, approved in 28 countries, the idea behind GW Pharmaceuticals now looks pretty mainstream.

This success hasn’t stopped the company looking at its model and making some major changes, switching its R&D from larger indications to smaller and more challenging areas within orphan diseases.

Patients have self-medicated with cannabis for many years, using it to relieve pain and help with symptoms of MS, psychiatric disorders (e.g., depression, anxiety), nausea and vomiting (including chemotherapy-induced nausea), glaucoma, diabetes, and wasting caused by cancer and AIDS. As a response to calls in the UK from physicians, patients, and regulators to find a way to make a standardized cannabis pharmaceutical, Dr. Geoffrey Guy and Dr. Brian Whittle formed GW Pharmaceuticals in 1998 to create standardized and testable therapeutics from the plant sources, in a story told in Life Science Leader in October of 2007. At that time, GW Pharmaceuticals’ focus was on the use of cannabis to relieve spasticity from MS, leading to the development of its first product, Sativex (nabiximols), from a Cannabis sativa whole plant extract.

Sativex is an oromucosal spray containing THC (delta-9-tetrahydrocannabinol), cannabidiol (CBD), and a number of other naturally occurring cannabinoids and was the first cannabis-derived prescription product available on the market. Sativex is now available in 15 countries, including the UK, Spain, Italy, and Germany.

A SHIFT FROM PAIN TO ORPHAN INDICATIONS
What is interesting about GW Pharmaceuticals is how it has changed its approach since the 2007 article. Fastforwarding almost 20 years from 1998 to 2016, research at GW Pharmaceuticals, while still looking into drugs derived from cannabis, is taking a rather different focus. In a step away from large indications like cancer pain, MS, metabolic syndrome, and inflammatory conditions, GW Pharmaceuticals is moving its spotlight to rare and orphan indications, where there are limited or no other treatment options. Working in rare diseases is challenging because of lack of recognized outcome measures, small markets, and for the rarer diseases, difficulties in finding sufficient patients for clinical trials. However, Stephen Schultz, VP of investor relations for GW Pharmaceuticals, is convinced that the company is making the right move.

“These are areas where there are few or no therapeutic drugs approved, so there is a high level of unmet need and a significant demand for new treatments,” says Schultz. “Though the population for the marketed drug will be smaller, the clinical studies are likely to be smaller and shorter as well. The regulatory authorities also provide companies with incentives to develop drugs for these small populations, for example Fast Track designation to speed approval and orphan exclusivity to protect the drug from competition after launch.”

The initial focus will be on the development of a treatment for Lennox-Gastaut syndrome and Dravet syndrome, also known as severe myoclonic epilepsy of infancy (SMEI). These are both rare and difficult-to-treat forms of childhood-onset epilepsy. Other potential indications are expected to include tuberous sclerosis complex, a rare genetic condition that causes epilepsy following on from the growth of benign tumors in the brain, and also intractable childhood epilepsy. In this form of childhood epilepsy, the repeated seizures can lead to brain damage, and the disease is very hard to treat successfully.

“The current drugs are not working in rare epilepsy disorders and treatment-resistant epilepsy, so these untreated conditions can lead to significant longterm health challenges that have a major impact on the families and, in many cases, lead to hospitalization. If the use of new drugs can reduce the length of an expensive hospital stay, even if they are higher cost than existing treatments, they should offer value to the payers,” says Schultz.

THE EPIDIOLEX STORY
There have been anecdotal reports of cannabis helping people with epilepsy over the last 150 years. In the U.S., where CBD-enriched cannabis oils can be accessed from certain dispensaries, parents have tried to use these to control their children’s seizures with varying levels of success. However, these so called “artisanal”’ preparations are only available in some states, and the active ingredients are often not as described. According to Schultz, the FDA tested 18 artisanal CBD oils and found that around a third contained no cannabinoids at all, and others contained high levels of THC, which can act as a proconvulsant. Schultz added that the parents of children with treatment-resistant disease were reading papers and publications about the use of GW’s CBD in epilepsy.

“We had been working on Epidiolex, a liquid formulation of pure, plant-derived CBD, in preclinical studies and had gained orphan drug designation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome, along with Fast Track designation for Dravet syndrome. The parents of a boy with intractable epilepsy found out that GW Pharmaceuticals was behind the science, and they and their son’s physician approached us about getting the drug for the boy, even though it was still in early development. This initial patient led to a compassionate access program and helped us move into clinical trials.”

Epidiolex has been made available under expanded access investigational new drug (INDs) applications in patients with Dravet syndrome, Lennox Gastaut syndrome, and 14 other types of severe epilepsy including tuberous sclerosis complex, Aicardi syndrome, and Doose syndrome. The results from the expanded access program, which involves around 450 children and is still ongoing, showed that Epidiolex reduced seizure frequency and was generally well-tolerated.

Epidiolex is also in Phase 3 clinical trials with two safety and efficacy studies in Lennox Gastaut syndrome and two in Dravet syndrome. Initial data is expected in the first quarter of 2016, with a submission for approval planned for both indications in the fourth quarter of 2016.

“The dispensary-based cannabis tinctures, oils, and pills can be highly variable and are not supported by data,” says Schultz. “We are dealing with treatmentresistant children who are highly sensitive to changes in their medications, so giving them uncharacterized products can be challenging. While dispensary-based medical cannabis may continue to be used, forms approved by the regulatory authorities should be wellreceived, as they demonstrate safety and efficacy in controlled clinical environment and meet a true medical need.”

EXPANDING THE EPILEPSY PORTFOLIO
GW Pharmaceuticals is developing another epilepsy therapeutic, GWP42006, a formulation of the nonpsychoactive cannabinoid cannabidivarin (CBDV). This was well-tolerated in a Phase 1 trial and is now in a Phase 2 trial with 130 patients who have inadequately controlled focal seizures. CBDV may also have potential in other epilepsy-related conditions.

After signing a memorandum of understanding, GW Pharmaceuticals is working with the government of New South Wales in Australia to carry out research in severe, drug-resistant childhood epilepsy with Epidiolex and GWP42006, including the first Phase 2 trial of GWP42006 worldwide in children, compassionate access for Epidiolex in Lennox Gastaut and Dravet syndromes, and additional Phase 3 trials and a Phase 4 trial in children with treatment-resistant epilepsy.

Other products for orphan indications in GW Pharmaceuticals’ pipeline include GWP42003, an IV therapeutic for neonatal hypoxic ischemic encephalopathy (NHIE) that has a Phase 1 trial expected to begin in the second half of 2016, and a cannabinoid combination of GWP42002 and GWP42003, currently in Phase 2 clinical trials in recurrent glioblastoma multiforme. Clinical trials are also under way in the larger indications of type 2 diabetes (GWP42004) and schizophrenia (GWP42003).

“Our development platform allows us to evaluate cannabinoids rapidly alone or in combination against different therapeutic targets,” says Schultz. “There is significant scientific evidence for cannabis-derived drugs for a wide variety of different diseases, and as research advances, I expect to see more opportunities opening up for GW Pharmaceuticals.”

CHANGING THE REGULATORS’ PERSPECTIVE ON CANNABINOIDS
While an increasing number of states are legalizing medical cannabis, and others are decriminalizing and even legalizing recreational forms of the drug, the legalization of marijuana is still controversial in the U.S. While GW Pharmaceuticals products in the U.S. have yet to be approved for use, Schultz has seen his company used as an example by the FDA of how cannabinoids should be handled in clinical trials.

“We are still one of only a few pharmaceutical companies working on drugs derived from cannabis. When we started, there was less of a known pathway for cannabinoid- based drugs. Since then, we have become better at creating reproducible and fully characterized pharmaceutical medicines, designing clinical trials, and navigating the regulatory pathways. We have seen the EMA’s (European Medicines Agency) and FDA’s perspectives on cannabinoids change, and we are confident that we have been part of this evolution. They now have more confidence in the ability of companies to develop therapeutics from botanical sources, creating consistent products that meet or exceed the regulatory authorities’ requirements. It’s still challenging to test scheduled drugs, and we are bound by specific requirements related to handling, storage, and accounting by the DEA, as is each clinical site and all the physicians involved in the studies,” says Schultz. “But it is possible, and it has actually become a core competency of the company, to be able to navigate these regulations.”

Sativex, which contains THC, is a Schedule 4 Part 1 drug in the UK, which means that it is a prescription-only medicine (POM) and does not have to be recorded in controlled drug registers. Before April 2014, it was categorized as a Schedule 1 controlled drug, requiring specific reporting and recording requirements. Even though Epidiolex only contains CBD, it is still likely to have restrictions.

“Although GW has been developing cannabis-based medicines longer than any other company in the world, working in cannabis isn’t really what makes us different — it just happens to be the area of our focus. What makes us different is that we have a very well-described process, strong regulatory expertise, a world-leading understanding of cannabinoid science, GMP manufacturing expertise, and a proven record to execute clinical trials and secure regulatory approvals. We have evolved a lot over almost 20 years. We started off with large therapeutic areas and have focused down to identifying therapeutic targets in rare diseases with areas of significant unmet need where cannabinoids offer promise. We are expecting results from eight different placebo-controlled clinical trials over the next year. These are exciting times!” concludes Schultz.