SCIENCE
OUR APPROACH
Recardio is developing novel therapies that modulate and utilize the body’s own repair mechanisms in cardiovascular and other diseases. Our lead candidate Dutogliptin is intended to enable cardiac regeneration in patients with Acute Myocardial Infarction (AMI) and Advanced Heart Failure (HF).
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The small molecule dutogliptin is the lead product candidate that builds the foundation of our clinical development programs. Dutogliptin is a protein that belongs to a class of enzyme inhibitors called gliptins or DPP-IV inhibitors, which are used extensively in the treatment of Diabetes mellitus. Dutogliptin is a 2nd generation DPP-IV inhibitor with a favorable cardiovascular pharmacological profile that already has a huge preclinical data base and proven safety in multiple safety and efficacy clinical studies. While RECARDIO is not pursuing a diabetes indication, it is utilizing other biological functions of dutogliptin to benefit other indications.
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​In our lead program, dutogliptin is employed to boost and prolong the supply of stem cells to the heart after it has been damaged by an infarct. Dutogliptin accomplishes this by sustaining the activity of SDF-1, a chemokine that plays a major role in cell trafficking and stem cell migration to damaged tissue. During the healing process, cells from the affected organ highly express SDF-1 causing an elevation of localized SDF-1 levels. However, SDF-1 is then quickly neutralized by the inhibitor DPP-IV. Recardio’s dutogliptin effectively inhibits DPP-IV thus preserving SDF-1 over extended periods of time so that stem cell homing to the injury site can be retained. Stem cells play a fundamental role in tissue repair by secreting factors that stimulate cellular healing mechanisms and the generation of new tissue in what is called the paracrine effect, a fundamental element of regenerative medicine.
BACKGROUND
Cardiovascular diseases (CVDs) are the number one cause of death globally. In 2015, there were an estimated 423 million cases of CVD and 18 million CVD deaths. Of these, 9 million were attributed to ischemic heart disease (also known as Coronary Heart Disease) representing the leading cause of CVD in each world region. The cost of treating ischemic heart disease is staggering. In the US alone, over $20 billion are spent annually, of which $12 billion go to the treatment of acute myocardial infarcts.
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Ischemic heart disease is caused by the inadequate supply of blood and, consequently, vital oxygen to the heart muscle. When the blood flow to the heart muscle is completely blocked, the heart muscle cells die, which is termed a heart attack or acute myocardial infarction (AMI). Short-term mortality rates caused directly by the infarct have been reduced significantly by re-establishing the blood flow with Percutaneous Coronary Intervention (PCI) and stents. However, the damage to the heart muscle and subsequent reperfusion injury often lead to complications. As the infarcted area begins to heal and to scar, drugs do not contribute to recovery or regeneration of the damaged tissue. A negative remodeling process eventually leading to HF often ensues. First year mortality for patients experiencing the most severe form of an infarct known as STEMI remains high at 7-18%. 48% of patients undergoing a PCI after AMI are re-hospitalized within a year.
AMI THERAPY
To limit the damage and to better repair the heart muscle following an infarct, numerous clinical trials have attempted cardiac tissue regeneration with stem cell therapy. Results of larger randomized, controlled studies have been generally disappointing. Recardio’s approach consists of a new regenerative alternative.
Recardio has shown that stem cell homing and retention as well as an improvement in cardiac output are possible using an in-vivo approach that does not rely on the collection, processing, and injection of stem cells to the heart. First, G-CSF, a cytokine that has been used clinically with success for three decades, is given to mobilize bone marrow stem cells in great numbers into circulating blood. Second, our lead candidate dutogliptin is administered over several days. Dutogliptin inhibits DPP-IV which enables the sustained preservation of SDF-1, a chemokine that is critical for homing of stem cells to the site of injury. This is a crucial step as numerous clinical studies have shown that G-CSF alone does not lead to a clinical improvement in this condition. The combination of G-CSF with dutogliptin significantly enhanced survival and reduced infarct size in a pre-clinical model. The clinical evaluation of this therapy is now under way in Recardio’s lead clinical program.
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The approach with dutogliptin in co-administration with G-CSF is practical and reproducible. Once the diagnosis of AMI is confirmed and PCI and stent implantation are completed, patients receive or can self-administer daily sub cute injections of dutogliptin for 2 weeks in co-administration with G-CSF for 5 days. Due to its easy-to-use and simplicity, this therapeutic strategy can be applied in a wide spectrum of healthcare facilities. Stem cell collections, processing and intracoronary reinfusion are not required.