Breakthrough Clinical Results
Cantargia AB announced promising preclinical results for CAN10, an antibody targeting IL1RAP, in vascular inflammation models. The study, published in the Journal of the American Heart Association, showed CAN10 effectively inhibits the release of inflammatory mediators and reduces endothelial permeability and neutrophil adhesion. IL1RAP levels in human atherosclerotic plaques correlated with inflammatory markers, suggesting translational potential for cardiovascular diseases (CVDs). CAN10's unique mechanism simultaneously inhibits signaling via IL-1, IL-33, and IL-36, offering a novel approach to treating inflammatory diseases. A Phase 1 clinical trial in healthy volunteers and psoriasis patients is ongoing.
Key Highlights
- Preclinical data shows CAN10 effectively inhibits vascular inflammation.
- IL1RAP levels correlate with inflammatory markers in human atherosclerotic plaques.
- CAN10 simultaneously inhibits signaling via IL-1, IL-33, and IL-36.
- Phase 1 clinical trial of CAN10 is ongoing.
Incidence and Prevalence
Global Burden of Cardiovascular Diseases (CVDs): Latest Estimates
Cardiovascular diseases (CVDs) remain a significant global health challenge. Determining the most recent incidence and prevalence estimates requires careful consideration of data sources and publication dates. The Global Burden of Disease (GBD) studies provide the most comprehensive data, and it's essential to cite the most recent GBD data available.
2021 Estimates (GBD 2021):
- Prevalence: In 2021, there were 612 million cases of CVD globally. The global age-standardized prevalence rate rose to 7,179 cases per 100,000 individuals.
- Incidence: While the provided text doesn't explicitly state the global incidence number for 2021, it mentions a rising prevalence and highlights ischemic heart disease (IHD) and stroke as significant contributors among CVD subtypes. Other sources within the provided text offer incidence data for specific years or regions, but not a global figure for 2021.
- Mortality: CVDs accounted for 26.8% of all deaths globally in 2021. The global age-standardized mortality rate fell to 235 deaths per 100,000 individuals.
Key Trends and Observations:
- Rising Prevalence: Despite advancements in CVD care, the global prevalence of CVDs is increasing, posing ongoing challenges to health systems worldwide.
- Declining Mortality and DALYs: While prevalence is rising, age-standardized mortality and DALY rates are declining, indicating improvements in medical care and interventions following diagnosis.
- Regional Disparities: The CVD burden varies significantly across regions, with the highest burden observed in low- and lower-middle Socio-demographic Index (SDI) regions. Regional differences in health system outcomes and SDI-related inequalities persist.
- Age and Sex Differences: The burden of CVDs is more pronounced in older age groups and in men.
- Risk Factors: A significant proportion of CVD disability-adjusted life years (DALYs) are attributable to modifiable risk factors, with high Body Mass Index (BMI) showing the most significant increase.
- Impact of COVID-19: The COVID-19 pandemic has further underscored the challenges in CVD prevention and care, potentially influencing longer-term trends.
Other Relevant Information from Provided Texts:
- Projections for CVD burden from 2025 to 2050 indicate a substantial increase in prevalence and crude mortality, driven primarily by population growth and aging. However, age-standardized prevalence is expected to remain relatively constant, with decreasing age-standardized mortality and DALYs.
- Analysis of CVD trends from 1990 to 2019 reveals a consistent decrease in age-standardized incidence and mortality in most countries, although some regions, particularly low- to middle-SDI regions, show worrying increases in CVD cases and deaths.
- The impact of the COVID-19 pandemic on longer-term CVD trends is yet to be fully established, but there are indications that it may have attenuated declines in age-standardized CVD rates.
It's important to note that these estimates and trends are based on available data and may be subject to limitations. Continuous monitoring and updated analyses are crucial for understanding the evolving global burden of CVDs and informing effective public health strategies.
Emerging Mechanism of Action
Cardiovascular diseases (CVDs) remain a significant global health concern, and research continues to explore the underlying mechanisms of disease and potential therapeutic targets. Based on publications in PubMed over the past 3 years, several key mechanisms of action (MoAs) are emerging:
-
Inflammation and Immune Response:
-
NLRP3 Inflammasome: This complex plays a crucial role in innate immunity and inflammation, triggering the release of pro-inflammatory cytokines. Its activation is implicated in various CVDs, including atherosclerosis, ischemia/reperfusion injury, and heart failure. Targeting NLRP3 inflammasome components is a potential therapeutic strategy.
-
Chronic Inflammation: Sustained inflammatory responses contribute to tissue and organ damage, promoting CVD development and progression. Natural products with anti-inflammatory properties are being investigated as potential treatments.
-
Immune-mediated Inflammatory Diseases: While not specific to CVDs, advances in understanding immune-mediated inflammation have led to the development of highly targeted therapies, offering potential applications in CVD treatment.
-
Metabolic Dysfunction:
-
Insulin Resistance (IR): IR is linked to CVD through various mechanisms, including hyperglycemia, compensatory hyperinsulinemia, and alterations in insulin signaling pathways. Managing IR through lifestyle modifications and pharmacological agents is crucial for CVD prevention.
-
Metabolic Disorders: Genetically predicted metabolic disorders increase the risk of various CVDs, including coronary heart disease, myocardial infarction, heart failure, hypertension, and stroke. Addressing metabolic disorders is essential for reducing CVD development.
-
Ceramide: This sphingolipid metabolite contributes to insulin resistance and dyslipidemia, increasing adverse cardiovascular risks. Inhibiting ceramide synthesis or promoting its degradation shows promise in improving CVD outcomes.
-
TyG Index: The triglyceride-glucose (TyG) index, a reliable biomarker of IR, is associated with CVD development and prognosis. Its application as a CVD marker is being actively evaluated.
-
Oxidative Stress:
-
Oxidative Homeostasis Imbalance: Increased oxidative stress damages cellular components, contributing to inflammation and cell death. Antioxidants, including nutritional supplements and novel agents, are being studied as potential treatments for oxidative stress-associated CVDs.
-
Mitochondrial Dysfunction: Mitochondria play a vital role in cardiovascular health, and their dysfunction contributes to CVD development. Therapies targeting mitochondrial function, such as SIRT3 agonists, are being explored.
-
Endothelial Dysfunction:
-
Nitric Oxide (NO) Impairment: NO is a crucial mediator of vasodilation and vascular health. Impaired NO production or bioavailability contributes to various CVDs. Therapeutic strategies targeting NO pathways are under investigation.
-
Other Emerging MoAs:
-
Ferroptosis: This iron-dependent form of regulated cell death is implicated in various CVDs. Modulating ferroptosis pathways may offer therapeutic potential.
-
Gut Microbiota Dysbiosis: Imbalances in the gut microbial community are linked to CVD development. Microbiota-based therapies, such as prebiotics, probiotics, and trimethylamine-N-oxide inhibitors, are being investigated.
-
Epigenetic Modifications: Epigenetic alterations, including DNA methylation and histone modification, are increasingly recognized as contributors to CVDs. Targeting epigenetic mechanisms may offer new diagnostic and therapeutic avenues.
It's important to note that research on these MoAs is ongoing, and further studies are needed to fully elucidate their roles in CVDs and to develop effective targeted therapies.
Drug used in other indications
CAN04 is a first-in-class monoclonal antibody that targets IL1RAP, a protein essential for IL-1 signaling. This signaling pathway is implicated in various pro-tumoral processes, including proliferation, immune evasion, metastasis, and chemoresistance. A phase 1 study (NCT03267316) investigated CAN04's safety, recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity in patients with advanced solid tumors expressing IL1RAP and refractory to standard treatments.
The study enrolled 22 patients and evaluated five dose levels (1.0-10.0 mg/kg) of weekly CAN04. The most common adverse events observed were infusion-related reactions (41%), fatigue (32%), and gastrointestinal issues like constipation, diarrhea, decreased appetite, nausea, and vomiting (each occurring in 23-27% of patients). Only one dose-limiting toxicity was reported, and no maximum tolerated dose was identified. Pharmacokinetic analyses showed higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and C-reactive protein (CRP) were observed, suggesting target engagement and IL-1 pathway inhibition. Of the 21 patients evaluable for response, 43% experienced stable disease according to immune-related response criteria, with no partial or complete responses observed.
Based on these findings, 10.0 mg/kg weekly was defined as the recommended phase 2 dose. While the study did not demonstrate significant anti-tumor activity in this initial phase, the safety profile and biomarker data support further investigation of CAN04 in larger trials and potentially in combination with other therapies. It is important to note that this trial focused on solid tumors expressing IL1RAP, and the specific cancer types included were not detailed in the provided abstract.