On 25h June 2018, the US Food and Drug Administration (FDA) approved Epidiolex, a cannabinoid-based medicine for treating seizures in two forms of severe epilepsy. The drug, developed by the British company GW Pharmaceutical, can now be prescribed for Lennox-Gastaut syndrome and Dravet syndrome, in patients two years old and over. Both conditions are otherwise resistant to treatment.
The approval is not just notable for the patients who will benefit from it. It also marks the first time a marijuana-based drug has been approved in the US, and represents a milestone on the federal level.
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“This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies,” said FDA commissioner Scott Gottlieb in a statement. “And, the FDA is committed to this kind of careful scientific research and drug development.”
How does cannabidiol improve epilepsy outcomes?
The drug itself is a highly purified oral solution, synthesised from cannabidiol (CBD). CBD is one of dozens of compounds found in the cannabis plant, and is often contrasted with another compound, tetrahydrocannabinol (THC). Unlike THC, it is not psychoactive, and therefore does not contribute to the ‘high’ associated with cannabis.
It is also widely thought to have medicinal properties. Although CBD has not been widely tested in human clinical trials, users have credited the chemical as assuaging everything from anxiety to diabetes. In the UK, it is viewed as a dietary supplement and can be purchased easily from shops such as Holland & Barrett.
However, in the US it is classed as a Schedule 1 substance, the strictest possible classification, meaning it is subject to the same controls as heroin and cocaine. It can be purchased only in states where marijuana itself is legal, meaning lawmakers have failed to differentiate between the psychoactive drug and its non-psychoactive components.
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By GlobalDataThis means the approval of Epidiolex is a major victory for patients who would otherwise have had to break the law to obtain CBD. Taking CBD for epilepsy is nothing new: it first attracted widespread attention in 2013, when a CNN documentary called ‘Weed’ aired in the US. The documentary featured a young girl named Charlotte who suffered with Dravet syndrome, and experienced up to 300 seizures a week. When Charlotte was given oil derived from high-CBD cannabis, her seizures stopped almost completely.
More recently, we have seen several high-profile cases in the UK where severely epileptic children are all-but cured with cannabis oil. Alfie Dingley (six) and Billy Caldwell (12) both suffer with rare and devastating forms of epilepsy that cannot be treated with conventional medicines. After a long battle, their doctors have been granted licenses to prescribe them cannabis oil (which is slightly different from, albeit related to, pure CBD).
Surmounting the legal hurdles surrounding cannabinoid medicines
Epidiolex, then, could bring relief to other long-suffering children, this time without the legal headaches. As a spokesperson for GW Pharma explains, GW’s proprietary cannabis plants are grown to meet strict pharmaceutical standards, and are therefore able to meet the exacting standards set out by the regulatory authorities.
“The manufacturing process for Epidiolex itself involves many steps and is subject to rigorous controls that ensure consistency in the content of the active ingredient – an important distinguishing factor compared with CBD-containing products that have not gone through the FDA process,” says the spokesperson.
This is not the first time GW Pharma has developed a drug derived from cannabis. The company, in fact, specialises in prescription cannabinoid medicines, and has been working in this field for 20 years.
Its first cannabis-based medicine, Sativex, was approved in the UK in 2010 to treat the symptoms of multiple sclerosis. While this drug has never been approved in the US, it is now available on prescription in 29 countries.
“GW was only allowed to start marketing Sativex once it had carried out extensive clinical trials to prove it was effective with an acceptable safety profile,” says the spokesperson. “GW has been following the same process of rigorous, placebo-controlled trials on its second medicine Epidiolex. Its priority is to bring medicines to market as fast as possible but in a way that allows physicians and patients to be confident about their safety and efficacy.”
A new treatment option for vulnerable epilepsy patients
For patients with Lennox-Gastaut syndrome and Dravet syndrome, the treatment could make a very real difference. These are some of the most vulnerable epilepsy patients, who generally don’t benefit from standard anti-epileptic drugs.
Dravet syndrome is a severe infantile-onset condition, often associated with a genetic mutation. While patients can develop multiple types of seizure, they are prone to prolonged, life-threatening seizures known as status epilepticus, and have an elevated risk of premature death. It is estimated to affect between 1/20,000 and 1/40,000 children worldwide.
Lennox-Gastaut syndrome, a similar condition, has a range of possible causes and typically first emerges in children aged three to five. Sufferers experience a variety of seizure types, often accompanied by cognitive impairment. Its annual incidence in the EU is estimated at 1/50,000.
“Despite the availability of a broad range of anti-epileptic drugs, seizure control remains inadequate due to varied responses to currently available therapies and the highly refractory nature of the seizures,” says the GW Pharma spokesperson. “There are currently no European Medicines Agency (EMA)-approved treatments for DS and LGS, with nearly all patients continuing to have uncontrolled seizures and other medical needs throughout their lifetime.”
Benefits vs side effects: the efficacy and safety of Epidiolex
Epidiolex’s effectiveness was studied in three randomised, double-blind, placebo-controlled clinical trials. Together, these involved 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. When used alongside other medications, Epidiolex was shown to be better at reducing seizure frequency than the placebo.
One of the studies, which enrolled 120 children with Dravet syndrome, saw patients receive Epidiolex, or a placebo, over the course of a 14-week treatment period. The findings, published in the New England Journal of Medicine in May, were very positive: the median number of seizures in the Epidiolex group dropped from 12.4 to 5.9 a month, compared to 14.9 to 14.1 in the placebo group. Five percent of the cannabidiol patients saw their seizures vanish altogether.
The drug did cause some side effects, most commonly somnolence, decreased appetite, diarrhoea and fatigue. In the trial mentioned above, eight patients dropped out because the side effects were too severe.
However, the drug was unanimously recommended at the FDA Advisory Committee Meeting in April, meaning its eventual approval was widely anticipated. GW Pharma had already been granted Priority Review designation for its application, along with fast-track designation for Dravet syndrome and orphan drug designation for both indications. Such designations reflect a high level of unmet need.
A blockbuster in the making?
Currently, Epidiolex is under review by the EMA, with an initial decision expected by the end of 2018. If this decision is positive, the medicine will receive a European Commission approval in Q1 2019 and will be the first in a new class of anti-epileptic drugs.
According to analysts Evaluate Group, Epidiolex could reach $960m in sales, just shy of the $1bn needed to be classed as a blockbuster. Others have placed the estimate at $2bn, well into blockbuster territory.
There may also be hope for the medical marijuana market more broadly. While warning against ‘the illegal marketing of CBD-containing products’, the FDA has reinforced its support for companies like GW Pharma.
“We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products,” said Scott Gottlieb.
