Bayer's $5.5 Billion Bet on Asundexian Falters as Phase III Trial Against Eliquis Fails

On September 1, The New England Journal of Medicine published a research article on the Phase III clinical trial data of Bayer’s new drug, asundexian. The trial was terminated early because asundexian demonstrated inferior efficacy to Pfizer’s Eliquis (apixaban) in stroke prevention.

The study data disclosed in the article show that, in a Phase III international double-blind trial, high-risk patients with atrial fibrillation were randomized in a 1:1 ratio to receive either once-daily 50 mg asundexian or standard-dose Eliquis. The primary efficacy objective was to determine whether asundexian was at least non-inferior to apixaban in preventing stroke or systemic embolism. The primary safety objective was to determine whether asundexian was superior to apixaban in terms of major bleeding events.

In the period leading up to the early termination of this clinical trial, among patients with atrial fibrillation at risk of stroke, those receiving once-daily 50 mg doses of asundexian had a higher incidence of stroke or systemic embolism compared with those receiving standard-dose apixaban. During this period, major bleeding events were less frequent in patients taking asundexian than in those taking apixaban.

The Phase III clinical trial was terminated early due to concerning trends observed in the data. The failure of this asundexian clinical trial has once again cast a shadow over Bayer’s strategic layout in the cardiovascular disease sector. Previously, Bayer had projected that asundexian, as a potential therapeutic agent for the prevention of thromboembolism and stroke, could generate annual revenues of $5.5 billion.

Anticoagulant therapy is the primary approach for the prevention and treatment of thromboembolic diseases.

Among anticoagulant drugs, Xarelto (rivaroxaban), co-developed by Bayer and Johnson & Johnson, was once a top-10 global blockbuster small-molecule drug, with sales reaching approximately $6 billion in 2022. However, to address the impending loss of patent protection for Xarelto in recent years, Bayer began seeking a successor early on, with asundexian emerging as its leading candidate drug.

Asundexian is a novel oral anticoagulant and Factor XIa (FXIa) inhibitor that prevents pathological thrombosis by inhibiting Factor XIa, thereby reducing the risk of recurrent ischemic events. The drug is considered to have the potential to surpass Pfizer’s Eliquis.

Pfizer’s Eliquis targets Factor Xa, an activated form of an enzyme that is essential for initiating the coagulation cascade. By preventing clot formation when platelets aggregate and form thrombi, it reduces the likelihood of clots forming and traveling to the brain to cause a stroke; however, it also increases the risk of dangerous bleeding due to the body’s diminished ability to halt blood flow.

In light of the limitations of Eliquis, Bayer has placed high expectations on the development potential of asundexian. As a Factor XIa (FXIa) inhibitor, Bayer is highly confident in the safety profile of asundexian, believing that it can prevent the formation of venous blood clots without increasing the risk of bleeding, thereby offering the efficacy of Eliquis (apixaban) without its adverse effects.

However, according to the latest released trial results, in this clinical study involving 14,810 patients with atrial fibrillation, 98 patients taking Bayer’s drug experienced stroke or systemic embolism, compared with 26 patients taking Eliquis.

The incidence of adverse events with asundexian was similar to that with Eliquis. However, 147 patients discontinued Bayer’s drug due to adverse events, compared with 118 discontinuations in the Eliquis group. The number of patients treated with asundexian who died from myocardial infarction, stroke, or other cardiovascular events totaled 155, which was twice the number in the Eliquis group (77 deaths).

Atrial fibrillation is a common arrhythmia characterized by an irregular and often rapid heart rate, which increases the risk of stroke and heart failure. Bayer has sought to mitigate bleeding risks by targeting Factor XIa, a downstream factor in the coagulation cascade. Asundexian has demonstrated success in this regard, meeting the trial’s primary safety endpoint: only 17 patients receiving asundexian experienced major bleeding, compared with 53 patients receiving Eliquis.

However, data indicate that this improvement in safety came at the cost of lost efficacy. Researchers have proposed several theories to explain why asundexian, despite its promise in treating atrial fibrillation via the Factor XIa mechanism, ultimately failed. They suggest that the dose of asundexian used in the trial (50 mg once daily) may have been too low to achieve sufficiently high levels of Factor XIa inhibition. In the earlier PACIFIC-AF trial, this dose reduced Factor XIa activity by 94% at peak concentration, whereas the investigators believe that preventing harmful thrombus formation may require nearly 100% suppression of Factor XIa activity.

The clinical trial was originally scheduled to conclude after 350 patients experienced stroke or embolism; however, Bayer terminated the trial upon the recommendation of the Independent Data Monitoring Committee when it had progressed one-third of the way.

In the competitive landscape of anticoagulant drugs, the blockbuster status of Pfizer’s multi-billion-dollar molecule, Eliquis, remains unchallenged. Co-developed by Bristol Myers Squibb (BMS) and Pfizer, the drug generated $18.269 billion in sales in 2022. However, Eliquis is set to face patent expiration in the coming years, leaving it vulnerable to market share erosion from generic competitors. If asundexian demonstrates superior efficacy to Eliquis in clinical trials, it will possess strong market potential.

Asundexian has garnered favor from Bayer. In 2022, asundexian received U.S. FDA Fast Track designation for secondary prevention in patients with non-cardioembolic ischemic stroke. In May 2023, asundexian again received U.S. FDA Fast Track designation as a potential therapy for stroke and systemic embolism prevention in patients with atrial fibrillation.

Nevertheless, despite high expectations, asundexian has shown mediocre clinical performance. Although the drug can reduce bleeding rates in patients with ventricular fibrillation, it failed to meet the goal of reducing ischemic events in other Phase II clinical trials. In 2022, asundexian failed to outperform placebo in two mid-stage trials involving patients recovering from heart attacks and strokes; the drug did not reduce the composite incidence of covert brain infarction or ischemic stroke.

At the end of 2023, asundexian failed once again in the Phase III clinical trial named OCEANIC-AF. This study aimed to compare the efficacy of asundexian with Eliquis in 18,000 patients with atrial fibrillation (AF) at risk of stroke. In the OCEANIC-AF trial, AF patients at risk of stroke were randomly assigned to two groups to receive either asundexian or Eliquis. The Independent Data Monitoring Committee concluded that asundexian demonstrated inferior efficacy compared to the control group and therefore recommended terminating the trial.

In recent years, the market for oral anticoagulants has continued to expand. As leading agents in this class, Factor XIa (FXIa) inhibitors offer faster onset of action, a wider therapeutic window, and improved safety compared with the anticoagulant warfarin. Bayer’s Xarelto and Bristol Myers Squibb/Pfizer’s Eliquis are representative FXIa inhibitors.

Notably, as patents for blockbuster drugs are set to expire, a wave of novel anticoagulants is emerging. In addition to Bayer’s asundexian, milvexian—developed through a collaboration between Bristol Myers Squibb (BMS) and Johnson & Johnson—is also hailed for its potential to protect patients from stroke while reducing the bleeding risks associated with Factor Xa (FXa) inhibitors. Analysts at SVB Securities have described milvexian as BMS’s “largest potential sales opportunity,” projecting annual sales could exceed $5 billion, a possibility acknowledged by BMS executives.

However, the development of next-generation FXIa inhibitors has not proceeded smoothly. Asundexian encountered setbacks in clinical trials, and milvexian was no exception. In 2022, at the annual meeting of the European Society of Cardiology, Bristol Myers Squibb (BMS) announced the interim results from the Phase II clinical trial of milvexian, which showed that the drug failed to meet its primary endpoint. This primary endpoint was a composite measure assessing both the dose-response relationship compared with placebo in terms of stroke incidence and the biomarker of cerebral infarction (i.e., lesions that may occur in the absence of clinical stroke). The final results demonstrated that the drug did not achieve this composite endpoint.

Nevertheless, Bayer and BMS remain confident in their respective products. BMS and its partner Johnson & Johnson have designed Phase III clinical trials to demonstrate the efficacy of milvexian.

As for Bayer, the company plans to analyze the data to understand the reasons for asundexian’s suboptimal performance and to reevaluate another Phase III clinical trial, OCEANIC-AFINA. This trial targets patients with atrial fibrillation who are at high risk of stroke or systemic embolism and are unsuitable for oral anticoagulant therapy. Meanwhile, another clinical trial, OCEANIC-STROKE, is ongoing; it aims to evaluate the efficacy of asundexian versus standard antiplatelet therapy in preventing ischemic stroke. The trial is expected to enroll 12,300 patients and will be completed in October 2025.