It was always a gamble to submit Xarelto for approval in acute coronary syndrome, given that the product was the only one of the new generation of blood thinners to attempt to crack that very difficult indication. The fine line between prevention of blood clots and dangerous bleeding is a difficult one to tread, so it is perhaps not surprising that Johnson & Johnson has received a second complete response letter.
The FDA’s no should provide some satisfaction that Bristol-Myers Squibb and Boehringer Ingelheim were right to focus late-stage work for Eliquis and Pradaxa on stroke prevention and deep-vein thrombosis. It will provide little incentive for developers to enter the ACS space, even if the incumbent in this indication, Plavix, has the disadvantages of a long half-life and its own bleeding risks.
More answers needed
J&J did not disclose the reasons for the complete response letter, although UBS analysts noted that a focus on bleeding risks in the company’s press release suggested a possibility. Xarelto, originated by Bayer, did not increase bleeding deaths in ACS patients but did increase the number of major bleeding incidents when compared with placebo in the pivotal Atlas ACS-2 trial.
This study established that when compared with placebo a 2.5mg twice-daily dose of Xarelto reduced by 34% the relative risk of death from cardiovascular causes; the main adverse event was elevated rates of bleeding incidents, an unsurprising finding given the placebo comparator.
An FDA advisory committee had raised concerns about dropouts from the 15,000-patient trial (Adcom vote clouds Xarelto’s future in ACS, May 24, 2012); the first complete response letter sought that data. J&J said investigators had tracked down and established vital statistics on 843 of the 1,338 patients who withdrew; 37 had died since last evaluation.
EvaluatePharma forecasts 15% of the $956m in US sales in 2018 would be derived from the ACS indication. The UBS analysts said investor expectations of success had been low – indeed, J&J shares were up less than 1% at $77.51 in early trading this morning, while Bayer stock was up more than 2% at €77.35 in mid-afternoon trading.
The fact that Xarelto has struggled to persuade regulators and that the other novel oral blood thinners have shied away from the indication suggest that the standard secondary prevention therapy of aspirin or Plavix with aspirin will not be dethroned. AstraZeneca’s Brilinta and Eli Lilly’s Effient have entered the space but have faced an uphill battle.
Recent trial data have suggested the Medicines Company’s cangrelor can have some benefit in patients undergoing percutaneous coronary intervention following a cardiovascular event (Cangrelor trial success quickens pulses of Medicines Company investors, January 9, 2013). Meanwhile, Sanofi’s otamixaban – which, like Xarelto and Eliquis is a factor Xa inhibitor – is due to report phase III data in the second quarter of 2013.
However, both target patients in hospital undergoing heart procedures, entering a space occupied by Lovenox, and thus will not take a role in secondary prevention following discharge, as Xarelto had been hoping to do.
J&J said it would “respond to the agency’s questions”. Given that Xarelto is on the market in its most lucrative indication, there is not necessarily a burning reason for the New Jersey group to continue.
On the other hand, it has already invested hundreds of millions of dollars in a massive trial. And given the medical need and concerns about Plavix – the drug requires a five-day washout for any patient undergoing a surgical procedure – it would not be surprising to see J&J persevere. Having come this far, there seems to be plenty of reasons to try again.