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Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis

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Abstract

Background

Tanezumab, a humanized anti-nerve growth factor antibody, was developed for the treatment of pain associated with osteoarthritis. Due to its mechanism of action, peripheral nerve safety was assessed in all clinical studies.

Objectives

To summarize the neurological safety of intravenous (IV) and subcutaneous (SC) tanezumab versus placebo in patients with osteoarthritis.

Methods

Data were pooled from 3389 patients across seven studies that investigated IV administration, and from 1840 patients across three studies that investigated SC administration. The treatment period of each study ranged from 16 to 24 weeks, and follow-up periods ranged from 8 to 24 weeks. Neurological safety evaluations focused on adverse events (AEs) of abnormal peripheral sensation (APS), neurologic examinations, and consultations.

Results

Across datasets, the incidence of AEs of APS was higher in tanezumab groups versus placebo. Paresthesia and hypoesthesia were the most frequently reported AEs in tanezumab-treated patients, compared with placebo. In both datasets, most AEs were of mild severity, resolved, and rarely resulted in discontinuation. In all treatment groups in both IV and SC studies, over 90% of patients had no new or worsened neurological examination abnormalities at the last study visit. Across datasets, mononeuropathy was diagnosed more frequently in tanezumab groups compared with placebo. Polyneuropathy was diagnosed in ≤ 0.9% of patients in tanezumab and placebo groups.

Conclusions

Tanezumab IV or SC had an increased incidence of AEs of APS, such as paresthesia and hypoesthesia, and diagnoses of mononeuropathy compared with placebo. However, tanezumab was not associated with generalized peripheral neuropathy.

ClinicalTrials.gov identifiers

NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00863772, NCT01089725, NCT00985621, NCT02697773, and NCT02709486.

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References

  1. Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987;237(4819):1154–62.

    Article  CAS  PubMed  Google Scholar 

  2. Schmelz M, Mantyh P, Malfait AM, Farrar J, Yaksh T, Tive L, et al. Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety. Pain. 2019;160(10):2210–20.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts-Meek S, Armanini MP, et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell. 1994;76(6):1001–11.

    Article  CAS  PubMed  Google Scholar 

  4. Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology. 2011;115(1):189–204.

    Article  PubMed  Google Scholar 

  5. Brown MT, Herrmann DN, Goldstein M, Burr AM, Smith MD, West CR, et al. Nerve safety of tanezumab, a nerve growth factor inhibitor for pain treatment. J Neurol Sci. 2014;345(1–2):139–47.

    Article  CAS  PubMed  Google Scholar 

  6. 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):1795–803.

    Article  CAS  PubMed  Google Scholar 

  7. 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):790–8.

    Article  CAS  PubMed  Google Scholar 

  8. Ekman EF, Gimbel JS, Bello AE, Smith MD, Keller DS, Annis KM, 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):2249–59.

    Article  CAS  PubMed  Google Scholar 

  9. Tive L, Bello AE, Radin D, Schnitzer TJ, Nguyen H, Brown MT, 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;12:975–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schnitzer TJ, Easton R, Pang S, Levinson DJ, Pixton G, Viktrup L, et al. Effect of tanezumab on joint pain, physical function, and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee: a randomized clinical trial. JAMA. 2019;322(1):37–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Berenbaum F, Blanco FJ, Guermazi A, Miki K, Yamabe T, Viktrup L, et al. 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. Ann Rheum Dis. 2020;79(6):800–10.

    Article  CAS  PubMed  Google Scholar 

  12. Brown MT, Sandroni P, Low PA, Gorson KC, Hunter DJ, Pixton GC, et al. Neurological safety of subcutaneous tanezumab versus NSAID in patients with osteoarthritis. J Neurol Sci. 2022;15(434): 120184.

    Article  Google Scholar 

  13. Food and Drug Administration. Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee; 2021.

  14. Hochberg MC, Tive LA, Abramson SB, Vignon E, Verburg KM, West CR, 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):382–91.

    Article  CAS  PubMed  Google Scholar 

  15. Hochberg MC, Carrino JA, Schnitzer TJ, Guermazi A, Walsh DA, White A, et al. Long-term safety and efficacy of subcutaneous tanezumab versus nonsteroidal antiinflammatory drugs for hip or knee osteoarthritis: a randomized trial. Arthritis Rheumatol. 2021;73(7):1167–77.

    Article  CAS  PubMed  Google Scholar 

  16. Pfizer. Pfizer reports third-quarter 2021 results; 2021. https://investors.pfizer.com/investor-news/press-release-details/2021/PFIZER-REPORTS-THIRD-QUARTER-2021-RESULTS/default.aspx. Cited 11 Apr 2022.

  17. Eli Lilly and Company. Lilly reports robust third-quarter 2021 financial results as pipeline success strengthens future growth potential; 2021. https://investor.lilly.com/static-files/a0b77c52-a997-41c1-9534-5f465903a0b4. Cited 11 Apr 2022.

  18. Dyck PJ, Sherman WR, Hallcher LM, Service FJ, Obrien PC, Grina LA, et al. Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol. 1980;8(6):590–6.

    Article  CAS  PubMed  Google Scholar 

  19. Bramson C, Herrmann DN, Carey W, Keller D, Brown MT, West CR, et al. Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain. Pain Med. 2015;16(6):1163–76.

    Article  PubMed  Google Scholar 

  20. Dakin P, DiMartino SJ, Gao H, Maloney J, Kivitz AJ, Schnitzer TJ, et al. The efficacy, tolerability, and joint safety of fasinumab in osteoarthritis pain: a phase IIB/III double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheumatol. 2019;71(11):1824–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dakin P, Kivitz AJ, Gimbel JS, Skrepnik N, DiMartino SJ, Emeremni CA, et al. Efficacy and safety of fasinumab in patients with chronic low back pain: a phase II/III randomised clinical trial. Ann Rheum Dis. 2021;80:509–17.

    Article  CAS  PubMed  Google Scholar 

  22. Sanga P, Katz N, Polverejan E, Wang S, Kelly KM, Haeussler J, et al. Long-term safety and efficacy of fulranumab in patients with moderate-to-severe osteoarthritis pain: a phase ii randomized, double-blind, placebo-controlled extension study. Arthritis Rheumatol. 2017;69(4):763–73.

    Article  CAS  PubMed  Google Scholar 

  23. Janssen. Janssen Announces Discontinuation of Fulranumab Phase 3 Development Program in Osteoarthritis Pain; 2016. https://www.jnj.com/media-center/press-releases/janssen-announces-discontinuation-of-fulranumab-phase-3-development-program-in-osteoarthritis-pain#:~:text=TITUSVILLE%2C%20NJ%20(March%2031%2C,for%20fulranumab%20in%20osteoarthritis%20pain [cited 2023 May 21].

  24. Regeneron. Regeneron provides update on fasinumab program; 2020. https://investor.regeneron.com/static-files/e5ebab0a-f9b3-461c-aeaf-47fcb4e00242 [cited 2023 May 21].

  25. AstraZeneca. A Study of the Efficacy and Safety of MEDI7352 in Subjects With Painful Osteoarthritis of the Knee (BESPOKE). https://clinicaltrials.gov/ct2/show/NCT04675034.

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Acknowledgements

Medical writing support was provided by Steven Moore, Ph.D., of Engage Scientific Solutions and was funded by Pfizer and Eli Lilly and Company.

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Authors and Affiliations

  1. Pfizer Inc., Groton, CT, USA

    Mark T. Brown, Anne Hickman, Puneet Gaitonde & Christine R. West

  2. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

    David R. Cornblath

  3. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK

    Martin Koltzenburg

  4. St. Elizabeth’s Medical Center, Boston, MA, USA

    Kenneth C. Gorson

  5. Pfizer Inc., Morrisville, NC, USA

    Glenn C. Pixton

  6. Eli Lilly and Company, Indianapolis, IN, USA

    Lars Viktrup

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  1. Mark T. Brown
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Corresponding author

Correspondence to Mark T. Brown.

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Funding

This work was funded by Pfizer and Eli Lilly and Company. Pfizer and Eli Lilly 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.

Conflict of Interest

DRC has served as a consultant for AlgoTX, Amgen Inc., Annexon Biosciences, Boehringer Ingelheim, Cigna Health Management Inc., CSL Behring, Grifols S.A., Johnson & Johnson, Nervosave, Nurobio, Octapharma AG, Passage Bio, Pfizer Inc., Pharnext SAS, Roche, Seattle Genetics Inc., and ValenzaBio. He sits on the Data Safety Monitoring Board for Anavex Life Sciences Corp, Passage Bio, PledPharma AB, Hansa Medical AB, and Mitsubishi Tanabe Pharma Corporation. Through Johns Hopkins University, he receives royalties for technology licensing from AstraZeneca Pharmaceuticals, LP, Genentech Inc., Levicept Inc., Seattle Genetics Inc., and Merrimack Pharmaceuticals. He sits on the Scientific Advisory Board for AlgoTx and Sinomab. MK is director of Neurophysiology Consulting Ltd and QTMS Science Ltd. During the past 5 years he has been an ad hoc consultant and the speaker bureau for Eli Lilly, GSK, Levicept, Marks & Clerk Law, Merck, Neursentis, Pfizer, Richmond Pharmaceuticals Ltd., and Roche. KG has served as a consultant for Argenx, Annexon, Janssen, Pfizer, and UCB Pharma. MTB, AH, GCP, PG, and CRW own stock in and are full-time employees of Pfizer. LV owns stocks in and is a full-time employee of Eli Lilly and Company.

Availability of data and material

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Ethics Approval

The protocol for each clinical trial was approved by an institutional review board or independent ethics committee at each participating investigational center. The studies were conducted in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice Guidelines.

Consent for publication

Not applicable.

Consent to participate

All patients provided written informed consent before entering the studies.

Author Contributions

Mark Brown: Conceptualization, data curation, investigation, methodology, supervision, visualization, and writing (review and editing). David Cornblath: Investigation, supervision, and writing (review and editing). Martin Koltzenburg: Investigation, supervision, and writing (review and editing). Kenneth Gorson: Investigation, supervision, and writing (review and editing). Anne Hickman: Conceptualization, data curation, investigation, methodology, supervision, visualization, and writing (review and editing). Glenn C. Pixton: Conceptualization, data curation, formal analysis, investigation, methodology, supervision, visualization, and writing (review and editing). Puneet Gaitonde: Data curation, investigation, methodology, supervision, visualization, and writing (review and editing). Lars Viktrup: Conceptualization, methodology, supervision, visualization, and writing (review and editing). Christine West: Conceptualization, data curation, investigation, methodology, supervision, visualization, and writing (review and editing).

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Brown, M.T., Cornblath, D.R., Koltzenburg, M. et al. Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis. Clin Drug Investig 43, 551–563 (2023). https://doi.org/10.1007/s40261-023-01286-3

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