Safety warnings will hold back new obesity treatment Contrave

Takeda and Orexigen have been given FDA clearance to market their obesity treatment Contrave – but sales of the drug will be curtailed by a long list of severe side-effect risks.

Contrave (naltrexone HCI and bupropion HCI) extended-release tablets have been approved as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related co-morbidity.

Orexigen's trial data based on around 4,500 patients, suggested up to 42 per cent of patients saw at least 5% reduction in their weight, in combination with diet and exercise routines. In contrast, only 17 per cent of patients on placebo achieved the same reduction.

The approval is long-awaited: the companies have been seeking approval for a number of years, the two-in-one drug combination having been rejected in 2011 because of concerns about its cardiovascular safety.

Contrave joins Vivus' Qsymia (phentermine/topiramate) and Arena/Eisai's Belviq (lorcaserin), but both of these drugs have produced underwhelming sales because of lingering doubts about their safety and efficacy.

It looks almost certain that Contrave will suffer a similar fate, as the FDA has insisted on it carrying a very long list of safety warnings. Chief among these is a warning of potential suicidal thoughts and behaviours and neuropsychiatric reactions.

In particular, the drug's label requires all patients being treated with antidepressants for any indication to be monitored and observed for clinical worsening, suicidality, and unusual changes in behaviour, especially during first months of a course of drug therapy or when doses are either increased or decreased.

The drug is also contraindicated in a long list of patients, including those with uncontrolled hypertension, seizure disorder, or current or prior diagnosis of anorexia nervosa or bulimia; in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; with use of other bupropion-containing products; for use with chronic opioids or opiate agonists (eg, methadone) and more.

Severe side-effects were also common in trials: around a third of patients experienced nausea, nearly 20% experienced constipation, with headache (17.6 per cent), vomiting (10.7 per cent), dizziness (9.9 per cent), insomnia (9.2 per cent), dry mouth (8.1 per cent), and diarrhoea (7.1 per cent) also frequently recorded.

Despite these drawbacks, some analysts believe the drug could reach peak sales of around $600 million, or up to $1.2 billion if Orexigen wins additional approval for use in treating diabetes.

"The FDA approval of Contrave is a significant milestone in Takeda's and Orexigen's commitment to leading innovation in medicine for patients and physicians dealing with chronic conditions and diseases, such as obesity," said Douglas Cole, president, Takeda Pharmaceuticals USA. "It's important that physicians and appropriate patients have options when discussing weight management, especially when you look at the prevalence of obesity in today's society. We're excited about the addition of Contrave to our cardiovascular and metabolic disease portfolio."

Takeda and Orexigen have agreed to several post-marketing requirements, including studies to assess the safety and efficacy of Contrave for weight management in obese paediatric patients. There will also be a new randomised double-blind, placebo-controlled study to evaluate the effects of long-term treatment with Contrave on the incidence of major adverse cardiovascular (CV) events in overweight and obese subjects with CV disease or multiple CV risk factors.

Meanwhile, another a rival obesity treatment from Novo Nordisk looks like it could be a more credible player in the field.

Novo Nordisk yesterday announced that its drug Saxenda had received a 14-1 vote in favour of approval from an FDA advisory committee for its approval in treating obesity. The drug is liraglutide, a once-daily human GLP-1 analogue which the company markets as a diabetes treatment as Victoza.