Posts Tagged Epidiolex
Epilepsy drugs don’t work well, or at all, for about one-third of people with the condition. Unfortunately, these hard-to-treat epilepsies are associated with an increased risk of premature death.
Anecdotal evidence suggests that cannabis oil may help some of these people control their seizures and potentially save their lives. A small number of studies have shown that adding cannabis oil to existing medication may be effective in devastating, hard-to-treat epilepsy in children and adolescents.
One of those people is 12-year-old Billy Caldwell. Billy was in the UK news recently after the cannabis oil prescribed for him was confiscated at Heathrow airport by the authorities. Billy’s mother, Charlotte, was attempting to bring the cannabis oil into the UK from Canada, where cannabis oil is legal.
Billy was seizure-free for more than 250 days when taking the oil, but his seizures started again when his cannabis oil was withdrawn. The home secretary, Sajid Javid, was persuaded to intervene and one of the seven bottles of cannabis oil was returned, with a 20-day licence to administer the medicine.
In a similar case, six-year-old Alfie Dingle, who suffers from severe epilepsy, had been successful[ly] treated with cannabis oil in the Netherlands. Alfie’s mother, Hannah Deacon, has been campaigning to allow her son to be provided with cannabis oil in the UK.
The government has now also relented in Alfie’s case following the concerns raised around the confiscation and return of Billy Caldwell’s medicine.
What the evidence shows
So what do we know about cannabis oil and its effects on epilepsy seizures?
The two main constituents of cannabis oil are THC (tetrahydrocannabinol) and CBD (cannabidiol). Oil containing CBD alone (CBD oil) can be legally bought in the UK without a prescription because it contains only very low quantities of THC. But cannabis oil that contains THC at higher levels (more than 0.3%) is illegal. THC is a schedule 1 drug, that is to say, it is deemed to have no medicinal value.
The reason that Billy’s cannabis oil was seized at Heathrow airport was that it didn’t just contain CBD, it also contained THC at higher levels than legally permitted.
There is good evidence in robust human clinical trials that CBD is of benefit for specific epilepsies, such as Dravet syndrome and Lennox Gastaut syndrome. An advantage for the pharmaceutical industry is that these rare diseases with no cure can be fast-tracked for drug development. On this basis, the US Food and Drug Administration is widely expected to grant a licence for CBD (under the tradename Epidiolex) to treat these epilepsies. If so, Epidiolex is likely to be available in US by late 2018. European approval is likely to follow.
It should be noted that Epidiolex is designed as standardised oral solution of pure plant-derived CBD. It is not the same as the non-standardised, viscous CBD oils that contain varying amounts of CBD and can be purchased in health food shops. There is currently no good evidence that formulations of CBD oil (or indeed cannabis oil) are as effective on epilepsy seizures. Equally, there is no robust evidence – just anecdotal reports – that THC helps reduce epilepsy seizures human.
In [animal studies], THC has weak overall effects in reducing seizures and has also been shown to be a less effective anticonvulsant than CBD. THC, being a psychoactive substance, also has a number of side effects, including the well-known euphoric “high” associated with recreational use – which is a significant disincentive for the pharmaceutical industry to develop a medicine containing this compound.
We now need to decide if we should expand human trials with better defined THC-containing cannabis oil, or if we should focus on CBD. The fact that Epidiolex has progressed towards approval in the US may encourage the latter course. CBD lacks psychoactive effects associated with THC and, in general, is regarded as a safe compound.
If Epidiolex is granted regulatory approval, it will also need to be monitored in a larger number of patients – in what’s known as “phase 4 post-marketing surveillance” – to ensure that it is safe and effective in a broader population. For any cannabis-based product, only large-scale clinical trials can provide definitive answers about effectiveness and safety.
A new class of epilepsy drugs based on a marijuana ingredient could be become available in the United States as early as the second half of 2018 pending approval from the Food and Drug Administration.
GW Pharmaceuticals, the maker of the drug called Epidiolex, announced on Wednesday the promising results of a clinical study of the drug.
A group of 171 individuals were randomly assigned to either receive Epidiolex treatment or placebo. The participants were between 2 and 55 years old with a condition called Lennox-Gastaut syndrome. They were also suffering from seizures existing drugs cannot efficiently control.
The participants on average had tried and discontinued use of six anti-seizure treatments and were experiencing 74 “drop” seizures per month. This particular seizure involves the entire body, head and trunk, and often leads to fall and other injuries.
LGS Patients Taking Epidiolex Sees Significant Reduction Seizures
Results of the study, which was reported in the journal Lancet, showed that over a period of 14 weeks, 44 percent of the patients taking the drug saw significant reduction in seizures. The rate is significantly higher compared with the 22 percent in the placebo group. More of those who were given the experimental drug also experienced a 50 percent or greater reduction in drop seizures.
“LGS is one of the most difficult types of epilepsy to treat and the majority of patients do not have an adequate response to existing therapies,” said Elizabeth Thiele, from Harvard Medical School. “These results show that Epidiolex may provide clinically meaningful benefits for patients with LGS.”
Adverse Events Linked To Use Of Epidiolex
Adverse events associated with use of the drug include diarrhea, decreased appetite, sleepiness, vomiting, and fever. Once given the go-signal to be marketed in the United States, the drug is intended to be used as a prescription drug to be dispensed by doctors.
“Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial,” investigators wrote in their report.
GW Pharmaceuticals has not yet disclosed the pricing of the drug, but Justin Gover, GW’s chief executive officer, said that the company is already in talks with health insurers about coverage.
PHILADELPHIA — New open-label data from the expanded-access treatment program involving the cannabidiol Epidiolex (GW Pharma) show the median reduction in frequency of convulsive seizures after 3 months of treatment was 45% in all patients but higher in those with Dravet syndrome, among the most severe types of epilepsy.
The data are “very positive and promising,” said lead author Orrin Devinsky, MD, professor, neurology, neurosurgery and psychiatry, and director, New York University Comprehensive Epilepsy Center.
A “big caveat,” however, is that this was an open-label study, he said. Results of the first of four placebo-controlled trials of this cannabidiol product are expected early next year.
Dr Devinsky reported the findings here during the American Epilepsy (AES) 69th Annual Meeting.
Epidiolex is a purified cannabidiol compound in an oil base that is administered as a liquid.
The efficacy analysis included 261 patients with continuous exposure to the drug and on whom investigators had evaluable data. These patients ranged in age from 4 months to 41 years with a median of 11.8 years.
In these patients, 19% had a known cause of their epilepsy. The most common diagnoses were Dravet syndrome (17%), Lennox-Gastaut syndrome (LGS), or another rare type of epilepsy (15%).
The median number of convulsive seizures per 28 days in these patients was 31, so this was a group of children and young adults with “very frequent seizures,” commented Dr Devinsky.
Patients started cannabidiol at a dose of 2 to 5 mg/kg per day, which was gradually increased to a maximum dose of 25 mg/kg per day. They were also taking an average of three antiepileptic drugs (AEDs).
The primary outcome was change in the number of convulsive seizures, which are relatively easy to count, said Dr Devinsky.
“The seizure had to last at least 3 to 5 seconds with convulsive activity, cause the child to drop or fall to the floor or have a tonic-clonic convulsive event,” he noted. These are readily identifiable by most parents who tracked these events in seizure diaries, he said.
The median convulsive seizure frequency reduction was 45.1% in all patients and 62.7% in patients with Dravet syndrome. The median reduction of atonic seizures was 71.1% in patients with LGS.
In terms of achieving a greater than 50% reduction in seizures, this rate was 47% among all patients. During the last 4 weeks of the trial (between weeks 9 and 12), 9% of all patients and 13% of patients with Dravet syndrome were seizure-free.
“These are numbers that are much greater than what I would have predicted, and certainly would have ever predicted for a placebo response,” said Dr Devinsky.
He stressed that the study population was “an extremely treatment-refractory group.” Such patients are at high risk for sudden unexpected death from epilepsy and status epilepticus.
Safety data were available on 313 treated patients. The most common adverse effects were somnolence (23%), diarrhea (23%), fatigue (17%), decreased appetite (17%), convulsion (17%), and vomiting (10%).
Dr Devinsky stressed that only 4% of all patients stopped the study medication because of adverse effects. “For an antiepileptic drug trial, that is relatively low.”
About 12% of patients withdrew because of lack of effectiveness, which “again was relatively small” in this type of trial, said Dr Devinsky.
Serious adverse events were reported in 34% of patients and included seven deaths. “None of these were felt by investigators to be related to the study medicine,” said Dr Devinsky.
Although these new results “add more fuel to the fire showing that this drug is likely to be effective for some people,” without a double-blind study “we are essentially blind to know what the truth is,” said Dr Devinsky.
An interesting study finding was that patients who were taking the AED clobazam had a better overall rate of treatment response (57% with a 50% or greater seizure reduction compared with 39%). This may reflect elevations in the desmethyl clobazam metabolite, he said.
“We think that some of the efficacy — and some of the toxicity — in some patients may have been related to the clobazam,” said Dr Devinsky.
He noted, however, that there was “absolutely no difference” in the response rate between patients with Dravet syndrome and LGS taking clobazam and those not taking that drug.
Asked whether increasing the dose of clobazam in patients already receiving this drug might have resulted in the same improved treatment response, Kelly Knupp, MD, Children’s Hospital, Aurora, Colorado, said that’s “possible.”
Increased clobazam levels probably reflect “some drug-to-drug interactions that need to be sorted out,” said Dr Knupp, who treats children with epilepsy.
She, too, is keen to know what the placebo effect is. “The value of doing a double-blind randomized study is that it takes into account that placebo effect; we just don’t really understand it here.”
In the meantime, she said she’s “guardedly hopeful” about the new results.
The study was funded by GW Pharma. Dr Devinsky reports receiving research support from GW Pharma.