The big medical conferences continue in full swing next week with the American Heart Association’s annual meeting. The huge meeting promises interesting research on new and existing cardiac therapies, with the new classes of oral blood thinners gradually reaching the market likely to receive much attention.
Fresh from approval in the US in the all important stroke prevention indication, data on Bayer’s Xarelto in patients with acute coronary syndromes will be particularly interesting considering the failure of competing agents in this tough setting – the first presentation of Merck’s failed trial of voraxapar will demonstrate the challenges. Other highlights include the full Saturn data, AstraZeneca’s high risk Crestor-versus-Lipitor gamble and studies of drugs seeking to raise levels of HDL or good cholesterol, including Eli Lilly’s phase II CETP inhibitor candidate, evacetrapib.
Stopped early after the drug was linked to intracranial haemorrhage in patients with a history of stroke, the doomed Tracer trial conducted with Merck’s vorapaxar is still likely to attract much attention. A novel agent and the most advanced of its class, vorapaxar or SCH 530348 works by blocking the PAR-1 receptor, the site at which thrombin binds to a platelet, inhibiting the thrombotic process.
The seeming unacceptable risk profile of the drug looks likely to spell its end, a big blow for Merck which is struggling with a lacklustre pipeline. The drug represented one of its biggest hopes, acquired with the $41bn acquisition of Schering-Plough in 2009 (Hopes fading for Merck's anticoagulant, January 14, 2011).
A safety monitoring board halted the 13,000 Tracer trial in January, but the study had already accumulated the predefined number of primary and secondary endpoints – the former being time to first occurrence of cardiovascular event. Tracer was conducted in patients with acute coronary sundrome, to see if adding vorapaxar to standard of care – aspirin and Plavix – could prevent more heart attacks and strokes.
Due to be presented on Sunday, the first look at detailed data from this trial will be of interest, particularly considering another huge study is continuing. In a so-called secondary prevention setting, TRA-2P TIMI 50 will examine 20,000 patients with a history of atherosclerosis to see if vorapaxar can prevent more heart attacks and strokes. Data are likely to emerge next year; following the safety finding in Tracer patients with a history of stroke have now been excluded, which Merck estimates represents about a quarter of ACS patients.
Many will be looking for indications at the conference to see if there is any likely path forward for this drug.
Following the Tracer data and also attracting interest in the acute coronary syndrome setting will be results from the Atlas study conducted with Xarelto, seemingly the first factor Xa inhibitor to succeed in these patients.
Rival Eliquis, widely viewed as holding the most potential in stroke prevention in atrial fibrillation patients, failed in the ACS setting last year – a trial called Appraise-2 was stopped early following the finding of higher bleeding risk.
Brief top line results from Atlas released by Bayer at the end of September revealed only that deaths and cardiovascular events had been significantly reduced – the study’s primary endpoint – alongside significantly increased bleeding.
Balancing the risk of bleeding with a reduction of cardiovascular events is a precise art with all blood thinning agents, new and old. This is particularly true in patients with acute coronary syndrome – who have suffered a stroke or heart attack - and who will be already on several other blood thinners such as aspirin and Plavix.
This is why so many drugs have failed in this setting and as such Xarelto’s performance will be interesting, in particular whether any subgroups seemed to benefit more. Should the drug look approvable in ACS it could gain an advantage over rivals Eliquis and Pradaxa, neither of which have generated positive data in this setting.
Eliquis, meanwhile, will feature mainly at the conference in results from the Adopt trial, conducted in patients classed as "medically ill". Prior failure for Xarelto in these acutely ill patients has likely prepared Bristol-Myers Squibb and Pfizer for disappointment (Xarelto misses on Magellan, April 6, 2011). The very ill nature and heterogeneity of the population in the Adopt trial – patients must be hospitalised for conditions ranging from congestive heart failure to inflammatory bowel disease – will make proving a benefit over Lovenox a big ask in preventing venous thromboembolisms and VTE related deaths.
Magellan had mixed results – Xarelto was equal to Lovenox at 10 days and superior at 35 days at preventing clots – but caused significantly more bleeding events, and thus could not demonstrate a clinical benefit. Success for Eliquis – like Xarelto, a factor Xa inhibitor - in the same population would be viewed as an unexpected source of potential sales.
As Eliquis is by far the biggest driver of sales growth for Bristol-Myers Squibb, this would likely provide an uplift to the New York company’s shares, and with no details to emerge at all to date, interest will be high.
On the Tuesday full results from AstraZeneca’s Saturn study will be presented, a trial that did not yield as conclusive results as the company was no doubt hoping (Astra will reap few benefits from high risk Crestor study, September 2, 2011).
Pitted against Pfizer’s Lipitor, which loses patent protection at the end of the month, the study used ultrasound to measure how the volume of plaque in a patient’s artery changed over the course of the trial. It missed on the primary endpoint - percent atheroma volume in a small segment of the coronary artery – but on the secondary measure - total atheroma volume within the coronary artery – Crestor produced a significantly greater reduction than Lipitor.
Full details are awaited with interest, in particular tolerability readings, an area which could help confirm advantages of the Astra pill, which is soon to become relatively more expensive.
Raising the good
Meanwhile studies conducted with agents that raise HDL will be of interest as the debate around how this potent anti-inflammatory molecule can be harnessed to protect the heart continues. Further results from the AIM-HIGH study conducted with niacin will be presented – essentially a failed study, but a big piece of research into this field from which lessons are still be learned.
And with a large ongoing study of Tredaptive - niacin plus Merck’s experimental agent laropiprant, which reduces the unwanted flushing effects – encouraging signals from cuts of the AIM-HIGH data could raise hopes for this combination agent.
Phase II data on Lilly’s CETP inhibitor evacetrapib, if successful, would provide important encouragement for both the drug class and for the Indiana company’s pipeline-driven growth strategy. Since the safety scare that derailed Pfizer’s entry, torcetrapib, five years ago, observers have taken a cautious approach to the drug class that seeks to prevent cardiovascular events mainly by raising HDL particles, which remove LDL from blood-vessel walls.
The CETP inhibitor class has undergone a quiet renaissance since AHA in 2010, when results from a trial of Merck’s anacetrapib were positive enough to announce the initiation of a new 30,000-patient trial (AHA 2010 – Benefits of Merck's HDL booster could be revealed by 2014, August 30, 2011).
Since then, Roche has released encouraging phase II data on dalcetrapib, fuelling additional optimism for the class (ESC - Jury remains out on dalcetrapib despite 'safe so far' verdict, August 30, 2011)
Lilly will release results from its 430-patient phase II US-European trial of evacetrapib monotherapy and in combination with statins to detect any improvement in blood lipids, any sign of drug interactions and any safety signals. Given some growing optimism about the class positive results will support advancing the compound into more extensive trials.