Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in treatment of patients with moderate-to-severe osteoarthritis pain

Sanga, Panna; Katz, Nathaniel; Polverejan, Elena; Wang, S.; Kelly, K.; Oh, Charles; Thipphawong, John

doi:10.1016/j.jpain.2011.02.216

Cited by 12 publications

(28 citation statements)

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“…Upon NGF application, mechanical and heat hyperal-gesia can be evoked in human volunteers (Petty et al, 1994;Svensson et al, 2003;Rukwied et al, 2010;Weinkauf et al, 2012) and an increased axonal excitability has been recorded recently following intracutaneous NGF injection in both volunteers and pig skin (Obreja et al, 2011a,b;Hirth et al, 2013). NGFinduced nociceptor sensitization appears to be of major clinical relevance as antibodies against NGF have profound analgesic effects in chronic pain patients (Katz et al, 2011;Sanga et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Axonal hyperexcitability after combined NGF sensitization and UV‐B inflammation in humans

Rukwied

Weinkauf

Main

et al. 2013

European Journal of Pain

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Section: Introductionmentioning

confidence: 99%

Axonal hyperexcitability after combined NGF sensitization and UV‐B inflammation in humans

Rukwied

Weinkauf

Main

et al. 2013

European Journal of Pain

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“…Anti-NGF therapies are currently tested in clinical trials for chronic LBP and pain from osteoarthritis of hip or knee joints, with good preliminary results. 24,27,39 Our study shows that NGF potentially influences the process of IVD matrix breakdown, in addition to contributing to pain pathways, and that these activities may be blocked by specific NGF inhibitors. Novel treatments targeting NGF/NGFRs have the potential to influence a range of adverse biological responses, including neurite and vascular infiltration and tissue degeneration, that result in the clinical symptoms and pathology of IVD disease.…”

Section: Discussionmentioning

confidence: 74%

Nerve growth factor promotes expression of novel genes in intervertebral disc cells that regulate tissue degradation

Kao

Peng

Tsou

et al. 2014

SPI

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Object Increased neurotrophin activity in degenerative intervertebral discs (IVDs) is one potential cause of chronic low-back pain (LBP). The aim of the study was to assess if nerve growth factor (NGF) might alter gene expression of IVD cells and contribute to disc degeneration by enhancing expression or activity of factors that cause breakdown of IVD matrix. Methods Rat-tail IVD cells were stimulated by NGF and subjected to microarray analysis. Real-time polymerase chain reaction, Western blotting, and immunocytochemistry of rat and human IVD cells and tissues treated with NGF in vitro in the absence or presence of the NGF inhibitor Ro 08-2750 were used to confirm findings of the microarray studies. Phosphorylation of mitogen-activated protein kinase (MAPK) was used to identify cell signaling pathways involved in NGF stimulation in the absence or presence of Ro 08-2750. Results Microarray analysis demonstrated increased expression of chitinase 3-like 1 (Chi3l1), lipocalin 2 (Lcn2), and matrix metalloproteinase–3 (Mmp3) following NGF stimulation of rat IVD cells in vitro. Increased gene expression was confirmed by real-time polymerase chain reaction with a relative increase in the Mmp/Timp ratio. Increased expression of Chi3l1, Lcn2, and Mmp3 following NGF stimulation was also demonstrated in rat cells and human tissue in vitro. Effects of NGF on protein expression were blocked by an NGF inhibitor and appear to function through the extracellular-regulation kinase 1/2 (ERK1/2) MAPK pathway. Conclusions Nerve growth factor has potential effects on matrix turnover activity and influences the catabolic/anabolic balance of IVD cells in an adverse way that may potentiate IVD degeneration. Anti-NGF treatment might be beneficial to ameliorate progressive tissue breakdown in IVD degeneration and may lead to pain relief.

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“…Consistent with the primary efficacy results, significant improvement in outcomes of all secondary efficacy parameters (except pain assessment, ≥ 30% improvement for 9mgQ4wk) was noted vs. oxycodone CR. The efficacy of fulranumab (3mgQ4wk based on NRS and WOMAC physical function scale) as well as other pain-related therapies (acetaminophen, NSAIDs and opioids) were expressed as a standardised effect size (SES) in an earlier report, where fulranumab's SES (observed in that study) was larger than other therapies (calculated based on published meta-analyses) (2,3,19,27). The outcomes for efficacy parameters observed for fulranumab vs. oxycodone CR in this study are consistent with those results (2,3,27).…”

Section: Discussionmentioning

confidence: 99%

“…Fulranumab is a human recombinant immunoglobulin G2 monoclonal antibody that specifically neutralises the biological action of human-NGF. In a previous study, fulranumab at four dose levels [1mg every 4 weeks (Q4 wk), 3mgQ8wk, 3mgQ4wk, 6mgQ8wk and 10mgQ8wk] in patients with OA of the hip or knee, demonstrated significant decrease in average OA-related pain intensity (OAPI) scores and improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscale of pain, stiffness and physical function vs. placebo at all doses except 1mg, and was generally well-tolerated (19). However, fulranumab was administered as adjunctive therapy, and an active comparator was not included in that study.…”

Section: Introductionmentioning

confidence: 98%

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Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial

et al. 2016

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Aims:The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). Methods: In this phase-2, double-blind (DB), double-dummy, placebo-and active-controlled study, patients (40-80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. Results: As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. Conclusion: Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated. Trial registration: ClinicalTrials.gov: NCT01094262.

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Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in treatment of patients with moderate-to-severe osteoarthritis pain

Cited by 12 publications

References 0 publications

Axonal hyperexcitability after combined NGF sensitization and UV‐B inflammation in humans

Axonal hyperexcitability after combined NGF sensitization and UV‐B inflammation in humans

Nerve growth factor promotes expression of novel genes in intervertebral disc cells that regulate tissue degradation

Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial

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