Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period

Abstract

Objective: Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up.

Methods: This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient's Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study.

Results: From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE -0.62±0.18, p=0.0006), WOMAC Physical Function (-0.71±0.17, p<0.0001) and PGA-OA (-0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%-7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo.

Conclusion: Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups.

Trial registration number: NCT02709486.

Keywords: analgesics; knee osteoarthritis; osteoarthritis.

Conflict of interest statement

Competing interests: FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, outside the submitted work. FJB reports grants and personal fees from Pfizer, and grants from AbbVie, UCB, Bristol-Meyers Squibb, Roche, Servier, Bioiberica, Sanofi, Grunenthal, GlaxoSmithKline, Lilly, Janssen, Regeneron, Amgen and TRB Chemedica, outside the submitted work. AG reports personal fees from Merck Serono, Pfizer, TissueGene, Roche, Galapagos, AstraZeneca, personal fees from Boston Imaging Core Lab, LLC, outside the submitted work. KM reports personal fees from Merck, Pfizer, Lilly, Ayumi, Mundi Pharma, Janssen, Nippon Zok, outside the submitted work. LV reports personal fees and other from Eli Lilly and Company, outside the submitted work. TY reports personal fees and other from Pfizer outside the submitted work. RJ reports personal fees and other from Pfizer outside the submitted work. WC reports personal fees and other from Pfizer outside the submitted work. MTB reports personal fees and other from Pfizer outside the submitted work, and has a patent pending (Tanezumab Method of Treatment). CRW reports personal fees and other from Pfizer outside the submitted work, and has a patent pending (Tanezumab Method of Treatment). KMV reports personal fees and other from Pfizer outside the submitted work.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC-ND. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study design. Scheduled in-clinic visits occurred at screening, baseline and weeks 2, 4, 8, 12, 16, 24, 32 and 48, with telephone contact scheduled for weeks 20, 28, 36, 40 and 44. Patients who did not complete the double-blind treatment period were still followed through the 24-week safety follow-up period.

Figure 2

Patient disposition. *Patients screened but not randomised for a reason not related to a specific eligibility criterion. †After either completing the treatment period or discontinuing the treatment period.

Figure 3

Change from baseline to week 24 in the co-primary end points: WOMAC Pain subscale score, WOMAC Physical Function subscale score and PGA-OA score. *p≤0.05; **p≤0.01; ***p≤0.001 vs placebo. WOMAC Pain assessed pain over the previous 48 hours in the index joint, and was the mean of five questions each scored on an 11-point numerical rating scale (NRS), from 0 to 10 with higher score indicating more pain. WOMAC Physical Function assessed ability to move around and perform activities of daily living over the previous 48 hours in the index joint, and was the mean of 17 questions each scored on an 11-point NRS, from 0 to 10 with higher score indicating worse function. PGA-OA was rated on a 5-point Likert scale from 1=‘very good’ (asymptomatic and no limitation of normal activities) to 5=‘very poor’ (very severe symptoms which are intolerable and inability to carry out all normal activities) in answer to the question “Considering all the ways your osteoarthritis in your hip/knee affects you, how are you doing today?” Reproduced from Berenbaum F, Blanco F, Guermazi A, Vignon E, Miki K, Yamabe T, Viktrup L, Junor R, Carey W, Brown M, Verburg K, West C. Ann Rheum Dis. 2019;78(suppl 2):262–263, with permission from BMJ Publishing Group Ltd. LS, least squares; PGA-OA, Patient’s Global Assessment of osteoarthritis; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 4

Proportion of patients achieving at least 30%, 50%, 70% and 90% reductions in WOMAC Pain subscale score at week 24. *P≤0.05; **p≤0.01; ***p≤0.001 vs placebo. Mixed baseline/last observation carried forward. Nominal, unadjusted p value. In line with the predefined gatekeeping strategy, hypothesis testing of the three key secondary end points could not be performed: no key secondary end points can be declared as statistically significantly better than placebo treatment. WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.