Early Results on Rodatristat Ethyl Support Launch of Phase 2 Trial in PAH Patients

Early Results on Rodatristat Ethyl Support Launch of Phase 2 Trial in PAH Patients

Preclinical and early clinical data showing the safety and potential therapeutic activity of rodatristat ethyl support its progression into Phase 2 trials in patients with pulmonary arterial hypertension (PAH).

The most recent findings on Altavant Sciences’ lead therapy candidate were presented at the recent 13th Annual World Congress on Pulmonary Vascular Disease of the Pulmonary Vascular Research Institute (PVRI) in Barcelona, Spain.

The poster, “Translational Analysis of RVT-1201 Nonclinical and Clinical Pharmacokinetic and Pharmacodynamic Biomarker Data to Predict Clinical Dose of a Novel TPH Inhibitor for Treatment of Pulmonary Arterial Hypertension,” was presented by Steve Wring, PhD, senior director of translational medicine at Altavant.

Rodatristat ethyl, also known as RVT-1201, is a tryptophan hydroxylase inhibitor designed to prevent the production of serotonin, which is a hormone that can trigger signals involved in the tightening and growth of pulmonary artery muscle cells, resulting in narrow arteries and contributing to the development of PAH.

A previous study showed that blocking the serotonin receptor with a serotonin antagonist could relieve PAH symptoms in mice, suggesting that targeting serotonin signals could be an attractive therapeutic approach for patients.

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Results from preclinical studies presented at the conference showed that the median effective dose of rodatristat ethyl could reduce serotonin production by approximately 50 percent. This had a positive impact on blood vessel remodeling in a rat model of PAH, with significant reduction of the wall thickness in the pulmonary artery.

“Nonclinical data generated to date suggest that by reducing serotonin through a novel mechanism of action, rodatristat ethyl may provide a disease-modifying therapy that could improve symptoms and survival rates in patients,” William T. Symonds, CEO of Altavant, said in a press release. “Altavant looks forward to confirming these improvements through its planned and future clinical trials.”

Furthermore, initial results from an ongoing clinical study in healthy volunteers demonstrated dose-proportional increases in exposure following administration of rodatristat ethyl as an immediate-release tablet formulation. Food did not interfere with the stability of the therapeutic agent.

To date, all tested doses and regimens were generally well-tolerated, with no reports of serious adverse events or dose-limiting toxicities.

Analysis of a serotonin production biomarker — 5‑hydroxyindoleacetic acid (5‑HIAA) — revealed similar effects across several studies in healthy volunteers, with a reduction of about 50 percent with a mid-level dose of rodatristat ethyl (400 mg twice daily).

Treatment stability and bioavailability predicted that administration of 400 to 600 mg twice daily of rodatristat ethyl should be sufficient to achieve the target exposure, and consequent reduction of about 50 percent in serotonin production.

With this approach, researchers believe it will be possible to induce significant vessel remodeling, which could result in a reduction of PAH symptoms, similar to what was observed in animal models.

“The results presented at PVRI, especially the biomarker findings, suggest that rodatristat ethyl has successfully engaged its target, lowering peripheral serotonin levels by a degree that we believe will be clinically meaningful,” Symonds said. “We look forward to further characterizing its activity in PAH patients in our planned clinical program.”

Supported by these positive early clinical data, the company is planning a Phase 2 trial to explore the safety and effectiveness of oral rodatristat ethyl in patients with PAH. The trial is expected to be launched in the first half of this year.

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