Date: 2014-06-17
Type of information: Publication of results in a medical journal
phase:
Announcement: publication of results in The Lancet Neurology
Company: GW Pharmaceuticals (UK)
Product: Epidiolex® (cannabidiol)
Action
mechanism: cannabinol derivative/endocannabinoid modulator
Disease: treatment-resistant epilepsy
Therapeutic area: CNS diseases - Neurological diseases
Country:
Trial details:
Latest
news: *On December 24, 2015, GW Pharmaceuticals announced that Epidiolex® (cannabidiol or CBD) data from the physician-led expanded access program in treatment-resistant epilepsy were published in The Lancet Neurology (Devinsky et al., Cannabidiol in Patients with Treatment Resistant Epilepsy: an open-label interventional trial, Lancet Neurology December 23, 2015). The published paper reports that Epidiolex® reduced seizure frequency across multiple drug-resistant epilepsy syndromes and seizure types and was generally well tolerated. The authors note that the administration of Epidiolex® as an add-on treatment led to a clinically meaningful reduction in seizure frequency in many patients and had an adequate safety profile in this patient population with highly treatment-resistant epilepsies. The safety and tolerability profile of Epidiolex was favorable with only 3 percent of patients terminating therapy due to an adverse event. The authors note that without a control group, the results regarding efficacy and safety should be interpreted cautiously. * On June 17, 2014,GW Pharmaceuticals announced physician reports of efficacy and safety data on 27 children and young adults with treatment-resistant epilepsy who have been treated with GW’s investigational cannabidiol (CBD) product candidate, Epidiolex®, for a period of 12 weeks. The treatment-resistant patients suffer from a range of epilepsies in which current anti-epileptic drugs have been unsuccessful in adequately controlling seizures, and included such severe forms of epilepsy as Dravet syndrome and Lennox-Gastaut syndrome. Uncontrolled data from two hospital sites in the United States that were generated under expanded access Investigational New Drug applications (INDs) authorized by the FDA were made available to the Company. Data were made available on 27 patients whom have been treated with Epidiolex for at least 12 weeks. Two patients commenced treatment in 2013 and the remaining 25 patients commenced treatment in the first quarter of 2014. All patients were treated at New York University Langone Medical Center (NYU) or the University of California at San Francisco (UCSF). Treatment effect data have been calculated in a manner consistent with the FDA\'s recommended endpoint for evaluating efficacy, which compares percent change in the average 4 week seizure frequency throughout the 12 week treatment period to seizure frequency during a 4 week baseline period. The same approach of average 4 week seizure frequency throughout the 12 week treatment period has been used in a responder analysis. In addition, safety data have been collected to date on a total of 62 patients (27 patients with 12 weeks treatment plus 35 additional patients who have commenced treatment under the expanded access treatment program but have yet to reach 12 weeks of treatment from NYU, UCSF and Massachusetts General Hospital in Boston). Data were collected at hospital sites by the local medical teams and sent to GW for compiling into a database. It should be noted that expanded access studies, sometimes called “compassionate use”, are uncontrolled, carried out by individual investigators, not conducted in strict compliance with Good Clinical Practices and not intended to be analyzed together as study data. Therefore, the data reported from these programs may not be indicative of results from, or duplicated in, placebo-controlled company-sponsored clinical trials. Of the 27 patients, the largest single type of epilepsy was Dravet syndrome (n=9). The remaining patients comprise a range of treatment-resistant epilepsies with convulsive and/or non-convulsive seizures. The 27 patients were predominately children with an average age of 10.5 years (26 of the 27 patients were between 3 to 18 years of age, and 1 patient was 26 years of age). In all cases, Epidiolex was added to current anti-epileptic drugs (AEDs). On average, patients were taking 2.7 other AEDs. Data were made available on all 27 patients and includes information collected on all seizures (convulsive and non-convulsive) reported for each patient. The mean overall reduction in seizure frequency as compared to baseline seizure frequency was 44% and median overall reduction in seizure frequency as compared to baseline seizure frequency was 42% 48% of all patients obtained at least a 50% reduction in seizure frequency as compared to baseline seizure frequency. 41% of all patients obtained at least a 70% reduction in seizure frequency as compared to baseline seizure frequency. 22% of all patients obtained at least a 90% reduction in seizure frequency as compared to baseline seizure frequency. At the end of 12 weeks, 15% of all patients were seizure-free Clinical Effect Data – Dravet syndrome patients only With respect to the 9 patients with Dravet syndrome, the data presented below include only convulsive seizures reported for each patient, the only types of seizures considered by FDA in assessing primary efficacy for Dravet syndrome trials. The 9 patients with Dravet syndrome ranged from 3 years to 16 years of age with an average age of 8.3 years. The mean reduction in seizure frequency as compared to baseline seizure frequency was 52% and median reduction in seizure frequency as compared to baseline seizure frequency was 63% Safety data were made available on 62 patients and represents approximately 120 patient-months of treatment with Epidiolex. At least one adverse event was reported in 81% (50) of patients. The most common adverse events (occurring in 10% or more patients and resulting from all causes) were: Somnolence 40% of patients Fatigue 26% of patients Diarrhea 16% of patients Decreased appetite 11% of patients Increased appetite 10% of patients 80% of reported adverse events were mild or moderate.There were no withdrawals from treatment due to adverse events There was 1 withdrawal from treatment due to lack of clinical effect. An additional 2 patients are currently being gradually withdrawn from treatment after 3 months due to lack of clinical effect Serious adverse events were reported in 7 patients, including 1 death of a patient from SUDEP (sudden unexpected death in epilepsy). None of these serious adverse events, including the 1 reported death, were deemed related to Epidiolex by the independent investigators. In some instances, the addition of Epidiolex may be associated with changes in serum concentrations of concomitant anti-epileptic drugs In addition to the expanded access IND patients, 5 patients have commenced treatment with Epidiolex under emergency access INDs. GW has received information from the treating physicians that 3 of these patients reported perceived benefits after treatment with Epidiolex and all 5 patients remain on treatment. GW is currently developing Epidiolex® in the treatment of Dravet syndrome, for which the Company has received both orphan drug designation and Fast Track designation from the FDA. A company-sponsored IND is open with the FDA and a Phase 2/3 trial is expected to commence in the second half of 2014. GW anticipates commencing an additional Phase 3 trial in Dravet syndrome in the first quarter of 2015. In addition to Dravet syndrome, GW plans to conduct a clinical development program for Epidiolex in the treatment of Lennox-Gastaut syndrome (LGS). Following receipt earlier in 2014 of orphan drug designation by the FDA, GW expects to hold a pre-IND meeting with the FDA for Epidiolex in the treatment of LGS in mid-2014, and expects to conduct two Phase 3 trials in LGS during 2015.
The expanded access program is a non-placebo controlled “compassionate access” program carried out by individual investigators independent from GW. Patients enrolled in the expanded access program were some of the most treatment-resistant patients being treated at each of the epilepsy centers. Prior to participating in the expanded access program, many of these patients failed to achieve seizure control despite treatment with antiepileptic drugs, dietary therapies, surgical therapies, and vagus nerve stimulation. The median number of concomitant antiepileptic drugs at the start of the trial was three. Data in the paper are from 11 independent epilepsy centers in the U.S.; 162 patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 patients were included in the efficacy analysis. Of these 162 patients, there were 33 patients with Dravet syndrome and 31 patients with Lennox-Gastaut syndrome (LGS). Dravet syndrome and LGS are two rare, extremely debilitating epilepsy syndromes that begin in infancy or early childhood. Ninety percent or more of people with Dravet Syndrome and LGS are considered treatment resistant.
The Lancet Neurology paper provides a more expansive description of data previously presented at the American Academy of Neurology Annual Meeting in April 2015. Since that time, additional expanded access data, encompassing almost twice the number of patients, were presented as a late-breaking poster at the American Epilepsy Society Annual Meeting earlier this month2.
“We are pleased that these Epidiolex data were selected for publication in The Lancet Neurology. The treatment effect seen in this open label study of Epidiolex in our initial target indications of Dravet syndrome and Lennox-Gastaut syndrome shows consistency with other data disclosures, and also demonstrates the effect of Epidiolex across multiple drug-resistant epilepsy syndromes and seizure types,” stated Justin Gover, GW’s Chief Executive Officer. “GW’s Phase 3 pivotal safety and efficacy studies in Dravet syndrome and Lennox-Gastaut Syndrome are now nearing completion and will provide the placebo-controlled efficacy and safety profile that patients and physicians have been calling for. We look forward to these results in 2016.”
Treatment effect data analysis used in this publication mainly focused on monthly seizure frequency calculated over the entire 12-week treatment period (including a 4-week dose titration period) compared to monthly seizure frequency during a 4-week baseline observation period. This calculation is similar to the approach being utilized in calculating the U.S. Food and Drug Administration’s (FDA) recommended primary efficacy endpoint in GW’s Epidiolex Phase 3 pivotal trials, which compare percent change in the monthly seizure frequency over the entire 14-week treatment period (including a 2-week dose titration period) to monthly seizure frequency during the 4-week baseline observation period.
Highlights from the publication of particular relevance to GW’s pivotal trials program in Dravet syndrome and LGS include:
Dravet syndrome: The median reduction in monthly motor (i.e., convulsive) seizures was 49.8% (n=32). 50% of Dravet syndrome patients had a 50% or greater reduction in monthly motor seizures. During the last 4 weeks of therapy, 13% (n=4) were free of motor seizures; these patients were also free of all other seizure types. In Dravet syndrome patients who experienced them at baseline, there was a median 69.2% reduction in monthly tonic seizures (n=6), 46.7% reduction in monthly tonic-clonic seizures (n=29), and 83.3% reduction in non-motor focal seizures (n=10).
LGS: A median 68.8% reduction in average monthly atonic seizures was observed (n=14). During the last 4 weeks of therapy, 21% (n=3) were free of atonic seizures and 3% (n=1) were totally seizure free. In LGS patients who experienced motor and tonic seizures at baseline, there were median 36.8% (n=30) and 44% (n=21) reductions, respectively.
Adverse events occurred in 79% of all patients treated with cannabidiol (n=162). Adverse events reported in greater than 10% of patients were somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%) and convulsion (11%). Most adverse events were mild or moderate and transient. Five patients (3%) discontinued treatment due to an adverse event.
Serious adverse events were reported in 48 patients (30%), including one death, regarded as unrelated to CBD. Serious adverse events which were deemed possibly related to CBD occurred in 20 patients.
GW is conducting two Phase 3 trials in Dravet syndrome and two Phase 3 trials in LGS. GW also expects to commence Phase 3 clinical development of Epidiolex in Tuberous Sclerosis Complex (TSC) in early 2016. For Dravet syndrome, GW expects to report top-line results from the Phase 2/3 pivotal safety and efficacy study in the first quarter of 2016 and results from the second Phase 3 trial around mid-2016. The primary measure of efficacy in both trials will be the comparison between Epidiolex and placebo in the percentage change in number of monthly convulsive seizures (reported tonic-clonic, tonic, clonic and atonic seizures) during the 14 week treatment period compared with the 4 week baseline observation period.
For LGS, GW expects to report top-line results from both Phase 3 trials in the second quarter of 2016. The primary measure of efficacy in both trials will be the comparison between Epidiolex and placebo in the percentage change in number of monthly drop seizures (the sum of all reported atonic, tonic and tonic-clonic seizures that were also deemed drop seizures (involving the entire body, trunk or head that led or could have led to a fall, injury, slumping in a chair or hitting the patient’s head on a surface) during the 14 week treatment period compared with the 4 week baseline observation period.
56% of Dravet patients obtained at least a 50% reduction in seizure frequency as compared to baseline seizure frequency
44% of Dravet patients obtained at least a 70% reduction in seizure frequency as compared to baseline seizure frequency
33% of Dravet patients obtained at least a 90% reduction in seizure frequency as compared to baseline seizure frequency
At the end of 12 weeks, 33% of Dravet patients were seizure-free
