Skip to main content
Log in

Targeting Nerve Growth Factor (NGF) for Pain Management: What Does the Future Hold for NGF Antagonists?

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

It is unanimously accepted that there is an unmet need for pain medications that are both effective and safe. Unfortunately, no really novel analgesics have been approved over the past three decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, drug discovery efforts focusing on the development of anti-NGF agents have aroused particular interest. Several humanized anti-NGF monoclonal antibodies (mAbs) have entered clinical trials as potential analgesics. In this respect, tanezumab is at an advanced stage of clinical development while fulranumab, fasinumab and ABT-110, previously known as PG110, are in early phases of clinical development. This Current Opinion article aims at describing the rationale for targeting NGF for pain, reviewing the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies, conference abstracts, and the US Food and Drug Administration (FDA) website, and discussing the possible future of these agents in managing chronic pain. Anti-NGF mAbs produced significant pain relief and functional improvement in patients with osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain generated mixed results; overall, this condition appeared to be less responsive to anti-NGF agents than osteoarthritis. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in some types of chronic visceral or neuropathic pain. Furthermore, these studies raised safety concerns about anti-NGF mAbs. As a class, these drugs may cause or worsen peripheral neuropathies. But the most problematic issue—which prompted the FDA to place studies of these compounds on clinical hold in 2010—was rapid joint destruction leading to joint replacement surgery. The aetiologies of these side effects have been much debated and their pathophysiology is poorly understood. After an Arthritis Advisory Committee meeting held in March 2012, pharmaceutical companies negotiated with the FDA on the conditions for restarting clinical studies. Although the FDA lifted its clinical hold, there remain many unresolved issues about the long-term efficacy and safety of anti-NGF mAbs. While acknowledging that the future of these drugs is unforeseeable, it appears that they may not be the safe and effective painkillers that have been awaited for decades.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet. 2011;377:2226–35.

    Article  CAS  PubMed  Google Scholar 

  2. Bannwarth B, Kostine M, Shipley E. Nonspecific low back pain: assessment of available medications. Joint Bone Spine. 2012;79:134–6.

    Article  PubMed  Google Scholar 

  3. Woodcock J, Witter J, Dionne RA. Stimulating the development of mechanism-based, individualized pain therapies. Nat Rev Drug Discov. 2007;6:703–10.

    Article  CAS  PubMed  Google Scholar 

  4. Eibl JK, Strasser BC, Ross GM. Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int. 2012;61:1266–75.

    Article  CAS  PubMed  Google Scholar 

  5. Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharm Sci. 2006;27:85–91.

    Article  CAS  PubMed  Google Scholar 

  6. Watson JJ, Allen SJ, Drawbarn D. Targeting nerve growth factor in pain. What is the therapeutic potential? Biodrugs. 2008;22:349–59.

    Article  CAS  PubMed  Google Scholar 

  7. Seidel MF, Herguijuela M, Forkert R, et al. Nerve growth factor in rheumatic diseases. Semin Arthritis Rheum. 2010;40:109–26.

    Article  CAS  PubMed  Google Scholar 

  8. Seidel MF, Wise BL, Lane NE. Nerve growth factor: an update on the science and therapy. Osteoarthritis Cartilage. 2013;21:1223–8.

    Article  CAS  PubMed  Google Scholar 

  9. Garber K. Fate of novel painkiller mAbs hangs in balance. Nat Biotechnol. 2011;29:173–4.

    Article  CAS  PubMed  Google Scholar 

  10. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363:1521–31.

    Article  CAS  PubMed  Google Scholar 

  11. Brown MT, Murphy FT, Radin DM, et al. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J Pain. 2012;13:790–8.

    Article  CAS  PubMed  Google Scholar 

  12. Brown MT, Murphy FT, Radin DM, et al. Tanezumab reduces osteoarthritic hip pain. Results of a randomized, double-blind, placebo-controlled phase III trial. Arthritis Rheum. 2013;65:1795–803.

    Article  CAS  PubMed  Google Scholar 

  13. Spierings ELH, Fidelholtz J, Wolfram G, et al. A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee. Pain. 2013;154:1603–12.

    Article  CAS  PubMed  Google Scholar 

  14. Balanescu AR, Feist E, Wolfram G, et al. Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial. Ann Rheum Dis. 2013 (in press).

  15. Yazici Y, Ekman EF, Greenberg HS, et al. Efficacy of tanezumab compared with non-steroidal anti-inflammatory drugs in patients with knee or hip osteoarthritis (NCT00809354) [abstract]. Arthritis Rheum. 2011;63(Suppl 10):S828.

    Google Scholar 

  16. Tive L, Dabezies EJ, Fountaine RJ, et al. Long-term safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis (NCT00994890) [abstract]. Arthritis Rheum. 2013;65(Suppl 10):S911–2.

    Google Scholar 

  17. Schnitzer TJ, Lane NE, Birbara C, et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage. 2011;19:639–46.

    Article  CAS  PubMed  Google Scholar 

  18. Sanga P, Katz N, Polverejan E, et al. Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain. Pain. 2013;154:1910–9.

    Article  CAS  PubMed  Google Scholar 

  19. Tiseo P, Kivitz AJ, Ervin JE, et al. REGN475/SAR164877, a nerve growth factor inhibitor, in osteoarthritis patients with moderate to severe knee pain [abstract]. Arthritis Rheum. 2010;62(Suppl 10):S710.

    Google Scholar 

  20. Katz N, Borenstein DG, Birbara C, et al. Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain. 2011;152:2248–58.

    Article  CAS  PubMed  Google Scholar 

  21. Kivitz AJ, Gimbel JS, Bramson C, et al. Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain. Pain. 2013;154:1009–21.

    Article  CAS  PubMed  Google Scholar 

  22. Sanga P, Karcher K, Wang K, et al. Efficacy, safety, and tolerability of fulranumab in treatment of patients with moderate-to-severe chronic low back pain [abstract]. J Pain. 2011;12(Suppl 4):P53.

    Google Scholar 

  23. Food and Drug Administration Center for Drug Evaluation and Research. Arthritis Advisory Committee Meeting; 2012. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ucm286552.htm, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM301302.pdf (Accessed 28 Dec 2013).

  24. Evans RJ, Moldwin RM, Cossons N, et al. Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis. J Urol. 2001;185:1716–21.

    Article  Google Scholar 

  25. Nickel JC, Atkinson G, Krieger JN, et al. Preliminary assessment of safety and efficacy in proof-of-concept, randomized clinical trial of tanezumab for chronic prostatitis/chronic pelvic pain syndrome. Urology. 2012;80:1105–10.

    Article  PubMed  Google Scholar 

  26. Wang H, Romano G, Frustaci ME, et al. Analgesic efficacy of fulranumab in patients with painful diabetic peripheral neuropathy in a randomized, placebo-controlled, double-blind study [abstract]. J Neurol Sci. 2013;333(Suppl 1):e522–3.

    Article  Google Scholar 

  27. Bramson C, Herrmann D, Biton V, et al. Efficacy and safety of subcutaneous tanezumab in patients with pain related to diabetic peripheral neuropathy (NCT01087203) [abstract]. J Pain. 2013;14(Suppl 4):S68.

    Article  Google Scholar 

  28. Romano G, Wang H, Ritz J, et al. Analgesic efficacy of fulranumab in patients with neuropathic pain in a randomized, placebo-controlled, double blind study. 14th World Congress on Pain, Milano; 2012, abstract PT452. http://www.abstracts2view.com/iasp/view.php?nu=107827&type=abstract (Accessed 28 Dec 2013).

  29. Holmes D. Anti-NGF painkillers back on track? Nat Rev Drug Discov. 2012;11:337–8.

    Article  CAS  PubMed  Google Scholar 

  30. Food and Drug Administration Center for Drug Evaluation and Research. Summary minutes of the Arthritis Advisory Committee Meeting; 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM307879.pdf (Accessed 15 Jan 2014).

  31. Moss AC, Brinks V, Carpenter JF. Immunogenicity of anti-TNF biologics in IBD—the role of patient, product and prescriber factors. Aliment Pharmacol Ther. 2013;38:1188–97.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments and Conflicts of Interest

B. Bannwarth has received consulting fees from Janssen R&D, and honoraria from Pfizer. M. Kostine has no conflicts of interest. No sources of funding were used to support the writing of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernard Bannwarth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bannwarth, B., Kostine, M. Targeting Nerve Growth Factor (NGF) for Pain Management: What Does the Future Hold for NGF Antagonists?. Drugs 74, 619–626 (2014). https://doi.org/10.1007/s40265-014-0208-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-014-0208-6

Keywords

Navigation