ESC - Aristotle data confirm Eliquis as strong contender

A closer look at hotly anticipated apixaban data from the Aristotle study, Bristol-Myers Squibb and Pfizer’s contribution to the new wave of oral anticoagulants, did not disappoint. Released yesterday at the European Society of Cardiology in Paris the results confirm the product, branded Eliquis, is most likely to become the pill of choice to prevent stroke in patients with atrial fibrillation (Strong Eliquis result to repaint picture of blood thinner market, June 23, 2011).

With Pradaxa already available and Xarelto expected to receive a green light later this year, the strong data means Eliquis should not suffer from being third to market. However, in the absence of real head-to-head data comparisons of the three are hard to make, many doctors at the conference cautioned, particularly given that all represent an improvement over warfarin. Which means in cost conscious regions the relative price of these agents, to each other and warfarin, is likely to play a major role in determining uptake.

Impressive data

The Aristotle data were impressive when compared to warfarin and, on many measures, to the results from Re-ly and Rocket-AF, the pivotal atrial fibrillation studies respectively conducted for Boehringer Ingelheim’s Pradaxa and Bayer and Johnson & Johnson’s Xarelto.

In the primary endpoint of the study, Eliquis cut the risk of stroke or systemic embolism by 21% compared with warfarin. Xarelto reduced this risk by 12%, a result that established the agent only as equivalent to warfarin, while Pradaxa was approved on the basis of a significant 35% reduction.

This apparent lower effectiveness than the Boehringer pill might have raised eyebrows had Eliquis not blown it out the water on safety measures. On the major bleeding measure, Pradaxa and Xarelto were only established as similar to warfarin – Eliquis cut the risk by a highly significant 31%. On intracranial bleeding – considered important because the often elderly patients who will take these drugs are prone to falls - the pill cut the risk by 58%, similar to Pradaxa and much better than Xarelto.

The icing on the cake was an 11% reduction in mortality – or death by any cause – a significant reduction that other candidates did not establish statistically, albeit only just in Pradaxa’s case.

Marketing message

A hard to hit measure, Eliquis only just scraped into statistical significance on mortality, and it seems likely this number will be more important to the marketing departments of the rival drug promoters than to doctors in practise.

And given the marginal measure – a p value of 0.47 was achieved, compared to 0.51 for Pradaxa - it is far from certain that regulators will allow a mortality claim on the label.

“It is a good argument if I want to sell the drug but one must be careful, it is not black or white,” commented Dr Heinz Drexel of the Vorarlberg Institute in Austria, and an ESC spokesperson who was not involved in the studies.

On a conference call following the results Jack Lawrence, who lead the development of apixaban for Bristol-Myers Squibb, admitted that the mortality reading was close to 0.5, but said they believed the reading was “statistically robust”.

“We expect the p value to be in the label, how it is described in words is a bit hard to call at the moment,” he said.

Hard to call

Overall, however, Dr Drexel said the Aristotle results were better than he had hoped.

“The results were excellent, high efficacy and low bleeding, it’s the perfect profile you would like to see,” he said, echoing the comments of many other physicians at the conference.

As to which one might be chosen over the others Dr Drexel was reluctant to be drawn, and like many doctors prefered to stress that without head to head data comparisons are very hard to make, given the different trial designs and patient populations.

“There is no reason to pick one over the other because there is no head to head comparison of the drugs. So therefore at present it would be availability and maybe pricing, but there is no objective way,” said Dr Michael Bohm of the University Hospital of Saarland in Germany.

An editorial in the New England Journal of Medicine by Dr Jessica Mega of Brigham and Women's Hospital in the US also chose to emphasise the similarities between the agents in terms of efficacy and safety, and again stressed the difficulties of comparing the studies.

Convenience factor

Dr Michael Ezekowitz, who presented a review of the Aristotle study following the presentation to the 30,000 delegates took a similar balanced tone, noting that it was encouraging to see that different mechanisms of action have succeeded in showing a reduction in stroke in these patients.

“The challenge is to translate these results into clinical practice,” said Dr Ezekowitz, of the Lankenau Medical Center in the US, who was co-principal investigator for Pradaxa’s Re-ly study.

He noted that discontinuation of therapy remains a major challenge for these patients, something that a daily or twice daily oral pill promises to help surmount.

Indeed Xarelto’s one-a-day schedule, versus twice a day for Pradaxa and Eliquis, may make up for its seeming lack of comparable efficacy and safety, representing an important reduction in pill burden for an elderly population. As a result, many believe Pradaxa could be pushed into third place by Eliquis' strong showing.

Picking a winner

The financial community, however, was not shy in picking a winner.

“We see the results as near best case,” analysts at UBS wrote this morning, saying the results confirm the bank’s estimates of sales of $2.4bn by 2015.

Leerink Swann described the results as “excellent” and substantially raised their sales forecasts, saying apixaban is positioned to be the top drug in the warfarin-replacement market based on the fact it is clearly better than the generic incumbent with safety similar to aspirin – the bank’s analysts lifted their 2017 estimate by $1.1bn to $4.2bn.

The table below shows where consensus currently stands – the top line data prompted a 9% jump in Eliquis consensus last month and it seems further hikes are on the way, probably at the expense of Pradaxa.

Analysts at Bernstein struck a slightly more cautious tone, highlighting commentary in the NEJM editorial that pointed out that warfarin remains cost effective even with the monitoring required. Switching to a new agent may not be necessary for a patient adequately controlled on warfarin, the reviewer added.

Outside the US in particular, it seems likely these companies will have to mount convincing arguments about the cost effectiveness of what are likely to be much more expensive treatment options.

However, as Dr Ezekowitz pointed out, the decision on whether to use warfarin is driven by what a physician might cause – bleeding – rather than what might be prevented. In the case of atrial fibrillation this is debilitating or fatal strokes and many are now convinced these agents are safer and more effective, and represent an important step forward for these patients.

New oral anti-coagulants - consensus before Aristotle Annual Sales in stroke prevention in AF ($m) 
Product Generic Name Company Pharmacological Class 2010 2012 2014 2016 WW Indication Status
Xarelto rivaroxaban Bayer/Johnson & Johnson Factor Xa inhibitor  748  2,451  2,942 Marketed
Pradaxa dabigatran etexilate mesylate Boehringer Ingelheim Thrombin inhibitor  638  1,161  1,907  2,288 Filed
Eliquis apixaban Bristol-Myers Squibb Factor Xa inhibitor  -  81  971  1,985 Phase III
Total  638  1,990  5,329  7,214
Source: EvaluatePharma

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