Orexigen to file obesity drug Contrave after positive Phase III data
This article was originally published in Scrip
Orexigen's lead candidate Contrave (naltrexone sustained-release/bupropion SR) has met the co-primary endpoints of three pivotal Phase III trials, COR-I, COR-II and COR-diabetes, for the treatment of obesity.
Upon the announcement, the San Diego-based firm's share price jumped by 26% to close at $6.97 on Nasdaq on July 20th.
The drug also exceeded the US FDA efficacy benchmark of a minimum placebo-adjusted weight loss of 5% of body weight, for obesity trials across two of the three studies.
Based on these positive results, and those from a previous Phase III trial (scripnews.com, January 19th, 2009), the company plans to file an NDA in the US in the first half of 2010.
An approval could make Contrave a potential blockbuster since obesity has become a serious worldwide health problem and the quest for effective obesity drugs has proved challenging. For instance, last year saw the failure of the cannabinoid CB1 class of anti-obesity drugs, which included Sanofi-Aventis's Acomplia (rimonabant) and Merck & Co's taranabant, due to safety concerns.
"The data are remarkably constant across the COR programme, giving us greater confidence that Contrave has the potential to help obese patients, even those with diabetes, to initiate and sustain weight loss and improve their health," said Dr Ken Fujioka, lead investigator of the trials and director of nutrition and metabolic research at Scripps Clinic in San Diego. "These results mark the beginning of an exciting new era in the treatment of the global obesity where drug therapies may play and increasingly important role."
Contrave is a formulation of two approved drugs that have been used separately in patients for more than 20 years: the opioid antagonist naltrexone which is used to treat alcohol and opioid dependencies and bupropion, approved for the treatment of depression and smoking cessation.
According to Orexigen, naltrexone combined with bupropion has a unique dual mechanism of action within the central nervous system. One is designed to control the balance of food intake and metabolism and another designed to control food preference, reward and cravings.
The three 56-week double-blind trials randomised obese patients to receive placebo or Contrave twice-daily with a four week titration period, in addition to a diet and exercise regimen.
In the diabetes study, patients were allowed to remain on stable doses of background diabetes therapy, which included insulin sensitisers, metformin, sulphonylureas, and DPP-4 inhibitors.
The co-primary endpoints for all three trials were the proportion of patients achieving at least 5% weight loss and the change in body weight compared with placebo at 56 weeks.
Secondary endpoints included measurements of cardio-metabolic risk, food cravings and eating control, as well as HbA1c in the COR-diabetes trial.
COR-I
COR-I evaluated Contrave32 (naltrexone SR 32mg/bupropion SR 360mg) and Contrave16 (naltrexone SR 16mg/ bupropion SR 360mg) versus placebo in 1,742 obese patients. At baseline, the patients had an average age of 44, 85% were female, and had an average weight of 100kg.
After 56 weeks, patients on Contrave32 had a mean weight loss of 8.1% of their body weight, the equivalent to 17.6lb), and patients receiving placebo had a mean weight loss of 1.8% of their body weight (4.1lb, p0.001).
The percentages of patients who experienced a weight loss of 10% or more of their body weight were 61.8% for those on Contrave32 and 23.1% for placebo (p<>
COR-II
COR-II compared Contrave32 with placebo in 1,496 obese patients with an average age of 44 years and average weight of 100kg.
After week 28, patients not achieving a 5% weight loss were re-randomised in a blinded fashion to assess whether increasing the dose to Contrave48 (naltrexone SR 48mg/bupropion SR 360mg) would result in an additional weight loss.
At the end of the trial, patients receiving Contrave experienced a weight loss equivalent to 8.2% of their body weight (17.5lb) and those on placebo had a weight loss equal to 1.5% of their body weight (3.4lb, p<0.001).>
75.8% of those receiving Contrave achieved a 10% or greater weight loss, versus 21.7% of those on placebo (p<>
There was no significant difference between the patients who were re-randomised to Contrave32 or Contrave48.
COR-diabetes
COR-diabetes compared Contrave32 with placebo in 505 obese patients with type 2 diabetes. Patients enrolled had an average age of 54, were 56% female, and had an average weight of 106kg.
Patients receiving Contrave32 lost an average of 5.9% of their body weight (13.5lb) and those on placebo lost an average of 2.2% (5.1lb, p<0.001). 53.1%="" of="" those="" receiving="" contrave32="" had="" a="" weight="" loss="" of="" greater="" than="" 10%="" of="" their="" body="" weight,="" compared="" with="" 24.0%="" on="" placebo=""><>
Patients on Contrave also experienced a placebo-adjusted reduction in HbA1c levels of approximately 0.5%.
"This magnitude of improvement in glycaemic control is significant," said Dr Dennis Kim, Orexigen's senior vice president of medical affairs and communications. "Some of the diabetes medications on the market today, produce HbA1c lowering effects in the range of 0.3% to 0.5%. A clinically meaningful improvement in A1c, coupled with significant weight loss represents an exciting additional area of potential research."
safety
Across the entire COR programme, seven serious adverse events were attributed to Contrave by investigators. They were cholecystitis (gallbladder inflammation), seizure, palpitations, paraesthesia and vertigo. Treatment with Contrave was not associated with increases in symptoms of depression or suicidal ideation, which had been seen with the failed cannabinoid CB1 class.
Nausea was the leading adverse event that resulted in patients discontinuing the trials.
At week 56, the mean blood pressure was generally unchanged from baseline in Contrave patients compared with placebo patients – who experienced a slight decrease of 2mg Hg).
The company said that this may be because bupropion is associated with a modest increase in blood pressure.
There was also an increase in pulse rate of approximately one beat per minute in Contrave patients compared with placebo patients, whose pulse was unchanged. According to the company, there were no meaningful treatment effects on ECGs or laboratory measures including liver function tests.
Across all trials, Contrave also improved waist circumference, fasting HDL cholesterol, fasting triglycerides, fasting insulin, fasting blood glucose, total body fat and total visceral fat.
Patient-reported quality of life outcomes also showed that Contrave assisted with controlling hunger, fullness, cravings, and general control of eating.
There are many other obesity candidates in development. They include Takeda's lipase inhibitor cetilistat (ATL-962) and Boehringer Ingelheim's angiotensin II 1 antagonist telmisartan, which are both in Phase III.
Additionally, the marketed GLP-1 analogue treatments for type 2 diabetes have demonstrated weight loss in clinical trials and Novo Nordisk's Victoza (liraglutide) is in a pivotal Phase III trial for obesity in diabetic patients which is due to be completed in 2011.