Clinical Trials

Date: 2015-10-25

Type of information: Results

phase: 3

Announcement: results

Company: GW Pharmaceuticals (UK) Otsuka Pharmaceuticals (Japan)

Product: Sativex® (Delta-9-Tetrahydro-cannabinol (THC) and Cannabidiol (CBD)

Action mechanism: cannabinol derivative/endocannabinoid modulator. Sativex® is an endocannabinoid modulator made of two actives - THC (delta-9-tetrahydrocannabinol) and CBD (cannabidiol). As part of the human endocannabinoid system (ECS), cannabinoid receptors, CB1 and CB2 receptors are found predominantly at nerve terminals where they have a role in retrograde regulation of synaptic function. THC acts as a partial agonist at both CB1 and CB2 receptors, mimicking the effects of the endocannabinoids, which may modulate the effects of neurotransmitters (e.g. reduce effects of excitatory neurotransmitters such as glutamate).

Disease: pain in patients with advanced cancer

Therapeutic area: Cancer - Oncology - CNS diseases

Country:

Trial details: Two pivotal 380 patient Phase III cancer pain studies have already been intiated. Both of them are proceeding on track and are expected to complete recruitment around the end of 2013. The third Phase III trial differs in design from the first two studies, employing an “enriched study design” akin to that which was successfully employed in the multiple sclerosis spasticity trials programme. The study involves exposing patients to Sativex®in a single blind phase of two weeks duration (“Phase A”), following which responders will be randomised either to stay on Sativex®or switch to placebo in a double blind phase for a five week treatment period (“Phase B”). The primary efficacy analysis will be the mean change from baseline in Phase B as measured using a 0-10 Numeric Rating Scale (NRS). The study will aim to recruit 540 patients into Phase A and target 216 patients to enter Phase B.  

Latest news:

• • On October 27,2015, GW Pharmaceuticals and Otsuka Pharmaceutical Development & Commercialization reported top-line results from the remaining two Phase 3 trials for the investigational product Sativex® in the treatment of pain in patients with advanced cancer who experience inadequate analgesia during optimized chronic opioid therapy. Consistent with the previously reported Phase 3 trial, Sativex did not meet the primary endpoint in these trials. However, a pre-specified pooled analysis of patients across the two Phase 3 trials which involved clinical sites in the U.S. showed a statistically significant improvement for Sativex® compared with placebo (p=0.024), with several secondary efficacy endpoints exhibiting p-values of less than 0.05. GW and Otsuka have submitted a request to meet with the FDA to discuss the clinical relevance of these data and to determine potential paths forward.
• Trial2 Efficacy: This randomized, double-blind, placebo-controlled, parallel-group study was identical in design to the previously reported Phase 3 trial. The trial recruited a total of 397 patients at clinical sites in the U.S., Mexico and Europe. Patients received Sativex® or placebo as adjunctive treatment to optimized opioid therapy and remained on stable doses of their background opioid therapy during the study. The primary efficacy measure of this study was a patient assessment of pain using a 0-to-10 Numeric Rating Scale (NRS) which was analysed using percent improvement from baseline as the primary analysis. In addition, improvement was also analysed using a cumulative-proportion-of-responders analysis, which analyses the full range of responses achieved across the entire patient population within a trial.
• In this trial, the primary endpoint was in favour of Sativex and approached statistical significance for the intention-to-treat (ITT) population (p=0.085). The secondary endpoints followed the pattern of the primary endpoint with a significant reduction seen in sleep disruption (p=0.027) and a number of other endpoints approaching statistical significance. U.S. Analyses In this study, the U.S. was the largest single recruiting country, with patients from the U.S. representing 30 percent of the overall trial population. The efficacy data from U.S. sites alone showed more positive trends than those in non-U.S. sites, which is consistent with data from the first Phase 3 trial and the Phase 2b trial. In pre-specified pooled analyses of both this trial and the previously reported Phase 3 trial, which had an identical design, patients at clinical sites in the U.S. (n=248) demonstrated a statistically significant result for the primary endpoint (p=0.024) as well as a number of secondary endpoints including subject global impression of change (p=0.0004) and physician global impression of change (p<0.0001). Trial 3 Efficacy: A third study, which was conducted entirely outside the U.S. and which used a different clinical design, failed to show separation from placebo on the primary endpoint. Safety The safety profile of Sativex in the clinical development program in treatment of pain in patients with advanced cancer who experience inadequate analgesia during optimized chronic opioid therapy was consistent with the known effects of Sativex and with the clinical profile of this specific patient population. The only adverse event (apart from progression of the underlying cancer) reported at greater than 10 percent for the Sativex population was nausea (15.6% Sativex vs 10.6% placebo in Trial 2). All three Sativex Phase 3 studies were carried out by GW and Otsuka as part of the development program aimed at securing regulatory approval for Sativex in cancer pain.
• • On January 8, 2015, GW Pharmaceuticals and Otsuka Pharmaceutical Development & Commercialization reported the top-line results from the first of three Phase 3 trials for the investigational product Sativex® in the treatment of pain in patients with advanced cancer who experience inadequate analgesia during optimized chronic opioid therapy. In this first trial, Sativex® (as adjunctive treatment to optimized chronic opioid therapy) did not meet the primary endpoint of demonstrating a statistically significant difference from placebo. GW Pharmaceuticals looks forward to results from the two further studies later this year. If positive, these two trials may allow the submission of a New Drug Application with the FDA. Efficacy: The primary efficacy measure of the study was a patient assessment of pain using a 0-to-10 Numeric Rating Scale (NRS) which was analysed using percent improvement from baseline as the primary analysis. In addition, improvement was also analysed using a cumulative proportion of responders analysis (CPRA), which analyses the full range of responses achieved across the entire patient population within a trial. In this trial, these analyses did not show a statistically significant difference between Sativex and placebo. The secondary endpoints followed the pattern of the primary endpoint. In this study, the United States was the largest single recruiting country. Although not statistically significant, the efficacy data from U.S. sites showed more positive trends than those in non-U.S. sites. This is consistent with data from the Phase 2b trial.
• Safety: The safety profile of Sativex in this Phase 3 trial was consistent with previous studies in this patient population. Overall, Sativex was well tolerated. The only adverse events reported at greater than 10% for the Sativex population were neoplasm progression (16% on Sativex vs 18% on placebo) and somnolence (12% on Sativex vs 4% on placebo). The other most frequently reported adverse event on Sativex was dizziness (8% on Sativex vs 5% on placebo). Otherwise, there was little difference in the adverse event pattern between Sativex and placebo. There were 38 (19%) withdrawals due to adverse events on Sativex compared with 29 (15%) on placebo. This randomized double-blind placebo-controlled parallel-group study recruited a total of 399 patients at clinical sites in the U.S., Mexico and Europe. This trial evaluated Sativex at a dose range of 3-to-10 sprays per day over a 5-week treatment period with an additional 5-to-14 day stabilization period at the beginning of the trial and a one?week follow?up at the end of the trial. Patients received the active investigational agent or placebo as add-on treatment to optimized opioid therapy and remained on stable doses of their background opioid therapy during the study. Following completion of the randomized phase, all patients were eligible to enter a long?term extension trial. This study is the first of three Phase 3 trials carried out by GW and Otsuka as part of the development program aimed at securing regulatory approval for Sativex in cancer pain from the FDA and other regulatory authorities around the world. A second Phase 3 pivotal trial, identical to the first, is expected to report top line results in the second quarter of 2015. GW and Otsuka are also in the process of conducting a third Phase 3 trial, which is expected to enroll approximately 540 patients and designed to provide additional information on the effects of Sativex in treating opioid-resistant cancer pain. The third Phase 3 trial differs in design from the first two trials, employing a two?part “enriched trial design” akin to that which was successfully employed in the Sativex MS spasticity trials program in Europe. The results of this third trial are expected towards the end of 2015. GW will continue to be the holder of the IND until the filing of a New Drug Application, which will be in Otsuka’s name.
• • On May 22, 2012, GW Pharmaceuticals has announced the initiation of a third Phase III Sativex®clinical trial in the treatment of pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy.
• GW’s cancer pain clinical programme is being wholly funded by Otsuka Pharmaceutical Co. Ltd, which has licensed the US commercialisation rights to this product. The trials are designed to obtain approval in this indication from the FDA in the US, and these data will also be used by GW for future regulatory applications in this indication in Europe and around the world.
• GW has previously started two pivotal 380 patient Phase III cancer pain studies, both of which are proceeding on track and are expected to complete recruitment around the end of 2013. Regulatory filings are intended to be made upon completion of these two studies. This newly commenced third Phase III trial is a supportive study intended to provide, as needed, supplementary data to that generated in the first two studies.
• Prior to commencing the Phase III programme, GW completed two Phase II studies with positive results including over 500 patients in total. The most recent Phase IIb study was recently published in the Journal of Pain, the official journal of the American Pain Society (Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial. The Journal of Pain Volume 13, Issue 5 , Pages 438-449, May 2012)

Is general: Yes