Kardigan has announced the completion of enrolment in the phase 2b KATALYST-AV trial of ataciguat in people with aortic stenosis (AS).
The company has also shared insights from a preplanned analysis of the trial’s baseline data, as well as new evidence on disease progression from one of the largest real-world analyses conducted in approximately 45,000 people with AS. These analyses support the primary endpoint assessment of aortic valve calcium (AVC) at week 48, alongside measures of cardiac structure and function, and an internal interim analysis at week 24, the company states.
“Completing enrolment in KATALYST-AV is a foundational milestone for our programme and an important one for people with aortic stenosis,” said Tassos Gianakakos, co-founder, CEO and board chair of Kardigan. “As with our other clinical programmes, KATALYST-AV was specifically designed to enable us to learn and adapt as evidence accumulates. The real-world data give us a clearer picture of which AS patients progress more quickly to worsening outcomes and the markers associated with that progression, directly informing how we design our upcoming registrational trial. In addition, our analysis of aortic valve calcium in the KATALYST-AV baseline data is consistent with the variability observed in the real-world data, which indicates more time is needed to assess a robust reduction in calcium with ataciguat versus placebo. Together, these findings reinforce our development strategy addressing both valve calcification and ventricular dysfunction with ataciguat and strengthen our confidence in its potential to become the first therapy to slow the progression of aortic stenosis.”
The preplanned analysis of the trial baseline characteristics showed that AVC varied widely across the enrolled population. Baseline data from the first 139 participants (out of 156 total enrolled) in the KATALYST-AV intent-to-treat population are consistent with the real-world findings of markers and predictors of rapid progression, including 30% with left ventricular (LV) hypertrophy, 21% with elevated filling pressures, 14% with low flow and 26% with left atrial enlargement. Baseline AVC ranged from 320 to 1,983 Agatston units, with substantial overlap in participants with or without ventricular dysfunction.
Because calcium accrues at each patient’s own rate across this wide range, the company amended the KATALYST-AV protocol to allow more time to assess the change in AVC with the treatment of ataciguat versus placebo in people with aortic stenosis. An interim analysis at week 24 will be reviewed internally to evaluate rates of progression and directional mechanistic trends of ataciguat on the valve and the ventricle to further inform the design of the phase 3 registrational trial.
The company analysed disease progression in a retrospective, deidentified dataset of approximately 45,000 people with mild-to-moderate AS from multiple US academic medical centres. The real-world analysis showed that AS progresses through both the valve and the myocardium, two areas potentially targeted by the mechanism of ataciguat. Notably, AS patients with signs of cardiac damage on routine echocardiography were more likely to progress rapidly and experience worse outcomes. This analysis was designed to identify at-risk patients for the upcoming phase 3 registrational trial for ataciguat.
In the analysis, baseline aortic valve area (AVA) was the strongest predictor of progression. Approximately 27% of patients progressed rapidly (defined as a decline in AVA of at least 0.1cm²/year), across both mild and moderate AS. Patients with signs of cardiac damage on routine echocardiography (LV hypertrophy, enlarged left atrium, low flow, or impaired relaxation) were more likely to progress rapidly, and rapid progression predicted higher rates of valve replacement, hospitalisation and worsening heart failure.
“These data add to the growing body of evidence that mild-to-moderate aortic stenosis is a continuum, with valvular disease and cardiac remodelling evolving at different rates across patients,” said Philippe Pibarot (Université Laval, Quebec City, Canada). “Assessing changes in valve calcium over a longer period, alongside measures of disease progression, will provide a more complete picture of how changes in the valve relate to the course of the disease and outcomes that matter to patients.”
