Seeing yesterday’s headlines describing Eisal’s Belviq as the “holy grail” of obesity treatment some investors might be wondering why the originator, Arena Pharmaceuticals, washed its hands of the drug last year for just $23m.
The answer is, of course, that the UK national press was simply indulging in hyperbole on a slow news day. Still, Camellia-Timi, the Belviq study that caused such excitement at the European Society of Cardiology conference over the weekend, does point the way forward to a combination of Belviq with phentermine.
Many have long suspected that only such a combo could dial up efficacy sufficiently. Arena itself had floated the possibility way back in 2012, but faced with a cash crunch in the wake of underwhelming Belviq sales it saw no other option but to refocus on other assets (Arena says the magic combo word as reality hits Vivus, November 7, 2012).
As far as a combo goes, the spectre of Fen-Phen, the efficacious obesity cocktail that was withdrawn owing to cardiovascular side effects, still looms large.
This is why it was so important that Brigham and Women's Hospital’s Dr Erin Bohula, presenting the Camellia-Timi data at ESC on Sunday, was able to say: “This is the first time, in a rigorous trial, that we’ve been able to document safety.” Clearly, the finding also vindicates Eisai’s decision to fund this 12,000-patient trial.
Camellia-Timi’s key conclusion was that, at 3.3 years’ median follow-up, there was no significant difference in major adverse cardiovascular events between the 10mg US-approved dose of Belviq and placebo. Valvulopathy – the side effect that brought down Fen-Phen – was rare, seen in 30 Belviq versus 22 placebo recipients.
Most pivotal studies in obesity have sought to demonstrate an effect at 12 months, and long-term treatment is avoided for fear of adverse events. Indeed, Belviq’s label mandates discontinuation if 5% weight loss is not achieved by week 12; such efficacy is relatively unlikely, the label citing average 5.8% weight reduction at 52 weeks in patients who completed two trials.
Camellia-Timi mirrored this lamentable efficacy, showing that at one year patients lost just 2.8kg when adjusted for placebo. As such – the headlines notwithstanding – Dr Bohula called the data a “landmark” and a “step forward”, but specifically refused to call Belviq a holy grail when pressed on the point at Sunday’s press conference.
Whether non-inferiority on safety is enough seems to be a moot point; Novo Nordisk’s GLP1 agonist liraglutide has shown superiority on cardiovascular events, but only at diabetes dosing, and not at the higher dose of Saxenda, its anti-obesity incarnation, Dr Bohula stated.
The best she would say was that doctors and patients would now be more likely to use Belviq, and that with the study results Eisai now had data to show EU regulators, who have not approved the drug owing to lack of safety.
A safe Fen-Phen?
Still, it is important to bear in mind the precedent of Fen-Phen, which was brought down by the cardiovascular toxicity of its fenfluramine component.
Arena had for a long time billed Belviq, a 5-HT2C agonist, as a safe version of fenfluramine, which has broad 5-HT2 activity, arguing that valvulopathy was the result of agonism at the 2B receptor subtype. Backing for this thesis in a large, randomised trial is Camellia-Timi’s most important message.
The discussant of the data, Professor Peter Nilsson, from Lund University, had criticisms beyond lack of standalone efficacy, highlighting Camellia-Timi’s imbalance in hospitalisations due to severe hypoglycaemia, though with small numbers. “Safety is excellent, but we hope for more,” he cautioned.
The ultimate verdict was that of the doctors assembled at the ESC presentation. When asked whether they would consider more frequent medical weight loss treatment based on Camellia-Timi 41% said no, versus 26% who voted in the affirmative; the remainder said they needed more data.
This is hardly an endorsement of Belviq, but in running such a trial Eisai has made it clear that it is playing the long game. It will be years before Bel-Phen has a chance to reach the market, but with Camellia-Timi the foundation stone has been laid.