KER-012 Again Shows Potential as PAH Treatment in Preclinical Studies
A research form of Keros Therapeutics’ investigational therapy KER-012, called RKER-012, reduced lung inflammation and scarring (fibrosis) in a rat model of pulmonary arterial hypertension (PAH). The therapy also prevented an increase in the levels of a heart damage marker, the company announced in a press release.
The findings were presented in the poster “RKER-012, a Novel Activin Receptor Type IIB (ActRIIB) Ligand Trap, Reduced Cardiac and Pulmonary Pathology in a Sugen/Hypoxia (SH) Model of Pulmonary Arterial Hypertension (PAH),” at the Pulmonary Hypertension Association 2022 International PH Conference and Scientific Sessions, held June 10–12 in Atlanta and virtually.
PAH is a rare disease characterized by the narrowing of the pulmonary arteries, or the small blood vessels that supply blood to the lungs. This raises arterial blood pressure and places a burden on the right ventricle of the heart. As the blood flow is reduced in the lungs, patients may experience severe shortness of breath, fatigue, and dizziness, among other symptoms. A later complication of PAH includes right heart failure.
Arterial narrowing occurs as the result of pulmonary vascular remodeling, a process that involves the abnormal growth of smooth muscle cells, which progressively thicken the arterial walls.
KER-012 was designed to increase bone morphogenic protein (BMP) signaling, a pathway whose impairment is thought to drive PAH development and progression. BMP signaling not only plays a role in the maintenance of healthy lung blood vessels, but also promotes bone growth.
The therapy works by trapping ligands that typically bind to the activin receptor type-2B (ActvRIIB), including activin A and B — which are involved in the regulation of BMP signaling and in problems in endothelial cells (endothelial dysfunction), the cells that line blood vessels.
Scientists at Keros tested the effects of a research form of KER-012 — coined RKER-012 — in rats with induced PAH-like disease. A combination of a compound called Sugen5416 and prolonged exposure to hypoxia (low oxygen levels) was used to promote the disease.
Adult male rats with PAH-like disease were given under-the-skin injections of either 10 mg/kg of RKER-012, 10 mg/kg of ActRIIA-Fc (another type of activin ligand trap), or a solution without any compound (used as a control), twice weekly for three weeks.
Consistent with PAH progression, the control rats (untreated) showed a significant increase in pulmonary arterial pressure and in the Fulton index — a measure of enlargement of the heart’s right ventricle — compared with healthy rats.
While treatment with ActRIIA-Fc failed to reduce pulmonary arterial pressure and the Fulton index, RKER-012 significantly dropped both parameters in the animals.
RKER-012 also significantly reduced lung inflammation, lung fibrosis, and arterial wall thickening, as well as the levels of atrial natriuretic peptide, a heart damage marker. These benefits were accompanied with significant drops in the levels of markers of inflammation and fibrosis in the lung and heart — hallmarks of PAH disease.
RKER-012’s beneficial effects were generally superior to those of ActRIIA-Fc.
Researchers also observed that RKER-012 reversed hypoxia-mediated increase in activin A levels in human pulmonary arterial endothelial cells.
Further analysis also confirmed the therapy’s target engagement, preferentially binding to ActvRIIB over other BMP-related molecules, and thereby suppressing the effects of activins A and B.
Overall, the findings “provide early evidence that KER-012 has the potential to benefit lung and heart tissues in PAH, and support continued clinical development in patients,” the researchers wrote.
Notably, these results are consistent with previous studies showing that KER-012 safely and effectively reduced PAH-associated inflammation, vascular remodeling, and heart damage in a rat model of the disease. The therapy’s effect on heart damage was also demonstrated in a mouse model of pulmonary hypertension.
Keros is conducting a placebo-controlled Phase 1 trial to evaluate single and multiple ascending doses of KER-012 in healthy volunteers. Previous, preliminary data showed that single doses of the therapy were generally safe and well tolerated at all evaluated doses and were associated with a favorable pharmacological profile and effective target engagement.
Additional data from multiple-ascending doses are expected later this year. Should the therapy’s favorable safety profile be confirmed, Keros expects to launch a Phase 2 trial to test KER-012 in people with PAH.
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