Acute Hemodynamic Effects of TPN171H in Pulmonary Arterial Hypertension: A Randomized, Controlled, Phase 2a Trial

Pulmonary arterial hypertension (PAH) has a poor prognosis despite available treatments. TPN171H, structurally modified from traditional Chinese medicine (Epimedium), was reported to have a high affinity for phosphodiesterase type 5, and exhibit anti-inflammatory and vasodilatory effects in preclinical studies. This phase 2a randomized trial (NCT04483115) evaluated the hemodynamic effects and safety of TPN171H in PAH. Sixty patients with PAH were randomly assigned to receive placebo, TPN171H (2.5, 5 or 10 mg) or Tadalafil (20 or 40 mg), and evaluated for hemodynamic changes for 24 hours. The primary endpoint was the maximum change (%) in pulmonary vascular resistance (PVR) from baseline. The key secondary endpoint was the change (%) in PVR to systemic vascular resistance (SVR) ratio at each observation point from baseline. Compared to the placebo group, the least square mean differences in the maximum change of PVR were -16.8% (95% CI, -29.1 to -4.5, p = 0.008) in TPN171H 5 mg, -15.4% (95% CI, -28.2 to -2.7, p = 0.019) in Tadalafil 20 mg, and -13.3% (95% CI, -25.6 to -0.9, p = 0.036) in Tadalafil 40 mg group. Moreover, the TPN171H 5 mg, but none of Tadalafil doses, showed a significant reduction in PVR/SVR ratio at 2 hours (p = 0.026), 3 hours (p = 0.030) and 5 hours (p = 0.046), compared to the placebo group. No serious adverse events occurred. TPN171H 5 mg demonstrated favorable acute hemodynamic effects and an acceptable short-term safety profile in this exploratory trial, supporting further evaluation in longer-term, adequately powered trials.