Although standard-of-care anticoagulants target the extrinsic coagulation pathway, these monoclonal antibodies specifically target the intrinsic coagulation pathway.
In the amrecibart FIH study, 56 adults were randomized to receive either amrecibart (n=42) or placebo (n=14).
In the cenvacibart FIH study, 80 adults were randomized to receive either cenvacibart (n=60) or placebo (n=20).1Both monoclonal antibodies were well tolerated.
In the cenvacibart FIH study, 60.0% of patients in the cenvacibart group and 65.0% of patients in the placebo group experienced at least one TEAE.
For example, the randomized, findings from the phase 2 ROXI-VTE-I and ROXI-VTE-II studies showed the potential of FXI monoclonal antibodies for preventing venous thromboembolism in patients who had undergone knee arthroplasty.
The results were published in Blood by Dan Chalothorn, PhD, of Regeneron Pharmaceuticals, and colleagues. The research team first compared the mechanisms and coagulation effects of amrecibart and cenvacibart with other FXI-targeted monoclonal antibodies in both human and nonhuman primate plasma using an in vitro functional clotting assay.1
Targeting the Intrinsic Pathway
With unique FXI/FXIa-binding mechanisms, amrecibart and cenvacibart address an unmet need for novel treatments with a favorable risk-benefit profile because current standard-of-care anticoagulants carry a high risk for bleeding. Cenvacibart and amrecibart block FXI activity by targeting the catalytic domain and the apple 2 domain of FXI/FXIa, respectively. Although standard-of-care anticoagulants target the extrinsic coagulation pathway, these monoclonal antibodies specifically target the intrinsic coagulation pathway. Based on this mechanism, they both prolonged activated partial thromboplastin time (aPTT) and showed no impact on extrinsic-mediated coagulation in vitro.1
Cenvacibart also demonstrated greater aPTT prolongation compared with amrecibart and abelacimab and osocimab, two other FXI-targeted monoclonal antibodies that target the catalytic domain. Despite the difference in mechanisms, amrecibart showed aPTT prolongation comparable to that achieved with abelacimab and osocimab. The small molecules asundexian and milvexian were not as effective, requiring higher concentrations to achieve an aPTT ratio similar to that achieved with amrecibart, abelacimab, and osocimab and much higher concentrations to achieve an aPTT ratio similar to that achieved with cenvacibart.1
Using a thrombin generation assay—a more sensitive functional assay than the clotting assay—amrecibart and cenvacibart reduced intrinsic pathway–mediated endogenous thrombin potential by 72% and 62% from baseline, respectively. Compared with other FXI inhibitors, amrecibart and cenvacibart inhibited intrinsic pathway–triggered thrombin generation to a similar or greater extent.1
First-In-Human Results and Future Data
To develop these findings further, two first-in-human (FIH) phase 1, randomized, double-blind studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of amrecibart and cenvacibart in single ascending doses in healthy adult participants with low risk for bleeding or thrombosis. In the amrecibart FIH study, 56 adults were randomized to receive either amrecibart (n=42) or placebo (n=14). In the cenvacibart FIH study, 80 adults were randomized to receive either cenvacibart (n=60) or placebo (n=20).1
Both monoclonal antibodies were well tolerated. In the amrecibart FIH study, 42.9% of patients in the amrecibart group and 21.4% of patients in the placebo group experienced at least one treatment-emergent adverse event (TEAE). In the cenvacibart FIH study, 60.0% of patients in the cenvacibart group and 65.0% of patients in the placebo group experienced at least one TEAE. One patient experienced a TEAE related to amrecibart (mild fatigue). The most common TEAEs related to cenvacibart were headache, back pain, cough, and rhinitis. However, Dr. Chalothorn and colleagues note that amrecibart’s clinical safety profile remains unclear because proteases such as kallikrein may convert FXI to FXIa in vivo.1
“Amrecibart may mildly disrupt several functions of FXI/FXIa that are relevant to hemostasis,” the authors wrote.1 “Thus, extensive future studies are warranted to differentiate the relative safety of amrecibart compared to cenvacibart or other FXI inhibitors.”
In terms of pharmacodynamics, cenvacibart resulted in rapid and prolonged aPTT in a dose-dependent manner and to a greater extent than amrecibart. Adults who received IV cenvacibart at a dose of 30 mg or more achieved a threefold increase in aPTT in 30 minutes, which was maintained for at least 21 days. At the same dose level, subcutaneous cenvacibart prolonged aPTT at a slower rate but with a greater effect.1
Amrecibart and cenvacibart are currently under further investigation in ongoing phase 1 and 2 studies for various indications and patient populations. For example, the randomized, findings from the phase 2 ROXI-VTE-I and ROXI-VTE-II studies showed the potential of FXI monoclonal antibodies for preventing venous thromboembolism in patients who had undergone knee arthroplasty. Results showed that cenvacibart, but not amrecibart, was superior to the anticoagulant enoxaparin at preventing venous thromboembolism.2
“Overall, our findings support the continued development of amrecibart and cenvacibart as anticoagulants that may carry less risk of bleeding than existing therapies,” Dr. Chalothorn and colleagues concluded.1
