Study Suggests Serotonin Not a Useful Target for PAH

Despite years of scientific attention and strong preclinical data, a new report casts doubt on the potential utility of serotonin as a target for the treatment of pulmonary arterial hypertension (PAH).

The report found a drug designed to reduce peripheral serotonin concentrations did not improve PAH symptoms. In fact, patients receiving the therapy saw their condition worsen compared to participants given placebo. The findings could bring an abrupt end to efforts to exploit serotonin as a target in PAH.

The idea that serotonin may be a target for PAH therapies dates back decades. It originally emerged when investigators started seeing cases of pulmonary hypertension arise in patients who took diet pills that affected the serotonergic system. In the past decade preclinical studies of the links between serotonin and PAH have intensified.

Marc Humbert, M.D., Ph.D.

“Indeed, serotonin has been shown to induce pulmonary artery smooth muscle cell contraction and proliferation, and to contribute to fibrosis through activation of pulmonary arterial fibroblasts,” noted Marc Humbert, M.D., Ph.D., of the Université Paris-Saclay and colleagues, in a newly published study in The Lancet Respiratory Medicine.

The complexity of the serotonergic system has made it difficult to study the potential utility of serotonin as a PAH therapeutic target, Humbert and colleagues said. However, new drugs targeting the serotonin-producing TPH1 enzyme have opened up new research opportunities.

Rodatristat ethyl is a TPH inhibitor that has been shown to reduce peripheral serotonin plasma levels in both animals and healthy humans. Those findings were good enough for the FDA to grant the therapy orphan drug status in 2015. The findings also led to the launch of the phase 2b ELEVATE-2 trial, which sought to evaluate the therapy in patients with PAH. The results of that trial were the subject of the new report.

In the double-blind study, 108 adults with World Health Organization functional class II or III PAH were randomized into three equal-sized groups. Each group was given two pills, twice daily. One group received a pair of placebo pills for each dose. Another group received one placebo pill and one 300-milligram (mg) pill of rodatristat ethyl for each dose. The final group received two 300-mg pills of the therapy for each dose.

After 24 weeks, 76 patients continued on in an open-label extension, with 37 patients receiving the 300-mg dosage and the other 39 receiving 600-mg doses.

Investigators hoped the therapy would lead to an improvement in pulmonary vascular resistance (PVR) among patients receiving the therapy. Instead, however, the opposite happened.

“Overall, treatment with rodatristat ethyl resulted in significant increases in PVR compared with placebo at week 24,” Humbert and colleagues found. “Moreover, the rodatristat ethyl groups had increased NT-proBNP and worsened right atrial pressure, mPAP [mean pulmonary arterial pressure], stroke volume, and cardiac index.”

The least-squares mean percent change in PVR from baseline to week 24 was 5.8% (standard error 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, they found.

Ultimately, they concluded rodatristat ethyl “is not an appropriate treatment for pulmonary arterial hypertension.” Moreover, they said the data suggest modulating serotonin concentrations is likely ineffective as well.

Marcin Kurzyna, M.D., Ph.D.

In an accompanying commentary, Marcin Kurzyna, M.D., Ph.D., of the Center of Postgraduate Medical Education, in Warsaw, Poland, said one reason there was hope around rodatristat ethyl is that it is suitable for oral delivery, whereas the recently approved Winrevair (sotatercept) requires parenteral administration.

Kurzyna said it’s likely these data will discourage future studies that use the serotonin pathway as a target for PAH, and he praised the investigators for being willing to publish a trial with disappointing results.

“While negative trials are not always published, it is essential for understanding the pathophysiology of pulmonary circulation and in preventing unnecessary repetition in the future,” he wrote.