Kardigan Completes Enrollment in Phase 2b KATALYST-AV Trial of Ataciguat, Advances Plans for Aortic Stenosis Development
Kardigan®, Inc., a precision cardiovascular company, has announced the completion of enrollment in its Phase 2b KATALYST-AV clinical trial evaluating ataciguat in people with aortic stenosis (AS). Alongside this development milestone, the company shared findings from a pre-planned analysis of baseline characteristics in the clinical trial and new real-world evidence examining disease progression among approximately 45,000 people with aortic stenosis.
The analyses are expected to help guide the continued development of ataciguat and support the design of a future Phase 3 registrational study. The company is evaluating changes in aortic valve calcium (AVC), together with measures of cardiac structure and function, to better understand the potential effects of treatment on both the valve and the heart muscle.
KATALYST-AV is designed to assess whether ataciguat can influence disease progression in patients with aortic stenosis, a condition characterized by narrowing of the aortic valve that can restrict blood flow from the heart to the rest of the body. The trial’s primary endpoint will now be assessed at Week 48, rather than the originally planned earlier assessment. The company also plans to conduct an internal interim analysis at Week 24 to examine disease progression rates and directional treatment effects on the aortic valve and ventricle.
According to Kardigan, the updated analysis of baseline clinical trial data showed substantial variability in aortic valve calcium levels among enrolled participants. This variability is consistent with findings from the company’s retrospective real-world analysis, which indicated that patients with aortic stenosis can experience different rates of disease progression even when they have similar disease classifications.
The combined findings are intended to help identify patients at greater risk of rapid progression and determine which clinical and imaging measures may be most useful in future clinical development.
Tassos Gianakakos, co-founder, chief executive officer and board chair of Kardigan, described completion of enrollment as an important milestone for the program and for people living with aortic stenosis. He said the KATALYST-AV study was designed to allow the company to learn from accumulating evidence and adapt its development strategy as additional information becomes available.
Gianakakos noted that the real-world analysis provides a clearer understanding of which patients with aortic stenosis are more likely to experience rapid disease progression and worsening outcomes. These findings are expected to directly inform the design of the company’s upcoming registrational trial.
He also explained that the variability in baseline aortic valve calcium measurements supports the decision to allow more time to evaluate the effects of ataciguat compared with placebo. Kardigan believes that assessing both valve calcification and ventricular dysfunction will be important in understanding the potential of ataciguat as a treatment intended to slow aortic stenosis progression.
KATALYST-AV Baseline Analysis Shows Wide Variation in Aortic Valve Calcium
The pre-planned baseline analysis of KATALYST-AV examined clinical characteristics among the first 139 participants from the total 156 enrolled in the trial’s intent-to-treat population.
The findings demonstrated considerable variation in aortic valve calcium across the study population. Baseline AVC measurements ranged from 320 to 1,983 Agatston units, indicating that participants entered the trial with substantially different levels of valve calcification.
Aortic valve calcium is an important measure in aortic stenosis because calcium accumulation contributes to the thickening and stiffening of the aortic valve. As the condition progresses, the valve may become increasingly restricted, reducing the opening available for blood to flow from the left ventricle into the aorta.
However, the baseline analysis indicated that calcium levels overlapped substantially between participants with and without ventricular dysfunction. This suggests that a single measurement of valve calcium may not fully capture the different ways in which aortic stenosis affects individual patients.
The analysis also identified several indicators of cardiac damage among participants at baseline. Approximately 30% had left ventricular (LV) hypertrophy, 21% had elevated filling pressures, 14% had low flow and 26% had left atrial enlargement.
These findings are consistent with the company’s real-world observations that aortic stenosis involves more than changes to the aortic valve itself. The disease can also affect the heart muscle and its ability to fill and pump blood effectively.
LV hypertrophy refers to thickening of the muscular wall of the left ventricle, which can develop as the heart works harder to pump blood through a narrowed aortic valve. Elevated filling pressures may indicate that the ventricle is experiencing difficulty relaxing or filling adequately. Low flow and left atrial enlargement can also reflect changes in cardiac function associated with the disease.
The presence of these characteristics among KATALYST-AV participants provides additional information about the clinical diversity of the enrolled population.
Protocol Amendment Extends Primary Endpoint Assessment to Week 48
Based on the variability observed in baseline aortic valve calcium measurements, Kardigan amended the KATALYST-AV protocol to allow additional time to assess changes in AVC following treatment with ataciguat or placebo.
The company explained that calcium accumulates at different rates among individual patients. Consequently, a relatively short assessment period may not provide sufficient time to distinguish a treatment-related effect on valve calcification from the natural variability in disease progression.
Under the amended protocol, the primary endpoint of the study, which evaluates aortic valve calcium, will be assessed at Week 48.
The extended assessment period is intended to provide a more informative evaluation of whether ataciguat can influence the progression of valve calcification compared with placebo. The Week 48 analysis will also be considered alongside additional measures of cardiac structure and function.
These include:
- Aortic valve area (AVA).
- Left ventricular mass index.
- Stroke volume index.
- E/e′, a measure used to assess aspects of cardiac filling and diastolic function.
Evaluating these measures together may provide a more comprehensive understanding of how changes in valve calcification relate to the broader clinical course of aortic stenosis.
Kardigan stated that the study remains powered at Week 48 to detect the same treatment effect assumed in the original trial design. The protocol amendment was made under blinded conditions, without reviewing unblinded efficacy data, and was not prompted by any safety finding.
This distinction is important because the change was based on considerations related to disease variability and the time required to evaluate the primary endpoint, rather than an adverse safety observation or an assessment of unblinded treatment results.
Week 24 Interim Analysis to Examine Disease Progression
In addition to the Week 48 primary endpoint assessment, Kardigan plans to conduct an internal interim analysis at Week 24.
The interim analysis will evaluate rates of disease progression and directional mechanistic trends associated with ataciguat treatment on both the aortic valve and the ventricle.
The company intends to use these findings, together with the Week 48 results, to inform the design and operational planning of its Phase 3 registrational trial.
Several important elements of the future study may be guided by the analyses, including patient inclusion and exclusion criteria, endpoint selection, sample size and follow-up duration.
The Week 24 assessment is expected to provide an earlier opportunity to examine how the disease is progressing among participants and whether there are preliminary signals of treatment activity. The Week 48 assessment will provide the longer-term evaluation of the primary endpoint.
By considering both time points, Kardigan aims to develop a clearer understanding of the relationship between changes in valve calcium, cardiac remodeling and clinical progression.
The company expects to provide an update on its Phase 3 development plans in the first half of 2027 and report topline Week 48 results from KATALYST-AV in the second half of 2027.
Real-World Analysis Examines Disease Progression in Approximately 45,000 Patients
Alongside the clinical trial baseline analysis, Kardigan shared findings from a retrospective, de-identified real-world dataset involving approximately 45,000 people with mild-to-moderate aortic stenosis.
The analysis included data from multiple academic medical centers across the United States and was designed to better understand how aortic stenosis progresses in routine clinical settings.
The company used the analysis to identify characteristics associated with faster disease progression and worse clinical outcomes. The findings are also intended to help identify higher-risk patients who may be suitable for inclusion in the upcoming Phase 3 registrational trial of ataciguat.
The real-world analysis showed that aortic stenosis progresses through two closely related areas: the aortic valve and the myocardium, which is the heart muscle.
This observation is relevant to the development of ataciguat because Kardigan is investigating the treatment’s potential to address both valve calcification and ventricular dysfunction.
The analysis also found that patients with evidence of cardiac damage on routine echocardiography were more likely to experience rapid disease progression and worse outcomes.
These findings support the view that aortic stenosis is not solely a valve-related condition. Changes in cardiac structure and function may occur alongside valve narrowing and can provide important information about the overall course of the disease.
Aortic Valve Area Identified as the Strongest Predictor of Progression
One of the central findings from the real-world analysis was that baseline aortic valve area was the strongest predictor of subsequent disease progression.
Aortic valve area measures the size of the opening through which blood flows from the left ventricle into the aorta. As aortic stenosis becomes more severe, this opening generally becomes smaller, increasing the resistance to blood flow.
The analysis found that approximately 27% of patients experienced rapid progression. Rapid progression was defined as a decline in aortic valve area of at least 0.1 square centimeters per year.
This pattern was observed among patients with both mild and moderate aortic stenosis, indicating that faster progression is not limited to individuals who already have more advanced disease.
The findings highlight the variability of aortic stenosis and the importance of monitoring patients over time. Individuals with the same broad disease classification may experience different rates of deterioration, making it important to identify clinical indicators that can help distinguish those at greater risk.
The analysis also showed that patients with signs of cardiac damage on routine echocardiography were more likely to progress rapidly.
The relevant indicators included:
- Left ventricular hypertrophy.
- Enlarged left atrium.
- Low stroke volume or low-flow characteristics.
- Impaired relaxation of the heart muscle.
These findings suggest that cardiac remodeling and functional changes may provide additional information about the likelihood of disease progression.
Rapid Progression Associated With Worse Clinical Outcomes
The real-world analysis further demonstrated that rapid progression of aortic stenosis was associated with higher rates of adverse clinical outcomes.
Patients whose aortic valve area declined more quickly experienced higher rates of valve replacement, hospitalization and worsening heart failure.
These observations underscore the potential clinical importance of identifying patients at risk of faster disease progression.
Aortic valve replacement is an established intervention for patients whose disease reaches a stage requiring procedural treatment. However, the timing of intervention depends on disease severity, symptoms, cardiac function and other clinical considerations.
For patients with mild-to-moderate aortic stenosis, identifying those who are likely to progress more rapidly may help improve risk assessment and inform monitoring strategies.
The association between rapid progression and hospitalization or worsening heart failure also highlights the broader impact of the condition on cardiovascular health.
Kardigan intends to use these real-world findings to guide the selection of patients for its future Phase 3 program. Identifying individuals with a greater likelihood of progression could help researchers evaluate the potential effects of ataciguat in a population with measurable disease activity.
Aortic Valve Calcium Alone Did Not Distinguish Rapid Progressors
Although aortic valve calcium is an established predictor of adverse outcomes and an important mechanistic marker for evaluating ataciguat, the exploratory real-world analysis found that baseline AVC did not distinguish between patients with rapid and normal disease progression.
AVC levels varied widely across the real-world population, similar to the variability observed in the KATALYST-AV baseline analysis.
The findings suggest that a single baseline calcium measurement may provide information about disease risk but may not reliably indicate how quickly an individual patient’s aortic stenosis will progress.
This distinction has implications for clinical trial design. While valve calcium is an important measure of calcification, assessing changes over time may be more informative than relying exclusively on a single measurement.
It also supports the company’s decision to extend the primary endpoint assessment in KATALYST-AV to Week 48. The longer observation period is intended to provide additional time to evaluate whether treatment produces a meaningful difference in valve calcium progression compared with placebo.
The company plans to interpret the calcium findings alongside changes in aortic valve area and measures of ventricular structure and function.
Cardiovascular Experts Emphasize the Importance of Monitoring Both Valve and Heart Muscle
Philippe Pibarot, DVM, PhD, FAHA, head of cardiology research at Université Laval, commented on the implications of the real-world findings.
Dr. Pibarot said the results add to the growing evidence that mild-to-moderate aortic stenosis represents a continuum in which valvular disease and cardiac remodeling may evolve at different rates across patients.
He emphasized that evaluating changes in valve calcium over a longer period, together with other measures of disease progression, could provide a more complete understanding of how changes in the aortic valve relate to the overall course of the condition.
According to Dr. Pibarot, combining these assessments may also help clarify the relationship between disease progression and outcomes that are important to patients.
His comments reflect the need to consider both the valve and the myocardium when evaluating aortic stenosis. Although valve narrowing is a defining feature of the condition, the heart muscle may undergo structural and functional changes as it responds to increased pressure and workload.
Understanding these changes may help researchers identify patients at greater risk and develop more comprehensive approaches to evaluating potential disease-modifying treatments.
Ataciguat Development Strategy Focuses on Valve Calcification and Ventricular Dysfunction
Kardigan is developing ataciguat as a potential treatment to slow the progression of aortic stenosis. The company’s strategy focuses on evaluating the treatment’s effects on both aortic valve calcification and ventricular dysfunction.
The clinical and real-world analyses announced alongside enrollment completion provide additional context for this development approach.
The KATALYST-AV baseline findings demonstrate that patients entering the trial have widely varying levels of valve calcium and different indicators of cardiac damage. Meanwhile, the real-world analysis suggests that cardiac damage markers may help identify patients who are more likely to experience rapid progression and adverse outcomes.
Together, these findings may help determine how patients should be selected for future studies and which clinical measures should be prioritized.
A treatment that can slow disease progression could potentially address an important unmet need in aortic stenosis. However, ataciguat remains under clinical investigation, and the announced analyses do not establish that the treatment has demonstrated a disease-modifying benefit. The upcoming Week 24 and Week 48 assessments will be important for evaluating its potential effects.
Kardigan to Present Findings at Investor Webcast
Kardigan will host an investor webcast on Saturday, November 7, 2026, at 8:00 a.m. Eastern Time, during the American Heart Association Scientific Sessions.
The webcast will provide additional information about the real-world analysis of aortic stenosis progression and the baseline findings from KATALYST-AV.
Registration is available through the Investors and Media section of the company’s website at Kardigan Investor Relations. A replay of the presentations will be made available on the website for a limited period following the event.
Upcoming Milestones for the KATALYST-AV Program
With enrollment now complete, Kardigan will continue evaluating ataciguat through the amended KATALYST-AV study schedule. The internal Week 24 interim analysis will examine disease progression rates and directional treatment effects on the valve and ventricle, while the Week 48 assessment will evaluate the primary endpoint of aortic valve calcium alongside additional measures of cardiac structure and function.
The company expects to provide an update on its Phase 3 development strategy in the first half of 2027, followed by topline Week 48 results in the second half of 2027.
Overall, completion of enrollment in KATALYST-AV marks an important step in Kardigan’s clinical development program. The combination of trial baseline data and a large real-world analysis involving approximately 45,000 people provides additional insight into the variability of aortic stenosis progression and the characteristics associated with worsening disease.
As the study advances, the upcoming analyses will help inform the design of the next stage of clinical development and provide further evidence about whether ataciguat may have the potential to slow aortic stenosis progression by addressing both valve calcification and cardiac dysfunction.
About Ataciguat
Ataciguat is a once-daily, oral soluble guanylate cyclase activator being developed as a potential first-in-class treatment for AS and an alternative to the current “watchful waiting” approach and progression to valve replacement that is today’s standard of care. Ataciguat has the potential to revolutionize the management of AS as the first pharmacological therapy. Kardigan acquired rights to ataciguat, an investigational drug developed by, and in-licensed from, Sanofi and Mayo Clinic.
About Kardigan
Kardigan is a clinical-stage precision cardiovascular company developing medicines that target the root cause of specific cardiovascular diseases where no approved treatments exist. Led by a proven and experienced management team, Kardigan is reimagining cardiovascular drug discovery and development through an integrated approach that unites deep cardiovascular biology, real-world patient data, and advanced analytics to enable more precise, efficient, and informed development of novel therapies. Learn more about Kardigan and its mission at Kardigan.bio.