ACC.25 Highlights: Robust CV Outcomes in PAD from Merck, Alnylam’s new siRNA therapeutic in ATTR-CM, and exciting biomarker data from novel agents
Highly anticipated cardiovascular outcomes trial (CVOT) data took the stage as late-breakers at #ACC25, where Merck’s Phase 3 ZENITH trial of Winrevair (sotatercept) demonstrated a 76% reduction in major morbidity and mortality events in patients with pulmonary arterial hypertension (PAH) compared to placebo. This was the first trial in this rare, rapidly progressive disease to be stopped early due to overwhelming efficacy, where the ongoing HYPERION trial was pushed to final analysis as all placebo patients were ethically required to be offered this first-in-class activin signaling inhibitor. Further CVOT data came from Novo with the Phase 3b SOUL trial showing Rybelsus (oral semaglutide) reduced the risk of major adverse cardiovascular events (MACE) by 14% in patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) and/or chronic kidney disease (CKD). Additional semaglutide data from the Phase 3 STRIDE trial showed Ozempic (SC semaglutide) improved maximum walking distance by 14% and demonstrated positive QoL outcomes versus placebo in patients with T2D and peripheral artery disease (PAD).
The recent FDA approval of Alnylam’s Amvuttra (vutrisiran) couldn’t be missed throughout #ACC25 (and downtown Chicago!), bringing an injectable siRNA gene silencer to ATTR patients with cardiomyopathy alongside existing oral TTR stabilizers such as Pfizer’s Vyndamax (tafamidis) and BridgeBio’s Attruby (acoramidis). However, drawing conclusions on which treatment is best for this “not-so-rare rare disease” is difficult with unequal patient populations between the pivotal trials. Pricing dynamics are expected to come into play in the future upon tafamidis patent expiry and differences in associated out of pocket costs.
Looking ahead into earlier clinical development, Lilly’s siRNA therapeutics, lepodisiran and solbinsiran, and AstraZeneca’s oral PCSK9 inhibitor, AZD0780, showed significant reductions in key biomarkers, lowering Lp(a), ApoB, and LDL-C, respectively. Mineralys’ aldosterone synthase inhibitor, lorundrostat, also delivered positive BP reduction results in u/r HTN, challenging baxdrostat in this “tricky-to-treat” patient population.
As GLP-1s continue to deliver groundbreaking results and siRNA therapeutics show promising effects across key biomarkers, anticipation builds for further pivotal data from these innovative mechanisms to address the significant unmet need that remains across cardiovascular diseases.
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