Background/Purpose:

ONO-4474 is an orally available, peripheral-specific, pan-tropomyosin receptor kinase (pan-Trk) inhibitor currently under development for treatment of musculoskeletal pain in OA patients. This study assessed the efficacy, safety, and tolerability of ONO-4474 in Japanese patients with OA of the knee with inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs).

Methods:

Male and female Japanese patients with moderate-to-severe OA of the knee and inadequate response to NSAIDs, who were aged 40 to <75 years with a body mass index between 18.5 and <39.0 kg/m² were recruited in this study. After a 14-day screening period, patients entered a 28-day, double-blind treatment period and were randomized to receive ONO-4474 200 mg/day (100 mg twice daily after meals) or placebo. Patients then entered a 14-day follow-up period. The primary efficacy endpoint was change in knee pain during walking, assessed over 24 hours, calculated as the difference in posterior mean of changes in VAS₂₄ scores from baseline versus placebo at Week 4. Other efficacy endpoints included WOMAC scores, Patients’ Global Assessment (PGA) scores, and frequency of rescue treatment use. Safety endpoints were vital signs, 12-lead ECG, laboratory tests, neurological examinations, Columbia Suicide Severity Rating Scale (C-SSRS), and adverse events (AEs).

Results:

The full analysis and safety analysis sets included 110 patients (ONO-4474 and placebo, both n = 55). The difference in posterior mean change in VAS₂₄ from baseline ± posterior standard deviation (95% confidence interval [CI]) (ONO-4474 group – placebo group) was −5.8±4.4 mm [−14.3, 2.8] at Week 4 and the posterior probability that the difference was less than 0 mm was 90.6%, indicating an improvement with ONO-4474 versus placebo. At Week 4, the difference for ONO-4474 versus placebo in the least-squares (LS) mean changes in WOMAC total and pain scores from baseline ± standard error [95% CI] were −3.6 ± 3.5 mm [−10.5, 3.3] and −4.1 ± 3.8 mm [−11.7, 3.5]. The difference in the LS mean change of PGA from baseline ± standard error [95% CI] was −6.4 ± 4.5 mm [−15.4, 2.6]. Fewer patients in the ONO-4474 group than the placebo group required rescue therapy. Treatment-emergent AEs (TEAEs) occurred in 41.8% of patients in the ONO-4474 group and 18.2% in the placebo group. The most common TEAE in the ONO-4474 group was myalgia (7.3%). In the ONO-4474 group, TEAEs related to the peripheral and central nervous system included dizziness and hypoaesthesia (3.6% each), and dysaesthesia, dysgeusia, feeling abnormal, skin warm, and hypoaesthesia oral (1.8% each), while TEAEs related to the musculoskeletal system included myalgia (7.3%), arthralgia (5.5%), and pain in extremity (1.8%). Four patients in the ONO-4474 group and one patient in the placebo group withdrew from treatment because of TEAEs, none of which were considered serious, and those patients recovered or were recovering after drug discontinuation. There were no clinically significant changes in vital signs, 12-lead ECG, laboratory tests, or C-SSRS scores.

Conclusion:

ONO-4474 may be a tolerable and effective analgesic in patients with moderate-to-severe OA of the knee.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/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-pl/