Acute myocardial infarction (AMI) poses a significant global health threat, leading in both morbidity and mortality and acting as a precursor to heart failure. Despite extensive research over decades, effective pharmaceutical interventions for preventing organ damage from acute ischaemic injuries are lacking. This blog post examines recent scientific trends in the myocardial infarction landscape, exploring evolving therapeutic strategies to address the increasing global burden of heart failure. From market analyses to renewed interest in acid-sensitive cardiac ion channels, we navigate advancements in drug, gene, and cell-based regenerative technologies, shedding light on their potential implications. Emphasizing the need for improved preclinical pipelines and increased investment in elucidating drug targets is crucial to counter the rising impact of heart failure on global health.
Unmet Need
Diseases stemming from cardiac ischemia are a primary emergency facet of cardiovascular disease (CVD). Despite improved reperfusion therapy, the absence of effective treatments for ischemic injuries leads to high mortality rates, contributing to the rising healthcare burden of heart failure (HF). Globally, 20% of people develop HF, with an annual financial burden exceeding US$108 billion, expected to escalate due to comorbidities. Sensitivity to ischemic injury results in the discarding of 75% of donor hearts, exacerbating the public health impact. Projected growth rates suggest an increase in the burden of heart disease through 2030, emphasizing the urgent unmet need for drugs addressing cardiac ischemia–reperfusion injury (IRI) as heart disease persists as the leading global cause of death.
Addressable Markets
Globally, over 150 million people grapple with ischaemic heart disease, leading to 12 million annual deaths from acute myocardial infarction (AMI). Despite improved reperfusion therapies, AMI mortality remains high at 22%, contributing to substantial rehospitalizations and making AMI one of the costliest medical conditions, with an annual US cost of $12.1 billion.
Standard care involves thrombolysis and percutaneous coronary intervention (PCI) to restore blood flow in injured myocardium. However, abrupt reperfusion paradoxically leads to cardiac ischaemia–reperfusion injury (IRI), the primary cause of cardiovascular morbidity and mortality. The absence of drugs blocking the acute injury response underscores the critical importance of minimizing post-infarct injury and myocardial remodelling through timely reperfusion.
In 2015, 25 million diagnosed acute coronary syndrome (ACS) patients were diagnosed, with the USA representing approximately 50%. Existing figures exclude potential markets in Africa, Asia, Eastern Europe, and South America. The lack of clinical therapies post-MI complicates estimating potential savings from new developments. Nevertheless, assuming a conservative 10% reduction in hospitalization costs from new cardioprotective drugs could yield an initial global savings of $3.4 billion across two million AMI hospitalizations, with additional savings from reduced recurrent AMI and other cardiovascular events.
Reasons for Drug Development Failures in MI
Despite progress in post-myocardial infarction (MI) mortality, a substantial number of patients still develop heart failure (HF), underscoring a persistent unmet need and the ongoing shortcomings of drug development pipelines for ischaemic heart disease.
The failure of specific therapies to address multifactorial clinical cases is attributed to the complex and varied mechanisms underlying MI and reperfusion injury.
Complex cell-type specific responses to injury pose a challenge, as therapeutic mechanisms may influence healing processes in one cell type while adversely impacting other organ-level responses, leading to unpredictable outcomes.
The optimal timing of therapy administration in pre-clinical models may not align with practical clinical practice, particularly concerning mechanisms related to pre-conditioning.
Comorbidities, such as diabetes, hypercholesterolaemia, sex, and age, which significantly impact treatment efficacy, are often overlooked in preclinical modelling studies.
Consequently, a meticulous evaluation of standards and processes is imperative for the successful translation of drug candidates. The discordance in evaluation methods between preclinical studies using animal models and clinical trials on patients with diverse co-morbidities contributes to the challenge of drug development for ischaemic heart disease, resulting in the failure to replicate preclinical findings.
Promising Next-Generation Assets to Watch
The persistent burden of heart disease, accompanied by the ongoing challenges in drug development pipelines preventing heart injury, is instigating a notable global shift towards investing in post-injury therapeutic strategies. Current therapeutic endeavors primarily concentrate on addressing post-infarct remodelling, utilizing regenerative medicine or mitigating fibrotic remodelling responses associated with the progression into heart failure (HF).
Significant growth in the regenerative medicine sector, driven by advances in pluripotent stem cell biology, is evident with companies like Tenaya Therapeutics developing AAV-based gene therapy approaches combining three genes that can drive robust in vivo reprogramming of cardiac fibroblasts to cardiomyocytes.
RNA-targeting therapeutics, exemplified by HAYA Therapeutic's lncRNA Wisper and Cardior's microRNA-132 inhibitor CDR132L, are gaining commercial traction to address non-coding transcriptome-related injury response mechanisms, particularly in reducing post-infarct organ fibrosis.
While drugs like neucardin (targeting ErbB2/ErbB4 receptor) and contractile modulators show promise in Phase III clinical trials, notably addressing HF, there is a conspicuous absence of significant commercial efforts targeting upstream myocardial ischaemic stress responses. This highlights an ongoing unmet need to prevent the foundational damage leading to HF, presenting a critical avenue for future therapeutic exploration. Here, Infensa Biosciences develops ASIC1a inhibitors to with greatly improved outcomes after stroke and heart attack in preclinical studies, highlighting the critical role played by this ion channel in mediating tissue injury during these life-threatening events.
Summary & Outlook
By 2035, CVD is expected to afflict 45% of the US population, with an annual cost of US$1.1 trillion. MI will contribute to 16% of global deaths, causing 8.9 million fatalities annually. The inability of the heart to prevent injury spread and tissue damage from ischaemia leads to adverse organ remodelling and HF. Despite improving outcomes, there are no drugs preventing heart muscle cell death due to reduced blood flow.
Emerging cardioprotective drugs, like ASIC1a-targeting candidates, hold promise for MI treatment, but historical drug failures necessitate robust pipeline analysis. Molecular characterizations, improved models, and a growing genetic database offer opportunities to identify new targets and alleviate the CVD burden. Collaborative efforts across disciplines are crucial for overcoming historical failures in cardiac drug discovery.
Insights into cardiomyocyte cell stress during IRI inform acute injury drug development and influence regenerative medicine. Proteins like ASIC1a may enhance the regenerative benefits of cell therapies through gene modification of induced pluripotent stem cells. Genes with no known deleterious effects, like ASIC1a, are promising candidates for gene or drug therapies. The current era of expanding drug target identification holds promise for advancements in cardiovascular therapeutics.
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