Stable Angina

Chest pain from angina can feel like a heart attack. Stable angina affects more than 4% of the adult population and leads to significant reduction in quality of life.

The overall prevalence of stable angina in the US population aged 20 and older from NHANES data 2015-2018 is estimated at 11.0 million (4.1% of adult population) (Virani et al 2021). The traditional hemodynamic approach to reduce oxygen demand by the use of β-blockers, calcium antagonists, and nitrates is well established. The principal mechanism of achieving a reduction in oxygen demand is by decreasing blood pressure, contractility, and heart rate. However, when titrated to effect, these agents often reach a plateau of hemodynamic suppression, where adding further dose increments or agents with a similar mechanism of action confers no benefit symptomatically, whereas adverse effects increase. This loss of risk/benefit may be especially problematic in the elderly where the hemodynamic side effects limit their quality of life.

Complementary metabolic mechanisms for reducing ischemia that do not reduce oxygen demand or increase blood supply offer an alternative therapeutic target. Under normal aerobic conditions, free fatty acids (FFA) account for 60% to 90% of the energy generated in the adult heart, whereas carbohydrates contribute to 10 to 40%. During ischemia, there is a shift towards glucose metabolism, which is advantageous because, to generate the same amount of ATP, fatty acids require 10 to 15% more oxygen than is required by glucose. As ischemia increases, the myocardium increases its utilization of glucose, even though FFA oxidation remains the major energy substrate. In addition to requiring more oxygen to generate energy, an increase in the rate of FFA oxidation leads to suppression of glucose oxidation as a result of inhibition of pyruvate dehydrogenase. This leads to the accumulation of lactate and protons in the ischemic cells, acidosis, and a reduction in contractile function, in addition to a decrease in the threshold to ventricular arrhythmias. One approach to shifting the metabolism from fatty acids to glucose oxidation is by partially inhibiting fatty acid oxidation.

The Imbria Solution

Our approach at Imbria is to improve the heart’s ability to manufacture the energy it needs so that it can maintain a more normal workload.

Under normal circumstances, a mix of both sugars (glucose) and fats (fatty acids) provides fuel for cardiac cells to create energy. This cellular metabolism is crucial to generating the energy required for the heart to pump effectively.

When blood flow is reduced and oxygen levels available to heart cells are lower than usual, as in patients with refractory angina, the use of fats for energy increases but this is an inefficient process since in these conditions, heart cells may need 10-to-15% more oxygen to generate the same amount of energy from fat versus from sugar. With fat as a primary energy source in a reduced oxygen environment, less energy is generated per molecule of oxygen resulting in a less oxygen efficient contraction of the heart muscle.

We are developing IMB-101 as a treatment for refractory angina. It is designed to bring the balance of fuels back towards normal equilibrium by decreasing fat metabolism and increasing glucose metabolism in the heart, resulting in more efficient energy production per molecule of oxygen consumed. We believe that more efficient energy production will enable the heart to carry a greater workload.

We believe that IMB-101 can be used in conjunction with current standards of care since it should not alter blood pressure or heart rate.