ESC22: Despite trial misses, Bayer preps phase 3 for asundexian

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Bayer is pressing ahead with a phase 3 trial of its oral Factor XIa inhibitor asundexian, a new anticoagulant, despite missing efficacy targets in two mid-stage studies.

The OCEANIC trial programme will investigate the potential of asundexian in up to 30,000 patients with atrial fibrillation (AF) as well as patients with a non-cardioembolic ischaemic stroke or high-risk transient ischemic attack (TIA), said Bayer.

The decision to move into phase 3 has come despite asundexian missing primary efficacy objectives in a pair of phase 2 studies in ischaemic stroke (PACIFIC-STROKE) and acute myocardial infarction (PACIFIC-AMI) reported at the European Society of Cardiology (ESC) congress in Barcelona, Spain.

The promise of the new class is that inhibiting Factor XIa seems to provide the same anticoagulant properties of current anticoagulants, without raising the risk of bleeding side effects.

Asundexian fulfilled its promise on safety in both PACIFIC studies, with "consistent safety results for asundexian comparable to placebo arm," regardless of background antiplatelet therapy, and without an increase in bleeding.

In PACIFIC-STROKE, Bayer's drug was unable to improve on placebo when given on top of antiplatelet therapy to prevent secondary strokes – MRI-detected covert brain infarcts or recurrent symptomatic ischaemic stroke – at six months.

There were trends towards reduced recurrent symptomatic ischaemic strokes and TIAs with the Factor XIa inhibitor, most apparent in the highest (50 mg) dose group where the risk was reduced by a third.

In PACIFIC-AMI, asundexian was unable to reduce the main efficacy outcome of cardiovascular death, myocardial infarction, stroke or stent thrombosis compared to placebo – both given alongside aspirin plus a P2Y12 inhibitor – at one year.

Once again, there was no significant observed increase in bleeding with asundexian at any dose or compared with placebo, backing up its safety, and according to the investigators the study was not large enough to detect a clinically meaningful reduction in cardiovascular events.

Bayer is sufficiently satisfied with the data to press ahead with its phase 3 programme, as it looks for a successor to Johnson & Johnson-partnered anticoagulant Xarelto (rivaroxaban), its biggest-selling drug which is facing the loss of patent protection in 2023.

"The underlying science of Factor XIa and the phase 2 data especially supporting the safety of asundexian make us confident to move the investigational compound forward into phase 3 addressing significant therapeutic areas," commented Bayer's head of R&D Christian Rommel.

BMS and J&J's milvexian

Bayer is in a race in the Factor Xia inhibitor category with Bristol-Myers Squibb and J&J, which also reported new data with their candidate milvexian in secondary stroke prevention at ESC.

In the AXIOMATIC-SSP trial, milvexian was compared to placebo in patients with prior ischaemic stroke or high-risk TIA, on top of aspirin and antiplatelet therapy.

The drug numerically reduced the risk of clinical ischaemic stroke (excluding covert brain infarction) at all but one of the five doses tested, with an overall 30% relative risk reduction compared to placebo, although there was no apparent dose-response and the study wasn't powered to make a judgment on efficacy. On safety, the incidence of major bleeding was low and similar to placebo.

"Based on the observed efficacy signal for ischaemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase III trial in a similar stroke population," said principal investigator Mukul Sharma of McMaster University in Ontario, Canada.

A phase 3 programme for the drug is due to start later this year, said BMS. Last year, BMS and J&J reported the first proof-of-concept data for milvexian in the AXIOMATIC-TKR trial, showing that the drug was able to prevent venous thromboembolism (VTE) in people undergoing total knee replacement surgery without  raising the risk of bleeding events.