Early plaque modification with siRNA PCSK9 inhibition

Primary prevention has long balanced feasibility with the need for meaningful signals of benefit. Traditional outcomes trials require large samples and long follow-up, delaying answers for years. By contrast, imaging endpoints can reveal biological change in months, particularly when the intervention directly targets lipoprotein pathways central to atherogenesis. Inclisiran lowers LDL-C by harnessing RNA interference to silence hepatic PCSK9, increasing LDL receptor recycling and LDL clearance. The VICTORION-PLAQUE primary prevention trial operationalizes this concept, asking whether upstream lipid modulation yields detectable plaque change early in the disease course.

From LDL lowering to plaque biology

LDL-C is causal in atherosclerosis, and intensive lowering reduces events across risk spectra. Yet the earliest promise of prevention is to alter the vessel wall long before symptoms appear. Plaque is a dynamic structure, with lipid pools, fibrous caps, inflammation, and microcalcification evolving under pressure from circulating lipoproteins. Sustained LDL-C reduction should decrease lipid retention and macrophage lipidation, stabilize caps, and attenuate progression. Linking pharmacodynamics in serum to structural change in the artery transforms the conversation from numbers to biology, anchoring prevention in tangible tissue effects rather than only in risk calculators.

Why siRNA and twice-yearly dosing matter

Inclisiran uses a GalNAc-conjugated siRNA to target PCSK9 mRNA in hepatocytes, producing durable knockdown and consistent LDL-C lowering between administrations. After a loading phase, the drug is given twice yearly, which may mitigate the adherence erosion seen with daily oral therapy. Improved medication adherence is more than convenience; it is a pharmacologic reliability advantage that can amplify the signal in imaging-based trials. When dosing is predictable, exposure-response relationships are easier to interpret, and imaging readouts are less likely to be confounded by missed doses. This reliability is particularly attractive in primary prevention, where long time horizons and low event rates complicate conventional trial designs.

Design features of the VICTORION-PLAQUE primary prevention trial

The VICTORION-PLAQUE primary prevention trial enrolls individuals with subclinical atherosclerosis identified in hospital-based screening but without prior cardiovascular events or significant flow-limiting lesions. This population targets the transition phase between risk factors and overt disease, where modification could have the most cumulative benefit. The protocol evaluates inclisiran dosing at day 0, month 3, and then every 6 months, enabling uniform exposure over the imaging window. Noninvasive imaging is employed to quantify plaque features that are both biologically meaningful and reproducible. A design and rationale summary is available via PubMed at https://pubmed.ncbi.nlm.nih.gov/40769373/.

Population and screening approach

Participants are screened to confirm the presence of subclinical atherosclerosis and to exclude flow-limiting lesions that would mandate revascularization or reclassify risk. This ensures the trial probes early disease, not advanced stenoses where plaque biology and hemodynamics are confounded. Selecting individuals without prior events reduces heterogeneity from scar, remodeling, or secondary prevention therapies. It also makes the imaging endpoints more sensitive to incremental lipid lowering. The focus on hospital-based screening leverages existing clinical infrastructure to identify eligible participants in a pragmatic way.

Intervention and schedule

Inclisiran is administered with a loading dose at baseline and month 3, followed by maintenance dosing every 6 months. This schedule, already used in practice, simplifies follow-up logistics and aligns with clinic workflows. The dosing cadence supports sustained lipid control over the imaging interval, strengthening causal inference between exposure and vascular changes. In primary prevention settings, where visit fatigue can undermine oral adherence, a twice-yearly injection can be an operational advantage as well as a biological one. The predictable pharmacology is a key design pillar for attributing changes in plaque to the intervention.

Imaging strategy and endpoints

The trial leverages advanced noninvasive imaging to quantify plaque characteristics at baseline and follow-up. Techniques commonly used in this space include coronary CT angiography for total and noncalcified plaque, as well as vascular MRI or ultrasound for vessel wall thickness and composition. While modalities vary across programs, the strategy is consistent: detect change in quantitative plaque metrics that reflect lipid content, inflammation, or fibrous cap features. Endpoints typically include change in plaque burden or components thereof, providing an earlier read on biological efficacy than waiting for clinical events. Imaging reproducibility, standardized acquisition, and centralized analysis are critical for signal fidelity.

Operational and analytic considerations

Imaging endpoints demand meticulous standardization to avoid noise overwhelming signal. Acquisition protocols, contrast timing, reconstruction parameters, and reader training all influence sensitivity to change. Statistical plans must prespecify primary and key secondary endpoints, manage multiplicity, and account for baseline plaque heterogeneity. The twice-yearly dosing cadence supports adherence, but visit schedules still need to minimize interval variability between dosing and imaging. By anchoring the analysis in biologically plausible endpoints that track with LDL-C change, the design aims to maximize assay sensitivity while preserving external validity.

Clinical and research horizons if imaging shows change

If imaging demonstrates favorable plaque modification with inclisiran in subclinical disease, the implications extend beyond a single drug. First, it would bolster the concept that intensive lipid lowering can alter vessel wall biology early, complementing risk calculators with tissue-level readouts. Second, it could validate imaging as a surrogate for outcomes in selected prevention contexts, accelerating hypothesis testing. Third, twice-yearly siRNA therapy might offer a scalable adherence solution where daily pills underperform. Finally, demonstration of change could invite broader exploration of combination prevention strategies, aligning lipid and inflammation targets for additive effects.

Potential practice impacts

Clinicians could gain a tool to personalize prevention, linking baseline plaque features with therapeutic response to refine decisions about adding nonstatin therapy. For example, noncalcified plaque metrics might guide intensification when LDL-C lowering alone is insufficient or when residual risk persists. Positive imaging results could support deploying inclisiran earlier for patients at elevated cardiovascular risk who struggle with oral adherence. Pathway clarity could also streamline payer discussions, as quantifiable changes in plaque provide tangible evidence of benefit. Importantly, a measured approach is needed, with decisions anchored in both imaging and clinical context.

Equity, cost, and access

Imaging-based strategies must be implemented thoughtfully to avoid widening disparities. Access to high-quality scanners, standardized protocols, and expert interpretation varies across settings. Cost-effectiveness will hinge on whether early detection of change translates into fewer downstream events and procedures. The infrequent dosing of inclisiran may reduce indirect costs from nonadherence, but direct drug cost and imaging expenses must be considered jointly. Programs that integrate imaging sparingly and purposefully, guided by risk and anticipated yield, are more likely to be equitable and sustainable.

Signals to watch next

Several signals will be closely watched as data emerge. Concordance between LDL-C reduction and imaging change will test mechanistic plausibility. The sensitivity of different imaging features to pharmacologic modulation will inform endpoint selection in future trials. The durability of change across intervals will matter for maintenance strategies and follow-up cadence. Finally, whether imaging shifts correlate with improvements in hard outcomes over time will determine how widely such approaches permeate clinical pathways. As data accumulate, imaging may evolve from a research tool to a pragmatic adjunct in prevention.

In sum, the VICTORION-PLAQUE primary prevention trial embodies a cautiously optimistic, solution-oriented blueprint for accelerating evidence in early atherosclerosis. By pairing siRNA-based PCSK9 inhibition with rigorous imaging, the design seeks to connect serum pharmacodynamics to vessel wall biology when the disease is still pliable. The twice-yearly schedule strengthens adherence and interpretability, while noninvasive imaging offers a near-term read on efficacy. Limitations include the need for standardization, potential modality variability, and uncertainty about surrogacy for clinical events. Still, the approach is timely, testable, and capable of guiding the next generation of prevention strategies.