AstraZeneca's Brilinta Reduces MACE Risk in Type 2 Diabetes Patients but Increases Major Bleeding Incidents

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After enduring multiple setbacks, AstraZeneca’s anticoagulant Brilinta (ticagrelor) finally achieved success in the Phase III THEMIS clinical trial. However, the complete data presented at the 2019 European Society of Cardiology (ESC) Congress recently dashed industry hopes that these results would boost Brilinta’s penetration among patients with type 2 diabetes and concurrent coronary artery disease.

This is because the therapeutic benefit of Brilinta in preventing cardiovascular events is offset by an increased risk of major bleeding. Dr. Dheepak Bhatt, a physician at Brigham and Women’s Hospital in Boston, warned at the ESC press conference against using Brilinta in this primary prevention population.

Nevertheless, there is still a glimmer of hope for AstraZeneca. A prespecified subgroup analysis published in The Lancet demonstrated a net benefit in patients who had previously undergone percutaneous coronary intervention (PCI), who accounted for approximately 58% of the THEMIS study population.

Results of the THEMIS Study

The THEMIS study enrolled more than 19,000 patients with type 2 diabetes and coronary artery disease but no history of myocardial infarction or stroke, to evaluate the effect of Brilinta combined with aspirin versus aspirin alone on major adverse cardiovascular events.

The results showed that, compared with aspirin alone, Brilinta combined with aspirin reduced the relative risk of major adverse cardiovascular events (MACE) by 10%, a difference that was statistically significant. However, there was no difference between the two groups in the risk of cardiovascular death; the overall result was driven by lower incidences of myocardial infarction and stroke in the Brilinta plus aspirin treatment group. Specifically, regarding the individual components of MACE: there was no difference in the risk of cardiovascular death, a 16% reduction in the relative risk of myocardial infarction, and a 20% reduction in the relative risk of stroke.

More concerning is that this therapeutic benefit is accompanied by a significant increase in the risk of major bleeding, a key safety outcome. Furthermore, Brilinta combined with aspirin also increases the risk of intracranial hemorrhage. Although there was no significant difference in the incidence of fatal bleeding, the rate was higher in the group treated with Brilinta plus aspirin.

Subgroup Hope

However, Dheepak Bhatt concluded that Brilinta should be considered for patients who have previously undergone PCI. He explained that, in essence, the focus should be on patients with a lower risk of bleeding, as these patients had previously tolerated dual antiplatelet therapy consisting of aspirin and a P2Y12 inhibitor such as Brilinta.

In patients who had previously undergone PCI, benefits were observed not only for the primary endpoint of MACE but also in terms of net clinical benefit when bleeding was taken into account. Specifically, a prespecified subgroup analysis from THEMIS-PCI demonstrated that in this patient subgroup, Brilinta combined with aspirin, compared with aspirin alone, reduced the relative risk of MACE by 15% and significantly reduced the risk of all-cause death, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage by 15%.

Patients undergoing PCI account for a large proportion of those with diabetes and coronary artery disease, but whether this is sufficient to justify AstraZeneca’s investment in Brilinta is another matter. The THEMIS trial is the final pivotal study within the company’s PARTHENON program, which encompasses more than 80,000 patients, although most studies to date have failed.

Brilinta is an oral, reversible, direct-acting P2Y12 receptor antagonist that works by inhibiting platelet activation. In patients with acute coronary syndrome (ACS) or a history of myocardial infarction, the combination of Brilinta and aspirin has been shown to significantly reduce the risk of major adverse cardiovascular events. The regimen of Brilinta combined with aspirin is indicated for adult patients with ACS, or those with a history of myocardial infarction who are at high risk of developing atherothrombotic events, for the prevention of atherothrombotic events.

Cardiovascular, Renal and Metabolism (CVRM) constitutes one of AstraZeneca’s three major therapeutic areas. In the CVRM segment, sales reached $4.004 billion in 2018, representing a 12% year-on-year increase. Among these, Brilinta generated $1.321 billion in sales, a 21% year-on-year increase, primarily driven by continued market penetration in the treatment of acute coronary syndrome (ACS) and in patients at high risk of cardiovascular events following myocardial infarction (HRPMI).

Brilinta was also one of AstraZeneca’s top 10 best-selling drugs in 2018. AstraZeneca once had high expectations for the drug. Five years ago, when rejecting Pfizer’s acquisition offer, the company stated that Brilinta’s peak sales could reach $3.5 billion. Currently, this figure appears to be nothing more than a pipe dream.

EvaluatePharma predicts that Brilinta’s sales will reach $2.2 billion in 2023, followed by a gradual decline. Data from the THEMIS study appear unlikely to halt Brilinta’s future sales downturn.

References:

1、Brilinta reduced the risk of cardiovascular events in patients with coronary artery disease and type-2 diabetes in Phase III THEMIS trial

2、ESC 2019 – Astra’s latest Brilinta hopes bleed out on full Themis data

3. AstraZeneca reported $22 billion in revenue for fiscal year 2018, with oncology drugs and the Chinese market driving a return to sales growth