AstraZeneca has dumped billions into Brilinta R&D, but will it ever pay off?

With a series of late-stage trial readouts in the past few years, AstraZeneca has invested heavily in outcomes R&D for its stalwart clotbuster Brilinta. But there's big problem with that approach, which was once one of CEO Pascal Soriot's pet projects.

AstraZeneca may never see a return on investment for the billions it's dumped into the drug.

With an estimated $5.4 billion in sunk costs in Brilinta, AstraZeneca will likely never turn a profit on the blood thinner with generics expected to hit the market in 2024 and marketing costs swallowing up any increase in the drug's already disappointing sales, EvaluatePharma said Tuesday.

Much of that R&D expense has been tied to AstraZeneca's Parthenon program, Evaluate reported, which has turned out a suite of trial data, including top-line results from the phase 3 Thales study released Monday.

Parthenon—and its six outcomes trials for Brilinta—has already swallowed $3.7 billion in R&D costs with an additional $1.7 billion tied up in more than 80 investigator-sponsored trials, Evaluate said. Of the six Parthenon studies, two have led to label updates, while another two were called "clear failures" by Evaluate.

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"Companies risk these sums for the rewards of owning a life-saving drug, but it is hard to argue that in this case the spend was worth it," Evaluate said.

In the most recent Parthenon trial––phase 3 Thales–– twice-daily Brilinta on top of aspirin significantly cut the risk of stroke or death over aspirin alone in patients who had suffered a stroke or transient ischemic attack and began treatment within 24 hours, according to top-line data released Monday.

However, patients also posted a higher bleeding risk than those in the control arm, a problem that has plagued the drug in its past trials. With further data set to be presented at an upcoming medical conference, Evaluate couldn't declare the study a clear winner without understanding the scope of Brilinta's efficacy.

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"Stroke is a notoriously tough setting with substantial unmet need, but given Brilinta's bleeding risk it is hard to handicap the product's chance of approval here without knowing the magnitude of the benefit," Evaluate said.

Although the Thales trial hit its primary endpoint, Evaluate highlighted two other Parthenon studies that missed their targets: Socrates, which showed Brilinta failed to prevent strokes in peripheral artery disease (PAD) patients, and Euclid, where Brilinta couldn't top Plavix in stopping PAD bleeding complications.

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Even a nominal trial win for Brilinta could turn into a snafu, as AstraZeneca is still working to identify a patient population that could benefit from its phase 3 Themis study, which showed Brilinta in tandem with aspirin slashed the combined risk of heart attack, stroke and cardiovascular death in patients with Type 2 diabetes and coronary artery disease (CAD) who hadn’t suffered prior heart attack or stroke.

With bleeding risks higher in the Brilinta arm in the overall patient population, AstraZeneca posted stronger results in a prespecified subgroup of patients who had previously undergone a percutaneous coronary intervention and were at a lower risk of bleeding.

In a conversation with AstraZeneca's R&D chief Mene Panagalos in September, Evaluate said the drugmaker was still looking for a population with "optimal benefit" from the Themis study before a possible regulator filing would be submitted.