Monotherapy with rodatristat ethyl reduces pulmonary vascular occlusions, according to results from a preclinical study in a rat model of pulmonary arterial hypertension (PAH). Treatment with a combination of rodatristat ethyl and ambrisentan, a type-A endothelin receptor antagonist, led to a synergistic benefit in reducing occlusions. They also reduced mean pulmonary arterial pressure. These results support the use of rodatristat ethyl in the clinic to treat PAH.

PAH is characterized by increased vascular resistance associated with the proliferation of smooth muscle cells in the pulmonary arteries. This proliferation is accompanied by increased serotonin biosynthesis due to the upregulation of tryptophan hydroxylase in PAH pulmonary arterial cells.

Rodatristat ethyl is a tryptophan hydroxylase inhibitor. It has been shown to reduce serotonin biosynthesis thereby reducing mean pulmonary arterial pressure and the thickness of blood vessel walls in nonclinical models of PAH. It is also being tested in a phase 2 clinical trial.


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Here, researchers compared rodatristat ethyl as a monotherapy and in combination with ambrisentan, a treatment approved for the treatment of PAH.

Read more about the pathophysiology of PAH

Monotherapy with low-dose rodatristat ethyl (50 mg/kg) largely prevented the development of occlusions while higher doses of the treatment reversed the posthypoxic incidence of occlusions. 

Treatment with rodatristat ethyl plus ambrisentan further reduced post hypoxia occlusions to levels comparable to normoxic controls. This reduction was even more pronounced than with treatment with a combination of ambrisentan and tadalafil, another used for PAH.

Monotherapy with rodatristat ethyl or ambrisentan, or combination therapy with ambrisentan plus tadalafil did not significantly lower mean pulmonary arterial pressure. This, the authors said, is “consistent with the multifaceted causes of vascular resistance.”

Combination therapy with rodatristat ethyl plus ambrisentan, on the other hand, did lower mean pulmonary arterial pressure. This finding supports the value of targeting complementary mechanisms in PAH treatment. These results were presented as a poster at the American Thoracic Society (ATS) 2022 International Conference held in San Francisco, California.

References

Palacios M, Wring S. Rodatristat ethyl monotherapy and combination with ambrisentan reverses incidence of vascular occlusions to baseline normoxic levels in the rat SUGEN-hypoxia model of pulmonary arterial hypertension. Poster presented at: 2022 American Thoracic Society International Conference; May 13-18, 2022; San Francisco CA. Poster 943.

Altavant Sciences presents data showing potential for combination of rodatristat ethyl and ambrisentan in model of pulmonary arterial hypertension. News release. Altavant Sciences; May 6, 2022.