Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis | Geriatrics | JN Learning | AMA Ed Hub [Skip to Content]
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Pain Medicine

Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients With Osteoarthritis of the Hip or KneeA Randomized Clinical Trial

Educational Objective
To review the effectiveness of tanezumab among patients with moderate to severe osteoarthritis of the knee or hip
1 Credit CME
JAMA
July 2, 2019
Original Investigation
Thomas J. Schnitzer, MD, PhD1;
Richard Easton, MD2;
Shirley Pang, MD3;
Dennis J. Levinson, MD4;
Glenn Pixton, MS5;
Lars Viktrup, MD, PhD6;
Isabelle Davignon, PhD7;
Mark T. Brown, MD7;
Christine R. West, PhD7;
Kenneth M. Verburg, PhD7
Author Affiliations
  • 1Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Michigan Orthopaedic & Spine Surgeons, Rochester Hills
  • 3St Joseph Heritage Healthcare, Fullerton, California
  • 4Chicago Clinical Research Institute, Chicago, Illinois
  • 5Pfizer Inc, Morrisville, North Carolina
  • 6Eli Lilly and Company, Indianapolis, Indiana
  • 7Pfizer Inc, Groton, Connecticut
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Key Points

Question  Among patients with moderate to severe osteoarthritis of the knee or hip and inadequate treatment response to standard analgesics, what is the effect of subcutaneous tanezumab on joint pain, physical function, and patient global assessment of osteoarthritis?

Findings  In this randomized clinical trial that enrolled 698 patients, subcutaneous tanezumab administered with fixed doses at 8-week intervals or with a forced titration at week 8, compared with placebo, resulted in statistically significant improvements in joint pain, physical function, and patient global assessment of osteoarthritis over 16 weeks, although the improvements were modest and tanezumab-treated patients had more joint safety events and total joint replacements.

Meaning  Further research is needed to determine the clinical importance of these efficacy and adverse event findings with regard to use of tanezumab for treatment of osteoarthritis.

Abstract

Importance  Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments.

Objective  To assess 2 subcutaneous tanezumab dosing regimens for OA.

Design, Setting, and Participants  A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions.

Interventions  Patients received by subcutaneous administration either tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232).

Main Outcomes and Measures  Co–primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores.

Results  Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the tanezumab, 2.5 mg, group; 7.3 to 3.6 in the tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were −0.60 [−1.07 to −0.13; P = .01] for tanezumab, 2.5 mg, and −0.73 [−1.20 to −0.26; P = .002] for tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, −0.66 [−1.14 to −0.19; P = .007] for tanezumab, 2.5 mg, and −0.89 [−1.37 to −0.42; P < .001] for tanezumab, 2.5/5 mg). Mean PGA-OA scores decreased from 3.4 to 2.4 in the 2.5-mg group, 3.5 to 2.4 in the 2.5/5-mg group, and 3.5 to 2.7 with placebo (differences vs placebo, −0.22 [−0.39 to −0.05; P = .01] for tanezumab, 2.5 mg, and −0.25 [−0.41 to −0.08; P = .004] for tanezumab, 2.5/5 mg). Rapidly progressive OA occurred only in tanezumab-treated patients (2.5 mg: n = 5, 2.2%; 2.5/5 mg: n = 1, 0.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab, 2.5 mg; tanezumab, 2.5/5 mg; and placebo groups, respectively.

Conclusions and Relevance  Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings.

Trial Registration  ClinicalTrials.gov Identifier: NCT02697773

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

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Geriatrics Orthopedics Osteoarthritis Rheumatology Pain Medicine
Article Information

Corresponding Author: Thomas J. Schnitzer, MD, PhD, Feinberg School of Medicine, Northwestern University, 710 N Lake Shore Dr, Abbot Hall, Ste 1020, Chicago, IL 60611 (tjs@northwestern.edu).

Accepted for Publication: May 22, 2019.

Author Contributions: Dr Schnitzer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Pixton, Viktrup, Davignon, Brown, West, Verburg.

Acquisition, analysis, or interpretation of data: Schnitzer, Easton, Pang, Levinson, Pixton, Viktrup, Davignon, Brown, West.

Drafting of the manuscript: Easton, Levinson, Pixton, Viktrup, Brown, West, Verburg.

Critical revision of the manuscript for important intellectual content: Schnitzer, Easton, Pang, Pixton, Viktrup, Davignon, Brown, West.

Statistical analysis: Pixton.

Administrative, technical, or material support: Easton, Levinson.

Supervision: Easton, Pang, Viktrup, Davignon, Brown, West, Verburg.

Conflict of Interest Disclosures: Dr Schnitzer reported receiving nonfinancial support from Pfizer during the conduct of the study and grants, personal fees, and nonfinancial support from Pfizer, Regeneron, AbbVie, and Kolon TissueGene; personal fees from Vertex, Sanofi, Astellas, and Calibr; grants and personal fees from Flexion; personal fees and nonfinancial support from GlaxoSmithKline and Aptinyx; and grants from Galapagos and Grunenthal outside the submitted work. Dr Schnitzer also reported performing clinical research for Pfizer Inc and Eli Lilly and Company and has received consulting fees from Pfizer Inc and Eli Lilly and Company. Dr Easton reported receiving compensation for participation in multiple Pfizer-sponsored clinical trials. Dr Pang reported receiving consulting fees from Pfizer Inc. Dr Levinson reported receiving grants from Pfizer during the conduct of the study and grants from Amgen, Regeneron, and AbbVie outside the submitted work. Mr Pixton and Drs Davignon, Brown, Verburg, and West are employees of Pfizer Inc and own stock. Dr Viktrup is an employee of Eli Lilly and Company. Drs Brown and West reported having tanezumab method of treatment patents pending. No other disclosures were reported.

Funding/Support: The study was sponsored by Pfizer Inc and Eli Lilly and Company.

Role of the Funder/Sponsor: Pfizer Inc and Eli Lily and Company contributed to the study design; Pfizer contributed to the management and collection of data. In their role as authors, employees of Pfizer and Eli Lilly were involved in the interpretation of data, preparation, review, and approval of the manuscript and the decision to submit for publication, along with their co-authors. The study sponsors approved the manuscript from an intellectual property perspective but had no right to veto the publication.

Additional Contributions: Editorial support was provided by Shannon Buckley, PhD, and Matt Soulsby, PhD, CMPP, of Engage Scientific Solutions and were funded by Pfizer and Eli Lilly and Company. We thank the central imaging readers: Ali Guermazi, MD, PhD, and Frank Roemer, MD, from Boston Imaging Core Lab, Boston, Massachusetts. We also thank the adjudication committee members for blinded adjudication of joint safety events: David Hungerford, MD (Johns Hopkins University), John Carrino, MD, MPH (Hospital for Special Surgery), Timothy McAlindon, MD, MPH (Tufts Medical Center), Eric Vignon, MD (Université Claude Bernard Lyon 1), and Edward McCarthy, MD (Johns Hopkins University). Central readers and adjudication committee members received financial compensation for these study activities.

Data Sharing Statement: See Supplement 4.

Additional Information: Pfizer Inc, in collaboration with Eli Lilly and Company, is the manufacturer of tanezumab, which is being investigated for the treatment of chronic pain.

References
1.
Donnerer  J, Schuligoi  R, Stein  C.  Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo.  Neuroscience. 1992;49(3):693-698. doi:10.1016/0306-4522(92)90237-VPubMedGoogle ScholarCrossref
2.
Dyck  PJ, Peroutka  S, Rask  C,  et al.  Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans.  Neurology. 1997;48(2):501-505. doi:10.1212/WNL.48.2.501PubMedGoogle ScholarCrossref
3.
Zhu  W, Oxford  GS.  Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1.  Mol Cell Neurosci. 2007;34(4):689-700. doi:10.1016/j.mcn.2007.01.005PubMedGoogle ScholarCrossref
4.
Woolf  CJ, Safieh-Garabedian  B, Ma  QP, Crilly  P, Winter  J.  Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity.  Neuroscience. 1994;62(2):327-331. doi:10.1016/0306-4522(94)90366-2PubMedGoogle ScholarCrossref
5.
Ghilardi  JR, Freeman  KT, Jimenez-Andrade  JM,  et al.  Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint.  Arthritis Rheum. 2012;64(7):2223-2232. doi:10.1002/art.34385PubMedGoogle ScholarCrossref
6.
Jimenez-Andrade  JM, Ghilardi  JR, Castañeda-Corral  G, Kuskowski  MA, Mantyh  PW.  Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain.  Pain. 2011;152(11):2564-2574. doi:10.1016/j.pain.2011.07.020PubMedGoogle ScholarCrossref
7.
Walsh  DA, McWilliams  DF, Turley  MJ,  et al.  Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis.  Rheumatology (Oxford). 2010;49(10):1852-1861. doi:10.1093/rheumatology/keq188PubMedGoogle ScholarCrossref
8.
Jimenez-Andrade  JM, Martin  CD, Koewler  NJ,  et al.  Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture.  Pain. 2007;133(1-3):183-196. doi:10.1016/j.pain.2007.06.016PubMedGoogle ScholarCrossref
9.
Abdiche  YN, Malashock  DS, Pons  J.  Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors.  Protein Sci. 2008;17(8):1326-1335. doi:10.1110/ps.035402.108PubMedGoogle ScholarCrossref
10.
Bélanger  P, West  CR, Brown  MT.  Development of pain therapies targeting nerve growth factor signal transduction and the strategies used to resolve safety issues.  J Toxicol Sci. 2018;43(1):1-10. doi:10.2131/jts.43.1PubMedGoogle ScholarCrossref
11.
Katz  N, Borenstein  DG, Birbara  C,  et al.  Efficacy and safety of tanezumab in the treatment of chronic low back pain.  Pain. 2011;152(10):2248-2258. doi:10.1016/j.pain.2011.05.003PubMedGoogle ScholarCrossref
12.
Brown  MT, Murphy  FT, Radin  DM, Davignon  I, Smith  MD, West  CR.  Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial.  J Pain. 2012;13(8):790-798. doi:10.1016/j.jpain.2012.05.006PubMedGoogle ScholarCrossref
13.
Brown  MT, Murphy  FT, Radin  DM, Davignon  I, Smith  MD, West  CR.  Tanezumab reduces osteoarthritic hip pain: results of a randomized, double-blind, placebo-controlled phase III trial.  Arthritis Rheum. 2013;65(7):1795-1803. doi:10.1002/art.37950PubMedGoogle ScholarCrossref
14.
Hochberg  MC.  Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies.  Osteoarthritis Cartilage. 2015;23(suppl 1):S18-S21. doi:10.1016/j.joca.2014.10.005PubMedGoogle ScholarCrossref
15.
Hochberg  MC, Tive  LA, Abramson  SB,  et al.  When is osteonecrosis not osteonecrosis? adjudication of reported serious adverse joint events in the tanezumab clinical development program.  Arthritis Rheumatol. 2016;68(2):382-391. doi:10.1002/art.39492PubMedGoogle ScholarCrossref
16.
 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) adopts Consolidated Guideline on Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use.  Int Dig Health Legis. 1997;48(2):231-234.PubMedGoogle Scholar
17.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.  JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
18.
Zilliox  L, Peltier  AC, Wren  PA,  et al.  Assessing autonomic dysfunction in early diabetic neuropathy: the Survey of Autonomic Symptoms.  Neurology. 2011;76(12):1099-1105. doi:10.1212/WNL.0b013e3182120147PubMedGoogle ScholarCrossref
19.
Theiler  R, Spielberger  J, Bischoff  HA, Bellamy  N, Huber  J, Kroesen  S.  Clinical evaluation of the WOMAC 3.0 OA Index in numeric rating scale format using a computerized touch screen version.  Osteoarthritis Cartilage. 2002;10(6):479-481. doi:10.1053/joca.2002.0807PubMedGoogle ScholarCrossref
20.
Stengaard-Pedersen  K, Ekesbo  R, Karvonen  AL, Lyster  M.  Celecoxib 200 mg qd is efficacious in the management of osteoarthritis of the knee or hip regardless of the time of dosing.  Rheumatology (Oxford). 2004;43(5):592-595. doi:10.1093/rheumatology/keh121PubMedGoogle ScholarCrossref
21.
Doganay Erdogan  B, Leung  YY, Pohl  C, Tennant  A, Conaghan  PG.  Minimal clinically important difference as applied in rheumatology: an OMERACT Rasch Working Group systematic review and critique.  J Rheumatol. 2016;43(1):194-202. doi:10.3899/jrheum.141150PubMedGoogle ScholarCrossref
22.
Ehrich  EW, Davies  GM, Watson  DJ, Bolognese  JA, Seidenberg  BC, Bellamy  N.  Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis.  J Rheumatol. 2000;27(11):2635-2641.PubMedGoogle Scholar
23.
Tubach  F, Ravaud  P, Baron  G,  et al.  Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement.  Ann Rheum Dis. 2005;64(1):29-33. doi:10.1136/ard.2004.022905PubMedGoogle ScholarCrossref
24.
Dyck  PJ, Litchy  WJ, Lehman  KA, Hokanson  JL, Low  PA, O’Brien  PC.  Variables influencing neuropathic endpoints: the Rochester Diabetic Neuropathy Study of Healthy Subjects.  Neurology. 1995;45(6):1115-1121. doi:10.1212/WNL.45.6.1115PubMedGoogle ScholarCrossref
25.
Miller  CG, Guermazi  A, Roemer  F.  The current status of imaging in anti-NGF clinical trials.  Osteoarthritis Cartilage. 2015;23(suppl 1):S3-S7. doi:10.1016/j.joca.2014.09.002PubMedGoogle ScholarCrossref
26.
Ekman  EF, Gimbel  JS, Bello  AE,  et al.  Efficacy and safety of intravenous tanezumab for the symptomatic treatment of osteoarthritis: 2 randomized controlled trials versus naproxen.  J Rheumatol. 2014;41(11):2249-2259. doi:10.3899/jrheum.131294PubMedGoogle ScholarCrossref
27.
Tive  L, Bello  AE, Radin  D,  et al.  Pooled analysis of tanezumab efficacy and safety with subgroup analyses of phase III clinical trials in patients with osteoarthritis pain of the knee or hip.  J Pain Res. 2019;12:975-995. doi:10.2147/JPR.S191297PubMedGoogle ScholarCrossref
28.
Birbara  C, Dabezies  EJ  Jr, Burr  AM,  et al.  Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis.  J Pain Res. 2018;11:151-164. doi:10.2147/JPR.S135257PubMedGoogle ScholarCrossref
29.
Pfizer and Lilly announce top-line results from long-term phase 3 study of tanezumab in patients with osteoarthritis [news release]. New York, NY: Pfizer; April 18, 2019. https://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_lilly_announce_top_line_results_from_long_term_phase_3_study_of_tanezumab_in_patients_with_osteoarthritis. Accessed April 30, 2019.
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