PAH therapy reverses blood vessel remodeling in preclinical model
Effects of CS014 provide 'very good basis' to target disease: Scientists
Cereno Scientific’s investigational therapy CS014 was found to reverse remodeling, meaning alterations in structure and arrangement, of pulmonary arteries in a preclinical model of pulmonary arterial hypertension (PAH).
According to the company, the new preclinical data “provide the most compelling evidence to date that CS014 offers a disease modifying approach to PAH and related pulmonary vascular diseases by robustly reversing pulmonary pathological [disease-causing] vascular remodeling and fibrosis,” or tissue thickening and scarring.
The preclinical model exhibits many features of PAH, including pulmonary vascular remodeling and fibrosis, per Cereno.
“The CS014 effects in the preclinical model are impressive and give us a very good basis to target diseases of vascular remodeling and fibrosis in future clinical trials,” Nicholas Oakes, PhD, Cereno’s head of preclinical development, said in a company press release.
Further details and results will be disclosed in a future scientific publication, the company said.
CS014 now being tested in Phase 1 clinical trial
PAH is characterized by the narrowing of the pulmonary arteries — the blood vessels that supply the lungs. Such narrowing restricts blood flow and increases blood pressure, potentially leading to right heart failure. Arterial narrowing occurs as a result of pulmonary vascular remodeling, a process that involves the uncontrolled growth of smooth muscle cells that progressively thicken the arterial walls.
CS014 works as an epigenetic modulator, meaning it makes changes to how genes are read, but not to the DNA sequence itself. It’s designed to block histone deacetylase (HDAC), a class of enzymes that make DNA less accessible for the production of proteins.
The therapy is being developed to prevent thrombosis — when blood clots block veins or arteries — without increasing the risk of bleeding. According to Cereno, additional benefits are expected, including less inflammation, fibrosis, and vascular remodeling, as well as lower blood pressure.
Besides a dose-dependent reversal of vascular remodeling in the lung, the results seen in the preclinical model included statistically significant reductions in small artery vessel occlusion, less fibrosis, and smaller plexiform lesions. These lesions are a PAH hallmark characterized by complex blood vessel formations originating from remodeled pulmonary arteries.
The results suggest that CS014 may be a disease-modifying therapy for PAH, according to Cereno.
A Phase 1 clinical trial testing the therapy’s safety, tolerability, and pharmacological properties started dosing patients in June. The trial will have two parts, with part one assessing the safety, tolerability and pharmacological profile of single ascending oral doses of CS014. Part two will explore the treatment candidate’s safety, tolerability, and pharmacology following multiple ascending doses given over seven days.
Results of the study are expected in approximately one year.
“I am happy to share progress in our HDAC inhibitor program, adding to the plethora of evidence supporting the concept of HDAC inhibition and epigenetic modulation as relevant approaches for disease modifying therapies in cardiovascular diseases,” said Sten R. Sörensen, CEO of Cereno.
The company is also developing another HDAC inhibitor, CS1, a reformulation of an antiseizure medication that also works as an epigenetic modulator. CS1 is undergoing a Phase 2 trial (NCT05224531) involving about 30 people. Preliminary results from the first participant who completed the study were positive, with reduced pulmonary hypertension and improved cardiac output — the amount of blood pumped by the heart — and physical function. Top-line data from that study are expected soon.
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