Treatment with KER-012, an experimental therapy Keros Therapeutics is developing to treat pulmonary arterial hypertension (PAH), lowered markers of heart damage, fibrosis, and inflammation in a Phase 1 clinical trial that tested the therapy in healthy postmenopausal women.
Keros presented the findings at the American Thoracic Society (ATS) 2023 International Conference. The company also shared new preclinical data shedding light on the molecular mechanisms of KER-012.
“We are pleased to present clinical and preclinical data from our KER-012 program at the ATS conference this year,” Jasbir Seehra, PhD, president and CEO of Keros, said in a company press release. “We believe these data support the potential of KER-012 to treat fibrosis and inflammation in patients with PAH and in patients with cardiovascular disease.”
KER-012 is designed to modulate the activity of the bone morphogenic protein signaling pathways. As its name suggests, this molecular signaling pathway is important for bone growth; it also plays a central role in regulating the health of blood vessels. The therapy is administered by subcutaneous (under-the-skin) injection.
PAH is characterized by increased pressure in the lung’s blood vessels, which puts strain on the right side of the heart that pumps blood to the lungs to pick up oxygen. PAH also is commonly marked by fibrosis (scarring) and inflammation in the lungs. In a preclinical model of PAH, a research form of KER-012 has been shown to reduce heart damage, lung fibrosis, and inflammation.
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Keros conducted a Phase 1 clinical trial, testing the therapy in healthy postmenopausal women. The first part of the study enrolled 40 participants who received a single dose of KER-012, at doses ranging from 0.75 to 5 mg/kg, or a placebo. Results announced last year showed the therapy was generally well tolerated, with no serious safety issues reported.
In the second part of the trial, 26 participants received three injections of KER-012 at 0.75, 1.5 or 4.5 mg/kg, or a placebo. The three injections were given with 28 days between each injection, and then participants were monitored for 16 weeks to assess safety outcomes. Preliminary safety data from the second part of the study, announced late last year, showed KER-012 to be generally well tolerated, with no serious side effects related to treatment reported so far.
Biomarker data measured in serum shared
At the ATS conference, researchers shared biomarker data measured in serum (the noncell portion of blood) from patients who were given the highest dose (4.5 mg/kg) of KER-012 in the trial.
Results showed KER-012 treatment led to sustained reductions in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), which is a well-established marker of heart damage.
Data also suggested the highest dose of KER-012 reduced the levels of signaling molecules that play a role in inflammation (specifically IL-6 and IL-11), while it increased levels of the anti-inflammatory molecules IL-4 and IL-35. Other data, including changes in matrix metalloproteinases and collagen fragments, suggested KER-012 treatment led to a reduction in fibrosis.
“From our completed Phase 1 clinical trial of KER-012 in healthy post-menopausal women, we presented new data with observed sustained changes in serum biomarkers of cardiac dysfunction, inflammation and fibrosis,” Seehra said.
Preclinical data shared at the ATS conference indicated a research version of KER-012 reduced heart damage and fibrosis, helping to improve heart function in a mouse model of heart failure.
Other experiments using human pulmonary arterial endothelial cells and smooth muscle cells — the main cell types that are involved in abnormal blood vessel growth contributing to PAH — suggested treatment with KER-012 could help to normalize cellular signaling under stress, such as when the cells were exposed to low oxygen levels.
“The preclinical presentations demonstrate observed ligand selectivity of KER-012 and changes in inflammation and fibrosis in models of PAH and cardiovascular diseases,” Seehra said.
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