Patients with heart failure (HF) are commonly divided into those with reduced ejection fraction (EF<40%) and those with preserved ejection fraction (HFpEF; EF>50%). HFpEF without overt coronary arterial disease (CAD) is strongly associated with age and linked to diastolic dysfunction due to myocardial stiffness causing increased left ventricular (LV) end-diastolic pressure pressure and reduced LV filling. For heart failure with reduced EF, a number of therapies have been found to improve patient morbidity and mortality, and treatment is guideline based. However, for patients with HFpEF no treatment has been found to have clinical benefit, and HFpEF is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. Thus, the lack of evidence-based treatment guidelines for HFpEF identifies a huge clinical need and an opportunity to develop novel drugs for almost half the population with heart failure. Moreover, improvements in exercise capacity and heart failure symptoms are key to HFpEF patients, and no current treatment can improve working capacity in HFpEF patients.
Microvascular dysfunction: A recent prospective multi-center study has provided evidence that impaired coronary microvascular function is highly prevalent in HFpEF patients and is associated with systemic endothelial dysfunction expressed as increased urinary albumin-to-creatinine ratio (UACR) and lower reactive hyperemic index (RHI). Renal microvascular dysfunction is major cause of CKD, and as coronary microvascular dysfunction is prevalent in HFpEF and associated with increased UACR and RHI, systemic microvascular dysfunction may be causative in both HFpEF and CKD. Thus, microvascular dysfunction may be a promising novel therapeutic target in HFpEF.
O304 and HFpEF: In preclinical species O304 increases LV stroke volume by increasing end-diastolic volume i.e. improves relaxation of the LV both in obese mice after 6 weeks treatment and after 8 months treatment in aged lean mice. O304 also increases peripheral microvascular perfusion and improves exercise endurance in mouse. In addition, a single dose of O304 lowers blood pressure in dog.
O304-Cardiac safety: The recently described AMPK activator by Merck, MK-8722, promoted glycogen accumulation and induced cardiac hypertrophy in preclinical species. O304 increases AMPK activity by a completely different mechanism than MK-8722, and O304 mimics the beneficial metabolic and cardiovascular effects of exercise. Consistently, in a 6 month rat tox study no clinical signs and no increase in heart weight was observed. In a 9 month tox study in dog, no clinical sign, no accumulation of glycogen in heart and no ECG adverse effects were observed. Thus, there is no concern for adverse cardiac effects with O304. In contrast, the beneficial cardiorenal and microvascular effects of O304 suggest that O304 could be developed into a long though after treatment for HFpEF.
Clinical: In a 28 day Phase IIa trial in T2D patients on metformin, compared to placebo O304 lowered blood pressure and increased microvascular perfusion in calf muscle. The microvascular effect of O304 was also manifested as an early and reversible reduction in estimated glomerular filtration rate (eGFR), also on top of standard of care (SoC) ACEi/ARB drugs. Thus, the beneficial metabolic, microvascular and cardiorenal effects of O304 indicate that O304 may be suitable as a novel treatment for HFpEF.