AstraZeneca spent four years and tested more than 20,000 patients trying to prove that the floundering cardiovascular pill Brilinta ought to be used long term after a heart attack. Those efforts have come to naught.
Readout of the Pegasus trial indicates that the risk of bleeding is too high to support the dual therapy of Brilinta with aspirin beyond the 12-month limit now recommended under medical guidelines. If Astra was expecting the anti-thrombotic pill to help lift sales of its currently marketed products to the heroic $45bn figure it forecast 10 months ago this result has dashed those hopes (Don’t blame Soriot, he’s just doing his job, May 7, 2014).
Pegasus compared two doses of Brilinta plus aspirin with aspirin plus placebo over a median treatment duration of 33 months in post-myocardial infarction patients, with the hope of detecting a reduction in the rate of cardiovascular death or other events. On safety, the study was to determine whether the pill caused an unacceptably high bleeding rate.
A detailed three-year analysis was presented at the American College of Cardiology meeting in San Diego on Saturday and simultaneously published in the New England Journal of Medicine. This analysis showed that efficacy and safety were largely a wash: in the 90mg twice-daily Brilinta arm 7.85% experienced a major cardiovascular event, in the 60mg twice-daily arm 7.77%, and in the placebo arm 9.04% (p=0.008 vs 90mg and p=0.004 vs 60mg).
Major bleeding events occurred in 2.6% of the 90mg patients and 2.3% of the 60mg patients, vs 1.06% for placebo patients (p<0.001 for each dose). There was no heightened risk of fatal bleeding, however.
Viewed more broadly, the investigators of the trial calculated that, for every 10,000 patients treated with the 90mg dose, 40 cardiovascular events would be averted and 41 bleeding events would be caused; at 60mg a more benign 42 cardiovascular events would be prevented and 31 bleeding occurrences caused.
The Brilinta label recommends a 90mg dose for immediate post-MI treatment, so the data allow some leeway for long-term treatment at a lower dose. However, Dr John Kearney, a University of Massachusetts cardiologist who commented in a NEJM editorial, describes the 60mg data as “close to an even proposition” between risk and benefit.
Leerink analyst Seamus Fernandez came to a similar conclusion after speaking with a cardiologist, writing yesterday that even the benefits of the 60mg dose were “not compelling enough”.
Proving its worth
Brilinta has hardly wowed investors and has underperformed compared with at-launch expectations of hitting blockbuster sales numbers by 2014; instead, they were less than half that, at $476m, although by 2020 the EvaluatePharma consensus forecasts $1.8bn in sales.
The UK group has is throwing a huge amount of money at an 80,000 post-marketing clinical programme attempting to show the drug's worth in conditions ranging from peripheral artery disease to atherosclerosis in diabetes (AstraZeneca summons the gods in efforts to boost Brilinta, November 15, 2013).
Astra got a win with Atlantic, a trial using Brilinta as an in-ambulance pre-treatment for MI patients heading for angioplasty, when it was released at ESC last year. However, given that this confirmed what is becoming standard practice, it offered little commercial benefit.
The biggest score could come from the 17,000-patient Themis trial, which tests the hypothesis that Brilinta could prevent cardiovascular events in type 2 diabetics with documented coronary artery disease, but without a history of MI.
That study is not likely to read out until 2017 – and the disappointing data so far do not necessarily give much cause for optimism here. On the other hand, maybe Astra reasons that it has nothing to lose – besides money, of course – by shooting for the stars, perhaps in the hopes that its own $3.5bn peak sales forecast could come true with a Themis triumph.
The data so far have revealed that Brilinta has a modest place in the cardiologists’ armoury. It will take better results than this to change the less than stellar outlook for this blood-thinner.
|Pegasus||vs placebo on an aspirin background in post-MI patients||NCT01225562|