Acute myocardial infarction (MI) is a major cause of death and disability worldwide. The treatment of choice for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion, using either thrombolytic therapy or primary percutaneous coronary intervention (PCI). Prompt restoration of blood flow to ischemic myocardium limits infarct size and reduces mortality. However, the return of blood flow can also result in additional cardiac damage and complications, referred to as myocardial ischemia reperfusion injury (IRI). The administration of a therapeutic strategy as an adjunct to reperfusion that is capable of reducing reperfusion injury would result in a smaller infarct size and maximize the benefits of myocardial reperfusion. There is still no effective therapy for preventing reperfusion injury.
Scientist at University of Oslo are developing small molecule drugs that selectively target the protein-protein interactions between AKAP18d and PLB, a key regulatory complex of the Ca2+ pump SERCA2, which controls pacing of the heart. The novel cardio-protective strategy is thought to result in more selective modulation of SERCA2 activity, by only affecting adrenergic regulation of SERCA and not basal activity. Furthermore, the strategy is thought to isolate one beneficial effect of beta blockers – the negative inotropic effect, without introducing a negative chronotropic effect. A leading compound has been extensively characterized and formulated to allow PK-characterization by multiple administration routes. Acute administration of the formulated drug by either the IV or per-oral route in a rat model of IRI has resulted in clinically relevant inhibition of infarction size (35-40%) at day 1, together with improvements in heart function at day 9, and expected bio-target modulation. Preliminary benchmarking to a commonly used beta blocker (metoprolol) indicates superior therapeutic effect with respect to initial infarction size. These results demonstrate the proof-of-concept (PoC) for the therapeutic strategy and warrant further pre-clinical development, including studies in larger animals (pigs). We plan to conduct further preclinical PoC studies in pig models of disease and safety/toxicity studies of our leading compound. Future clinical PoC trials are expected to evaluate the drug candidate in STEMI patients in an acute treatment setting, administered immediately before reperfusion. The envisioned primary outcome in a clinical PoC study is 3-month myocardial salvage index, with biomarkers as secondary outcome measures.
A patent application (WO 2013/171332A2) is currently pending in multiple jurisdictions (US, EP, JP).