Research Article| Volume 345, ISSUE 1-2, P139-147, October 15, 2014

Nerve safety of tanezumab, a nerve growth factor inhibitor for pain treatment


      • Differences in primary endpoint (NC measures and HRdb) were not significant.
      • Changes in IENF density with tanezumab were not significant versus placebo.
      • Tanezumab significantly improved pain, physical function, and PGA of OA.
      • Differences in the clinical neuropathy assessments were not significant.
      • Safety was similar to previous tanezumab clinical trials.



      To evaluate peripheral nerve safety and clinical efficacy of tanezumab in patients with painful osteoarthritis.


      Patients received intravenous tanezumab 5 mg, tanezumab 10 mg, or placebo every 8 weeks for 24 weeks. Neurological safety was evaluated via a composite score (nerve conduction attributes and heart rate variability with deep breathing; Σ5NC + HRdb), intraepidermal nerve fiber (IENF) density, and clinical assessments. Efficacy and general safety were also evaluated.


      The study was stopped prematurely by an FDA partial clinical hold (joint safety issues in other studies). Differences in change from baseline to Week 24 in Σ5NC + HRdb were not significant. Tanezumab 5 mg vs placebo exceeded the prespecified clinically important difference using last observation carried forward imputation, but not with observed data or when patients with evidence of neuropathy at baseline were excluded. No significant differences were found in individual nerve conduction measures. No treatment exceeded the prespecified clinically important decrease in IENF. Tanezumab resulted in significant improvement in pain, physical function, and Patient's Global Assessment. Safety was similar to previous tanezumab clinical trials.


      Tanezumab has a modulating effect on pain, does not appear to increase neurological safety signals, and offers a potentially promising, novel approach in treatment of pain.


      5 HT (serotonin), 5NC (5 individual NC tests), ASIC3 (acid-sensing ion channel 3), BDNF (brain-derived neurotrophic factor), BR2 (bradykinin receptor), CB1 (cannabinoid receptor 1), CGRP (calcitonin gene-related peptide), CI (confidence interval), CMAP (compound muscle action potential), DRG (dorsal root ganglia), H+ (proton), HRdb (heart rate deep breathing), IENF (intraepidermal nerve fiber), IPAP (Initial Pain Assessment Period), ITT (intent-to-treat), IV (intravenous), LLF (lower limb function), LOCF (last observation carried forward), LSM (least squares mean), MNCV (motor nerve conduction velocity), MNDL (motor nerve distal latency), NaV 1.8 (voltage-gated sodium channel 1.8), NC (nerve conduction), nd (normal deviate), NGF (nerve growth factor), NIS (neuropathy impairment score), NIS-R (NIS muscle stretch reflexes), NIS-S (NIS sensation), NIS-W (NIS weakness), NRS (numeric rating scale), NSC (neuropathy symptoms and change), NV (neurology visit), OA (osteoarthritis), P2X3 (purinergic 2X receptor 3), p75 (low-affinity p75 neurotrophin receptor), PGA (Patient's Global Assessment), PPAS (per-protocol analysis set), RV (recruitment site visit), SD (standard deviation), SE (standard error), SNAP (sensory nerve action potential), SP (substance P), trkA (tropomyosin-related kinase A), TrpA1 (transient receptor potential ankyrin subtype 1), TrpV1 (transient receptor potential vanilloid 1), WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Levi-Montalcini R.
        The nerve growth factor: thirty-five years later.
        Biosci Rep. 1987; 7: 681-699
        • Crowley C.
        • Spencer S.D.
        • Nishimura M.C.
        • Chen K.S.
        • Pitts-Meek S.
        • Armanini M.P.
        • et al.
        Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons.
        Cell. 1994; 76: 1001-1011
        • Mantyh P.W.
        • Koltzenburg M.
        • Mendell L.M.
        • Tive L.
        • Shelton D.L.
        Antagonism of nerve growth factor-TrkA signaling and the relief of pain.
        Anesthesiology. 2011; 115: 189-204
        • Apfel S.C.
        Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?.
        Int Rev Neurobiol. 2002; 50: 393-413
        • Apfel S.C.
        • Schwartz S.
        • Adornato B.T.
        • Freeman R.
        • Biton V.
        • Rendell M.
        • et al.
        Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. rhNGF Clinical Investigator Group.
        JAMA. 2000; 284: 2215-2221
        • Dyck P.J.
        • Peroutka S.
        • Rask C.
        • Burton E.
        • Baker M.K.
        • Lehman K.A.
        • et al.
        Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans.
        Neurology. 1997; 48: 501-505
        • Aloe L.
        • Tuveri M.A.
        • Carcassi U.
        • Levi-Montalcini R.
        Nerve growth factor in the synovial fluid of patients with chronic arthritis.
        Arthritis Rheum. 1992; 35: 351-355
        • Della Seta D.
        • de Acetis L.
        • Aloe L.
        • Alleva E.
        NGF effects on hot plate behaviors in mice.
        Pharmacol Biochem Behav. 1994; 49: 701-705
        • Halliday D.A.
        • Zettler C.
        • Rush R.A.
        • Scicchitano R.
        • McNeil J.D.
        Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease.
        Neurochem Res. 1998; 23: 919-922
        • Hefti F.F.
        • Rosenthal A.
        • Walicke P.A.
        • Wyatt S.
        • Vergara G.
        • Shelton D.L.
        • et al.
        Novel class of pain drugs based on antagonism of NGF.
        Trends Pharmacol Sci. 2006; 27: 85-91
        • Lewin G.R.
        • Rueff A.
        • Mendell L.M.
        Peripheral and central mechanisms of NGF-induced hyperalgesia.
        Eur J Neurosci. 1994; 6: 1903-1912
        • Lowe E.M.
        • Anand P.
        • Terenghi G.
        • Williams-Chestnut R.E.
        • Sinicropi D.V.
        • Osborne J.L.
        Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis.
        Br J Urol. 1997; 79: 572-577
        • McArthur J.C.
        • Yiannoutsos C.
        • Simpson D.M.
        • Adornato B.T.
        • Singer E.J.
        • Hollander H.
        • et al.
        A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291.
        Neurology. 2000; 54: 1080-1088
        • Miller L.J.
        • Fischer K.A.
        • Goralnick S.J.
        • Litt M.
        • Burleson J.A.
        • Albertsen P.
        • et al.
        Nerve growth factor and chronic prostatitis/chronic pelvic pain syndrome.
        Urology. 2002; 59: 603-608
        • Oddiah D.
        • Anand P.
        • McMahon S.B.
        • Rattray M.
        Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder.
        Neuroreport. 1998; 9: 1455-1458
        • Sarchielli P.
        • Alberti A.
        • Floridi A.
        • Gallai V.
        Levels of nerve growth factor in cerebrospinal fluid of chronic daily headache patients.
        Neurology. 2001; 57: 132-134
        • Woolf C.J.
        • Safieh-Garabedian B.
        • Ma Q.P.
        • Crilly P.
        • Winter J.
        Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity.
        Neuroscience. 1994; 62: 327-331
        • Abdiche Y.N.
        • Malashock D.S.
        • 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: 1326-1335
      1. Bramson C, Herrmann D, Biton V, Carey W, Keller D, Brown M, et al. Efficacy and safety of subcutaneous tanezumab in patients with pain related to diabetic peripheral neuropathy (NCT01087203). 32nd Annual Scientific Meeting of the American Pain Society (APS). New Orleans, LA.

        • Brown M.T.
        • Murphy F.T.
        • Radin D.M.
        • Davignon I.
        • Smith M.D.
        • West C.R.
        Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial.
        J Pain. 2012; 13: 790-798
        • Brown M.T.
        • Murphy F.T.
        • Radin D.M.
        • Davignon I.
        • Smith M.D.
        • West C.R.
        Tanezumab reduces osteoarthritic hip pain: results of a randomized, double-blind, placebo-controlled phase 3 trial.
        Arthritis Rheum. 2013; 65: 1795-1803
      2. Ekman EF, Gimbel JS, Bello AE, Smith MD, Keller DS, Annis KM, et al. Efficacy and safety of intravenous tanezumab in osteoarthritis hip and knee pain: comparison to placebo and naproxen in two phase III studies (NCT00830063 & NCT00863304). American Pain Society (APS) 30th Annual Scientific Meeting. Austin, TX.

        • Evans R.J.
        • Moldwin R.M.
        • Cossons N.
        • Darekar A.
        • Mills I.W.
        • Scholfield D.
        Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis.
        J Urol. 2011; 185: 1716-1721
        • Katz N.
        • Borenstein D.G.
        • Birbara C.
        • Bramson C.
        • Nemeth M.A.
        • Smith M.D.
        • et al.
        Efficacy and safety of tanezumab in the treatment of chronic low back pain.
        Pain. 2011; 152: 2248-2258
        • Kivitz A.J.
        • Gimbel J.S.
        • Bramson C.
        • Nemeth M.A.
        • Keller D.S.
        • Brown M.T.
        • et al.
        Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain.
        Pain. 2013; 154: 1009-1021
        • Lane N.E.
        • Schnitzer T.J.
        • Birbara C.A.
        • Mokhtarani M.
        • Shelton D.L.
        • Smith M.D.
        • et al.
        Tanezumab for treatment of knee osteoarthritis pain.
        N Engl J Med. 2010; 363: 1521-1531
        • Nagashima H.
        • Suzuki M.
        • Araki S.
        • Yamabe T.
        • Muto C.
        Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study.
        Osteoarthritis Cartilage. 2011; 19: 1405-1412
        • Schnitzer T.J.
        • Lane N.E.
        • Birbara C.
        • Smith M.D.
        • Simpson S.L.
        • Brown M.T.
        Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain.
        Osteoarthritis Cartilage. 2011; 19: 639-646
      3. Yazici Y, Ekman EF, Greenberg HS, Smith MD, Brown MT, West CR, et al. Efficacy of tanezumab compared with non-steroidal anti-inflammatory drugs in patients with knee or hip osteoarthritis (NCT00809354). American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) Annual Scientific Meeting. Chicago, IL.

        • Dyck P.J.
        • Norell J.E.
        • Tritschler H.
        • Schuette K.
        • Samigullin R.
        • Ziegler D.
        • et al.
        Challenges in design of multicenter trials: end points assessed longitudinally for change and monotonicity.
        Diabetes Care. 2007; 30: 2619-2625
        • Dyck P.J.
        • Davies J.L.
        • Litchy W.J.
        • O'Brien P.C.
        Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort.
        Neurology. 1997; 49: 229-239
        • Altman R.
        • Alarcon G.
        • Appelrouth D.
        • Bloch D.
        • Borenstein D.
        • Brandt K.
        • et al.
        The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip.
        Arthritis Rheum. 1991; 34: 505-514
        • Altman R.
        • Asch E.
        • Bloch D.
        • Bole G.
        • Borenstein D.
        • Brandt K.
        • et al.
        Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
        Arthritis Rheum. 1986; 29: 1039-1049
        • Kellgren J.H.
        • Lawrence J.S.
        Radiological assessment of osteo-arthrosis.
        Ann Rheum Dis. 1957; 16: 494-502
        • Lauria G.
        • Cornblath D.R.
        • Johansson O.
        • McArthur J.C.
        • Mellgren S.I.
        • Nolano M.
        • et al.
        EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy.
        Eur J Neurol. 2005; 12: 747-758
        • Schiffmann R.
        • Hauer P.
        • Freeman B.
        • Ries M.
        • Scott L.J.
        • Polydefkis M.
        • et al.
        Enzyme replacement therapy and intraepidermal innervation density in Fabry disease.
        Muscle Nerve. 2006; 34: 53-56
        • Bellamy N.
        • Buchanan W.W.
        • Goldsmith C.H.
        • Campbell J.
        • Stitt L.W.
        Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
        J Rheumatol. 1988; 15: 1833-1840
        • Stengaard-Pedersen K.
        • Ekesbo R.
        • Karvonen A.L.
        • Lyster M.
        Celecoxib 200 mg q.d. is efficacious in the management of osteoarthritis of the knee or hip regardless of the time of dosing.
        Rheumatology (Oxford). 2004; 43: 592-595
        • Dyck P.J.
        • Hughes R.A.
        • O’Brien P.
        Quantitating overall neuropathic symptoms, impairments and outcomes.
        in: Dyck P.J. Thomas P.K. Peripheral neuropathy. 4th ed. Elsevier, Philadelphia2005: 1031-1051
        • Nickel J.C.
        • Atkinson G.
        • Krieger J.N.
        • Mills I.W.
        • Pontari M.
        • Shoskes D.A.
        • 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: 1105-1110
        • Pittenger G.L.
        • Ray M.
        • Burcus N.I.
        • McNulty P.
        • Basta B.
        • Vinik A.I.
        Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients.
        Diabetes Care. 2004; 27: 1974-1979