• About Us
  • Company Overview
  • Leadership
  • Investors
  • Strategic Alliances
  • Contacts
  • FibroGen Europe
• Clinical
  • Current Trials
• Research & Development
  • Hypoxia-Inducible Factor
    HIF Biology

     

    HIF-PHI Therapy

     

    Anemia

     

    Cytoprotection/Inflammation
  • Connective Tissue Growth Factor
    CTGF Biology

     

    Anti-CTGF Therapy

     

    Chronic Kidney Disease

     

    Fibrotic Disease

     

    Cancer
  • Recombinant Human Collagen & Gelatin
• News & Events
  • Publications
  • Press Releases
  • Events
  • Email Sign up
• Careers
  • Job Search
  • Notice to Search Firms and Recruiters

Myocardial Infarction

Unmet Medical Need

Blockage of the blood vessels supplying the muscles of the heart can result in a myocardial infarction (MI), or heart attack. Without adequate blood supply, the affected muscle tissue is rapidly deprived of oxygen and essential nutrients, resulting in immediate and permanent damage. According to the American Heart Association, 80.7 million people in the US have cardiovascular disease and are at risk for MI. Every year there are an estimated 920,000 new and recurring MIs, and approximately 157,000 patients die as a result of MI.

Treatment for MI has improved greatly in recent years through use of devices (stents) or fibrolytic therapy (tPA) to facilitate tissue reperfusion (reinstate blood flow to the heart) after the infarct, and mortality rates have declined. The speedy restoration of blood flow is critical for salvaging heart tissue from further damage and limiting the area of cell death (infarct). However, reperfusion can cause further tissue damage as a result of inflammation and free radical damage associated with the reinstatement of blood flow to the heart. Currently, there is no treatment for the heart tissue that directly aims to preserve the heart muscle during the time of blood deprivation and protect against reperfusion injury.

MI survivors are also at risk for heart failure. Patients who survive MI will have scarred tissue, and their hearts become enlarged as they attempt to compensate for deficiency in delivering an adequate blood supply. According to the Center for Disease Control, there are approximately 5 million heart failure patients in the US. During the period from 1993 to 2003, deaths due to heart failure increased 20.5% while the overall US death rate declined 2%. A therapy that can preserve healthy heart tissue following a heart attack and help to remodel heart tissue in the weeks thereafter is greatly needed.

Cardioprotective HIF-PHI

FibroGen is developing cardioprotective HIF-PHI for acute treatment following MI to reduce myocardial cell death, promote cellular recovery, and reduce the incidence or severity of heart failure following MI. While the cells in the core of the infarcted heart tissue cannot be recovered, the region surrounding the infarct, which is less severely affected, may be salvaged.

HIF-mediated mechanisms may delay or prevent tissue damage until re-canalization is achieved, and protect against further damage from reperfusion injury. Ischemic pre-conditioning of the heart — exposing the heart to experimentally induced brief episodes of transient low oxygen prior to a heart attack — has been shown to reduce myocardial damage that would otherwise occur. This phenomenon also happens naturally as evidenced by research showing that patients with a history of unstable angina (chest pain) have better outcomes following a heart attack than patients without a history of chest pain. Recent research has demonstrated that HIF stabilization is central to cardioprotection achieved through ischemic preconditioning and that adenosine receptor signaling is involved.¹

FibroGen’s research has demonstrated that administration of prolyl hydroxylase inhibitors starting 48 hours post-MI to rats for 4 weeks resulted in early improvement of cardiac function. In a follow-up study employing 8 weeks of dosing, a reduction in mortality was observed as soon as one week post-MI between the treatment (100% alive) and non-treatment groups (~80% alive) with over 92% of the treatment group alive at 8 weeks versus 61% in the non-treatment group. The ability of prolyl hydroxylase inhibitors to preserve cardiac function post-MI is also observed when a “short-term treatment” regimen is employed.

More recent in-house MI studies have shown that treatment with HIF-PHI optimized to produce cytoprotective effects two hours after ischemia and reperfusion can substantially reduce infarct size. Studies are on-going to define the post-MI dose window and to define the optimal dosing regimen for acute treatment of MI.

References

1. Eckle T et al., Hypoxia-Inducible Factor-1 is Central to Cardioprotection: A New Paradigm for Ischemic Preconditioning. Circulation 118: 166-175 (2008).