Phase 2b Trial Opens for Rodatristat Ethyl, Potential PAH-modifying Therapy

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by Steve Bryson, PhD |

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Altavant Sciences has opened ELEVATE 2, its global Phase 2b clinical trial into the safety and efficacy of rodatristat ethyl, a potential disease-modifying oral therapy for people with pulmonary arterial hypertension (PAH).

The proof-of-concept study (NCT04712669) is expected to enroll about 90 adults with diagnosed, symptomatic WHO Group 1 PAH, which includes idiopathic (unknown cause), heritable, and toxin-induced disease. Contact information is available here, and the company expects sites to span the U.S., Canada, and Europe

 In an early clinical trial in healthy volunteers, rodatristat ethyl was seen to safely reduced the levels of serotonin — a hormone that promotes the tightening of pulmonary artery muscle cells when in excess.

“Dysregulated, excessive serotonin signaling in the lungs of patients with PAH is a life-threatening condition, causing excessive growth of pulmonary artery smooth muscle cells as well as the release of proinflammatory and profibrotic [scarring] molecules, all of which constrict pulmonary blood vessels,” Marc Humbert, MD, PhD, a professor of respiratory medicine at the Université Paris-Saclay and an investigator in ELEVATE 2, said in a press release.

Rodatristat ethyl is designed to block the serotonin-producing enzyme tryptophan hydroxylase (TPH). By lowering serotonin levels in the bloodstream, rodatristat may halt or reverse disease processes that are driven by excessive serotonin production, such as PAH, idiopathic pulmonary fibrosis and sarcoidosis.

“Decades of research point to the critical role of serotonin in PAH disease progression and support the hypothesis that by reducing levels of the hormone in the periphery [outside brain and spinal cord], we may be able to improve, and potentially even reverse, pulmonary remodeling in these patients,” Humbert added. 

Enrolled patients in ELEVATE 2 will be randomly assigned to either 300 mg or 600 mg of rodatristat ethyl or a placebo given twice daily, along with their current PAH treatments, for 24 weeks (about six months). 

Safety, efficacy, and pharmacokinetics movement of medicine into, through, and out of the body — will be assessed at various times throughout the study, with in-clinic follow-ups as well as home and telemedicine visits.

The study’s primary goal will be the change from study’s start (baseline) in pulmonary vascular resistance (PVR) after 24 weeks, as assessed by inserting a catheter into the right side of the heart (right heart catheterization). PVR evaluates the internal resistance to blood flow within the pulmonary arteries.

In addition to safety, secondary efficacy outcomes include changes in various validated PAH scales and the levels 5-hydroxyindoleacetic acid (5-HIAA), the main product resulting from the breakdown of serotonin and a biomarker of this hormone.

Investigators will also evaluate functional tests such as the six-minute walk test (distance walked in six minutes) and assess daily activity levels. 

In mouse models of PAH, rodatristat ethyl’s use was shown to reduce 5-HIAA and lessen the extent of structural changes in blood vessels. 

“Extensive in vivo and early clinical testing strongly support the rodatristat mechanism as a potential disease-modifying treatment for conditions characterized by excessive production of serotonin, including PAH,” said William Symonds, CEO of Altavant.

“We are excited to advance our lead candidate into Phase 2b development, and by the opportunity to provide meaningful benefit to patients with this disease,” he added.