Subcutaneous tanezumab 2.5 MG or 5 MG for patients with osteoarthritis of the knee or hip: onset and maintenance of efficacy over 24 weeks

Purpose: Tanezumab administered subcutaneously is being investigated for the treatment of osteoarthritis (OA). This 24-week analysis examined the onset and maintenance of improvement in pain and function in patients from Europe and Japan with difficult to treat, moderate-to-severe OA. Methods: This randomized 48-week (24-week double-blind treatment period and 24-week safety follow-up) phase 3 study (NCT02709486) enrolled patients from Europe and Japan with OA (hip or knee, Kellgren Lawrence [KL] grade ≥2), documented inadequacy or unsuitability of standard analgesics, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain score ≥5 (screening and baseline), and baseline WOMAC Physical Function score ≥5 and patient’s global assessment of osteoarthritis (PGA-OA) rating ‘fair’, ‘poor’ or ‘very poor’. Patients received three subcutaneous doses of placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Secondary endpoints included change from baseline in average daily index joint pain (daily during the first week, then weekly at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24, and also at Week 32), WOMAC Pain, Physical Function and PGA-OA (Weeks 2, 4, 8, 12, 16 and 24, and also at Week 32), and patients (%) meeting the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) treatment response criteria. Since the tanezumab 2.5 mg dose did not meet the co-primary endpoint using a graphical approach of gatekeeping strategy, all secondary endpoints were unadjusted for multiplicity. Results: The 849 patients (69.1% female) were enrolled in Europe (n=743) and Japan (n=106): the index joint was a knee for 83.0% and KL grade 3 or 4 for 80.2%. Baseline WOMAC Pain scores (mean±standard deviation [SD]) were 6.59±0.94 (placebo), 6.70±0.94 (tanezumab 2.5 mg) and 6.60±0.89 (tanezumab 5 mg). Compared with placebo, favorable improvements from baseline in average daily index joint pain were seen with tanezumab within the first week; at Day 2 for tanezumab 2.5 mg (least squares [LS] mean difference±standard error [SE] versus placebo -0.50±0.14, nominal P=0.0003) and at Day 4 for tanezumab 5 mg (-0.48±0.14, nominal P=0.0008). The improvements at Week 1 were -0.49±0.11 (tanezumab 2.5 mg, nominal P<0.0001) and -0.36±0.11 (tanezumab 5 mg, nominal P=0.0009). At first measurement (Week 2), for tanezumab 2.5 mg and tanezumab 5 mg, respectively, change from baseline (LS mean difference±SE versus placebo) was -0.67±0.14 (nominal P<0.0001) and -0.34±0.14 (nominal P=0.0149) for WOMAC Pain and -0.69±0.14 (nominal P<0.0001) and -0.43±0.14 (nominal P=0.0014) for WOMAC Physical Function; both doses improved PGA-OA compared with placebo. More tanezumab-treated patients (63.1% [tanezumab 2.5 mg, nominal P<0.0001], 54.9% [tanezumab 5 mg, nominal P=0.0085]) than placebo (44.1%) achieved OMERACT-OARSI response at Week 2. Both tanezumab doses demonstrated favorable improvements compared with placebo in average daily index joint pain from Week 2 through Week 24 (all nominal P<0.05), with the exception of tanezumab 2.5 mg at Week 24. Improvements in WOMAC Pain, Physical Function and PGA-OA in tanezumab-treated patients were better than placebo from Week 4 through Week 20 (both doses, all nominal P<0.05), and statistically significant at Week 24 (all P<0.05, except tanezumab 2.5 mg on PGA-OA). More tanezumab-treated patients (both doses) than placebo met the criteria for OMERACT-OARSI response at all time points (all nominal P<0.05), including at Week 24 (65.1% [placebo], 76.2% [tanezumab 2.5 mg], 77.1% [tanezumab 5 mg]). At Week 32, change from baseline (mean±SD, observed data) in average daily index joint pain was -2.19±2.40 (placebo), -2.07±2.33 (tanezumab 2.5 mg) and -2.13±2.40 (tanezumab 5 mg); there was also no evidence of rebound in WOMAC Pain (-2.70±2.06 [placebo], -2.29±1.95 [tanezumab 2.5 mg], -2.26±2.24 [tanezumab 5 mg]) or WOMAC Physical Function (-2.55±1.98 [placebo], -2.22±1.92 [tanezumab 2.5 mg], -2.24±2.09 [tanezumab 5 mg]). At Week 24, the efficacy of tanezumab (both doses) was better than placebo in patients with an index joint of KL grade 4 for WOMAC Pain (LS mean difference±SE versus placebo for tanezumab 2.5 mg, -0.19±0.23 [nominal P=0.419] for KL2/3 and -0.84±0.28 [nominal P=0.002] for KL4; and for tanezumab 5 mg, -0.32±0.23 [nominal P=0.173] for KL2/3 and -0.98±0.28 [nominal P=0.001] for KL4). The onset and maintenance of efficacy of tanezumab in patients from Japan generally reflected that seen in the total population. Conclusions: Subcutaneous tanezumab 2.5 mg and 5 mg improved pain compared with placebo within the first week, and improvements in pain and function were sustained overall between injections throughout the 24-week treatment period. Tanezumab was effective in patients with severe radiographic OA, notably in patients with an index joint of KL grade 4, and in patients from Japan.