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      Tanezumab: a selective humanized mAb for chronic lower back pain

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          Abstract

          Chronic lower back pain is a significant disease that affects nearly 20% of the worldwide population. Along with hindering patients’ quality of life, chronic lower back pain is considered to be the second most common cause of disability among Americans. Treating chronic lower back pain is often a challenge for providers, especially in light of our current opioid epidemic. With this epidemic and an increased aging population, there is an imminent need for development of new pharmacologic therapeutic options, which are not only effective but also pose minimal adverse effects to the patient. With these considerations, a novel therapeutic agent called tanezumab has been developed and studied. Tanezumab is a humanized monoclonal immunoglobulin G2 antibody that works by inhibiting the binding of NGF to its receptors. NGF is involved in the function of sensory neurons and fibers involved in nociceptive transduction. It is commonly seen in excess in inflammatory joint conditions and in chronic pain patients. Nociceptors are dependent on NGF for growth and ongoing function. The inhibition of NGF binding to its receptors is a mechanism by which pain pathways can be interrupted. In this article, a number of recent randomized controlled trials are examined relating to the efficacy and safety of tanezumab in the treatment of chronic lower back pain. Although tanezumab was shown to be an effective pain modulator in major trials, several adverse effects were seen among different doses of the medication, one of which led to a clinical hold placed by the US Food and Drug Administration. In summary, tanezumab is a promising agent that warrants further investigation into its analgesic properties and safety profile.

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          Most cited references 18

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          Diagnostic evaluation of low back pain with emphasis on imaging.

          To review evidence on the diagnostic accuracy of clinical information and imaging for patients with low back pain in primary care settings. MEDLINE search (January 1966 to September 2001) for articles and reviews relevant to the accuracy of the clinical and radiographic examination of patients with low back pain. The authors reviewed abstracts and selected articles for review on the basis of a combined judgment. Data on the clinical examination were based primarily on recent systematic reviews; data on imaging tests were based primarily on original articles. Diagnostic results were extracted by one or the other author. Quality of methods was evaluated informally. Major potential biases were identified, but neither quantitative data extraction nor scoring was done. Formal meta-analysis was not used because the diagnostic hardware and software, gold standards, and patient selection methods were heterogeneous and the number of studies was small. Sensitivity for cancer was highest for magnetic resonance imaging (0.83 to 0.93) and radionuclide scanning (0.74 to 0.98); specificity was highest for magnetic resonance imaging (0.9 to 0.97) and radiography (0.95 to 0.99). Magnetic resonance imaging was the most sensitive (0.96) and specific (0.92) test for infection. The sensitivity and specificity of magnetic resonance imaging for herniated discs were slightly higher than those for computed tomography but very similar for the diagnosis of spinal stenosis. The data suggest a diagnostic strategy similar to the 1994 Agency for Health Care Policy and Research guidelines. For adults younger than 50 years of age with no signs or symptoms of systemic disease, symptomatic therapy without imaging is appropriate. For patients 50 years of age and older or those whose findings suggest systemic disease, plain radiography and simple laboratory tests can almost completely rule out underlying systemic diseases. Advanced imaging should be reserved for patients who are considering surgery or those in whom systemic disease is strongly suspected.
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            Podocytes use FcRn to clear IgG from the glomerular basement membrane.

            The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). Here, we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an IgG and albumin transport receptor, is expressed in podocytes and functions to internalize IgG from the GBM. Mice lacking FcRn accumulated IgG in the GBM as they aged, and tracer studies showed delayed clearance of IgG from the kidneys of FcRn-deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism promoting glomerular diseases.
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              Efficacy and safety of tanezumab in the treatment of chronic low back pain.

              Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 μg/kg plus oral placebo (n=88), intravenous placebo plus oral naproxen 500 mg twice a day (n=88), or intravenous placebo plus oral placebo (n=41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients' Global Assessment of LBP, Patients' Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P=0.004) and placebo (P<0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P≤0.013) and placebo (P<0.001), and greater improvements in Roland-Morris Disability Questionnaire (P<0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients. Copyright © 2011. Published by Elsevier B.V.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2018
                21 February 2018
                : 14
                : 361-367
                Affiliations
                [1 ]Department of Anesthesiology, North Shore Hospital, Auckland, New Zealand
                [2 ]Department of Anesthesiology, LSU School of Medicine, New Orleans, LA, USA
                [3 ]Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                Author notes
                Correspondence: Richard D Urman, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA, Tel +1 617 732 8222, Fax +1 617 897 0879, Email rurman@ 123456bwh.harvard.edu
                Article
                tcrm-14-361
                10.2147/TCRM.S144125
                5825994
                © 2018 Webb et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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