The Medicines Company reels from harsh Cangrelor verdict

The FDA’s expert advisers’ judgement of The Medicines’ Company’s cangrelor was appropriately harsh. The 7-2 vote recommending against approval means the blood thinner is almost certain to face an agency rejection and will require several more years of research to support approval for use in patients undergoing cardiac stent procedures.

The resounding “no” is in the context of staff briefing documents that reproached researchers of Champion Phoenix – the only trial of three pivotal tests that showed cangrelor to be the equal of the standard of care, Plavix. It would be surprising to see The Medicines Company persist, should the FDA affirm its advisory committee; to remain in investors’ good graces the New Jersey group now needs to resolve patent cases over top-seller Angiomax and hope its thin pipeline performs.

Warning signs

Shares fell 14% today to $28.40 in early trading, their lowest since cangrelor data emerged a year ago (Cangrelor trial success quickens pulses of Medicines Company investors, January 9, 2013). Following the vote, ISI Group analyst Umer Raffat wrote that the current valuation is justifiable if Angiomax retains market exclusivity through 2019, not a guaranteed scenario given pending litigation.

What should have set off alarm bells, as EP Vantage pointed out when the trial reported, was the company’s efforts to design the trial to weed out pre-existing myocardial infarctions as well as allow investigators to use a 300mg loading dose of Plavix in the control arm, rather than the recommended 600mg. These were not agreed to in advance by the FDA.

They were two flaws called out by Dr Thomas Marciniak, medical team leader for the FDA’s division of cardiovascular and renal products, who also cited inappropriate delays in administration of Plavix as flaw. The difference in loading doses and delay in Plavix were “discretionary changes that would be expected to increase the likelihood that the cangrelor regimen appears superior.”

Indeed, because the investigators did not disclose the benefit of early administration of Plavix as part of informed consent documentations, Dr Marciniak argued the trial was unethical.

Thus it is even more surprising – and the reason analysts cautiously predicted a yes vote – that the assigned reviewers of the data recommended approval for patients undergoing percutaneous coronary interventions, based on Champion Phoenix data showing a significant reduction in myocardial infarctions and stent thrombosis in the albeit favourably-designed trial.

The reviewers recommended a complete response letter for the so-called “bridge” indication, in which acute coronary syndrome patients need to retain protection against thromboses while Plavix washes out prior to surgery. The bridge indication earned a unanimous negative vote.

The FDA seldom goes against negative adcom votes, so it is probable that the agency will demand a new set of clinical trials by the PDUFA action date of April 30. Champion Phoenix took more than two years to complete, and with another year for filing and decision, cangrelor could only launch in 2017. And that is only if The Medicines Company wants to persevere, which seems a foolhardy exercise.

What price?

The decision left analysts wondering what value is left in The Medicines Company. Angiomax is still fighting for exclusivity through 2019 – it deserves recalling that the group was only able to get it extended past 2010 by persuading an appeals court that its interpretation of “day,” and not the US Patent and Trademark Office’s, is the correct one under the law (Value returns to The Medicines Company with court decision, August 4, 2010).

A decision in litigation with Hospira is expected around mid-year, and a positive outcome for The Medicines Company would see exclusivity extended out to 2019. At $517m in sales in 2018, according to EvaluatePharma’s consensus, Angiomax is essential to its value – a negative decision that would allow generic entry in 2015 would see the value of the company drop to $8 a share, writes RBC Capital Markets analyst Adnan Butt. The remainder of the pipeline is worth as much as $22 a share, with antibiotic oritavancin possibly up for approval this year, RBC forecasts.

Cangrelor is probably a long way from the market if it has any chance at all, and it might be time to put it to rest. Although it has a fair pipeline beyond the blood-thinner, The Medicines Company is in need of a kick-start; its business development arm might want to get busy this year.

To contact the writer of this story email Jonathan Gardner at [email protected]  or follow @JonEPVantage on Twitter