Breakthrough Clinical Results
Tourmaline Bio announced positive data from the ongoing Phase 2 TRANQUILITY trial of pacibekitug, a long-acting anti-IL-6 monoclonal antibody, presented at the European Society of Cardiology (ESC) Congress 2025. The data showed consistent reductions in high-sensitivity C-reactive protein (hs-CRP) across various subgroups of patients with elevated hs-CRP and chronic kidney disease (CKD). Pacibekitug also demonstrated statistically significant reductions in secondary biomarkers of IL-6 pathway activity, including lipoprotein(a), fibrinogen, and serum amyloid A. These results support further development of pacibekitug in atherosclerotic cardiovascular disease and other inflammation-driven cardiovascular diseases, including plans for a Phase 3 trial and a Phase 2 proof-of-concept study in abdominal aortic aneurysm (AAA).
Key Highlights
- Consistent hs-CRP reductions across multiple subgroups in the TRANQUILITY trial.
- Statistically significant reductions in secondary biomarkers (lipoprotein(a), fibrinogen, serum amyloid A).
- Pacibekitug achieved >85% hs-CRP reduction with quarterly dosing.
- Plans to initiate a Phase 2 proof-of-concept study in AAA and a Phase 3 cardiovascular outcomes trial.
Clinical Trials of Pacibekitug Beyond ASCVD
Based on a comprehensive review of available information, there is insufficient data regarding clinical trials of Pacibekitug for indications beyond atherosclerotic cardiovascular disease (ASCVD).
While PCSK9 inhibitors as a class have established efficacy in treating ASCVD by reducing LDL cholesterol levels, specific information about Pacibekitug being tested for other therapeutic applications is not currently documented in reliable sources.
The pharmaceutical development of anti-PCSK9 monoclonal antibodies continues to evolve, with researchers exploring potential applications beyond their primary indication. However, for this specific agent (Pacibekitug), no clinical trials investigating alternative indications have been conclusively reported.
Without verified information about additional therapeutic targets or intervention models, it would be inappropriate to speculate about specific trial designs, dosing regimens, or treatment protocols that might be employed in testing this agent for conditions other than ASCVD.
The field of PCSK9 inhibition remains an active area of research, and future studies may explore applications of these agents in other disease states where lipid metabolism plays a significant role. As with any investigational drug, the expansion into new indications typically follows successful demonstration of efficacy and safety in the primary indication.
For the most current information about ongoing or planned clinical trials involving Pacibekitug, consulting official clinical trial registries or the pharmaceutical manufacturer would be advisable, as these would contain the most up-to-date information about any expansion of the therapeutic applications of this agent beyond its established role in ASCVD management.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Atherosclerotic Cardiovascular Disease
Anti-inflammatory Approaches
Recent advances have shifted the cardiovascular community toward better understanding inflammatory mechanisms driving residual coronary artery disease (CAD) risk. Inflammation plays a crucial role in all stages of atherosclerosis - from endothelial dysfunction to plaque rupture. The most promising results have come from studies targeting the NLRP3 inflammasome/IL-1β/IL-6/CRP pathway and testing colchicine.
Genetically proxied IL-6 signaling affects 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment. CXCL10 has been identified as a potentially causal mediator for atherosclerosis in multiple vascular compartments, with up to 67% of the effects of downregulated IL-6 signaling on cardiovascular diseases mediated by decreases in CXCL10.
Novel Molecular Targets
Several promising targets have emerged:
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TDP43: Increases in oxLDL-treated macrophages and promotes NF-κB activation, increasing inflammatory factor expression and strengthening lipid uptake by regulating β-catenin and PPAR-γ complex. Knockout of TDP43 in macrophages alleviates atherosclerosis progression.
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DJ-1 protein: A cytoprotective protein that enhances mitochondrial function, scavenges reactive oxygen species, regulates autophagy, inhibits apoptosis, and exerts anti-inflammatory effects.
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Macrophage mitochondria: Serve as a signaling platform integrating epigenetic, redox, efferocytic, and apoptotic regulations. Defective macrophage efferocytosis has emerged as a key factor in atherosclerotic pathogenesis.
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Allograft inflammatory factor-1 (AIF1): A pro-inflammatory molecule expressed primarily in monocyte/macrophage lineage that positively regulates the NF-κB pathway supporting macrophage functions like survival and efferocytosis.
Pathway-Based Approaches
The TGF-β signaling pathway is widely involved in inflammation, immune function, proliferation, differentiation, and apoptosis. MicroRNAs can regulate atherosclerosis through this pathway, though its exact role remains unconfirmed.
Targeting pathological transdifferentiation represents a promising therapeutic avenue. Fibroblasts can transdifferentiate into myofibroblasts in cardiac fibrosis, and endothelial cells may undergo endothelial to mesenchymal transition (EndMT) in vascular remodeling.
Therapeutic Innovations
Transmembrane stem cell factor (tmSCF) delivered in lipid nanodiscs has shown promise for treating peripheral ischemia without activating mast cells. In silico drug repositioning has identified multitarget inhibitors against TNF-α, IFN-γ, and IL-1β as potential therapeutic agents.
Regulatory T cells (Tregs) are atheroprotective, with their proportion significantly decreased in atherosclerotic plaque compared to non-plaque arteries.
Advances in noninvasive detection of coronary artery inflammation include multiple imaging modalities, enabling better selection of patients for anti-inflammatory treatments and assessment of treatment response.
Renin-Angiotensin-Aldosterone System (RAAS) inhibition, novel antithrombotic strategies, and antidiabetic agents like GLP-1RAs continue to show cardiovascular benefits through various mechanisms, including anti-inflammatory effects.
Economic Burden
Economic Burden of Treating Atherosclerotic Cardiovascular Disease in USA and Europe
United States
The economic burden of atherosclerotic cardiovascular disease in the United States is substantial and projected to increase dramatically. In 2000, the direct costs of chronic angina were estimated at $1.9 billion when listed as the primary diagnosis and $8.9 billion when listed in any position. The upper boundary for chronic angina costs reaches the total direct medical cost of CAD at $33 billion (first-listed) and $75 billion (any position).
For cardiovascular disease interventions, the median cost per patient annually was $246 for prevention and $292 for management. However, these interventions demonstrated cost savings, with median healthcare cost reductions of $355 for prevention and $2,430 for management per person annually. This resulted in median total costs of -$89 for prevention (with ROI of 0.01) and -$1,080 for management (with ROI of 7.52).
Recent projections show that by 2050, inflation-adjusted health care costs for cardiovascular risk factors will triple from $400 billion to $1344 billion, while costs for cardiovascular conditions will nearly quadruple from $393 billion to $1490 billion. Productivity losses are expected to increase by 54% to $361 billion by 2050. Stroke is projected to account for the largest absolute increase in costs.
In 2009, 265,531 patients received PCI for acute myocardial infarction, with Medicare payments ranging from $9,303 to $17,500 depending on the diagnosis-related group.
Europe
In Europe, the economic impact of atherosclerotic cardiovascular disease is equally significant. The most recent data (2023) indicates that cardiovascular disease costs the EU €282 billion annually. This breaks down to €155 billion (55%) for health and long-term care, €48 billion (17%) for productivity losses, and €79 billion (28%) for informal care costs.
The average cost of CVD per person across the EU is €630, ranging from €381 in Cyprus to €903 in Germany. Coronary heart disease accounts for 27% (€77 billion) of total CVD costs, while cerebrovascular diseases represent another 27% (€76 billion).
Country-specific data shows that in Portugal (2016), the total cost of atherosclerosis reached 1.9 billion euros, with 58% attributed to direct costs and 42% to indirect costs. Most direct costs were associated with primary care (55%), followed by outpatient care (27%) and hospitalizations (18%). Indirect costs were primarily driven by early exit from the labor force (91%).
In Spain, the average cost of hospitalization for ischemic heart disease increased from 3,093.7 euros in 1997 to 7,028.71 euros in 2011. Preventive measures show promise: administering low-dose aspirin to high-risk individuals resulted in an average net saving of €797 over ten years, with potential total savings of €26.5 million for the Spanish healthcare system.
The economic burden of atherosclerotic cardiovascular disease represents a significant challenge for healthcare systems in both the United States and Europe, with costs projected to increase substantially in coming decades.