What Now for Factor XI Inhibitors in AF

Factor XI inhibition was potentially the Goldilocks anticoagulant target with the promise of a reduction in thrombotic risk without a significant increase in bleeding. The early phase 2 data were encouraging, and the trials in orthopedic patients looked good.

Then the phase 3 OCEANIC-AF, trial comparing the novel factor XI inhibitor asundexian (Bayer) vs the direct-acting oral anticoagulant apixaban in patients with atrial fibrillation was stopped early for futility.

What are the implications for factor XI as a target, and where does it leave the ongoing trials with other drugs? Experts suggest all is not lost in this area of high unmet clinical need.

The currently available direct-acting oral anticoagulants, such as apixaban, rivaroxaban, edoxaban, which target factor Xa, and dabigatran, which blocks factor IIa, have significantly improved the management of patients in comparison with warfarin.

However, between 30% and 40% of US patients with atrial fibrillation are not receiving anticoagulation, while 5%-8% come off therapy in the first 6 months of initiating it, noted Manesh R. Patel, MD, chief of the Division of Cardiology and the Division of Clinical Pharmacology at Duke University School of Medicine, Durham, North Carolina, and coauthor of OCEANIC-AF.

Coupled with a projected increase in the prevalence of atrial fibrillation and in the incidence of stroke over the next 20 years, “the opportunity is huge,” he said.

“Some patients who are eligible for the [current] drugs do not receive them” due to the perceived risk of bleeding, “or they are used at inappropriately lower doses,” explained Felice Gragnano, MD, from the University of Campania “Luigi Vanvitelli,” Caserta, Italy.

The idea that a new drug could circumvent these issues simply by targeting another part of the coagulation cascade consequently generated a great deal of interest.

This was for a number of reasons, noted OCEANIC-AF first author Jonathan P. Piccini, MD, MHS, from Duke Clinical Research Institute at Duke University School of Medicine, including that people with factor XI deficiency experience bleeding after orthopedic surgery or other procedures but do not have spontaneous severe bleeding.

This, he explained, is because factor XI is primarily involved with hemostatic thrombus formation via the tissue factor pathway but is not involved to a significant degree in the development of pathologic thrombi.

“The science behind this class of drugs is obviously fascinating,” said Dominick J. Angiolillo, MD, PhD, Division of Cardiology, University of Florida College of Medicine — Jacksonville. He was not involved in OCEANIC-AF, which he described as the first adequately powered trial to assess safety and efficacy for a factor XI inhibitor. “There was definitely a lot of hope,” he added.

According to Gragnano, it could have been a “revolution” if the study had been positive, and the drugs would have become “the new standard of care in atrial fibrillation.”

But OCEANIC-AF was not a positive study. There was no evidence of superior stroke prevention with asundexian, and “in fact it was clearly inferior to apixaban,” said Piccini.

The patients who took asundexian had a several-fold higher risk for ischemic stroke. “The entire reason we give these medications is to prevent ischemic stroke, so…at least at this dose, in this population, the medication cannot effectively achieve its therapeutic goal.”

Gragnano believes that, from a methodological point of view, the trial was well conducted, and the study population, who were over 70 years on average with a CHA₂DS₂-VASc score of 4.3, was appropriate.

Dosing Issue

But one thing that all the experts who spoke with Medscape Medical News agreed on was that there was likely insufficient inhibition of factor XI.

In the PACIFIC-AF phase 2 dose-finding study of asundexian vs apixaban, giving the study drug at a dose of 50 mg once daily resulted in a 92%-94% reduction in factor XI activity, which “may not be enough,” Gragnano said.

He pointed out that in the AZALEA-TIMI 71 phase 2 trial of abelacimab (Anthos Therapeutics), a monoclonal antibody that uniquely inhibits both factor XI and its active form factor XIa, the 150-mg dose achieves around 99% inhibition of factor XI. The 100-mg dose of the factor XIa-targeting small molecule milvexian, which is currently being tested in the LIBREXIA-AF phase 3 trial, is also anticipated to achieve more than 95% inhibition.

Consequently, the “elephant in the room” with OCEANIC-AF is whether the dose chosen for the study was the right one, Angiolillo said.

“Maybe you need complete suppression of factor XI,” Piccini said, “and a higher dose would have been able to achieve that” and may have been effective at preventing ischemic stroke.

Alternatively, it might be that inhibition of both factor XI and XIa would result in more effective therapy, “and the reasons for that are quite complex,” he suggested.

“We will not know, of course, until we see the results from the other clinical trials.”

It is tempting to examine the subgroup analysis when seeking explanations for why OCEANIC-AF failed. This indicated that patients naive to anticoagulation prior to study entry had a smaller increase in stroke risk with asundexian than those previously treated.

Gragnano said the finding is “interesting,” although “it is not really clear why this should be the case.” From a biologic perspective, he added, “it is difficult to explain.”

Piccini suggested there may have been a selection bias at play because the previously treated patients had, by definition, demonstrated their ability to take a therapy, and so “we already knew they were going to do well with direct-acting oral anticoagulants.”

He believes that it may have been a better comparison to test asundexian and apixaban only in patients who had not previously been on an anticoagulant.

However, Gragnano cautioned that “we are discussing a negative trial with a negative primary finding, so investigating multiple subgroups, although prespecified, is, of course, dangerous,” as such analyses are “speculative” even in a clearly positive trial.

Off Target?

What does this all mean for factor XI inhibition as a therapeutic target?

“I personally think it’s very premature to conclude that the factor XI inhibitors are quote-unquote ‘ineffective,’” Piccini said. “We have a single clinical trial in a single population that demonstrated an increased risk of ischemic stroke with a small molecule factor XI inhibitor compared to a factor X inhibitor.”

“I am not convinced that we have the answer yet,” he added, noting that results from the other clinical trials in the field are still awaited.

Not least among these is LILAC-TIMI 76, which is comparing abelacimab with placebo in high-risk patients with atrial fibrillation who are deemed unsuitable for oral anticoagulation.

In addition to the small molecules and monoclonal antibodies, there are antisense oligonucleotides (ASOs) IONIS-FXRx, and fesomersen, in early development. The anticoagulant effect of ASOs takes several weeks to kick in, and their long half-life would allow less frequent dosing. Factor XI inhibitors are also being tested in phase 3 studies of patients with noncardioembolic stroke including the ongoing OCEANIC-Stroke study.

“The science is there,” Angiolillo said. “One of the things that we have learned over and over and over again when it comes to phase 3 testing, particularly for antithrombotic drugs [is that] the trials that turn out to be most successful are those where they’ve done better homework in earlier phase testing” and ensured, for example, the most appropriate dose is used.

However, Patel cautioned that “we often forget that many things failed” before warfarin was superseded in the clinic.

“In some of these indications, it takes these kinds of lessons, unfortunately,” in understanding which drug to use, how much inhibition is required, and the right study population. “Part of why we wanted to get these results out as fast as possible was both to inform the field but also to make sure everyone doing these studies recognizes the importance of doing them and that there’s still a huge unmet need.”

“It just emphasizes how critically important randomized studies are,” Piccini said. “Because if you were a betting individual, you surely would have bet that this drug was going to be positive and effective, based upon all the data we have from epidemiologic studies and what we know about factor XI deficiency.”

“So for me, one of the big messages is just the sheer critical importance of large randomized clinical trials.”

OCEANIC-AF was funded by Bayer.

Piccini declared relationships with Abbott Laboratories, Bayer, Biotronik, Boston Scientific, Medtronic, Milestone Scientific, Philips, and Sanofi.

Patel declared relationships with Bayer, HeartFlow, Janssen Pharmaceuticals, and Novartis.

Angiolillo declared relationships with Abbott Laboratories, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly and Company, Faraday, Haemonetics, Janssen Pharmaceuticals, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, Sanofi, Vectura, CeloNova, Eisai, Gilead, Matsutani Chemical Industry Co., Osprey Medical, RenalGuard Solutions, and Scott R. MacKenzie Foundation.

Gragnano declared no conflicts of interest.