Clinical Trials

Date: 2015-04-22

Type of information: Presentation of results at a congress

phase:

Announcement: presentation of results at the American Academy of Neurology annual meeting in Washington DC

Company: GW Pharmaceuticals (UK)

Product: Epidiolex® (cannabidiol (2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol)

Action mechanism:

cannabinol derivative/endocannabinoid modulator. 

Disease: Lennox-Gastaut syndrome

Therapeutic area: Rare diseases - CNS diseases - Neurological diseases

Country:

Trial details:

Latest news:

* On April 22, 2015, GW Pharmaceuticals announced new physician reports of clinical effect and safety associated with the Epidiolex® expanded access program. These data were presented by study authors at the American Academy of Neurology annual meeting in Washington DC.
Physician reports of clinical effect and safety data have been presented on 137 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 at least 12 weeks. These data are from eleven hospital sites in the United States and were generated under expanded access Investigational New Drug applications (INDs) authorized by the FDA. In addition, physician reports of safety data were presented on 213 patients (137 patients with 12 weeks treatment effect data plus additional patients still in their first 12 weeks of treatment or who withdrew from treatment). The expanded access program is comprised of clinical studies performed by individual physicians.
FDA authorized expanded access programs facilitate access to investigational drugs for treatment use for patients with a serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives. The patients included in the Epidiolex program had Dravet syndrome (18% of the total) and Lennox-Gastaut syndrome (LGS) (16% of the total), epilepsy types that can lead to intellectual disability and lifelong seizures, as well as 10 other types of severe epilepsy. Many of the 10 other types of epilepsy are extreme and rare, and several patients with these epilepsies have major congenital structural brain abnormalities.
The 137 patients were predominately children with an average age of 11 years. In all cases, Epidiolex was added to current anti-epileptic drug (AED) treatment regimes. On average, patients were taking approximately 3 other AEDs.

Clinical effect data - All patients: Data were presented on all 137 patients who had at least 12 weeks treatment. Treatment was open label. Of these 137 patients, 48 patients had also reached 24 weeks treatment at the time of data analysis. Information collected on all seizures (convulsive and non-convulsive) is reported for each patient. Data are presented showing the median reduction in seizure frequency and the proportion of patients achieving a response of 50% or greater compared to a 4-week baseline period.

	Week 4	Week 8	Week 12	Week 16	Week 24
Median reduction in seizure frequency	-40%	-48%	-54%	-51%	-45%
?50% responders	41%	49%	51%	52%	46%

At the end of 12 weeks, 9% of all patients were seizure-free.

Clinical Effect Data – Patients without Dravet syndrome
Data were made available on all 112 patients with diagnoses other than Dravet syndrome who had at least 12 weeks treatment. Of these 112 patients, 39 patients had also reached 24 weeks treatment at the time of data analysis. Information collected on all seizures (convulsive and non-convulsive) is reported for each patient. Data are presented showing the median reduction in seizure frequency and the proportion of patients achieving a response of 50% or greater compared to a 4-week baseline period.

 Clinical Effect Data – Dravet syndrome patients only: Data were presented on 25 patients with Dravet syndrome who had at least 12 weeks treatment data. Of these 25 patients, 9 patients had also reached 24 weeks treatment at the time of data analysis. Information collected on all seizures (convulsive and non-convulsive) is reported for each patient. Data are presented showing the median reduction in seizure frequency and the proportion of patients achieving a response of 50% or greater compared to a 4-week baseline period.

	Week 4	Week 8	Week 12	Week 16	Week 24
Median reduction in seizure frequency	-50%	-60%	-65%	-56%	-59%
?50% responders	52%	54%	56%	61%	67%

At the end of 12 weeks, 16% of Dravet syndrome patients were seizure-free.
Of the 25 patients with Dravet syndrome, 23 patients had convulsive seizures at baseline. At the end of 12 weeks, the median reduction in convulsive seizures in these patients was 53%2.
Clinical Effect Data – Drop (“atonic”) Seizures
Data were made available on 27 patients with drop seizures at baseline who had at least 12 weeks treatment, of which 11 patients had LGS2. Drop seizures are the types of seizures generally considered by FDA in assessing primary efficacy for LGS trials.
For all 27 patients with drop seizures, there was a 67% median reduction in the number of atonic seizures at the end of 12 weeks
For the 11 LGS patients with drop seizures, there was a 55% median reduction in the number of atonic seizures at the end of 12 weeks2
Safety Data: Safety data were made available on 213 patients (137 patients with 12 weeks treatment effect data plus 76 additional patients for whom 12 week treatment effect data are not yet available or who withdrew from treatment) and represents approximately 59 patient-years of exposure to Epidiolex.
The most common adverse events (occurring in 10% or more patients and resulting from all causes) were:
Somnolence - 21% of patients
Diarrhea – 17% of patients
Fatigue - 17% of patients
Decreased appetite – 16% of patients
Most adverse events were mild or moderate and transient
10 patients (5%) reported an adverse event leading to discontinuation, 3 of whom subsequently restarted treatment with Epidiolex
There were 14 withdrawals from treatment due to lack of clinical effect
Serious adverse events were reported in 52 patients. Of these, SAEs in 22 patients were deemed possibly related to treatment, including status epilepticus (10), diarrhea (3), weight loss (2), pneumonia (2), lethargy (1), and hepatotoxicity (1)
Serious adverse events include 2 deaths, neither of which were deemed related to Epidiolex by the independent investigators. One death was from SUDEP (sudden unexpected death in epilepsy) and one from respiratory failure due to aspiration.
There were no clinically significant changes in hematologic markers or renal function
Occasional increases in liver transaminases were noted, thought unlikely to be related to CBD by the independent investigators

GW Epidiolex Development Program – Dravet and LGS
GW’s initial focus is on conducting formal development programs for Epidiolex in the treatment of both Dravet syndrome and LGS. The Company has received from the FDA Orphan Drug Designations for Epidiolex for both Dravet syndrome and LGS, as well as Fast Track Designation for Dravet syndrome. GW has recently commenced two Phase 3 trials of Epidiolex in the treatment of Dravet syndrome. GW also expects to commence two Phase 3 trials in LGS in the second quarter of 2015.
Based on the findings in the expanded access program, GW has continued to explore options to commence clinical development of Epidiolex in an additional pediatric epilepsy indication. GW has now concluded that this additional target indication should be Tuberous Sclerosis Complex (TSC) and expects to commence clinical development in TSC later this year.
TSC is a genetic disorder that causes non-malignant tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. TSC results from a mutation in tumor suppression genes TSC1 or TSC2. TSC is estimated to affect approximately 50,000 patients in the U.S. The most common symptom of TSC is epilepsy, which occurs in 75-90% of patients, about 70% of whom experience seizure onset in their first year of life. Approximately 60% of TSC patients have treatment-resistant seizures. There are significant co-morbidities associated with TSC including cognitive impairment in 50%, autism spectrum disorders in up to 40% and neurobehavioral disorders in over 60% of individuals with TSC.
A number of patients with TSC have been treated with Epidiolex in the expanded access program. According to Geffrey AL et al in a poster presentation at the American Epilepsy Society annual meeting in December 2014, of 5 TSC patients treated with Epidiolex, 4 patients experienced a reduction in seizures of 97% (n=2), 77% (n=1) and 40% (n=1) at week 16 compared to a 4-week baseline period. All three patients with cognitive impairment experienced cognitive gains and one of the two subjects with behavioral problems showed improvements. Since this poster presentation, additional TSC patients have commenced treatment with Epidiolex in the expanded access program.

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