SR1375: Phase 1 results of a novel, orally administered lipoprotein‐associated phospholipase A2 inhibitor targeting diabetic macular oedema

Aims/Purpose: Lipoprotein‐associated phospholipase A2 (Lp‐PLA 2 ) activity have been linked to a higher risk of diabetic retinopathy and inhibiting Lp‐PLA 2 activity showed improvement in vision and macular oedema for patients with diabetic macular oedema (DME). SR1375 is an orally available, selective inhibitor of Lp‐PLA2 that shows significant retinal vascular leakage reduction in preclinical studies, and is being developed for DME. A phase 1, randomized, double‐blind, placebo‐controlled study is conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SR1375 in healthy subjects. Methods: A total of 72 healthy subjects were enrolled, with 54 had received SR1375. 48 subjects were in the single ascending dose arms (1, 3, 10, 30, 100 and 200 mg) while 24 subjects were in the multiple ascending dose arms (5, 15 and 50 mg once daily for 14 days). Results: SR1375 was safe and well tolerated across all doses. It had excellent oral absorption with the exposure level increasing in an approximately dose proportional manner after single and multiple doses. The elimination of SR1375 was slow with a long t 1/2 ranging from 28.8 to 90.0 h. The accumulation of SR1375 was not significant after multiple administrations. The plasma inhibition on Lp‐PLA 2 activity by SR1375 was strong (up to 95%) and enduring, which was correlated with the concentration of SR1375 (IC 50 as 1.41 ng/mL) and almost returned to basal level when the concentration of SR1375 was low enough. Conclusions: SR1375 was safe and effective in inhibiting plasma Lp‐PLA 2 . The safety and PK/PD profile supports the once daily therapy. A Phase 2 study for DME patients is planned later this year. It would be a 12‐week randomized, double‐blind and placebo‐controlled trial. The primary objective is to assess the effect of SR1375 on vision and oedema.