Abelacimab: the next frontier in safer anticoagulation therapy 

The landscape of anticoagulation therapy could be on the brink of a major transformation. In an interview with Dr. Dan Bloomfield, Cardiologist and CMO at Anthos Therapeutics, we explore the dramatic potential of abelacimab, an investigational Factor XI inhibitor currently being developed by Anthos Therapeutics, and its implications for patients with atrial fibrillation (AFib) and other thrombotic conditions. Bloomfield shares insights into his work and his belief that abelacimab could revolutionise the industry’s approach to anticoagulation, particularly for patients at high risk of bleeding. This development is not just a significant milestone in drug discovery, but also a potential breakthrough for clinical practice, as it may address a critical gap in current treatments by offering effective stroke prevention with a reduced risk of bleeding.

Addressing the unmet need in AFib care

Atrial fibrillation (AFib) is a type of irregular heartbeat, or arrhythmia, that occurs when the upper chambers of the heart (the atria) beat chaotically and out of sync with the lower chambers (the ventricles). This can lead to poor blood flow and an increased risk of stroke, heart failure and other complications. It’s one of the most common heart rhythm disorders and can be caused by conditions like high blood pressure and heart disease, or can sometimes occur without an obvious cause. Managing AFib often involves medication, lifestyle changes, and occasionally procedures to restore a normal heart rhythm.

While current anticoagulant medications are effective in stroke prevention, they also carry an elevated risk of bleeding. This presents a dilemma for both physicians and patients, forcing them to weigh the benefits of stroke prevention against the potential for serious bleeding complications. As Bloomfield explains, “In many patients with atrial fibrillation, their risk of having a stroke is high. While the currently available anticoagulants are effective in preventing strokes, all these agents also have an elevated risk of bleeding.” This challenge is particularly acute in elderly patients, those with a history of bleeding, or individuals taking other medications that increase bleeding risk, such as antiplatelet agents.

The AZALEA-TIMI 71 study, a crucial milestone in abelacimab’s development, demonstrated significant reductions in bleeding risks compared to rivaroxaban, a direct-acting oral anticoagulant (DOAC). For patients deemed to be at high risk of bleeding, abelacimab could offer a compelling alternative, if approved, potentially providing stroke protection without the constant fear of haemorrhagic events. This could be a critical advancement, as it may address a major barrier to effective anticoagulation in vulnerable patient populations.

The advantage of Factor XI inhibition

Abelacimab’s unique mechanism of action as a Factor XI inhibitor sets it apart from other existing anticoagulants. A Factor XI inhibitor is a type of anticoagulant that specifically targets Factor XI, a protein in the blood that plays a crucial role in the blood clotting process. Factor XI is part of the intrinsic pathway of coagulation, and its activation contributes to the formation of abnormal blood clots in blood vessels and the heart.  Importantly, Factor XI is not required to form normal blood clots that the body generates to stop bleeding.  This explains why inhibiting Factor XI may be beneficial in the prevention of strokes or deep venous thrombosis without causing an increase in bleeding,  This is in contrast to Factor Xa inhibitors (e.g., Eliquis, Xarelto) which prevent abnormal blood clots at the expense of an increase in bleeding  risk.

While the AZALEA trial primarily focused on safety, with efficacy data anticipated from the ongoing LILAC trial conducted by Anthos Therapeutics, the observed reductions in major and gastrointestinal (GI) bleeding are significant. Bloomfield points out a key difference in administration: “Factor Xa inhibitors are oral agents that are absorbed in the gut. As such, these agents can increase the risk of bleeding in the gut itself. Abelacimab is administered subcutaneously and absorbed into the systemic circulation; it never sees the inside of the gut. This may explain, in part, why the AZALEA study demonstrated an 89 percent reduction in GI bleeding compared to rivaroxaban.”

This difference in administration may be a significant factor in the reduced risk of GI bleeding, a common and often serious complication for AFib patients on anticoagulants. GI bleeding can lead to patients temporarily or permanently discontinuing their anticoagulation therapy, significantly increasing their stroke risk. “When someone has a GI bleed, they often stop taking their anticoagulant .  Without taking their anticoagulant, they face a five-fold increased risk of stroke,” explained Bloomfield. “Many AFib patients never go back on an anticoagulant, even when their GI bleeding subsides, because they fear another bleed. This is one of the major challenges that plagues current treatment of AFib.” The promising GI bleeding safety profile of abelacimab offers hope for addressing this critical challenge and improving long-term outcomes for AFib patients.

Expanding access to effective anticoagulation

A significant proportion of AFib patients are either undertreated or not prescribed anticoagulants at all, largely due to the fear of bleeding. Bloomfield believes abelacimab has the potential to address this unmet clinical need. “Fear of bleeding is the primary reason physicians hesitate to prescribe an anticoagulant to a patient at risk for stroke or other thrombotic conditions,” he said. “The safety data from the AZALEA trial suggest that abelacimab has a remarkably lower rate of bleeding compared to rivaroxaban, which directly addresses this fear.”

This concern extends not only to patients who are completely untreated but also to those receiving subtherapeutic doses of anticoagulants, which may not provide adequate stroke protection. Furthermore, patients taking an anticoagulant  at any dose, who experience bleeding or bruising may also benefit from a potentially safer alternative. “These patients may also benefit from abelacimab,” suggests BloomfieldIf approved for the prevention of stroke, abelacimab could expand access to effective anticoagulation to a wider range of patients if it is proven to mitigate the risk of bleeding, ultimately helping to prevent potentially devastating consequences like stroke.

This potential breakthrough could transform both drug discovery and clinical treatment strategies, with the possibility of enhancing patient safety and improving outcomes in thrombotic conditions like atrial fibrillation.

Regulatory approval and market introduction

Anthos Therapeutics is actively pursuing the clinical development of abelacimab. The LILAC study, a Phase III trial, is evaluating abelacimab in AFib patients who are deemed unsuitable for or unable to take existing anticoagulants due to bleeding risk. “This study will be the basis of a Biologics License Application (BLA) submission to the FDA for the approval of abelacimab,” Bloomfield noted. “LILAC is an event-driven study so we do not know exactly when the study will end, but we anticipate having final data in 2026.”

In addition to AFib, Anthos Therapeutics is also investigating abelacimab’s potential in cancer-associated thrombosis, for which there are currently no FDA approved products. Its ASTER and MAGNOLIA studies are evaluating abelacimab in cancer patients presenting with acute thrombotic events. These studies, anticipated to complete in  2027, could open doors for abelacimab’s approval in this indication. “We anticipate ASTER will complete in early 2027 and could form the basis for approval in the treatment and prevention of venous thrombotic events in patients with cancer,” Bloomfield said.

A shift in anticoagulation therapy

The implications of the AZALEA study and the ongoing clinical development programme for abelacimab are far-reaching. Bloomfield suggests that abelacimab could represent a paradigm shift in how we approach anticoagulation therapy. “The AZALEA study suggests that with abelacimab it is possible to anticoagulate patients without increasing the risk of bleeding, something that scientists and doctors thought impossible,” he explained. “This is a paradigm shift in our understanding of coagulation and could potentially transform how doctors will treat and/or protect patients from blood clots.”

For patients who are untreated or on subtherapeutic doses, abelacimab may offer the potential for effective stroke protection without the added risk of bleeding complications, if approved by the FDA. For those already using anticoagulants, it may provide a safer alternative with significantly reduced bleeding risks. This could be a key advancement in drug discovery, as it addresses a critical gap in current treatments. Traditional anticoagulants often require a delicate balance between preventing clots and minimising bleeding, a challenge that abelacimab could overcome. Ultimately, this development has the potential to address a longstanding gap in current treatments and improve patient outcomes and the future of anticoagulation therapy.

Meet Dr Dan Bloomfield

Dr Dan Bloomfield has more than 20 years in drug development, initially at Merck and most recently at Cardurion Pharmaceuticals. Bloomfield joined Cardurion in May 2017 as its first CEO after a diverse 14-year career at Merck & Co. (NYSE: MRK), which included leadership roles in early and late clinical development and cardiovascular discovery. He was actively involved in business development, acquisitions, and numerous licensing opportunities and spent a year as Chief of Staff for Merck’s CEO, Ken Frazier. Bloomfield’s career at Merck culminated as SVP and Therapeutic Area Head for Cardiovascular, Diabetes, Endocrine, and Women’s Health Programs and he was responsible for the central coordination and strategic oversight of Merck’s R&D organization in China across all therapeutic areas.

In addition to his executive duties, Bloomfield was a founding member and co-chair of the Cardiac Safety Research Consortium (a public-private partnership with the FDA, academia and industry) and served as Rapporteur for the ICH E14 implementation working group for nine years.

After finishing a BA in Chemistry at Haverford College, Bloomfield earned a master’s degree in Social Anthropology at Oxford University as a Rhodes Scholar. Upon his return to the US, he attended Harvard Medical School and subsequently did his Internal Medicine and Cardiology training at Columbia before joining the faculty. As an Associate Professor his academic research was supported by grants from the NIH (K08, R01, K24), multiple foundations and industry.