Oral therapy CS1 could help PAH patients stay the course longer
One-year findings show stable or improved measures in most completers
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Most patients who completed one year in an open-label expanded access program (EAP) of CS1, an experimental oral treatment being developed by Cereno Scientific for pulmonary arterial hypertension (PAH), remained stable or improved on several clinical measures.
The EAP (NCT06321705), also known as compassionate use, allowed patients who had completed a three-month Phase 2a clinical study (NCT05224531) to receive CS1 once daily for long-term treatment under a protocol approved by the U.S. Food and Drug Administration (FDA). The main goal was to see whether CS1 remained safe and well tolerated during long-term use.
Real-world data support next trial
The EAP did not begin immediately after the earlier clinical study. There was a gap of six to 25 months between the two studies, during which patients had changes to their background PAH treatments. That means the findings should be viewed as real-world clinical observations, not controlled efficacy results. Still, the data support continued testing in a larger Phase 2b clinical study planned to start this month.
“What is particularly meaningful to me is that these additional analyses provide important long-term clinical context for CS1 in PAH,” Rahul Agrawal, MD, Cereno’s chief medical officer and head of research and development, said in a company press release. “The EAP further reinforces the favorable safety and tolerability profile observed in the Phase IIa trial and shows that patients completing 12 months of treatment were generally stable or improved across several clinically relevant measures.”
In PAH, high blood pressure in the arteries of the lungs makes it difficult for the heart to pump blood. The disease usually gets worse over time, even with current treatments. CS1 is designed to inhibit HDACs, a family of enzymes that help control how genes are switched on and off. Inhibiting HDACs may reduce inflammation, scarring, and thickening of blood vessel walls, all of which are key drivers of PAH.
The earlier three-month clinical study enrolled 25 adults with PAH who were randomly assigned to receive 480 mg, 960 mg, or 1,920 mg of CS1 daily on top of their standard treatments. CS1 was safe and well tolerated, and among the 21 patients who completed treatment per protocol, 71% had stable or improved REVEAL risk scores, a measure used to estimate mortality risk in PAH.
Most completers remained stable or improved
Ten patients entered the EAP, but only six completed one year of treatment. Four patients stopped early for reasons unrelated to CS1. Two developed atrial fibrillation, an irregular heartbeat that can occur in people with PAH, and had to start treatment with blood thinners. Because taking blood thinners met an exclusion criterion in the EAP protocol, these patients had to stop CS1 treatment. One patient chose to leave the EAP, and another could not be contacted.
Among the six patients who completed one year of treatment, five had either stable or improved NYHA/WHO functional class, which rates how much PAH limits daily activities. Five patients also had stable or lower NT-proBNP, a blood marker that increases when the heart is under stress.
Three patients improved their six-minute walk distance, a common test that measures how far someone can walk in six minutes. Three patients also had stable or improved REVEAL risk scores. Among five patients with implanted CardioMEMS sensors, which allow daily, remote monitoring of pulmonary artery pressure, two had stable pulmonary artery pressure and one had lower pulmonary artery pressure.
“While conclusions regarding efficacy cannot be drawn from this small, non-controlled study, maintaining clinical stability over time in a progressive and fatal disease such as PAH is especially encouraging. These findings provide valuable momentum and support our continued conviction in the potential of CS1 as we advance the program,” Agrawal said.
No new safety concerns reported
There were no unexpected safety concerns and no deaths reported. The study also showed that CS1 could be taken alongside approved medications for PAH, including Winrevair (sotatercept), an injectable therapy approved for adults with PAH that targets a pathway involved in abnormal cell growth in the lung arteries.
“I have observed patients continue treatment with CS1 over a longer period in a real-world clinical setting in the EAP,” said Jason Guichard, MD, PhD, Prisma Health-Upstate, investigator in the EAP and Phase 2a clinical study. “For patients with PAH, where long-term disease management is critical, these observations are encouraging and support further evaluation of CS1 as a potential new treatment option.”
The planned Phase 2b clinical study will enroll up to 126 patients at up to 65 sites across 10 to 12 countries. It will test the safety, tolerability, and efficacy of CS1 compared with a placebo when added to standard treatments. The goal is to help identify the best dose for a larger Phase 3 clinical study.
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