Rafal Ziecina, Executive Director, Medical Affairs
The American College of Cardiology meeting in Chicago reliably features the field’s most anticipated trial readouts. In some years, the late-breaking data justify the anticipation. ACC.26 was one such year, not due to a single result, but because of what the collective data suggested about the future of cardiovascular medicine. Below, I discuss a few findings from the sessions that warrant further discussion.
LDL Lowering Is Moving Upstream
VESALIUS-CV answered a question that has been quietly building for a few years, which was, does PCSK9 inhibition still matter in patients who don’t yet have a substantial atherosclerotic burden? The results with evolocumab suggest yes. This has real implications for how we think about LDL-C targets and the timing of intervention, not just secondary prevention.
The more immediately practice-shaping story, though, was CORALreef AddOn. Enlicitide is an oral PCSK9 inhibitor, and Phase III data showed robust LDL-C reductions compared with ezetimibe and bempedoic acid. Oral delivery changes the conversation around self‑injection or clinic visits, which remain a key barrier to long‑term persistence in real‑world settings. If these results hold up through regulatory review, I expect both clinicians and sponsors to revisit the role of injectable PCSK9 inhibitors in patients for whom an oral option is available.
RNA-Targeted Therapy Lands in Hypertension
The RNA-targeted therapy was the result I found myself returning to most after the meeting. The Kardinal trial tested tonlamarsen, an antisense oligonucleotide, in patients with uncontrolled hypertension. The mechanism differs from any currently approved blood pressure management therapies. Rather than blocking a receptor or enzyme, it targets gene expression upstream. Phase II data were so striking that the study stood out amid an otherwise crowded program.
What makes this interesting beyond the efficacy numbers is what it implies about durability and patient segmentation. Modifying RNA rather than competing at the receptor level could, in theory, support longer-lasting effects with less frequent dosing. Whether that translates into a clinical advantage depends on long-term safety data we don’t yet have. But the fact that RNA-based approaches have now reached a condition as prevalent as hypertension, rather than remaining confined to rare monogenic diseases, is a meaningful signal about where this class of therapies is going.
HFpEF Has a Potentially Understood Biology Now
Heart failure with preserved ejection fraction (HFpEF) has frustrated trialists for years. Therapies that work in HFrEF often don’t translate, in part because HFpEF almost certainly encompasses several distinct disease processes under a single diagnostic label.
The CADENCE trial, sotatercept in CpcPH-HFpEF, was, in my view, the most scientifically interesting heart failure result at the meeting. CpcPH-HFpEF sits at the intersection of pulmonary vascular disease and left heart failure, a phenotype in which vascular remodeling drives a substantial portion of the pathophysiology. Sotatercept acts directly on that remodeling pathway, and the Phase II results showed a meaningful signal in this patient population.
The broader implication is that HFpEF is biologically tractable if you define patients by underlying mechanism rather than solely by ejection fraction. Vascular remodeling, systemic inflammation, and metabolic dysfunction are distinct problems that can produce similar hemodynamics. CADENCE won’t settle the question, but it reinforces the case for phenotype-driven trial design in this indication.
What Wasn’t There
There were no late-breaking gene therapy trials, AAV, or CRISPR data in cardiovascular disease. The contrast with RNA-based approaches is notable, and shows that the therapeutic innovation at ACC.26 came from oligonucleotide and biologic modulation, not from genomic editing. That likely reflects where most gene therapy cardiovascular programs sit developmentally rather than any loss of scientific interest. It suggests that RNA-based strategies currently have a clearer near-term path to late-phase development in CV.
What This Means for Sponsors Running Trials in This Space
A few considerations are worth thinking through if you are designing or planning studies in lipid management, hypertension, or heart failure.
On lipid lowering, VESALIUS-CV data will likely prompt questions about earlier intervention thresholds. Trial designs limited to secondary prevention populations may need to justify that boundary more explicitly going forward. On oral PCSK9, real-world adherence and access outcomes will become increasingly important in establishing where these agents fit relative to existing options.
For hypertension programs exploring RNA-based mechanisms, the mechanistic narrative matters both practically and scientifically. Investigators, study teams, and eventually patients will need to understand what an antisense oligonucleotide is doing — and that’s not a trivial communication challenge across a global trial.
In HFpEF, the direction from CADENCE aligns with the field’s movement toward phenotype-defined patient selection and biomarker-anchored endpoints. Protocols enrolling broad HFpEF populations without biological stratification will face increasingly difficult questions from regulators and reviewers.
