Efficacy, Safety, and Tolerability of ONO‐4474, an Orally Available Pan‐Tropomyosin Receptor Kinase Inhibitor, in Japanese Patients With Moderate to Severe Osteoarthritis of the Knee: A Randomized, Placebo‐Controlled, Double‐Blind, Parallel‐Group Comparative Study

Abstract

We examined the efficacy, safety, and tolerability of ONO‐4474 in Japanese patients with osteoarthritis (OA) of the knee. In this multicenter, placebo‐controlled, randomized, double‐blind, parallel‐group comparative study, patients with moderate to severe OA who were refractory to nonsteroidal anti‐inflammatory drugs were orally administered 100 mg of ONO‐4474 twice daily for 28 days. The primary end point was knee pain during walking, assessed by visual analog scale over 24 hours (VAS24). Treatment‐emergent adverse events (TEAEs) and adverse drug reactions were reported for safety. In total, 110 patients were randomized (1:1) to receive placebo or ONO‐4474. The mean (standard deviation) change in VAS24 scores at week 4 was −26.9 (25.0) mm in the ONO‐4474 group and −19.5 (19.6) mm in the placebo group. The difference (ONO‐4474 group − placebo group) in posterior mean change in VAS24 at week 4 was −5.8 (posterior standard deviation, 4.4; 95% confidence interval, −14.3 to 2.8) mm. TEAEs were reported in 41.8% of patients in the ONO‐4474 group and 18.2% of patients in the placebo group. The most common TEAEs in the ONO‐4474 group related to the musculoskeletal system and the peripheral and central nervous systems were myalgia (7.3%), arthralgia (5.5%), dizziness (3.6%), and hypoesthesia (3.6%). Four patients from the ONO‐4474 group and 1 patient from the placebo group discontinued treatment because of AEs; however, none were judged to be serious, and all patients recovered or were recovering after discontinuation. ONO‐4474 is a novel tropomyosin receptor kinase inhibitor that has an analgesic effect in patients with OA.

Tyrosine kinases regulate chondrocyte hypertrophy: promising drug targets for Osteoarthritis

“…Since 2015, a number of randomized clinical trials have been performed to evaluate the efficacy of TrkA inhibitors GZ389988, ASP7962 and ONO-4474 as treatment for OA knee pain and physical function. Whereas ASP7962 was unable to ameliorate pain and physical function, GZ389988 and ONO-4474 were able to safely reduce pain and gain physical function 36,37,40 . However, no structural changes were measured that could be associated with hypertrophy.…”

Brain-Derived Neurotrophic Factor, Nociception and Pain

“…Certain compounds, such as ARRY-470 [303] or PF-06273340A [304], demonstrate antinociceptive effects in animal models of chronic pain. The efficacy of the pan-trk inhibitor ONO-4474 as an analgesic in patients with moderate to severe osteoarthritis was demonstrated in a recent randomized, double-blinded clinical trial [305]. However, it is probable that these chemicals also affect peripheral trk receptors in addition to trkB, such as trkA.…”

Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance

“…Some of these molecules, e.g., ARRY-470 [197] or PF-06273340A [198], exhibit antinociceptive effects in animal models of chronic pain. In a recent ran-domized, doubleblinded clinical trial, the pan-Trk inhibitor ONO-4474 was proved to be analgesic in patients with moderate to severe osteoarthritis [199]. Yet, it is likely that all these molecules also target peripheral Trk receptors other than TrkB (e.g., TrkA).…”