HDAC Inhibitor Lowers Risk, Improves Functional Class in Some Patients with PAH

An investigational pulmonary arterial hypertension (PAH) therapy appears to improve risk levels and functional classes in certain patients, and stabilize other patients.

Cereno Scientific says its histone deacetylase (HDAC) inhibitor, CS1, led to stabilization or improvement in the majority of patients who participated in their phase IIa study.

“Key results from the study demonstrate both that the primary endpoint was met with good safety and tolerability of CS1 in patients with PAH, and, in addition, we also show a positive impact already after 12 weeks on clinical parameters meaningful to patients and regulatory authorities,” said Sten R. Sörensen, the company’s chief executive, in a news release.

PAH is driven by epigenetic mechanisms that lead to disease progression and patient deterioration. Remodeling of pulmonary small arteries leads to poor lung function, right heart failure, and even death, the company noted. The epigenetic mutations behind PAH have become a popular therapeutic target as drugmakers aim to improve the standard of care for the disease.

In this case, CS1 is designed to work through epigenetic modification by inhibiting HDAC. In doing so, Cereno hopes the therapy can reverse vascular remodeling of the small lung arteries.

As a phase 2a study with a primary goal of assessing safety and tolerability, the study had a small patient population. Investigators recruited 25 patients at 10 clinical sites in the US; 21 participants completed the study and were included in the analysis.

In terms of safety, Cereno said no patients had serious adverse events, none were hospitalized, and none died. They also found no clinically significant changes in drug-related platelets or bleeding, and no changes in participant’s liver lab values.

However, they also found that nine of the participants had an improved score on the REVEAL risk assessment after 12 weeks, and another six patients had a stable risk score. In addition, seven patients had an improved functional class after therapy, and 11 more were stable. Two-thirds of patients had sustained reductions in mean pulmonary arterial pressure.

Jason Guichard, M.D., Ph.D.

“Their improvements in health and well-being are encouraging and reflect the potential effectiveness of the therapy,” said study investigator Jason Guichard, M.D., Ph.D., of the University of South Carolina School of Medicine, in the news release.

HDAC inhibitors have largely been developed as cancer therapies, primarily for hematologic malignancies. However, in recent years, drug developers have explored their potential in a range of other diseases, including cardiovascular disease.

Cereno said it will now begin discussions with regulatory authorities in order to prepare a pivotal trial. They also said they have received approval from the FDA for an expanded access program for patients that have completed the phase IIa trial and saw positive results.

“The judgment here by physicians in the trial and by patients [who were] willing to participate is that they have seen some benefits already in this trial and don’t want to wait to get hold of the drug,” said Sörensen, in a webcast announcing the results. “We feel that that’s a very strong signal that there is something positive going on with the drug in these patients.”

The company says it hopes to get approval from the FDA for its pivotal trial within the first half of next year. One key question will be how the therapy will perform over a longer period than the initial 12 weeks of the phase 2a study. Rahul Agarwal, M.D., M.B.A, the company’s chief medical officer, said during the webcast that he is optimistic.

“If one keeps in mind that this is a progressive, continuous disease, we hope to see, of course, better and even more pronounced results over a longer treatment period,” he said.