HRS-5965

HRS-5965 is an oral selective small-molecule inhibitor of complement factor B, a key component of the alternative pathway. This study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of HRS-5965 in healthy participants and participants with renal insufficiency.

The first-in-human, phase 1 study consisted of 3 parts (ClinicalTrials.gov: NCT05505955). Part 1 was a single-ascending-dose, randomized, double-blind study with 5 dose groups preset, including a food effect evaluation. Part 2 was a multiple-ascending-dose, randomized, double-blind study with 9 dose groups preset. Part 3 was an open-label, single-dose study on severe renal insufficiency. The primary endpoints were safety and tolerability.

A total of 82 participants were enrolled and received either HRS-5965 or placebo (26 in part 1, 40 in part 2, and 16 in part 3). HRS-5965 was well tolerated. Treatment-emergent adverse events were comparable between the HRS-5965 groups and placebo groups in part 1 (17/20 [85.0%] vs. 6/6 [100.0%]) and part 2 (27/30 [90.0%] vs. 10/10 [100.0%]). No deaths were reported. HRS-5965 was absorbed rapidly, with a median time to reach peak concentration (T_max) ranging from 0.75 to 1.50 h in fasted states and 2.00 h in fed states. Pharmacokinetics was nonlinear, and food delayed the absorption of HRS-5965 but did not impact the exposure. Alternative pathway activity was inhibited by over 80% with HRS-5965, compared to less than 20% with placebo.

HRS-5965 demonstrated favorable safety and robust inhibition of alternative pathway activity, supporting further clinical development.

The study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.