Safety trumps efficacy as FDA approves novel sleeping pill

The US FDA resolved its concerns about next-day somnolence resulting from Merck & Co’s suvorexant in a curious way: it approved the sleeping pill at doses that have not been shown to help patients fall asleep faster.

Now branded as Belsomra, the pill will be on the market at 5mg, 10mg, 15mg and 20mg. Only the last two of these were tested in Merck’s phase III programme, and both demonstrated inconsistent effects on helping patients fall asleep. But at least the FDA and Merck can take some solace in the low doses' relative safety, and the possibility of averting some automobile accidents.

A couple of firsts

Belsomra is the first novel sleeping product to receive approval in almost a decade and represents the first approval for an orexin inhibitor. Because of regulators’ concerns about sleep-driving and other complex sleep behaviours, it is increasingly hard to get insomnia products approved; the commercial pull is not there, as former big sellers like Sanofi’s Ambien and Eisai’s Lunesta have lost patent protection.

Merck’s pivotal programme saw Belsomra tested in doses as high as 40mg in the non-elderly. The FDA was not satisfied with the safety at that dosage, and took the position that the pill should only be approved at the lowest effective dose (Suvorexant gets adcom backing, the yes that means maybe, May 23, 2013). The pivotal programme tested a low dose of 20mg in the non-elderly and 15mg in the elderly.

This is where efficacy can be called into question. Although it scored on other measures, throughout the three-month clinical programme Belsomra’s 15/20mg dose showed “inconsistent improvements on sleep onset endpoints”, according to the FDA’s assessment before the May 2013 FDA advisory committee meeting.

At that meeting, at which Belsomra received a 13-3 recommendation, FDA staff made the case to its advisers that dose-response and exposure-response evaluations of phase III data did not suggest that lower doses would be ineffective. The lower doses, it argued, could improve next-day “hangover” effects and other complex sleep behaviours.

The agency appears to have followed through on that assertion – albeit 15 months later – by approving the low doses.

Faded star

Belsomra was once a star of a struggling Merck pipeline, but has faded from significance as the New Jersey-based group has seen its immuno-oncology project pembrolizumab and hepatitis C combination rise to prominence.

It is difficult to see how Belsomra competes in this increasingly genericised space. With likely cautions against next-day driving it might be hard to promote it as a safer alternative, and its efficacy at lower doses has not been established in a large trial.

Analysts have made a similar judgement, consensus for sales in 2018 has more than halved over the last 12 months to $259m, according to EvaluatePharma. The 2020 forecast stands at $349m.

Now that it has approval, Merck needs to figure out its sales pitch. Whether it is worth a big effort given the modest sales forecasts is an open question.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter

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