Ataciguat Shows Potential for Curbing Progression of Aortic Stenosis

Ataciguat, a novel anthranilic acid derivative, may safely slow progression of valve calcification and potentially delay the need for intervention in patients with fibrocalcific aortic valve stenosis, new phase II data hint.

TAVR and surgical AVR have changed the landscape for patients with aortic stenosis, with recent studies such as EARLY TAVR, AVATAR, and RECOVERY showing promise even in asymptomatic individuals. But not as much progress has been made with pharmaceuticals to prevent the worsening calcification. Many patients spend years being evaluated, waiting for the go-ahead to undergo a procedure without having anything that might prevent progression of their disease.

Ataciguat, part of the sGC activator drug class previously studied in angina and peripheral arterial disease, both with negative results, restores nitric oxide signaling by binding to its receptor enzyme, oxidized soluble guanylate cyclase.

As senior author Jordan Miller, PhD (Mayo Clinic, Rochester, MN), explained to TCTMD, “When that drug binds to the receptor, it reduces the molecular cascades that drive calcification in the valve. It ultimately slows progression of that valve calcium and then subsequently valvular stenosis.”

Moreover, the drug “appears to act preferentially only where there's a lot of disease and a lot of oxidative stress, which we know happens in the valve,” he added.

In their phase II study of 33 patients with mild/moderate fibrocalcific aortic valve stenosis, published online this week in Circulation with first author Bin Zhang, MD (Mayo Clinic), the researchers detected a 69.8% reduction in aortic valve calcification progression with ataciguat (200 mg daily) compared with placebo at 6 months, a difference that narrowly missed statistical significance (P = 0.051). Further, there was significant progression of calcification from baseline to 6 months in the placebo group (P < 0.01) but not in the ataciguat group (P = 0.12), and CT analysis hinted at a greater benefit with the drug in men compared with women.

Those receiving the study drug reported better cardiac function with fewer increases in LV mass index and declines in LV systolic function compared with those receiving placebo.

Miller said the side effects noted with ataciguat are “on par” with placebo, with no participants in phase I studies stopping the drug. No prior research with the drug identified any worrying signals either, he added. It’s possible the drug could lead to bone ossification over time, but animal models have shown no reason, as of yet, for concern. Admittedly, though, “patients shouldn't have to have that trade-off of: ‘Do I need my valve replaced or do I want osteoporosis?” he said.

While these are relatively early data, Miller said ataciguat seems like it might eventually be an option for most patients with documented aortic stenosis, even those with bicuspid and tricuspid anatomy. There may be a significant interaction with warfarin, he noted, but with the advent of other antithrombogenic drugs, “we anticipate that [the affected] population is going to be relatively small.”

Commenting on the study for TCTMD, Brian Lindman, MD (Vanderbilt University Medical Center, Nashville, TN), acknowledged the “unmet need to slow progression of earlier stage [aortic stenosis] to delay the need for procedural therapy, which may obviate the need for AVR in some patients or reduce the number of serial procedures for others depending on their age.” With no effective medical therapy yet identified, “these promising preclinical and early stage clinical data are welcome and encouraging,” he said in an email.

As ataciguat appears to slow aortic valve calcification while being well-tolerated, “there is reason to be hopeful and optimistic, but also circumspect given the very small number of patients studied over a short period of time.”

Phase III trials are underway with ataciguat, Miller reported. “This really is the foundation for that launching of a multicenter, phase III trial that we hope, for the sake of our patients, will end up being successful and being a first-in-class treatment for patients with this disease.”