Analysis Supports Efficacy of Rodatristat Ethyl Doses in ELEVATE 2 Trial

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A new analysis suggests that the doses of rodatristat ethyl — an investigational therapy for pulmonary arterial hypertension (PAH) — now being evaluated in the Phase 2b ELEVATE 2 clinical trial are likely to reduce levels of the hormone serotonin to an extent that has been demonstrated to be therapeutic in animal models of PAH.

These findings were presented at the American Thoracic Society (ATS) 2021 International Conference, held virtually May 14–19. The talk was titled “A Pharmacokinetic/Pharmacodynamic Based Rationale for Dose Selection of the TPH Inhibitor Rodatristat Ethyl in ELEVATE-2 — a Phase 2b Study in Pulmonary Arterial Hypertension.”

Serotonin is a hormone that helps regulate many biological processes. In the brain, serotonin is used as a signaling molecule that helps brain cells communicate to regulate mood, cognition, sleep, and other processes.

Peripheral serotonin — that is, serotonin outside of the brain — is known to help coordinate alterations to the structure of blood vessels, called vascular remodeling.

Abnormal vascular remodeling has been implicated in the progression of PAH. As such, investigators believe that reducing the levels of peripheral serotonin may be a useful therapeutic strategy for the disease.

According to Altavant Sciences, the company developing rodatristat ethyl, reducing peripheral serotonin production by 40% showed substantial benefits in animal models of PAH.

Rodatristat ethyl is an oral prodrug — an inactive compound that, once within the body, is metabolized into its active form (rodatristat). The active medication inhibits tryptophan hydroxylase, an enzyme that is critical for the production of serotonin.

Data from early studies in healthy volunteers have indicated that treatment with rodatristat ethyl reduces levels of serotonin in the body, and that the investigational medication is generally safe and well-tolerated.

In the ATS presentation, researchers from Altavant and other institutions used data from these early studies to create pharmacokinetic and pharmacodynamic models of the investigational medication. Conceptually, these models aimed to assess how the investigational medication is processed by the body, and its effects on the body, particularly with regard to the production of peripheral serotonin.

Specifically, the researchers estimated the likelihood that a 40% reduction in peripheral serotonin would be achieved after 14 days of treatment with different doses of rodatristat ethyl. They found that the likelihood of such a reduction was 61% for 300 mg and 84% for 600 mg of the medication, taken twice daily.

The results from the model indicate that these dosages have a high probability of lowering peripheral serotonin levels to an extent that has proven beneficial in animal models, according to the scientists.

Altavant is currently sponsoring a Phase 2b clinical trial called ELEVATE 2 (NCT04712669). The trial is expected to enroll about 90 adults with WHO Group 1 PAH, which includes idiopathic disease — when it has an unknown cause — as well as its heritable, and toxin-induced forms.

The trial is actively recruiting at the University of Kansas Medical Center in Kansas City, and at Tufts Medical Center, in Boston. Additional sites in the U.S., Canada, and Europe also are expected to open. Additional information on contacts and locations is available here.

In ELEVATE 2, participants will receive 300 mg or 600 mg rodatristat ethyl, or a placebo, twice daily for 24 weeks (about six months). Patients will be allowed to continue on their other PAH medications.

The study’s main goal is to assess the effect of treatment on pulmonary vascular resistance — the internal resistance to blood flow within the lung’s blood vessels — as measured by right heart catheterization.

The new analysis suggests that the doses being tested in ELEVATE “have the potential to improve exercise capacity over the 24-week treatment period of ELEVATE-2,” the researchers wrote.

“In preparation for initiating ELEVATE 2, we conducted extensive nonclinical and clinical research on the pharmacokinetics and pharmacodynamics of rodatristat ethyl,” Bill Symonds, Altavant’s CEO, said in a press release.

“Now that we have identified the optimal dose levels, we are excited to begin enrolling patients into the ELEVATE 2 study,” Symonds said.