Vericiguat for the Inhibition of Calcific Aortic Valve Stenosis Progression

AORTIC VALVE DISEASES, Aortic Valve Stenosis, Calcific Aortic Valve Disease

Vericiguat, BAY1021189, Soluble Guanylyl Cyclase, sGC stimulator, sGC activator, Cyclic GMP

Calcific aortic valve stenosis (CAVS) is a condition in which the aortic valve progressively narrows and stiffens due to calcium deposition, eventually impairing blood flow from the heart to the body. No drug therapy has been proven to slow CAVS progression. Individuals with mild-to-moderate CAVS are managed with periodic monitoring until the stenosis becomes severe, at which point surgical or transcatheter valve replacement is the only treatment option. The goal of this clinical trial is to determine whether vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, can slow the progression of mild-to-moderate CAVS. The primary questions this study aims to answer are: Does vericiguat reduce the risk of death, delay the need for aortic valve events, or slow the rate of calcium accumulation on the aortic valve over 24 months of treatment? The study will compare vericiguat against a placebo (an inactive pill that is identical in appearance but contains no active drug). Both participants and the research team will not know which treatment each participant is receiving throughout the study. Participants will: Take vericiguat or placebo orally once daily for 24 months; Begin treatment at 2.5 mg/day and undergo a stepwise dose increase every two weeks to a target dose of 10 mg/day, provided the drug is tolerated; Attend approximately 8 scheduled study visits over two years, during which they will undergo cardiac imaging examinations (transthoracic echocardiography and non-contrast cardiac CT), blood sample collection, physical assessment, and completion of standardized questionnaires on quality of life and heart failure symptoms; Undergo cardiac magnetic resonance imaging (MRI) at the beginning and end of the study, if there are no contraindications. Approximately 238 participants will be enrolled across roughly 19 hospitals in China.

BACKGROUND AND UNMET NEED Calcific aortic valve stenosis is the most common valvular heart disease worldwide and a leading cause of heart failure, valve replacement, and cardiovascular death in older adults. In Western populations, the prevalence of CAVS reaches 1-2% among individuals aged ≥65 years and approximately 12% in those aged ≥75 years. In China, prevalence is rising sharply as the population ages. Once the aortic valve peak velocity exceeds 2.0 m/s, the disease typically progresses to severe stenosis within a decade. Among patients with symptomatic severe aortic stenosis who do not undergo intervention, two-year mortality approaches 50%. Aortic valve replacement-either surgical (SAVR) or transcatheter (TAVI)-is currently the only effective treatment for severe CAVS. However, valve replacement carries substantial procedural risks (stroke, conduction block, paravalvular leak, bleeding, infection) and imposes a heavy economic burden. There is therefore an urgent clinical need for a pharmacological intervention that can slow CAVS progression at the mild-to-moderate stage and thereby reduce the proportion of patients who progress to severe stenosis requiring valve replacement. Over the past two decades, numerous randomized controlled trials have tested pharmacological strategies for slowing CAVS progression, including intensive statin therapy (SALTIRE, TASS, ASTRONOMER), anti-osteoporotic agents (SALTIRE-2: denosumab and alendronate), vitamin K2 plus vitamin D supplementation, and DPP-4 inhibitors (evogliptin). All have yielded negative results. Recent evidence has reframed CAVS as an active fibro-calcific disease driven by valvular interstitial cell (VIC) osteogenic differentiation, endothelial dysfunction, and inflammatory signaling, rather than a passive degenerative process. The consistent failure of prior trials highlights the need for mechanistically novel therapeutic targets. RATIONALE FOR TARGETING THE NO-sGC-cGMP PATHWAY Cyclic guanosine monophosphate (cGMP) is a critical second messenger in cardiovascular homeostasis, synthesized from GTP by guanylate cyclases. Soluble guanylate cyclase -the principal receptor for nitric oxide (NO)-is widely expressed in valvular endothelial cells and VICs. cGMP activates protein kinase G (PKG), which exerts multiple protective effects including suppression of VIC osteogenic differentiation, preservation of mitochondrial function, and attenuation of oxidative stress. In calcified aortic valve tissue, the NO-sGC-cGMP signaling axis is markedly impaired despite compensatory upregulation of sGC subunits. The key mechanism involves localized oxidative stress that converts sGC from its active (reduced, heme-containing) form to an oxidized or heme-free form that is insensitive to endogenous NO, thereby limiting cGMP production. Our group has further demonstrated that serum cGMP concentrations are significantly reduced in patients with CAVS and correlate inversely with CT-derived aortic valve calcium (AVC) scores and echocardiographic mean pressure gradients, supporting cGMP-PKG pathway downregulation as a hallmark of CAVS progression. sGC stimulators are a novel drug class that can restore this pathway through a dual mechanism: (1) direct, NO-independent stimulation of sGC to generate cGMP, and (2) enhancement of sGC sensitivity to residual endogenous NO. This property allows sGC stimulators to function effectively in the oxidative valvular microenvironment, overcoming the limitation of conventional NO donors. PRECLINICAL EVIDENCE FOR VERICIGUAT IN CAVS Vericiguat is a novel oral sGC stimulator with a long half-life (\ 22 hours) enabling once-daily dosing and favorable pharmacokinetics. Our research group has systematically characterized its anti-calcification effects across three experimental levels: 1. Cellular level: In human VICs cultured under calcifying conditions, vericiguat (500 nM and 1 μM) significantly reduced osteogenic markers, including alkaline phosphatase (ALP) activity and RUNX2 protein expression (P\<0.01). Among multiple cGMP agonists tested (BNP, sildenafil, vericiguat), vericiguat exhibited the most potent anti-calcification effect. 2. Tissue level: In ex vivo human aortic valve tissue cultured under pro-calcific conditions, vericiguat (1 μM) intervention for 21 days markedly reduced calcium deposition as assessed by Alizarin Red and von Kossa staining. 3. Animal level: In two established mouse models of CAVD-LDLR-/- mice fed a high-fat diet and a wire-injury aortic valve model-vericiguat (3-10 mg/kg/day) significantly reduced leaflet calcification and thickening and improved hemodynamic parameters (peak transvalvular velocity, aortic valve area). The high-dose group (10 mg/kg/day) showed the greatest efficacy. Mechanistically, integrated transcriptomic, proteomic, and phosphoproteomic analyses revealed that PKGI phosphorylates ULK1 at Ser556, enhancing autophagic flux, preserving mitochondrial function, and reducing oxidative stress, thereby suppressing VIC osteogenic differentiation. Prkg1+/- heterozygous knockout mouse studies confirmed PKGI as the critical mediator of vericiguat's anti-calcification effect. CLINICAL EVIDENCE SUPPORTING sGC STIMULATION IN CAVS Clinical validation of sGC pathway targeting in CAVS comes from an independent study of ataciguat, another sGC activator. In human ex vivo valve tissue, ataciguat enhanced sGC signaling and reduced BMP2 signaling. In a murine CAVS model, ataciguat significantly reduced aortic valve calcification. In its phase II randomized controlled trial, ataciguat slowed AVC score progression by approximately 70% over 6 months (P=0.051), providing the first human evidence that sGC pathway activation may exert disease-modifying effects in CAVS. In the VICTORIA trial (N=5,050), vericiguat significantly reduced the composite of cardiovascular death and heart failure hospitalization (HR 0.90, P=0.019) in patients with heart failure with reduced ejection fraction without increasing symptomatic hypotension or syncope. This safety profile is critical for CAVS patients, in whom hypotension could exacerbate transvalvular gradients and impair coronary perfusion. STUDY DESIGN RATIONALE Randomized, double-blind, placebo-controlled design: A placebo control is appropriate because no drug has been proven effective for slowing CAVS progression. The current standard of care for mild-to-moderate CAVS is watchful waiting with guideline-directed management of comorbidities (hypertension, hyperlipidemia, diabetes). Both trial arms receive optimal background therapy. The double-dummy design-in which placebo tablets match the three dose strengths of vericiguat (2.5 mg, 5 mg, 10 mg) in size, shape, color, and texture-ensures that participants, treating investigators, imaging personnel, and outcome assessors remain blinded throughout the study. Hierarchical composite primary endpoint with Win Ratio analysis: A three-tier hierarchical composite endpoint was selected to integrate hard clinical outcomes with an imaging surrogate while preserving clinical interpretability. In descending order of clinical importance, the tiers are: (1) time to all-cause death, (2) time to aortic valve-related clinical events (aortic valve replacement or first hospitalization for aortic stenosis), and (3) change in log-transformed AVC score from baseline at 24 months. The Win Ratio method compares each vericiguat-treated participant against each placebo-treated participant across the tiers in hierarchical order, ensuring that death and serious clinical events receive highest priority. This approach allows detection of a clinically meaningful treatment effect within a feasible sample size. POPULATION RATIONALE The study enrolls patients aged 35-80 years with mild-to-moderate CAVS. Mild-to-moderate disease is the optimal window for pharmacological intervention: the valve leaflets retain plasticity and have not yet undergone irreversible fibro-calcific remodeling, whereas patients with severe stenosis are likely to require valve replacement within a short timeframe. The lower bound for inclusion (aortic valve peak velocity ≥2.5 m/s and AVC score ≥200 Agatston units) ensures that enrolled patients have established, quantifiable valve calcification and hemodynamic abnormality rather than uncertain or very mild changes. This threshold also provides sufficient statistical power to detect AVC score changes over 24 months. Randomization is stratified by baseline AVC score (200-600 AU vs. ≥600 AU) to ensure balance in calcification severity. Key exclusion criteria-left ventricular ejection fraction less than 50%, NYHA class III-IV, and systolic blood pressure less than 120 mmHg or history of symptomatic hypotension-avoid confounding from concomitant heart failure and mitigate the risk of drug-related hypotension in a population with pre-existing afterload limitation. DOSE SELECTION RATIONALE The dosing regimen mirrors the established titration schedule from the VICTORIA trial: vericiguat 2.5 mg once daily, doubled every 2 weeks to a target maintenance dose of 10 mg once daily. The rationale is as follows: Phase I data: Across six phase I studies (265 participants), vericiguat was well tolerated at doses up to 10 mg once daily, with plasma cGMP concentrations rising in a dose-dependent manner. At 15 mg, dose-limiting pharmacodynamic effects (orthostatic reactions and syncope) were observed, establishing 10 mg as the safe upper limit. The half-life of approximately 22 hours supports once-daily dosing. Phase II data: In the SOCRATES-REDUCED trial, vericiguat dose-dependently reduced NT-proBNP with the 10 mg target dose showing the most favorable efficacy signal while maintaining acceptable tolerability. Phase III data: The VICTORIA trial confirmed that the 2.5→5→10 mg titration schedule achieved both efficacy and safety in a large heart failure population, importantly without excess symptomatic hypotension or syncope. Preclinical dose-response: In LDLR-/- mice fed a high-fat diet, vericiguat at 10 mg/kg/day reduced peak transvalvular velocity by approximately 40% (P=0.0002), leaflet calcification area by approximately 50% (P\<0.0001), leaflet thickness from approximately 150 μm to 80 μm (P=0.0088), and RUNX2 expression by approximately 65% (P\<0.0001), with the 10 mg/kg/day dose consistently outperforming 3 mg/kg/day. SAFETY MONITORING AND RISK MITIGATION The primary anticipated risk of vericiguat in the CAVS population is hypotensive effects, given its vasodilatory mechanism. Several measures are implemented to mitigate this risk: (1) exclusion of participants with baseline SBP less than 120 mmHg or history of symptomatic hypotension; (2) a conservative dose-titration schedule (2.5 mg starting dose, doubling every 2 weeks) with built-in dose-reduction rules when SBP falls below 90 mmHg or participants develop hypotensive symptoms; (3) investigator discretion to reduce concomitant non-evidence-based medications (e.g., diuretics, calcium channel blockers, alpha-blockers) before reducing study drug; (4) continuous blood pressure monitoring at all scheduled and unscheduled visits. In the event of drug intolerance requiring temporary interruption, a structured re-titration protocol guides dose re-escalation upon clinical stabilization. Participants who permanently discontinue study drug are followed for the full 24-month study duration to permit intention-to-treat analysis. An independent Data and Safety Monitoring Board (DSMB) will conduct periodic reviews of unblinded safety data. Key safety events of special interest include symptomatic hypotension, syncope (particularly in CAVS patients, where syncope may also indicate progression to severe stenosis), liver function abnormalities (ALT or AST ≥3× ULN with total bilirubin ≥2× ULN), and anemia. STUDY PROCEDURES AND ASSESSMENTS Screening (Visit 1, within 30 days prior to enrollment): Informed consent, inclusion/exclusion assessment, demographic and medical history, physical examination (height, weight, heart rate, blood pressure, waist circumference), 12-lead ECG, transthoracic echocardiography, cardiac non-contrast and contrast-enhanced CT for AVC quantification, NYHA classification, Kansas City Cardiomyopathy Questionnaire (KCCQ), blood tests (including NT-proBNP, CRP, IL-6, cGMP, biochemistry panel, complete blood count), and biospecimen collection (fasting venous blood for serum, plasma, and leukocyte banking). Cardiac MRI is performed in eligible participants without contraindications. Enrollment and randomization (Visit 2): Confirmation of eligibility, IWRS-based randomization stratified by AVC score, and first dose dispensing. Dose titration visits (Visits 3 and 4, at 14±3 and 28±4 days): Concomitant medication review, vital signs (heart rate, blood pressure), dose assessment and adjustment per protocol-defined SBP criteria, NYHA classification, medication adherence evaluation, clinical event assessment, and adverse event evaluation. Follow-up visits (Visits 5, 6, 7, and 8 at 6, 12, 18, and 24 months): Comprehensive assessments including echocardiography at 6, 12, 18, and 24 months; cardiac CT at 12 and 24 months; cardiac MRI at 24 months; KCCQ at 6, 12, and 24 months; ECG, blood tests, and biospecimen collection at 6 and 24 months; and medication adherence, clinical events, and adverse events at every visit. All imaging data are transmitted to the independent core laboratory at West China Hospital for standardized central reading. Clinical events are adjudicated by an independent Clinical Endpoint Committee (CEC) blinded to treatment assignment. EMERGENCY UNBLINDING The IWRS includes an emergency unblinding function, activated only when a serious adverse event occurs and the treating physician must know the treatment assignment to make an acute medical decision. Unblinding is authorized by the principal investigator on a single-participant basis and must be reported to the ethics committee and sponsor within 24 hours. Formal database unblinding occurs only after database lock, following independent statistical programming and DSMB confirmation of the analysis plan.

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