Inhibiting Serotonin Synthesis for the Treatment of Pulmonary Arterial Hypertension
https://doi.org/10.1002/pul2.70100
Abstract
Substantial evidence from animal models supports the concept of inhibiting peripheral serotonin synthesis for the treatment of pulmonary arterial hypertension (PAH), as demonstrated by pharmacological blockade or genetic deletion of tryptophan hydroxylase 1 (TPH1) [1-5]. Most recently, we have shown that daily inhalation of TPT-004, a novel class TPH1 inhibitor, can alleviate PAH in the Sugen-hypoxia (SuHx) rat model [1]. However, the clinical phase 2b ELEVATE-2 trial, using the TPH inhibitor rodatristat ethyl (NCT04712669), reported disappointing results, including worsened hemodynamics in PAH patients [6]. Rodatristat ethyl (KAR5585) had previously shown only very mild beneficial effects in the rat monocrotaline model of PAH [2]. However, this model is highly criticized as the histological pulmonary vascular changes are clearly distinct from human PAH, and nearly all published interventions appear to be effective [7]. In the clinically more relevant SuHx rat model, rodatristat ethyl even at a very high dose of 100 mg/kg/d as oral monotherapy, had no significant effect on pulmonary hemodynamics and only marginally reduced the relative pulmonary vessel wall thickness [2]. Rodatristat ethyl was only effective in lowering mean pulmonary arterial pressure (mPAP) when combined with the endothelin antagonist, ambrisentan [2]. In contrast, other published TPH inhibitors with different chemical structure had exerted clear benefits as monotherapy in the SuHx rat model (KAR5416 [2], TPT-001 [3], TPT-004 [1, 4]).