Kardigan announced positive Phase 2 results for ataciguat, an investigational oral soluble guanylate cyclase activator, in patients with moderate calcific aortic valve stenosis at the American Heart Association Scientific Sessions 2025. The study demonstrated that ataciguat slowed the progression of aortic valve calcium while improving cardiac function and output compared to placebo, potentially offering the first medical treatment for a condition that currently has no approved therapies.
Clinical Trial Results Show Cardiac Function Improvements
The Phase 2, randomized, double-blind clinical trial included 23 patients who received either 200 mg ataciguat (n=12) or placebo (n=11) once daily for 12 months. Treatment with ataciguat resulted in improvements in left ventricle ejection fraction (LVEF) and cardiac output, and slowed the progression of worsening diastolic function at six months compared to placebo.
Notably, participants with the least increase in aortic valve calcium had the largest increase in cardiac output. The treatment also slowed the progression of aortic valve resistance, an alternative measure for assessing valvular compliance, compared to placebo at six months. Changes in aortic valve resistance correlated with changes in left ventricular remodeling, specifically left ventricular mass index.
"The primary driver of calcific aortic valve stenosis is the accrual of aortic valve calcium, which causes chronic left ventricular pressure overload, leading to maladaptive ventricular remodeling and dysfunction," said Brian Lindman, M.D., MSCI, medical director, Structural Heart and Valve Center, Vanderbilt University Medical Center. "The data presented on ataciguat at AHA reinforce the potential to deliver the first medical treatment for moderate calcific aortic valve stenosis that targets the root cause of the disease, moving us beyond passive monitoring toward earlier, disease-modifying intervention."
Addressing Significant Unmet Medical Need
Calcific aortic valve stenosis is a progressive disease characterized by calcification of the aortic valve and reduced blood flow from the heart. In the U.S. alone, more than 3.4 million people are living with this condition. Calcium buildup on the aortic valve is the leading cause of calcific aortic valve stenosis in adults in the U.S. and EU, and is known to lead to heart failure and death without intervention.
Currently, patients with calcific aortic valve stenosis face "watchful waiting" as the standard of care until the condition advances to the severe stage, which requires procedural intervention. No approved treatments exist for this progressive disease.
"For the millions of patients diagnosed with moderate calcific aortic valve stenosis each year, there are no treatment options except to watch and wait for their disease to progress to a point where surgical intervention is necessary to replace the valve," said Jay Edelberg, M.D., Ph.D., co-founder and chief medical officer, Kardigan. "The Phase 2 data on ataciguat presented at AHA reinforce our hypothesis that slowing the buildup of aortic valve calcium is associated with improvements in cardiac output and function."
Phase 3 Trial Initiated
Based on these promising results, Kardigan has initiated the KATALYST-AV Phase 3 clinical trial to assess ataciguat versus placebo in the preservation of functional capacity through myocardial and valvular effects, and in slowing the progression to valve replacement. The primary Phase 2 clinical trial results were published in Circulation in February 2025.
Ataciguat is being developed as a potential first-in-class treatment for calcific aortic valve stenosis and represents an alternative to the current "watchful waiting" approach. The drug has the potential to revolutionize the management of calcific aortic valve stenosis as the first pharmacological therapy by targeting calcium as the underlying driver of disease progression. Kardigan acquired rights to ataciguat from Sanofi and Mayo Clinic.
Broader Pipeline Development
Ataciguat is one of three late-stage investigational candidates in Kardigan's portfolio of targeted medicines designed to modify the underlying cause of various cardiovascular diseases. The company is also developing tonlamarsen, an angiotensinogen-targeted bridging therapy for acute severe hypertension, and danicamtiv, a potential first-in-class direct cardiac myosin activator targeting genetic dilated cardiomyopathy driven by sarcomeric variants.
