EMA green light for weight-loss product under fire from French and Irish regulators
This article was originally published in SRA
The decision by the European Medicines Agency's committee for evaluating human drugs (CHMP) to recommend the approval of Orexigen's weight loss combination product Mysimba (naltrexone/bupropion) is under fire.
French and Irish regulatory agency representatives voted against the product's recommended approval on safety and efficacy grounds at the December meeting of the CHMP; they have detailed their objections in a written statement1. The committee's decision has also been attacked by the French drug bulletin Prescrire, which says the product is a "dangerous" amphetamine-type drug and that the CHMP's positive opinion is "an unacceptable EMA recommendation that must be overturned"2.
The positive opinion is now with the European Commission, which will decide on whether to accept the EMA's recommendation and issue an EU-wide marketing authorization. Whether or not the French and Irish concerns will have any impact on the commission's decision remains to be seen. Following a positive opinion by the CHMP, the commission usually takes two or three months to reach a decision; it generally follows the CHMP's advice, but it is not legally bound to do so.
Mysimba was given the OK by the CHMP for use in treating obese or overweight adults with one or more weight-related complications, in addition to a reduced-calorie diet and physical activity.
Although the positive opinion still has to be confirmed by the commission, Mysimba appears to be succeeding where competitors have failed: Arena/Eisai's Belviq (lorcaserin) filing was withdrawn in 2013, and the CHMP has twice rejected Vivus' phentermine/topiramate combination Qsymia.
In issuing its recommendation, the CHMP said that the main safety concerns with Mysimba were gastrointestinal and CNS, and that there were also some longer-term cardiovascular uncertainties, although it added that interim results from an ongoing cardiovascular outcomes trial were "reassuring", and that a second study is planned to monitor the drug's longer-term CV safety.
Benefit-risk profile "unfavorable"
In a report on the outcome of the CHMP meeting, France's ANSM said that "France voted against this opinion, believing that the safety of the product has not been sufficiently established" and that it had filed a "minority statement" to this effect. It said the statement was also signed by Ireland's Health Products Regulatory Authority as both agencies considered the product's benefit-risk profile to be unfavorable.
It is unusual for regulatory agencies to publicize their objections to a CHMP opinion, but in this case the ANSM in particular seems to be sufficiently concerned to make it clear that France and Ireland have taken a divergent position from the other 26 EU member states.
ANSM said that it "considered Mysimba's benefit-risk profile to be negative since the CHMP began evaluating it", and gave the following reasons:
- Limited effects on weight loss (less than 5% compared with placebo).
- Uncertainties over maintenance of weight loss and risk of putting weight back on once treatment stops.
- No demonstration of beneficial effects on morbidities associated with overweight or obesity, above all in the absence of Phase III studies (one study is under way) on cardiovascular safety.
- Uncertainties over the neuropsychiatric risks – depression and suicide.
- Limited tolerance, with a large number of patients stopping treatment prematurely.
French regulators are particularly sensitive to safety issues surrounding anti-obesity drugs, not least because of the withdrawal of several other products, in particular Mediator, Servier's benfluorex-containing product. Mediator, which had been presented as an antidiabetic but was actually more akin to an anorectic drug, was finally pulled out in 2010 over safety concerns, amid evidence that ANSM's predecessor, AFSSAPS, had kept the product on the market despite growing evidence of its risks, a situation compounded by conflicts of interest and industry influence. The affair resulted in a wholesale restructuring of France's regulatory system.
"Dangerous drug"
Prescrire conducts its own benefit-risk evaluations of medicines and has frequently targeted anti-obesity medications.
Noting that bupropion used to be known as amfebutamone, Prescrire says that "amfebutamone is an amphetamine drug, as is amfepramone". It notes that in 2000, the EU marketing authorizations of "several appetite suppressants with a similar mechanism of action to that of amfepramone (clobenzorex, dexfenfluramine, fenfluramine, fenproporex, etc)" were withdrawn.
Prescrire also cites the 2009 EU withdrawal of sibutramine, "an appetite suppressant structurally related to amphetamines", because of "disproportionate and serious adverse drug reactions", as well as the 2010 withdrawal of Mediator.
In light of these precedents, Prescrire asks: "How is it possible the CHMP now takes an incongruent position on the fixed-dose weight-control combination naltrexone + amfebutamone (also known as bupropion) (Contrave/Mysimba)?"
Health authorities "should learn from past public health disasters", Prescrire says, adding that losing "a few kilograms" through drug therapy "cannot in itself justify exposing obese or simply overweight patients to a disproportionate risk of adverse drug reactions, especially since the weight lost is very often regained within months of discontinuing treatment". It urges those member states who voted against the drug at the CHMP meeting (ie France and Ireland) to "insist that patients' safety be defended", noting that they "still can and should require arbitration by the European Commission and convene a [pharmaceutical] Standing Committee meeting".
The naltrexone/bupropion combination is already marketed in the US as Orixegen/Takeda's Contrave following its approval in September last year, but here too safety concerns have been raised. The Food and Drug Administration has asked for a post-approval cardiovascular outcomes trial and for two efficacy, safety and clinical pharmacology studies in pediatric patients, while the product's labelling carries warnings about an increased risk of suicidal thoughts and behavior associated with the bupropion component.
References
- ANSM's report on CHMP decisions taken during December 2014 meeting, 29 December 2014, http://ansm.sante.fr/S-informer/Actualite/Sept-avis-favorables-pour-de-nouvelles-AMM-retour-sur-la-reunion-de-decembre-2014-du-CHMP-Point-d-Informationhttp://ansm.sante.fr/S-informer/Actualite/Sept-avis-favorables-pour-de-nouvelles-AMM-retour-sur-la-reunion-de-decembre-2014-du-CHMP-Point-d-Information
- Prescrire in English, 19 December 2014, http://english.prescrire.org/en/79/207/46302/4018/3303/SubReportDetails.aspx
The ANSM and Prescrire provided comment for this article by email.