Upcoming Phase 3 Trials to Evaluate Efficacy, Safety of Milvexian in Patients with Cardiovascular Conditions

In an interview with Pharmacy Times, former American Heart Association president Robert Harrington, MD, professor of medicine at Stanford University, phase 3 program chair, cardiologist, dean of Weill Cornell Medicine, and provost for medical affairs at Cornell University, discussed the Librexia program and how it aims to enhance the benefit-risk profile in patients with cardiovascular conditions by using milvexian as treatment. Further information will be presented during the American Heart Association conference in Philadelphia, Pennsylvania (November 11, 2023, to November 13, 2023).

Pharmacy Times: Can you provide an overview of the key objectives and areas of investigation within the Librexia program?

Robert Harrington: Within the Librexia program, what we're trying to do is understand in common cardiovascular thrombotic conditions of whether or not the addition of factor 11 (FXI) inhibition might improve clinical outcomes. And to do that, is going to require 3 very large trials done simultaneously; 1 in atrial fibrillation against an active comparator, a factor 10 inhibitor; 1 in secondary prevention of stroke, against placebo on a backdrop of antiplatelet therapy; and in 1 in the post-acute coronary syndrome setting, also against placebo, but on the backdrop of standard therapy with dual or single antiplatelet therapy. So, pretty comprehensive to really help us understand does FIX(a) inhibition add to what we're currently doing.

Pharmacy Times: How does milvexian aim to enhance the benefit-risk profile for patients, and what makes it stand out in the context of treating acute coronary syndromes, stroke prevention, etc.?

Harrington: So, milvexian is a FIX(a) inhibitor, and what we're trying to understand is [if] milvexian adds to current therapy in preventing the thrombotic complications of atrial fibrillation, secondary prevention of stroke, and in the post-acute coronary syndrome state. We're going to be looking both at efficacy—does it reduce things like cardiovascular death and heart attacks and stroke—and we're also going to be looking at safety. Is there bleeding risk that's improved relative to current therapy, or when going against placebo does FIX(a) inhibition with milvexian lead to improve ischemic outcomes with tolerable or acceptable bleeding risks?

Pharmacy Times: The program targets reduced thrombotic events with no increased risk of bleeding. Can you elaborate on the significance of this goal and how it addresses current challenges or limitations in existing treatment options?

Harrington: For decades, as we've both studied and used antithrombotic therapies, there's always been this balance and trade-off, and the trade-off is increased efficacy with reduction of thrombotic events, but frequently associated with an increased risk of bleeding as 1 provides more potent antithrombotic effects. With FIX(a) inhibition with milvexian, the biologic hypothesis is that we can uncouple thrombotic effects from hemostatic effects and that has to do with the role that FIX(a) plays in the coagulation system. What we're really trying to understand clinically is can we get efficacy without a marked increase in bleeding? And in some cases—particularly against the active control FIX inhibitors—can we get less bleeding than therapies which have already been shown to be beneficial against the oral vitamin K antagonists both with regard to ischemic events and bleeding.

Pharmacy Times: Phase 2 trial data are the foundation for the Librexia program. What key insights and findings from the phase 2 trials support the program's objectives and the investigation?

Harrington: Two important phase 2 trials were done with milvexian, 1 was in total knee replacement in looking at venous thromboembolism occurrence. That's important because it really lays the foundation for is FXI inhibition with milvexian, an effective antithrombotic, can it prevent clot formation, and can it prevent clot formation against the current standard, which is low molecular weight heparin? And in fact, it does, you can reduce the risk of venous thromboembolism in the post-total knee replacement population with milvexian. And that tells us that there's the possibility that we can reduce thrombosis in other settings while minimizing or even decreasing bleeding risk.

In a similar way, a phase 2 trial was done in a stroke population to try to understand dosing, to try to understand different doses, and to try to understand this balance of efficacy and safety. The most important piece of information coming out of the stroke setting was that the drug can be given safely to people who have had a stroke as you try to prevent a second stroke. So, you take the 2 phase 2 trials in total, and we have the promise that sets up a hypothesis of thrombotic efficacy while minimizing bleeding, that we really are looking for the phase 3 programs.

Pharmacy Times: Can you discuss the potential of achieving an enhanced benefit-risk profile and how this goal may address unmet needs or improve outcomes in patients?

Harrington: This is a pretty ambitious program, milvexian, 3 big trials in common disease states, atrial fibrillation, acute coronary disease, and in the stroke setting. There is an enormous opportunity here given the size of those patient populations to make improvement on current standard of care, and what we also know is that there are other thrombotic disorders that could be studied. We have things like cancer-associated thrombosis, we have issues in children with congenital heart disease and thrombotic disorders, we have valvular heart disease. There are also some understudied populations. What about the patients with chronic kidney disease, [or] the patients with multiple comorbidities that might make physicians reluctant to use current anticoagulant therapy? All of these open up the possibilities that if milvexian is shown to be beneficial in the settings that we're currently studying, [it can] potentially expand into other areas.