Key Points
- Selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by uncoupling hemostasis from thrombosis and potentially providing protection from ischemic events without increasing bleeding risk among patients with acute myocardial infarction.
- The Phase 2 PACIFIC-AMI trial (n=1,601) compared Asundexian 10 mg, 20 mg and 50 mg versus placebo (on top of dual antiplatelet therapy) among patients suffering from acute myocardial infarction. Overall, all doses of Asundexian seemed to be safe as they had similar rates of BARC 2, 3 and 5 bleeding compared to placebo. However, even the highest dose of Asundexian did not result in a significant reduction in the primary ischemic outcome of cardiovascular death, MI, stroke or stent thrombosis (compared to placebo), perhaps due to a low event rate. Adequately powered Phase 3 data are therefore needed to understand whether Asundexian may provide additional protection from ischemic events among patients who have acute coronary syndromes.
During the American College of Cardiology (ACC) Conference in April 2022, the first in-human data from the novel anticoagulant Asundexian were presented to the scientific community. Asundexian is a Factor XIa inhibitor, which acts in a more targeted fashion compared to the DOACs that are already available on the market. Specifically, DOAC-mediated Factor Xa inhibition prevents the formation of pathological thrombi, but also blocks the tissue factor pathway, which in turns may prevent the formation of thrombin-mediated “beneficial clots” that are needed in routine homeostasis of blood vessels around the body. This status quo, however, could be revolutionized with selective Factor XIa inhibition, which would be capable of preventing the formation of pathological thrombi while still allowing activation of the tissue factor pathway and thus the formation of “beneficial clots”.
In the ACC 2022 conference, the randomized phase 2 dose-finding PACIFIC-AF trial (n=755) compared Asundexian 20 mg, Asundexian 50 mg and apixaban among patients with atrial fibrillation. In this study, Asundexian 50 mg showed a significant reduction in the primary outcome of major and non-major clinically relevant bleeding; the overall low bleeding rate, however, resulted in wide confidence intervals, and the even fewer ischemic events did not allow the pre-specified exploratory analyses to identify any major differences between the arms. These data, however, paved the way for larger Phase 3 randomized trials that will be forthcoming in the AF arena.
Importantly, Phase 1 trials of Asundexian generated sufficient evidence that this agent does not have a significant interaction with clopidogrel or impact on CYP3A4. As such, a dedicated trial was conceptualized to study the use of Asundexian on top of antiplatelet therapy among patients with acute myocardial infarction.
During the 2022 European Society of Cardiology Conference in Barcelona, Dr. John Alexander presented the results of the PACIFIC-AMI trial (NCT04304534). This multicenter, prospective, randomized, placebo-controlled, double-blind, dose-ranging study enrolled 1,601 patients with acute myocardial infarction and randomized them to Asundexian 50 mg (n=400), Asundexian 20 mg (n=400), Asundexian 10 mg (n=400), or placebo (n=400) on top of dual antiplatelet therapy. Patients were older (mean age 68 years), ~25% female, with about ~25% patients with prior MIs in both groups. Notably, there was a balanced 50/50 breakdown in terms of STEMI vs NSTEMI at the time of enrollment, and on average patients were enrolled within a median of 4 days from their index MI. In accordance with professional guidelines for ACS, the majority of patients (80%) were treated with a potent P2Y12 inhibitor (ticagrelor or prasugrel), and the remaining 20% received clopidogrel. Blood analysis confirmed a proportional inhibition of factor XIa with increasing doses of Asundexian, up to 90% inhibition with 50 mg of Asundexian.
With regard to safety outcomes, the primary analysis included events up to 2 days after discontinuation of the study drug. Asundexian 50 mg on top of DAPT, compared to placebo, was found to have similar rates of BARC 2, 3 and 5 bleeding (10.5% vs 9.0%, HR 1.20, 90% CI 0.83-1.75); similarly, the pooled comparison of all three Asundexian doses to placebo found similar rates of BARC bleeding (HR 0.98, 90% CI 0.71-1.35). Rates of other adverse events overall similar between Asundexian and placebo.
With regard to efficacy outcomes, the composite primary outcome of the intention-to-treat analysis included cardiovascular death, MI, stroke or stent thrombosis. Asundexian 50 mg on top of DAPT, compared to placebo, was found to have similar rates of the primary outcome (5.5% vs 5.5%, HR 1.01, 90% CI 0.61-1.66); similarly, a pooled comparison of the two higher doses of Asundexian (50 and 20 mg) versus placebo found similar rates of the primary outcome (HR 1.05, 90% CI 0.69-1.61). Similar to the prior PACIFIC-AF, the overall low event rate resulted in wide confidence intervals.
In conclusion, selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by finally uncoupling hemostasis from thrombosis and potentially allowing similar protection from ischemic events without increasing bleeding risk among patients with myocardial infarction. Larger Phase 3 trial data, however, continue to be needed in order to have a more definitive understanding of the efficacy and safety of this novel agent, and whether it may confer additional protection from ischemic events among patients who have acute coronary syndromes.