Phase 1 safety, tolerability, and pharmacokinetics of NS-863 supporting development for pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease
Y Tamura, M M Hoeper, M Humbert, I Preston, K Isogaya, S Kuriyama, M Palacio, N Shiota, S Tanaka, C Yamamoto, B MorcosAbstract
Background
Pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD) remain progressive and life-threatening disorders characterised by vascular remodelling, smooth muscle proliferation, and impaired pulmonary haemodynamics. Platelet-derived growth factor (PDGF) signalling contributes to these pathobiological processes. PDGFR inhibitors have shown efficacy in PAH, but tolerability or convenience remains a concern. NS-863 is a novel, orally administered, selective PDGFR inhibitor designed to maintain efficacy while improving the risk–benefit profile. NS-863 effectively attenuated pulmonary vascular remodelling and right ventricular hypertrophy in preclinical models of PAH and PH-ILD.
Purpose
This first-in-human Phase 1 study was conducted to characterise the safety, tolerability, and pharmacokinetics (PK) of NS-863 following single and multiple dosing. The study also evaluated the effect of food intake, sex- and race-related differences, and repeated administration to support the selection of an optimal regimen for global Phase 2 studies planned in patients with PAH and PH-ILD.
Methods
The study consisted of three parts in healthy Japanese and White adults. Part A (single ascending dose): 57 Japanese and White participants received NS-863 ranging from 3.48 to 232 mg under fasting conditions. Part B (food-effect study): 16 Japanese participants received 232 mg in a crossover design under fasting and non-fasting conditions. Part C (multiple ascending dose): 30 Japanese and White participants received NS-863 at 13.92–116 mg twice daily (BID) under non-fasting conditions for 7 days. Across all parts, PK assessment was evaluated and safety assessments included adverse events (AEs), vital signs, ECGs and clinical laboratory tests.
Results
All 103 participants received NS-863 across the three parts of the Phase 1 study. NS-863 plasma exposure was dose-proportional after both single and multiple dosing, and steady state was reached within 3–4 days. No clinically significant differences were observed between Japanese and White participants or between men and women. Food effects were observed on NS-863 plasma concentrations. The mean Cmax and AUCinf after non-fasting dose decreased by approximately 37% and 12%, respectively. NS-863 was generally well tolerated. AEs related to NS-863 included feeling abnormal, headache, diarrhoea, and petechiae in 4 out of 103 participants, all mild and resolved within one week. No clinically significant changes in vital signs, ECGs and laboratory values, including platelet count, were observed.
Conclusion
NS-863 demonstrated a favourable safety and tolerability profile up to a 232 mg single dose and 116 mg BID for 7 days, with linear and predictable PK across races, sex and food conditions. These results support the initiation of global Phase 2 studies evaluating the efficacy and safety of NS-863 in PAH and PH-ILD, planned to begin in 2026.