ERS – Ambition surprises and lends Letairis a hand

Actelion may have the products in the pulmonary arterial hypertension space widely viewed as best in class, but Gilead Sciences and GlaxoSmithKline have counterpunched with a combination that could help defend some market share.

Data released at the European Respiratory Society meeting in Munich showed that the combination of Letairis with United Therapeutics’ Adcirca can delay hospitalisation. This finding from the Ambition trial could help the two companies make a persuasive case to payers of the value of taking the two pills together, an issue that will only intensify competition for Actelion once both lose patent protection in the next three years.

Easy-to-beat low expectations

There were low expectations for Ambition heading into the conference, so the disclosure that Letairis-Adcirca was able to delay time to clinical failure – defined as death, hospitalisation for worsening disease, disease progression or unsatisfactory clinical response – could only be defined as a win for Gilead and Glaxo (Actelion’s Opsumit braces for ambitious one-two punch, August 28, 2014).

Patients were randomised into arms taking the combination or each agent as a monotherapy. Patients taking the combination were half as likely to have failed clinically as patients in a pooled group from the other two arms. The combination patient group also showed significant improvements against each arm in an individual comparison on the primary endpoint.

The effect on the primary endpoint was driven by a 63% reduction in hospitalisation. Letairis-Adcirca did not delay disease progression; the 500-patient trial was not big enough to show any mortality benefit. Actelion’s Opsumit is indicated to delay disease progression; the FDA did not sanction a specific claim to improve morbidity or mortality on its label, and Actelion has yet to reveal how follow-up agent selexipag has performed on survival endpoints (Selexipag hit puts Actelion back on the buyout radar, June 1, 2014).

Analysts wrote that while the morbidity-mortality endpoint from Opsumit’s pivotal Seraphin trial is regarded as a very clinically significant endpoint, Ambition’s clinical failure measure – which it emphatically achieved – is in reality also important.

Six to nine months

This tag ought to well serve Letairis, which Glaxo markets ex-US as Volibris. In the US, many payers have put Opsumit and Letairis, both endothelin receptor antagonists, on tier 3 or higher, requiring the highest levels of patient cost-sharing.

However, even without the Ambition data some were requiring failure on Letairis, an older drug, before moving to Opsumit. Others were requiring failure on at least one other endothelin receptor antagonist, a class of drug that includes Actelion’s Tracleer, which loses patent protection next year.

UBS analysts wrote that the hospitalisation benefit is important clinically and economically, justifying an increased trend toward “step therapy” with Letairis first line. This could typically delay use of Opsumit by six to nine months, following disease progression, wrote Guillaume van Renterghem, who covers Actelion for UBS.

Both Letairis and Adcirca lose patent protection in 2017, an event that should see them drop down to the cheapest tier of drug coverage. It will be fortunate for payers that the combination will be proven and clinicians accustomed to it when that event happens.

Actelion’s response as that date approaches should be interesting to watch.

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

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