KER-012 Prevents Heart Damage in PH Mice
The findings were showcased by KER-012’s developer, Keros Therapeutics, at the American Heart Association (AHA) 2021 Scientific Sessions, held Nov. 13–15, according to a company press release.
KER-012 is designed to increase the activity of a molecular signaling cascade called the bone morphogenic protein (BMP) pathway. As its name suggests, this pathway is important for bone growth, but it also helps to coordinate the development and function of blood cells.
According to Keros, reduced BMP signaling has been implicated in the development of pulmonary arterial hypertension (PAH). The company is developing KER-012 as a potential treatment for PAH, and also for conditions related to bone loss.
Pulmonary hypertension broadly refers to increased blood pressure in the vessels of the lungs. This puts strain on the right ventricle, which is the portion of the heart that pumps blood through the lungs to pick up oxygen. The oxygen-rich blood then travels to the other side of the heart, where the left ventricle pumps it to the rest of the body.
In order to test KER-012’s effect on heart damage, researchers at Keros used a mouse model called pulmonary arterial banding (PAB). This involves a surgical procedure to put a “band” around the main blood vessel that goes from the right ventricle to the lungs — the pulmonary artery.
Comparisons with mice given a sham operation demonstrated this procedure resulted in elevated pressure in the lung’s blood vessels, starting a day after the operation and lasting for at least three weeks. The PAB mice also had diminished heart function and signs of physical changes to heart tissue, consistent with right ventricle stress.
Results showed that treatment with KER-012 prevented these changes in the heart’s structure (tissue remodeling) and function in the PAB model, suggesting a cardio-protective action. In the experiments, PAB mice were given either KER-012 or a control, twice weekly for three weeks.
Notably, altering the BMP pathway can affect the production of red blood cells — the cells that ferry oxygen through the bloodstream using an iron-containing protein called hemoglobin.
“In a separate preclinical study, we demonstrated that KER-012 did not increase hemoglobin or red blood cells in non-human primates, which we believe will translate to a lack of a red blood cell effect in humans, as well,” Jasbir S. Seehra, PhD, president and CEO of Keros, said in a press release.
“These data, along with the preclinical data we presented at the AHA 2021 Scientific Sessions, support that the cardio-protective effects can be independent from red blood cell increases. Accordingly, we believe KER-012 has the potential to provide benefit in PAH without affecting red blood cells or hemoglobin,” Seehra added.
According to Keros, the company is currently conducting a randomized, double-blind, placebo-controlled, Phase 1 clinical trial to evaluate single- and multiple-ascending doses of KER-012 in healthy volunteers. Initial data from this trial is expected in the first half of 2022.