Robert Harrington, MD: Importance of Phase 3 Trial Program Evaluating Milvexian

Approximately 50,000 patients in three concurrent trials will comprise the phase 3 Factor XIa program evaluating the investigational oral inhibitor Milvexian for the prevention of thrombotic events.

Announced by Bristol Myers Squibb in collaboration with Janssen Pharmaceuticals, Inc, the phase 3 Milvexian program looks to improve patient outcomes in acute coronary syndromes, stroke prevention in atrial fibrillation, and stroke prevention after an acute ischemic stroke.

The HCPLive team spoke with the phase 3 program chair Robert Harrington, MD, Arthur L. Bloomfield Professor of Medicine, Stanford University, on the floor at the American College of Cardiology (ACC) 2023 Annual Scientific Sessions in New Orleans, Louisiana.

Harrington discussed each of the 3 trials in the program, the benefit of the large population size, and his hypotheses regarding the potential effects of the Factor XIa inhibitor. Harrington described the phase 2 AXIOMATIC trial program as informing safety and potential efficacy with clot formation prevention, ultimately allowing the clinical trial program to move towards phase 3.

“I think we learned some important things that inform phase 3, one of which is we learned that Factor XIa inhibition actively does prevent clot formation,” “...We also learned that even in a high-risk bleeding population like secondary prevention of stroke, that Factor XIa inhibition does not have a dose-dependent, bleeding risk associated with it.”

Harrington elaborated on the three trials included in the clinical trial program, which will each begin around the same time in the first half of 2023. The first is Librexia STROKE, evaluating milvexian in addition to standard-of-care antiplatelet therapy for stroke prevention in patients after an acute ischemic stroke or high-risk transient ischemic attack

The next is the Librexia AF trial which will investigate milvexian compared to apixaban in preventing stroke in patients with atrial fibrillation. Lastly, the Librexia ACS plans to evaluate event reduction in acute coronary syndromes in addition to standard-of-care antiplatelet therapy.

“Three big trials, each trial is in the 10 to 15,000 patient range,” Harrington said. “So, a large group of patients, and what's very unique about this program, is that we're going to be able to learn across the trials as we do all three, instead of learning sequentially.”

With such a large patient population, the studies will be conducted at over 1000 investigative sites globally. Harrington noted a single data safety monitoring board will assess unblinded data alongside the study to assure participant safety and integrity of the clinical trials.

“We're hopeful that this will lend efficiency, lend insight, and really, to me has been one of the most interesting aspects of putting this whole thing together,” Harrington said.

Across all three studies, Harrington discussed the hypotheses for each trial centered around Factor XIa inhibition, particularly its safety in that clinicians can potentially prevent thrombosis without increasing the risk of bleeding. He noted that with anticoagulant therapy, as you typically increase the dose, the risk of bleeding is increased linearly. However, early studies suggest this is not the case with Factor XIa inhibition.

“With factor XIa inhibition, the early studies would suggest you increase the risk of bleeding to a point, and then it's flat, independent of dose. That's unusual,” Harrington said. “And what that suggests is maybe we can prevent thrombosis without getting the big bleeding risk penalty.”

Disclosures: Harrington reports having received funds for consulting or research grants from Bristol-Myers Squibb Company, Cytokinetics, and Janssen Pharmaceuticals, Inc.