Safety and efficacy of rodatristat ethyl for the treatment of pulmonary arterial hypertension (ELEVATE-2): a dose-ranging, randomised, multicentre, phase 2b trial.

Background: The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results.
Methods: ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America. Eligible participants were aged 18 years or older, had pulmonary arterial hypertension with WHO functional class II or III symptom severity, and had received a stable dose and regimen of one or more pulmonary arterial hypertension treatments for at least 12 weeks. Participants were randomly assigned 1:1:1 to receive two placebo tablets, one placebo and one rodatristat ethyl 300 mg tablet, or two rodatristat ethyl 300 mg tablets twice daily using an interactive response system. Participants, investigators, site personnel, and sponsors were masked to treatment allocation. Participants who completed the 24 week treatment period were invited to continue in an open-label extension. The primary endpoint was percent change in pulmonary vascular resistance (PVR) from baseline to week 24. Primary efficacy analyses were conducted on the intention-to-treat population and analyses of harms were conducted in the safety population, which included all patients who received any amount of the study drug. This trial is registered with ClinicalTrials.gov, NCT04712669, and is now complete.
Findings: Between March 18, 2021 and Dec 13, 2022, 108 participants were enrolled and randomly assigned. 36 participants received placebo, 36 received rodatristat ethyl 300 mg, and 36 received rodatristat ethyl 600 mg twice daily. Overall, 85 (79%) of participants were female and 23 (21%) were male. The mean age was 52·8 years (SD 14·7) in the full analysis set. In the open-label extension phase, 62 (82%) of participants were female and 14 (18%) were male, and the mean age was 52·8 years (SD 14·7); this phase was terminated following sponsor review of unmasked main study results. Least-squares mean percent change in PVR from baseline to week 24 favoured placebo and was 5·8% (SE 18·1) for the placebo group, 63·1% (18·5) for the rodatristat ethyl 300 mg group, and 64·2% (18·0) for the rodatristat ethyl 600 mg group. Treatment-emergent adverse events (TEAE) were reported for 29 (81%) patients in the placebo group, 33 (92%) patients in the rodatristat ethyl 300 mg group, and all 36 (100%) patients in the rodatristat ethyl 600 mg group. TEAE leading to study discontinuation were reported for three (8%) patients in the placebo group, four (11%) patients in the rodatristat ethyl 300 mg group, and four (11%) in the rodatristat ethyl 600 mg group. There was one (3%) TEAE leading to death in the rodatristat ethyl 300 mg group.
Interpretation: Our results indicate that reducing peripheral serotonin concentrations via rodatristat ethyl has a negative effect on pulmonary haemodynamics and cardiac function in patients with pulmonary arterial hypertension. This finding suggests that manipulating this pathway might not be a suitable option for pulmonary arterial hypertension therapy.
Funding: Enzyvant Therapeutics (now Sumitomo Pharma America).
Competing Interests: Declaration of interests JD, RG, RJ, WK-K, MP, SW, and HN were all employees of Enzyvant at the time of the study. HML was Chief Medical Officer at Enzyvant at the time of the study. EP, GD, and TM were consultants at Enzyvant at the time of the study. OS received grants or contracts from Aerovate, AOP Orphan, Ferrer, Janssen, and MSD; received consulting fees from AOP Orphan, Enzyvant, Ferrer, Gossamer Bio, Janssen, Liquidia, MSD, and Respira Therapeutics; received honoraria from AOP Orphan, Ferrer, Janssen, and MSD; and has participated on the data monitoring committee or advisory boards for Enzyvant, Gossamer Bio, and Janssen. SS has received grants or contracts from United Therapeutics; received consulting fees for Keros, Liquidia, Merck, and Roivant; received honoraria from Actelion, Bayer, and United Therapeutics; participated on the drug safety monitoring board for the US National Institutes of Health K23 grants; acted as clinical trial endpoint adjudication committee member for a GSK-sponsored randomised controlled trial; and received research grant support from United Therapeutics. AS reports payments made to their institution for grants and contracts from Aerovate, AOP Orphan, Gossamer Bio, and Enzyvant; consulting fees from Liquidia and Merck; and support for meetings or travel from Enzyvant and Liquidia. MH received grants or contracts from Acceleron, AOP Orphan, Janssen, Merck, and Shou Ti; consulting fees from 35 Pharma, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Kerros, Merck, MorphogenIX, Shou Ti, and United Therapeutics; payment or honoraria from Janssen and Merck; and has participated in a drug safety monitoring board or committee for Acceleron, Altavant, Janssen, Merck, and United Therapeutics. DL received grants or contracts from Aerovate, Janssen, and Merck; acted as a consultant for Bayer, Janssen, and Merck; received honoraria from Janssen and Merck; received support for meetings or travel from Janssen and Merck; and participated as part of a data monitoring committee or advisory board for Insmed, Janssen, and Merck. JF, OAS, VM, and H-AG report no competing interests.
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