Early development of LRX712, preclinical chondroanabolic findings and results from a randomized first-in-human study

No disease-modifying drugs are approved for osteoarthritis (OA), a prevalent and debilitating chronic condition. Based on preclinical data, LRX712 was envisioned as a potential therapy to regenerate hyaline cartilage. We present key preclinical results and the first-in-human (FIH) study of intra-articular (i.a.) LRX712 in patients with mild-to-moderate knee OA. In vitro , the effect of LRX712 on chondrogenesis markers was evaluated using cell culture, PCR and RNA sequencing from one donor. The chondrogenic potential was further explored in vivo using a rat meniscal tear model. The FIH study used a double-blind, randomized, placebo-controlled, single ascending dose design across seven dose-levels (0.5 mg-75 mg) with safety and tolerability (primary endpoint), pharmacokinetic (secondary endpoint) and exploratory biomarkers monitored over 60 days. The Knee Injury and Osteoarthritis Outcome Score (KOOS) exploratorily evaluated preliminary effects on knee pain and function. LRX712 enhanced chondrogenic differentiation in vitro and stimulated cartilage repair in vivo in preclinical experiments. In the FIH study with 42 participants, no serious adverse events (AEs) occurred. The most frequently observed AEs were injection site joint reactions, which occurred particularly at higher doses. With doses of LRX712 > 15 mg, a post-hoc analysis identified a pattern of transient elevations in serum high sensitivity C-reactive protein (hsCRP) post-administration. PK analysis showed longer T 1/2 at higher dose levels, with large variation between participants. No clinically relevant changes were observed for exploratory biomarkers or KOOS. The pre-clinical and clinical data indicated that LRX712 has a tolerability- and PK-profile that could support further development. NCT03355196.