ESC 2022 preview – who’s got the XI factor?

Bristol Myers Squibb/Johnson & Johnson and Bayer will soon get more hints about whether their Eliquis and Xarelto follow-ons can cut it.

With the mega-blockbuster blood thinners Eliquis and Xarelto both set to come off patent in the next few years, the pressure is on the likes of Bristol Myers Squibb, Johnson & Johnson and Bayer to fill a massive looming hole.

As luck would have it, all of the aforementioned groups are already working on what could be the next big thing in anticoagulation, factor XI inhibition. And the upcoming European Society of Cardiology meeting will feature mid-stage data on the two most advanced oral candidates: Bristol/J&J’s milvexian and Bayer’s asundexian.

One question is whether these agents can, as hoped, provide similar or better efficacy to factor Xa inhibitors like Eliquis, but with a lower bleeding risk. And investors will also be wondering which indications their developers will be targeting in phase 3.

Another talking point is whether the big guns could be beaten to the market by the Novartis spin-off Anthos, which recently took its anti-factor XIa MAb abelacimab into phase 3 (Anthos goes pivotal as Novartis and Pfizer look on, May 6, 2022).

If the factor XI opportunity is as big as hoped, Anthos might attract a suitor – and it will not have gone unnoticed that Pfizer, which is partnered with Bristol on Eliquis, does not currently have a factor XI inhibitor in clinical development.

Pfizer has another option: Berenberg analysts have suggested that the big pharma might make a good US partner for Bayer on asundexian. They also said that a tie-up between Bayer and Novartis or Astrazeneca would make sense.

No better than Eliquis?

So far, though, Pfizer has played down the potential of factor XI inhibition. During the group’s second-quarter earnings call its chief executive officer, Albert Bourla, said: “We are looking for science that could provide hope that we can have something better than Eliquis. And we haven't found it yet.”

The company’s chief scientific officer, Mikael Dolsten, highlighted the “tremendously high R&D expense”, especially given the fact that, by the time factor XI inhibitors are set to reach the market, generic versions of Eliquis might already be available. He concluded: “For us, it doesn't look like the best area to deploy capital.”

Therefore, a big decision faced by factor XI developers is where to target their efforts. Berenberg reckons that going for large indications such as stroke prevention in atrial fibrillation, for which Eliquis and Xarelto are already used, could be a non-starter given that very large trials would be needed to show a safety advantage over the incumbents.

“We anticipate more targeted phase 3 trials, which will address smaller (but still meaningful) patient groups with high unmet need,” they wrote.

Meanwhile, SVB analysts have argued that the factor Xa inhibitors are underused in their approved indications, mainly because of bleeding risk, leaving the door open for safer alternatives. 

Potential target indications for phase 3 studies with Factor XI inhibitors
Indication No of US patients Note
Coronary/peripheral artery disease 20m Xarelto approved (Compass) but not widely used due to increased bleeding risk
Stroke prevention in atrial fibrillation 7.3m SOC is direct oral anticoagulants*, but these still have bleeding risk
Secondary myocardial infarction prevention 800,000 per yr SOC is aspirin + Plavix; in ACS, Eliquis failed (Appraise-2) & Xarelto showed benefit but increased major bleeding (Atlas ACS 2-TIMI 51)
Secondary stroke prevention 700,000 per yr SOC is aspirin or aspirin + Plavix
ESRD pts on dialysis 550,000 per yr No clear SOC
Cancer thrombosis prevention 200,000 per yr Direct oral anticoagulants* used in some pts, but not in GI/GU cancers owing to increased bleeding risk; here LMW heparin is SOC
Mechanical heart valves 100,000 per yr SOC is warfarin, direct oral anticoagulants* contraindicated
*Direct oral anticoagulants are Eliquis, Xarelto, Pradaxa, Lixiana; ACS=acute coronary syndrome; ESRD=end-stage renal disease; SOC=standard of care. Source: Berenberg note June 23, 2022.

One underserved niche is secondary stroke prevention, and here the ESC meeting will feature mid-stage data on both milvexian and asundexian. Bayer will also present results with asundexian in secondary myocardial infarction prevention.

In stroke, the factor XI inhibitors are being given on top of current standard of care, antiplatelet therapy, with primary endpoints evaluating the incidence of stroke or covert brain infarction.

According to a cardiologist cited by SVB, the ideal result in secondary stroke prevention would be 10-20% stroke reduction with no or low bleed risk and no intracranial haemorrhage.

The analysts pointed out differences that might favour asundexian’s Pacific-Stroke trial, including a longer duration of six months, versus three months for milvexian’s Axiomatic-SSP study. Pacific-Stroke also has a more flexible background therapy regimen of either dual or mono antiplatelet therapy, versus dual antiplatelet therapy in Axiomatic-SSP; SVB says the former is more in line with real-world use.

Meanwhile, Bayer’s Pacific-AMI study is evaluating asundexian alongside dual antiplatelet therapy – aspirin plus Plavix – in patients following a heart attack. The primary endpoint is a composite of cardiovascular death, myocardial infarction, stroke and stent thrombosis. This is a setting in which both Eliquis and Xarelto have been linked with increased rates of major bleeding, with the former failing to show a benefit on ischaemic events.

So far, promising phase 2 data have been seen with asundexian in stroke prevention in atrial fibrillation, and milvexian for venous thromboembolism prevention in patients undergoing total knee replacement.

More shots on goal

Meanwhile, Bayer has several more shots on goal in the factor XI space. Another of these recently took a step forward, with the group’s partner Ionis recently announcing positive results with the subcutaneously injected antisense contender fesomersen in end-stage renal disease patients on dialysis, without giving any detailed data.

Others are also looking at the renal niche: ESRD patients have a high risk of stroke, myocardial infarction and venous thromboembolism, but no antithrombotics are approved for this population.

Overall, of the factor XI agents in development, Berenberg says milvexian and asundexian have the biggest commercial potential, putting peak revenues at $10bn and $3.6bn respectively; however, they reckon the projects’ chances of success are only 50-50. SVB also sees a 50% chance of success for milvexian, but lower peak sales potential, pencilling in $4.4bn.

Bristol/J&J and Bayer will need to hit these kinds of figures if they are to replace their existing anticoagulant juggernauts.

Factor XI inhibitors in development
Project Company Description Trial details
Phase 3
Abelacimab (MAA868) Anthos Therapeutics (Novartis spin-out) Anti-factor XI & XIa MAb Cancer-associated VTEs: ph3 Aster vs Eliquis & Magnolia (GI/GU cancers) vs LMW heparin, both complete Sep 2023;
ph2 AZALEA-TIMI 71 vs Xarelto in AF, data due Q1 2023
Phase 2
Asundexian (BAY 2433334) Bayer Oral factor XIa inhibitor Pacific-AF vs Eliquis, data reported Apr 2022; data from Pacific-AMI & Pacific-Stroke due at ESC 2022
Milvexian (BMS-986177) Bristol Myers Squibb/Johnson & Johnson Oral factor XIa inhibitor Axiomatic-TKR presented at AHA 2021; data from Axiomatic-SSP due at ESC 2022
Fesomersen (BAY2976217/IONIS-FXI-LRx) Bayer/Ionis Factor XI antisense RE-THINc ESRD, in ESRD pts on dialysis, toplined positive Jul 2022
Osocimab (BAY1213790) Bayer/Aronora Anti-factor XIa MAb Convert in ESRD pts on dialysis, data due H2 2022
MK-2060 Merck & Co Anti-Factor XI & XIa MAb MK-2060-007 in ESRD pts on dialysis, data due H1 2023
AB023 Aronora Anti-factor XI & XII MAb

Ph2 data published in ESRD pts on dialysis; ph2 ongoing n cancer pts receiving chemo*

Phase 1
BMS-986209 Bristol Myers Squibb  Oral factor XIa inhibitor Completed ph1 Aug 2021
Ir-CPI Bioxodes Anti factor XI & XII protein Completed ph1 Jul 2020
*Investigator-sponsored. AF=atrial fibrillation; AMI=acute myocardial infarction; ESRD=end-stage renal disease; SSP=secondary stroke prevention; TKR=total knee replacement; Source: Evaluate Pharma &

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