A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction
Authors: Rao Sunil V. , Kirsch Bodo , Bhatt Deepak L. , Budaj Andrzej , Coppolecchia Rosa , Eikelboom John , James Stefan K. , Jones W. Schuyler , Merkely Bela , Keller Lars , Hermanides Renicus S. , Campo Gianluca , Ferreiro José Luis , Shibasaki Taro , Mundl Hardi , Alexander John H. , Hengstenberg Christian , Steinwender Clemens , Alber Hannes , Steringer-Mascherbauer Regina , Schober Andreas , Auer Johann , Roithinger Franz Xaver , von Lewinski Dirk , Moertl Deddo , Huber Kurt , Coussement Patrick , Hoffer Etienne , Beauloye Christophe , Janssens Luc , Vranckx Pascal , De Raedt Herbert , Vanassche Thomas , Vrolix Matthias , Rokyta Richard , Parenica Jiri , Pelouch Radek , Motovska Zuzanna , Alan David , Kettner Jiri , Polasek Rostislav , Cermak Ondrej , Sedlon Pavel , Hanis Jiri , Novak Martin , Belohlavek Jan , Horacek Thomas , Leggewie Stefan , Wenzel Philip , vom Dahl Juergen , Sievers Burkhard , Pulz Jan , Schellong Sebastian , Clemmensen Peter , Muller-Hennessen Matthias , Rassaf Tienush , Falukozi Jozsef , Ruzsa Zoltan , Tomcsanyi Janos , Csanadi Zoltan , Herczeg Bela , Koszegi Zsolt , Vorobcsuk Andras , Kiss Robert , Baranyai Csaba , Dezsi Csaba , Merkely Bela , Lupkovics Geza , Rossini Roberta , Scherillo Marino , Sergio Saba Pier , Calogero Campo Gianluca , Calo Leonardo , Nassiacos Daniele , Quadri Giorgio , Sciahbasi Alessandro , Silvio Marenzi Gian Carlo , Reimers Bernhard , Perna Gian Piero , Sacca Salvatore , Fattore Luciano , Brunelli Claudio , Picchi Andrea , Kuramochi Takehiko , Kondo Kazuhisa , Aoyama Takahiko , Kudoh Takashi , Yamamoto Tadashi , Takaya Tomofumi , Mukai Yasushi , Fukui Kazuki , Morioka Nobuyuki , Ando Kenji , Yamamuro Atsushi , Morita Yasuhiro , Koga Yasuaki , Watanabe Tetsuya , Sakamoto Tomohiro , Shibasaki Taro , Maebuchi Daisuke , Takahashi Akihiko , Yonetsu Taishi , Kakuta Tsunekazu , Nishina Hidetaka , Oemrawsingh Rohit , Dorman Reinhart , Oude Ophius Ton , Prins Paco , al Windy N.Y.Y. , Zoet-Nugteren S.K. , Hermanides Rik , van Eck Martijn , Scherptong Roderick , Cornel J.H. , Damman Peter , Bech Gerhard , Torquay R. , Kietselaer Bas , Grzelakowski Pawel , Krzysztof Dyrbus , Budaj Andrzej , Miekus Pawel , Przybylski Andrzej , Zarebinski Maciej , Balsam Pawel , Szachniewicz Joanna , Gierlotka Marek , Tycinska Agnieszka , Iniguez Romo Andres , Fernandez Ortiz Antonio , Carrasquer Cucarella Anna , Sanmartin Fernandez Marcelo , Sionis Alessandro , Bueno Zamora Hector , Ferreiro Gutierrez Jose Luis , Almenar Luis , Ferreira Gonzalez Ignacio , Pascual Figal Domingo A. , Almendro Delia Manuel , Jimenez Fernandez Miriam , Skeppholm Mika , Zedigh Crister , Angeras Oskar , Lauermann Jorg , Erlinge David , Gustafsson Robin , Mooe Thomas , Utreras Alejandro , James Stefan , Grimfjard Per , Pedrazzini Giovanni , Mach Francois , Fournier Stephane , Haegeli Laurent , Beer Jurg H. , Leibundgut Gregor , Kobza Richard , Kaiser Christoph , Kunadian Vijay , Al-Lamee Rasha , Gorog Diana , Khan Sohail , Trevelyan Jasper , Toor Iqbal , Smith James , Purushottam Bhaskar , Treasure Charles , Arena Frank , Vedere Amarnath , Henderson David , Gilani Syed , Jones Alonzo , Carrillo-Jimenez Rodolfo , Gillespie Eve , Marhefka Gregary , Wang David , Olson Charles , Bloom Stephen , Iftikhar Faizan , Brabham David , McGinty John , Thompson Charles , Talano James , Ginete Wilson , Williams Marcus , Masud Ali , Ariani Mehrdad , Bitar Fahed , Wang Thomas , Samuelson Bradley 
Published: August 2022

Background:
Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI).

Methods:
We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo.

Results:
The median age was 68 years, 23% of participants were women, 51% had ST-segment–elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71–1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69–1.61]).

Conclusions:
In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04304534; URL:
https://www.clinicaltrialsregister.eu/ctr-search/search
; Unique identifier: 2019-003244-79.