Bristol-Myers Squibb today may be regretting that it did not gamble more on hepatitis C three years ago. Its plan to launch Daklinza as an add-on to other marketed antivirals in the US have been set back significantly with an FDA complete response letter, potentially turning the NS5A inhibitor into even more of an also-ran in a quickly maturing space.
The molecule itself is by no means a complete loss, as it has secured European and Japanese approval and has achieved key readouts as part of three-drug combinations. But as Daklinza had been postulated as a partner to Gilead Sciences’ Sovaldi some time ago, and it must come as some disappointment that it may only begin to truly pay off as part of a third wave of hep C regimens that could launch in 2016 or later.
As complete response letters go this one appears relatively mild. Bristol-Myers’ original application for Daklinza proposed using it in combination with its protease inhibitor Sunvepra, a pairing that has earned Japanese approval. However, the latter agent was withdrawn from the US application late in the approval cycle.
As the application now specifies “other agents”, the FDA is seeking more data from those combinations. It was phase II results from Daklinza and Sovaldi three years ago that launched the latter into its coveted front-runner position, so persuasive data may not be hard to generate. Likewise, its performance with Sunvepra bodes well for a combination with Johnson & Johnson and Medivir’s marketed protease inhibitor Olysio – the two have completed phase II work.
Bristol-Myers did not specify timelines for resubmission nor what data it will provide to the regulator.
That Bristol-Myers Squibb has failed to reach the US market on a first cycle submission is just another example of the New York group’s hard luck in hep C. It had been a contender to acquire Sovaldi originator Pharmasset but likely balked at the $11bn price Gilead was willing to pay – its $2.5bn consolation prize, Inhibitex, turned out to be a dry hole.
When the pre-Gilead collaboration testing Sovaldi and Daklinza – generically, sofosbuvir and daclatasvir – generated such promising phase II data a few months later, Bristol-Myers was unable to persuade Gilead to stay on board, forcing it to turn to Sunvepra and a third agent, BMS-791325 (beclabuvir hydrochloride) as the cocktail of choice.
The Sunvepra-Daklinza combination has earned approval in Japan – beating Gilead’s follow-up Harvoni as the first all-oral, interferon- and ribavirin-free regimen – and Daklinza with other agents has been approved in Europe. Knocking Sunvepra off the US application was based on the fact that this specific combination was uniquely effective in the Japanese hep C population.
A fixed-dose triple combination that includes beclabuvir and Sunvepra, which Bristol-Myers calls DCV-TRIO, has generated positive data so far. The Unity-2 trial read out at the AASLD meeting earlier this month, achieving viral cure rates of 93% in never-treated genotype 1 patients and 87% in patients who have failed on other drugs. Slightly better cure rates were achieved when receiving a boost from the antiviral ribavirin.
Achieving cure rates of about 90% certainly makes DCV-TRIO a promising option, but it offers little differentiation from Gilead’s already approved Harvoni – apart from the potential to beat its $94,500 price, a tactic that companies such as AbbVie and Merck & Co may be forced to employ before Bristol-Myers can launch a Daklinza-based regimen.
As Daklinza showed clinical promise early in the hep C chase, it seems a shame that it has not been followed up by US regulatory success, a failing for which Bristol-Myers shares at least some of the blame. Patients and payers alike should benefit from the launch of new agents – a Daklinza delay strengthens only Gilead.