Now we know: the FDA delayed approval of Orexigen’s obesity drug Contrave by three months to allow time to finalise a yet further post-marketing commitment, including a new cardiovascular outcomes trial to satisfy a hurdle that could not, after all, be met by the ongoing Light study.
In any case, it is already clear that Contrave is not a blockbuster product and, together with Vivus and Arena, Orexigen is destined to remain a niche player. In Takeda it might have a decent partner, and Contrave could be the first European entrant, but this is now a fight over small advantages.
While yesterday’s US approval marks the end of a long and tortuous journey for Contrave, the focus is on the drug’s punitive label, which includes a black box warning of suicidal thoughts and behaviour, and neuropsychiatric reactions, and the requirement for six further post-marketing studies.
The main one of these is intended to exclude a 40% increase in risk of cardiovascular outcomes at the upper bound of its 95% confidence interval. Orexigen’s already begun Light trial was similar, and had delayed Contrave’s approval by two years (Orexigen sees Light at the end of the tunnel, November 25, 2013).
However, Light’s interim analysis had a less stringent goal: to rule out a doubling in risk of cardiovascular events at the upper confidence interval bound. On a call today Orexigen said relying on the final Light readout was no longer sufficient, since because of its design most future events would occur in patients not taking the drug.
Amending the Light study’s design was not an option because of risk of bias. Thus Orexigen is slapped with further expenses: continuing Light to its completion in 2018 will cost it up to $50m, and it is also obliged to pay the first $60m of the new commitment.
The new cardiovascular study could cost $150-200m, while the non-cardiovascular trials will come in at up to another $50m. After the $60m threshold is crossed Takeda will fund 75% of non-safety trials, while safety studies will be funded 50/50.
The Japanese group will pay Orexigen a $30m approval milestone plus $70m by Contrave’s launch, though this looks likely to be swallowed up by the increased study costs. Orexigen stock opened 10% off this morning.
There are other reasons for caution. There had been hopes that the Light data might have been cited on Contrave’s label as evidence that the product poses no increased risk of heart attack or other adverse cardiovascular events.
But Orexigen ruled this out, and the label spells out that “the effect of Contrave on cardiovascular morbidity and mortality has not been established”. It also states that safety and effectiveness of Contrave in combination has not been established. So much for the bull case that the drug will be boosted by future use with a DPP-IV or SGLT2 inhibitor.
At least it cannot now be said that the US FDA is apprehensive about approving obesity drugs, and yesterday’s nod bodes well for Novo Nordisk’s liraglutide, up before a US advisory panel today. And while Contrave’s efficacy is meagre – 4.1% placebo-adjusted weight loss over a year – it is better than Arena’s Eisai-partnered Belviq; Vivus’s Qnexa is more efficacious, but is unpartnered.
Two years after launch, Qsymia generated first-half revenue of $20.1m, while Eisai’s in-market Belviq sales were just $18.3m. Forecasts have come down, but Contrave’s 2020 sales expectations of $500m, according to EvaluatePharma consensus, now look like a wild overestimate.