Bringing a drug to market is always tough, but is getting approval for a cannabis extract any harder? It doesn’t seem that way for GW Pharmaceuticals.
Guy has many years of experience in drug development and commercialization, including drug delivery, narcotic analgesics, and plant-based therapeutics. Further, his team includes people with experience in plant sciences, drug development, and drug delivery.
“In the 1990s in the UK, MS patients were pushing for the legalization of cannabis. Based on the government’s response to these lobbyists, we created a proposal on how to make a modern medicine from a plant,” says Guy. “The UK regulators originally suggested a research focus on pain. However, as their guidelines fell in line with Europe, it became clear our data would not be sufficient, so we turned back to MS, another area of high unmet medical need.”
MS is a disabling neurological disease, and most people with MS develop muscle spasticity at some stage. The effect of cannabis on MS appears to be via the cannabinoids THC (delta-9-tetrahydrocannabinol) and cannabidiol. THC has analgesic and antispasmodic effects, but has a narrow therapeutic window. It is possible that cannabidiol alleviates some of the side effects of THC, making it easier to adjust the dose.
Raising Funds To Create Sativex
GW Pharmaceuticals started with funding from private investors, including friends, families, and colleagues. This first round in 1998 was oversubscribed, as was the second in 1999. “By this time, we had credible scientific and clinical evidence and wanted to expand our circle of investors, so we went to an IPO in 2001,” says Guy.
The product the company created was a first-in-class endocannabinoid system modulator called Sativex, which is an oromucosal spray containing THC and cannabidiol, amongst other naturally occurring cannabinoids. It is made from a Cannabis sativa whole plant extract and was the first cannabis-derived prescription product to reach the market for any indication.
The Prejudice Against Cannabis
As a recreational drug that is illegal in many countries, cannabis-derived in-licensed therapeutics might be expected to carry a stigma. GW Pharmaceuticals, however, did not have any issues with acceptance from patients during clinical trials, including more than 1,300 patient-years of safety data. In fact, the research has been welcomed by the MS community.
“We did face an issue with some physicians who suggested that patients were not actually getting an improvement in their symptoms but were getting a mild ‘high.’ However, the dose of Sativex is too low and administered over too long a period to trigger such a response. We had to provide good quality data and thoroughly validated endpoints that were credible to our audience. This isn’t unique to a cannabis-related product — it happens in the development of every drug,” says Dr. Guy.
In fact, according to Dr. Trung Huynh, a healthcare analyst with Datamonitor, “The approval in the UK, coupled with the advantages of spray delivery, will go some way to dispel the stigma associated with the medicinal use of cannabis.”
The Challenges Of Being First In Class
As the first company developing a C sativa extract, GW Pharmaceuticals had to tackle a number of hurdles in the development process, such as growing the plants, manufacturing the extract, delivering the active ingredients, and gaining market access. “Being the first in any indication is a landmark, but it requires the company to take on an educational role as well,” says Huynh.
One of the key issues GW Pharmaceuticals faced was the trial design. There have been no new medications or ratings scales for spasticity in MS for more than 20 years. In order to have credible endpoints, GW Pharmaceuticals, with key opinion leaders in neurorehabilitation, had to develop new scales.
MS patients are highly motivated, and there had been many discussions about Sativex in the MS community. Therefore, patients entering the Sativex trials had very high expectations, which may have caused increased levels of placebo responses. The company had to “design out” the expectations, which added time onto the development.
Another challenge was manufacturing. Because cannabis is a controlled drug, it must be grown, and Sativex must be manufactured under a Home Office license. Guy has extensive experience with research into controlled drugs, so he was able to gain a license relatively easily, crossing the company’s first regulatory hurdle.
Creating a usable and stable plant extract and developing a delivery system were two big obstacles. Smoking cannabis may be effective, but it raises ethical, health, and dosing issues. Cannabinoids are not best- suited for transdermal delivery, would be metabolized if they were given orally, and are insoluble in water. The company’s solution was to create an oromucosal spray that delivered a precisely measured dose for absorption through the inside of the cheek or under the tongue.
Finally, there was the regulatory hurdle. The current regulatory environment focuses on single synthetic chemicals. Plant extracts are complex and include many active ingredients. GW Pharmaceuticals had to develop techniques and standards for assessing plant extracts, in collaboration with the various standards committees.
The Problems In The United States
There have been concerns raised that Sativex will face problems in the United States because of the government’s opposition to medicinal cannabis use. However, Sativex has been through a number of clinical trials, and its UK and Spanish approvals are expected to clarify the separation between it and the herbal products.
GW Pharmaceuticals is focusing on Sativex in cancer pain in the United States. Not only will this be a large market, but the company could also face a more sympathetic approval process. “The United States has a draconian attitude toward cannabis, so we consciously selected a program that had a great perceived need. It was also a pragmatic decision — the long-term toxicity studies in cancer may be less extensive than those in MS,” says Dr. Guy.
In the United States, the FDA and the DEA have assessed the research program and raised no political obstacles. “The presence of a synthetic cannabinoid on the U.S. market will help Sativex’s acceptance. The FDA approving Sativex’s clinical trials is also a good sign,” says Huynh.
Making The Right Alliances
GW Pharmaceuticals’ approach to market was to make the right alliances with large pharmaceutical companies familiar with the MS market. It is working with Bayer Schering Pharma in the UK, Almirall in Europe outside the UK, and Otsuka in the United States. “While we have funded development in Europe, we knew it would be important to find a partner to fund development in the United States. We wanted to expand indications and geography, and a partnership effectively ‘derisked’ this process,” says Dr. Guy.
Following Europeanwide approval, sales will depend on recommendations by individual health advisory agencies. Sativex is likely to cost around $6,000 per patient, per year, and will be used as an add-on with disease-modifying MS drugs, which are around $15,000 and $30,000 a year, so price could be a key obstacle to Sativex’s success.
“The challenge that the company faces will be in differentiating Sativex from other antispasticity drugs that are not as expensive. As its proprietary product, Sativex is a breakthrough for GW Pharmaceuticals; however, indication and geographical expansions are needed to realize its full commercial potential,” says Huynh.
Analysts at Piper Jaffray suggest that European and Canadian annual sales of Sativex in MS spasticity could climb to around £121 million. Datamonitor, however, predicts annual sales in MS in the five major European markets to reach $28 million by 2019.
What’s next?
In 2005, Sativex became available in Canada for the treatment of central neuropathic pain, under a notice of compliance, and has been submitted for approval for neuropathic pain in MS and cancer pain. It has also been prescribed on a named-patient basis in 16 other countries. In 2010, it gained marketing approval in the UK and Spain for spasticity in MS. It is in Phase 3 trials in Europe and the United States for cancer pain and has completed some Phase 3 clinical trials in peripheral neuropathic pain.
There are nearly 70 cannabinoids in C sativa, and GW Pharmaceuticals is looking at 12 of these. “Once Sativex had validated the class of compounds and the platform, we were able to expand into other indications,” says Dr. Guy.
The company’s Japanese partner, Otsuka¸ is funding preclinical research with the cannabinoids in psychotic and CNS disorders and in cancer. The next step will be human proof-of-concept trials, and Otsuka has an option to license lead compounds. “These projects will provide us with useful preclinical and clinical data and are lower risk for us, as the research is funded by our partner,” says Dr. Guy.
In-house, GW Pharmaceuticals is developing cannabinoids for the treatment of metabolic syndrome and inflammatory conditions, and Phase 2 trials are planned. Over the long term, the company will look at using the extracts in neurodegenerative disease and regenerative medicine possibly through modulation of stem cell differentiation. During the next 10 to 15 years, the company hopes to have developed three to four more major products.
“GW Pharmaceuticals is based on serious science that just happens to be around cannabinoids. We have managed to achieve credibility, which has helped us to break down preconceptions. We gained a Home Office license, obtained an approved source of cannabis, moved into clinical trials, and now have approvals in key European markets,” says Dr. Guy.
Sativex Reaches The European Market
On June 21, 2010, GW Pharmaceuticals launched Sativex in the UK for the treatment of muscle spasticity in MS. The UK approval from the Medicines and Healthcare Products Regulator Agency (MHRA) is the oromucosal spray’s first full approval worldwide, and UK licensee Bayer Schering Pharma will market the drug. The UK will act as Reference Member State for the European Mutual Recognition Procedure (MRP), which will gain marketing authorization for Sativex in European member states.
Sativex gained approval in Spain on July 28, 2010, as an add-on therapy for moderate to severe spasticity in MS in patients who have not responded adequately to other antispasticity medications. GW Pharmaceuticals and its European (ex-UK) partner Almirall expect to launch the drug in the fourth quarter 2010, once it has received pricing and reimbursement approval from the Spanish Ministry of Health.