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Advances in Osteoarthritis of the Hip
Published in K. Mohan Iyer, Hip Joint in Adults: Advances and Developments, 2018
Pratham Surya, Sriram Srinivasan, Dipen K. Menon
Pharmacological manipulation of nerve growth factor (NGF) is another potential target area that is under trial. NGF is overexpressed in joint tissues and believed to have a role in the progression of OA. Tanezumab is a molecule that can inhibit NGF and its receptors. Tanezumab treatment has produced remarkable results in early clinical trials, providing hope for OA patients. Nitric oxide is a highly reactive cytotoxic free radical that is implicated in tissue injury, including cartilage. Inhibition of nitric oxide synthesis (nitric oxide synthase) is a therapeutic strategy in altering the course of OA. Synovitis is a common feature in OA. A mediator called bradykinin is released in synovitis. An antagonist of bradykinin is being developed. A recent phase 2 study showed its effectiveness in OA patients when compared with a placebo [22].
Nerve Growth Factor and Its Receptor System in Rheumatologic Diseases and Pain Management
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Smriti K. Raychaudhuri, Siba P. Raychaudhuri
The NGF monoclonal antibody tanezumab has been reported to have an excellent therapeutic agent; a patient with knee OA had significant pain reduction in phase I, phase II, and phase III trials [90–92]. Fasinumab, a newly developed anti-NGF agent and a high-affinity NGF-R inhibitor, is also demonstrating a significant analgesic effect in knee and hip OA arthritis, and initial results suggest that it is so far well tolerated [93]. However, there are also certain concerns; osteonecrosis and worsening of OA of the hip, knee, and shoulder were observed more in the study group than in the patients who did not receive tanezumab. It is important to address and overcome these two concerns: osteonecrosis and rapid progress of OA. The Food and Drug Administration (FDA) has concerns about these safety issues and is closely monitoring these aspects of anti-NGF preparations.
Development of palliative medicine in the United Kingdom and Ireland
Published in Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita, Textbook of Palliative Medicine and Supportive Care, 2015
135 Nagashima, H. et al., 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(12): 1405-1412.
What’s new in chronic pain pathophysiology
Published in Canadian Journal of Pain, 2020
It has been theorized that anti-NGF monoclonal antibodies might be able to intervene early in histamine activation and affect pain at the transcriptional level by decreasing production of cellular and subcellular elements critical to this pathway. Three antibody agents have been studied thus far. Tanezumab, a human immunoglobulin-2 NGF antibody, is being studied for osteoarthritis (OA), chronic low back pain, and metastatic bone lesions, among others. It has been found to be highly specific and selective for NGF, and in 2017 it was given fast-track status by the U.S. Food and Drug Administration. Meta-analysis of Phase 3 studies showed favorable outcomes versus placebo, naproxen, and oxycodone.2 Fasinumab is another agent in the final stages of trials for hip and knee OA. Fulranumab is a third agent that is no longer undergoing clinical investigation.
Pharmacotherapy for knee osteoarthritis: current and emerging therapies
Published in Expert Opinion on Pharmacotherapy, 2020
Peihua Cao, Yamin Li, Yujin Tang, Changhai Ding, David J. Hunter
The FDA placed a hold on all clinical trials of NGF antagonists in 2012 because tanezumab was found to be associated with rapid OA progression and a rare adverse effect, osteonecrosis. Mullard et al. reported a dose–response relationship between osteonecrosis and doses of tanezumab between 2.5, 5, and 10 mg [42]. Rapidly progressive OA appears to be dose-dependent with doses of tanezumab between 2.5 and 10 mg [43], and with doses of fasinumab between 3 and 9 mg [44]. Therefore, trials were resumed in 2015 with tanezumab use under the dose of 5 mg. Of note, tanezumab administered with NSAIDs increased the risk of rapid progression of OA [43,45]; therefore, the duration of NSAIDs use during anti-NGF treatment was severely limited in subsequent trials. Cost-effectiveness analyses suggest that rapid OA progression at rates observed in clinical trials, even at a rate of 10%, does not lead to an overall decrease in quality-adjusted life expectancy [46]. Future studies are warranted to determine the appropriate role of NGF antibodies in the treatment of OA, specifically at what part of the disease continuum these agents are appropriate, particularly given their cost and side-effect profile.
Antibodies to watch in 2018
Published in mAbs, 2018
Hélène Kaplon, Janice M. Reichert
Tanezumab (PF-04383119) is a humanized IgG2 mAb targeting nerve growth factor being investigated as a treatment for chronic low back pain (CLBP), moderate-to-severe osteoarthritis (OA) pain of the hip or knee, and pain due to cancer metastasis. The FDA has granted tanezumab fast-track designation as a treatment for chronic pain in patients with OA and CLBP. Pfizer Inc. and Eli Lilly and Company have a worldwide co-development and co-commercialization agreement for the advancement of the mAb. As of December 1, 2017, patients were being recruited for five Phase 3 studies, and one Phase 3 study designed to characterize the outcomes related to the development of infants up to the age of 15 months who were potentially exposed to tanezumab, placebo or comparator via maternal exposure or in utero in any tanezumab study was not yet recruiting patients. In total, the Phase 3 global clinical development program for tanezumab includes ∼ 7,000 patients with OA, CLBP or cancer pain who did not experience adequate pain relief with approved therapies. Two studies, NCT02528253 and NCT02697773, have primary completion dates in October and November 2017, respectively. The Phase 3 NCT02709486 study, which is evaluating the analgesic efficacy and safety of SC doses of 2.5 mg or 5 mg tanezumab in subjects with OA of the hip or knee, has a primary completion date in June 2018. The studies are investigating SC administration of tanezumab once every eight weeks for treatment periods ranging from 16 to 56 weeks, followed by a 24-week safety follow-up period. The results of these studies are projected to be available in 2018.