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Background Analysis: US FDA Advisory Committee to Review Epidiolex by GW Pharmaceuticals for the Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome and Dravet Syndrome – APR 19, 2018 (PCNS)
The US FDA has scheduled a half-day meeting of the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) for Thursday, April 19, 2018 to discuss a new drug application (NDA) for cannabidiol oral solution, sponsored by GW Pharmaceuticals (GW), for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years of age and older.
Description of Indication – Lennox-Gastaut syndrome
The onset of Lennox-Gastaut syndrome (LGS), which is a rare disease, typically occurs between ages of 3 to 5 years and can be caused by a number of conditions, including brain malformations, severe head injuries, central nervous system (CNS) infections, and genetic neuro-degenerative or metabolic conditions. In up to 30 percent of patients, no cause can be found. Patients with LGS commonly have multiple seizure types including drop and convulsive seizures, which frequently lead to falls and injuries, and non-convulsive seizures. Resistance to anti-epileptic drugs (AEDs) is common in patients with LGS. Most children with LGS experience some degree of intellectual impairment, as well as developmental delays and aberrant behaviors.
Description of Indication – Dravet syndrome
Dravet syndrome (DS) is a rare and severe infantile-onset and highly treatment-resistant epileptic encephalopathy frequently associated with genetic mutations in the SCN1A sodium channels. Onset of DS occurs typically during the first year of life in previously healthy and developmentally normal infants. Initial seizures are often body temperature related, severe, and long-lasting. Over time, patients with DS often develop multiple types of seizures, including tonic-clonic, myoclonic, and atypical absences and are prone to bouts of prolonged seizures including status epilepticus, which can be life-threatening. Risk of premature death including SUDEP (sudden unexpected death in epilepsy) is elevated in patients with DS. Additionally, the majority of those affected with DS will develop moderate to severe intellectual and development disabilities and require lifelong supervision and care.
Description of Product
Cannabidiol (CBD) is a non-psychoactive component of the cannabis plant. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors.
Epidiolex is formulated for administration as an oral solution that contains 100 mg/mL cannabidiol in sesame oil with anhydrous ethanol with added sweetener [sucralose] and strawberry flavoring.
Clinical Trials of Proposed Indication
In addition to the pivotal efficacy data, which are summarized further below, GW says their NDA provided the FDA with data from ten Phase 1 and Phase 2 studies, as well as safety data in more than 1,800 patients from both the expanded access program and pivotal programs, including more than 450 patients with one year or more of Epidiolex continuous exposure. The following results are presented based on information provided by GW in their press releases. More detailed results of the data provided in the NDA will be presented in FDA and Company briefing materials that the FDA will post ahead of the meeting. These data will be summarized on the day they are posted in our subsequent report, the Briefing Summary.
In one study (ClinicalTrials.Gov ID: NCT02091375) of patients with DS, Epidiolex achieved the primary endpoint of a significant reduction in convulsive seizures assessed over the entire treatment period compared with placebo (p=0.01). The study randomized 120 patients into two arms, Epidiolex 20mg/kg/day (n=61) and placebo (n=59). Epidiolex or placebo was added to current AED treatment regimens. On average, patients were taking approximately 3 AEDs, having previously tried and failed an average of more than 4 other AEDs. The average age of trial participants was 10 years, and 30 percent of patients were less than 6 years of age. The median baseline convulsive seizure frequency per month was 13.
The primary efficacy endpoint was a comparison between Epidiolex and placebo measuring the percentage change in the monthly frequency of convulsive seizures during the 14-week treatment period compared with the 4-week baseline observation period. In this study, patients taking Epidiolex achieved a median reduction in monthly convulsive seizures of 39 percent compared with a reduction on placebo of 13 percent, which was highly statistically significant (p=0.01). A series of sensitivity analyses of the primary endpoint confirmed the robustness of this result. The difference between Epidiolex and placebo emerged during the first month of treatment and was sustained during the entire treatment period.
Results from secondary efficacy endpoints reinforced the overall effectiveness observed with Epidiolex.
Epidiolex was generally well-tolerated. The most common adverse events (occurring in greater than ten percent of Epidiolex-treated patients) were: somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection and convulsion. Of those patients on Epidiolex that reported an adverse event (AE), 84 percent reported it to be mild or moderate. Ten patients on Epidiolex experienced a serious adverse event (SAE) compared with three patients on placebo. Eight patients on Epidiolex discontinued treatment due to adverse events compared with one patient on placebo.
GW is also enrolling a second trial in patients with DS (ClinicalTrials.Gov ID: NCT02224573) that plans to enroll 680 patients. This trial started in June 2015 and is estimated to complete in June 2019.
One study (ClinicalTrials.Gov ID: NCT02224690) of patients with LGS randomized 171 patients (86 to CBD; 85 to placebo) ages two to 55 years (average age 15), with LGS whose seizures were not controlled by their current AED regimen, to receive either Epidiolex (20mg/kg/day) or placebo, in addition to existing treatment. Patients were taking approximately three AEDs, having previously tried and discontinued an average of six other AEDs. At baseline, patients had a median frequency of 74 drop seizures per month (drop seizures were defined as atonic, tonic, or tonic-clonic 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).
Over the 14-week treatment period (two-week dose escalation period followed by 12 weeks of maintenance), patients taking Epidiolex had a significantly greater median reduction in drop seizures compared to placebo (44 percent vs 22 percent; p=0.0135), the study's primary endpoint. Sensitivity analyses confirmed that the treatment effect of CBD was established during the first month of treatment and was sustained over the entire treatment period.
Results from key secondary endpoints showed that significantly more patients on Epidiolex experienced a 50 percent or greater reduction in drop seizures compared to placebo (44 percent vs 24 percent; p=0.0043) and total seizure frequency was significantly reduced with Epidiolex compared to placebo (median percent reduction of 41 percent vs 14 percent; p=0.0005). CBD patients/caregivers were significantly more likely to report an improvement in overall condition with Epidiolex than placebo (58 percent vs 34 percent; OR 2.54, 95% CI 1.5-4; p=0.0012) based on the Subject/Caregiver Global Impression of Change (S/CGIC) scale.
Epidiolex was generally well-tolerated in the trial. The most common AEs (>10 percent) were diarrhea, somnolence, pyrexia, decreased appetite and vomiting. Overall, 86 percent of patients taking Epidiolex and 69 percent of patients taking placebo experienced an AE, and most were mild or moderate. Of those patients who experienced AEs, the events resolved by the end of the trial for 61 percent of Epidiolex patients and 64 percent of placebo patients.
Twenty patients on Epidiolex experienced serious AEs, including one fatal case of acute respiratory distress syndrome (considered unrelated by the Investigator), compared with four patients with serious AEs on placebo. Twelve patients taking Epidiolex discontinued treatment due to AEs, compared with one patient taking placebo.
In a second study (ClinicalTrials.Gov ID: NCT02224560) in patients with LGS (N=225), the drug was added to the patient’s current treatment. GW reports that this trial achieved the primary endpoint for both dose levels with high statistical significance. During the treatment period, patients taking Epidiolex 20mg/kg/day achieved a median reduction in monthly drop seizures of 42 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0047), and patients taking Epidiolex 10mg/kg/day achieved a median reduction in monthly drop seizures of 37 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0016).
In this trial, patients aged 2-55 years with a confirmed diagnosis of drug-resistant LGS currently uncontrolled on one or more concomitant AEDs were eligible to participate. The trial randomized 225 patients into three arms, where Epidiolex 20mg/kg/day (n=76), Epidiolex 10mg/kg/day (n=73), or placebo (n=76) was added to current AED treatment. On average, patients were taking approximately three AEDs, having previously tried and discontinued an average of seven other AEDs. The average age of trial participants was 16 years (30 percent were 18 years or older). The median drop seizure frequency over the 4 week baseline period was 85.
The primary efficacy endpoint of this trial was a comparison between Epidiolex and placebo in the percentage change in the monthly frequency of drop seizures during the 14-week treatment period (two week dose escalation period followed by 12 weeks of maintenance) compared to the 4-week baseline period before randomization. Drop seizures were defined as atonic, tonic, or tonic-clonic 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 treatment period, patients taking Epidiolex 20mg/kg/day achieved a median reduction in monthly drop seizures of 42 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0047), and patients taking Epidiolex 10mg/kg/day achieved a median reduction in monthly drop seizures of 37 percent compared with a reduction of 17 percent in patients taking placebo (p=0.0016).
A series of sensitivity analyses of the primary endpoint for both dose groups confirmed the robustness of these results. In both dose groups, the difference between Epidiolex and placebo emerged during the first month of treatment and was sustained during the entire treatment period. Results from secondary efficacy endpoints in both dose groups reinforced the overall effectiveness observed with Epidiolex.
Epidiolex was generally -well tolerated. The pattern of AEs was consistent with the patterns reported in the previous two Phase 3 studies. One patient on 10mg/kg Epidiolex discontinued treatment due to an AE compared with six patients on 20mg/kg and one patient on placebo.
Of the 84 percent of 10mg/kg patients who experienced an adverse event, 89 percent of them deemed it to be mild or moderate. Of the 94 percent of 20mg/kg patients who experienced an adverse event, 88 percent of them reported it to be mild or moderate. 72 percent of patients on placebo experienced an AE.
The most common AEs (occurring in greater than 10 percent of Epidiolex-treated patients) in the 10mg/kg group were: somnolence, decreased appetite, upper respiratory infection, diarrhea, and status epilepticus. None of the cases of status epilepticus in the 10mg/kg group was deemed treatment-related. The most common AEs (occurring in greater than 10 percent of Epidiolex-treated patients) in the 20mg/kg group were: somnolence, decreased appetite, diarrhea, upper respiratory infection, pyrexia, vomiting, and nasopharyngitis. Thirteen patients on Epidiolex 10mg/kg experienced an SAE-(two of which were deemed treatment related) compared with thirteen patients on 20mg/kg (five of which were deemed treatment-related), and eight patients on placebo (none of which were deemed treatment-related).
There were no deaths in this trial.
Of the patients who completed this trial, 99 percent have opted to continue into an open-label extension trial.
US Regulatory Background
June 27, 2018 – PDUFA date
October 30, 2017 – GW and its US subsidiary Greenwich Biosciences announced they had completed their rolling NDA (NDA 210365) for Epidiolex
Orphan Drug for both indications/Fast Track for DS
Ex-US Regulatory Background
December 29, 2017 – Marketing Authorization Application filing date to the European Medicines Association (EMA) for LG and DS
Orphan Drug for both indications (EMA)
Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.
Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.
METADATA: Sponsor: GW Pharmaceuticals Drug Name: cannabidiol oral solution Drug Class: cannabinoids Indication: seizures associated with Lennox-Gastaut syndrome or Dravet syndrome
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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.