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      Fasinumab (REGN475), an antinerve growth factor monoclonal antibody, for the treatment of acute sciatic pain: results of a proof-of-concept study

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          Abstract

          Objective

          To evaluate the efficacy and safety of subcutaneously administered fasinumab (REGN475), a nerve growth factor-neutralizing antibody, in patients with acute sciatic pain receiving standard of care therapy.

          Methods

          This was a double-blind, parallel-group, proof-of-concept study. Patients with unilateral, moderate-to-severe sciatic pain of 2–16 weeks’ duration were randomized to a subcutaneous dose of placebo (n=51), fasinumab 0.1 mg/kg (n=53), or 0.3 mg/kg (n=53); follow-up was 12 weeks. Pain was assessed in a daily diary using a numerical rating scale (NRS) (0= no pain, 10= worst pain) for average and worst leg and back pain. The primary efficacy end point was the area under the curve of NRS scores for average leg pain from baseline to week 4. Key secondary end points included changes in average and worst leg and back pain from baseline to the end of week 4 and to each weekly study visit. Patient functioning (Oswestry Disability Index) and concomitant analgesic use were also assessed. Safety and tolerability were evaluated by treatment-emergent adverse events (TEAEs).

          Results

          Demographic and clinical characteristics were similar among the treatment groups; 141 (88.7%) patients completed the study. For the primary end point, mean ± standard deviation area under the curve values from baseline to week 4 were not significantly different between placebo (96.8±6.0) and fasinumab 0.1 mg/kg (112.7±58.3; P=0.0610) or fasinumab 0.3 mg/kg (112.4±55.8; P=0.0923). All secondary efficacy end points of changes in pain and function demonstrated responses that were similar between placebo and fasinumab groups. Incidence of TEAEs was 45.1%, 50.9%, and 64.8% in the placebo, fasinumab 0.1mg/kg, and fasinumab 0.3 mg/kg groups, respectively. The most commonly reported TEAEs included paresthesia, arthralgia, pain in extremity, and headache.

          Conclusion

          Administration of fasinumab provided no significant clinical benefit compared with placebo for the pain or functional limitations associated with acute sciatica. Fasinumab was generally well tolerated and incidence of TEAEs appeared to be dose related.

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          Most cited references 32

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          The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain.

          In 2007, three times as many peer reviewed publications covering the biology and biotherapeutics of intervertebral disc (IVD) disease appeared in the literature than in 1997. This is testimony to the upsurge in interest in the IVD, mainly driven by the openings that modern molecular pathology has generated to investigate mechanisms of human disease and the potential offered by novel therapeutic technologies to use data coming from these studies to positively influence chronic discogenic back pain and sciatica. Molecular pathology has shown IVD degeneration, a major cause of low back pain, to be a complex, active disorder in which disturbed cytokine biology, cellular dysfunction and altered load responses play key roles. This has translated into a search for target molecules and disease processes that might be the focus of future, evidence-based therapies for back pain. It is not possible to describe the totality of advances that have been made in understanding the biology of the IVD in recent years, but in this review those areas of biology that are currently influencing, or could conceivably soon impinge on, clinical thinking or practice around IVD degeneration and discogenic back pain are described and discussed.
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            Neurotrophin signalling in health and disease.

            Neurotrophins are a unique family of polypeptide growth factors that influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells. They are essential for the health and well-being of the nervous system. NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3) and NT-4 (neurotrophin-4) also mediate additional higher-order activities, such as learning, memory and behaviour, in addition to their established functions for cell survival. The effects of neurotrophins depend upon their levels of availability, their affinity of binding to transmembrane receptors and the downstream signalling cascades that are stimulated after receptor activation. Alterations in neurotrophin levels have been implicated in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, as well as psychiatric disorders, including depression and substance abuse. Difficulties in administering trophic factors have led to the consideration of using small molecules, such as GPCR (G-protein-coupled receptor) ligands, which can participate in transactivation events. In this review, we consider the signalling pathways activated by neurotrophins in both health and disease states.
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              Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline.

              Medications are the most frequently prescribed therapy for low back pain. A challenge in choosing pharmacologic therapy is that each class of medication is associated with a unique balance of risks and benefits. To assess benefits and harms of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, benzodiazepines, antiepileptic drugs, skeletal muscle relaxants, opioid analgesics, tramadol, and systemic corticosteroids for acute or chronic low back pain (with or without leg pain). English-language studies were identified through searches of MEDLINE (through November 2006) and the Cochrane Database of Systematic Reviews (2006, Issue 4). These electronic searches were supplemented by hand searching reference lists and additional citations suggested by experts. Systematic reviews and randomized trials of dual therapy or monotherapy with 1 or more of the preceding medications for acute or chronic low back pain that reported pain outcomes, back-specific function, general health status, work disability, or patient satisfaction. We abstracted information about study design, population characteristics, interventions, outcomes, and adverse events. To grade methodological quality, we used the Oxman criteria for systematic reviews and the Cochrane Back Review Group criteria for individual trials. We found good evidence that NSAIDs, acetaminophen, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain) are effective for pain relief. The magnitude of benefit was moderate (effect size of 0.5 to 0.8, improvement of 10 to 20 points on a 100-point visual analogue pain scale, or relative risk of 1.25 to 2.00 for the proportion of patients experiencing clinically significant pain relief), except in the case of tricyclic antidepressants (for which the benefit was small to moderate). We also found fair evidence that opioids, tramadol, benzodiazepines, and gabapentin (for radiculopathy) are effective for pain relief. We found good evidence that systemic corticosteroids are ineffective. Adverse events, such as sedation, varied by medication, although reliable data on serious and long-term harms are sparse. Most trials were short term (< or =4 weeks). Few data address efficacy of dual-medication therapy compared with monotherapy, or beneficial effects on functional outcomes. Our primary source of data was systematic reviews. We included non-English-language trials only if they were included in English-language systematic reviews. Medications with good evidence of short-term effectiveness for low back pain are NSAIDs, acetaminophen, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain). Evidence is insufficient to identify one medication as offering a clear overall net advantage because of complex tradeoffs between benefits and harms. Individual patients are likely to differ in how they weigh potential benefits, harms, and costs of various medications.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2014
                22 August 2014
                : 7
                : 523-530
                Affiliations
                [1 ]Pharmacovigilance Operations and Risk Management, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
                [2 ]Biostatitics, Regeneron Pharmaceuticals, Inc., Basking Ridge, NJ, USA
                [3 ]Translational Medicine and Predictive Medicine, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
                Author notes
                Correspondence: Paul J Tiseo, Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA, Tel +1 914 847 7680, Fax +1 914 860 4192, Email paul.tiseo@ 123456regeneron.com
                Article
                jpr-7-523
                10.2147/JPR.S65974
                4155988
                © 2014 Tiseo et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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