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Keywords:

  • anti-NGF;
  • hereditary sensory autonomic neuro-pathies;
  • NGF ;
  • pain, Tanezumab

Abstract

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

Nerve growth factor (NGF) is the founding member of the neurotrophins family of proteins. It was discovered more than half a century ago through its ability to promote sensory and sympathetic neuronal survival and axonal growth during the development of the peripheral nervous system, and is the paradigmatic target-derived neurotrophic factor on which the neurotrophic hypothesis is based. Since that time, NGF has also been shown to play a key role in the generation of acute and chronic pain and in hyperalgesia in diverse pain states. NGF is expressed at high levels in damaged or inflamed tissues and facilitates pain transmission by nociceptive neurons through a variety of mechanisms. Genetic mutations in NGF or its tyrosine kinase receptor TrkA, lead to a congenital insensitivity or a decreased ability of humans to perceive pain. The hereditary sensory autonomic neuropathies (HSANs) encompass a spectrum of neuropathies that affect one's ability to perceive sensation. HSAN type IV and HSAN type V are caused by mutations in TrkA and NGF respectively. This review will focus firstly on the biology of NGF and its role in pain modulation. We will review neuropathies and clinical presentations that result from the disruption of NGF signalling in HSAN type IV and HSAN type V and review current advances in developing anti-NGF therapy for the clinical management of pain.

Abbreviations used
aLBPI

average LBP intensity

BDNF

brain-derived neurotrophic factor

CGRP

Calcitonin gene-related peptide

CIPA

Congenital Insensitivity to Pain with Anhidrosis

EMG

electromyography

FDA

Food and Drug Administration

HSANs

hereditary sensory autonomic neuropathies

i.v.

intravenous

IVD

intervertebral disc

LBP

low back pain

MAP

mitogen activated protein

NGF

nerve growth factor

NRS

numerical rating scale

NSAIDs

non-steroidal anti-inflammatory drugs

OA

osteoarthritis

p75NTR

p75 neurotrophin receptor

TNZ

Tanezumab

TrkA

tyrosine kinase receptor A

TRPV1

transient receptor potential cation channel subfamily V member 1

URTI

upper respiratory tract infection

VAS

visual-analogue scale

WOMAC

Western Ontario and McMaster Osteoarthritis Index

According to the International Association for the Study of Pain, pain can be defined as ‘an unpleasant sensory and emotional experience associated with potential or actual tissue damage, or described in terms of such damage’ (Merskey and Bogduk 1994). Chronic pain (also referred to as persistent pain), is defined as that which continues beyond the time normally associated with healing for a specific illness or injury (Siddall and Cousins 2004). Recent epidemiological studies on chronic pain have indicated that the prevalence of moderate to severe chronic pain (not associated with cancer) is 16–18% (Harker et al. 2012). Chronic pain has been consistently found to impact negatively on a patient's quality of life (Siddall and Cousins 2004; Harker et al. 2012). In a recent study examining the association between chronic pain and health related quality of life, half of respondents reported chronic pain as the major factor affecting their quality of life (Agborsangaya et al. 2012). The pains of urolithiasis (Bryant et al. 2012), chronic temporomandibular pain disorders (Calderon Pdos et al. 2012), fibromyalgia, characterized by chronic widespread pain and allodynia (Homann et al. 2012) and exostoses (new bone formation on existing bone surface) (Goud et al. 2012) are each associated with clinically significant impairments in a patient's quality of life.

Current pharmacologic management of pain includes the use of non-opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of mild to moderate pain and opioids for the treatment of moderate to severe pain (Katz and Barkin 2010). Although these classes of drugs do provide significant benefit; their long-term use in particular is associated with mild to severe adverse effects. An estimated 86 000 hospitalizations and 13 000 deaths per year are related to complications of NSAIDs in patients with osteoarthritis and rheumatoid arthritis in the United States (Singh 1998). NSAIDs also have a ‘ceiling effect’, meaning that, above a certain dose, their efficacy does not increase (Fishman and Teichera 2003). In addition, long-term NSAID use is associated with gastrointestinal ulcers, bleeding, fluid retention, hyperkalemia and acute renal failure (Wolfe et al. 1999; Whelton 2000). Long-term opioid use has been shown to result in constipation, nausea, vomiting, sedation, cognitive impairment, respiratory depression, dizziness, urinary retention, dependence and misuse in certain groups of patients (Cherny 1996; Barkin and Barkin 2001; Fishman and Teichera 2003). As only approximately one-third of patients with chronic pain receive adequate symptomatic relief from existing therapies (Kalso et al. 2004), there is a large unmet medical need for new classes of drug treatment for chronic pain. In this review, we outline the biology of nerve growth factor (NGF) and its role in the modulation of pain. We will review the importance of NGF for the development of nociception in humans and outline recent advances in the development of a new class of drugs for the treatment of chronic pain based on antagonism of NGF signalling.

NGF overview

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

NGF was discovered more than half a century ago through its ability to promote the survival and axonal growth of sensory and sympathetic neurons in the developing PNS and as it is the model target-derived neurotrophic factor on which the neurotrophic factor hypothesis is based (Levi-Montalcini 1987; Davies 2003). NGF is a target-derived neurotrophin and upon its release, binds to a receptor complex, located on the distal ends of axons that innervate the targets in which NGF is produced (Davies 2003). The effects of NGF are mediated by its binding to this receptor complex which consists of the receptor tyrosine kinase-A (TrkA) and the p75 neurotrophin receptor (p75NTR) (Klein et al. 1991; Smeyne et al. 1994; Davies 2003; Schor 2005). This neurotrophin–receptor complex undergoes endocytosis and retrograde transportation to the neuronal soma where it regulates gene expression (Ginty and Segal 2002). Mice lacking NGF or TrkA have severe sensory and sympathetic neuropathies and most die within 1 month of birth. They have extensive neuronal cell loss in NGF-dependent neuronal populations namely, the trigeminal, sympathetic and dorsal root ganglia, as well as a decrease in the cholinergic basal forebrain projections to the hippocampus and cortex (Crowley et al. 1994; Smeyne et al. 1994; Fagan et al. 1997; Ruberti et al. 2000; Middleton and Davies 2001; Glebova and Ginty 2004).

NGF and pain

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

In humans, the levels of NGF are elevated in a variety of acute and chronic pain states including rheumatoid arthritis and spondyloarthritis (Aloe et al. 1992; Halliday et al. 1998; Barthel et al. 2009) in neurogenic overactive bladder and interstitial cystitis (Lowe et al. 1997; Oddiah et al. 1998; Jacobs et al. 2010; Liu et al. 2010), cancer-induced pain (Ye et al. 2011), prostatitis (Miller et al. 2002; Watanabe et al. 2011), endometriosis (Barcena de Arellano et al. 2011) and in patients with degenerative intervertebral disc disease (Lee et al. 2009). The functional link between these increased levels of NGF and pain was determined through a variety of studies in animals and humans that modulated NGF levels and observed the resultant effects on the level of pain experienced. In humans, intramuscular injections of NGF in a randomized double-blind trial resulted in an increase in pain scores and increased pressure pain sensitivity in the NGF-injected muscle compared with baseline; these effects were resistant to local anaesthesia of the muscle (Gerber et al. 2011). NGF also induced non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin following local injection (Rukwied et al. 2010). Similarly, local injection of NGF into the masseter muscle induced mechanical allodynia and hyperalgesia that persisted for at least 7 days after administration of NGF (Svensson et al. 2008).

The molecular mechanisms through which NGF modulates pain and hypersensitivity centre around its effects on nociceptive neuron function either directly or indirectly via an action on mast cells. The NGF receptor TrkA is selectively expressed in nociceptive neurons (Fang et al. 2005; Franklin et al. 2009) that also express TRPV1 (Moran et al. 2004; Ramsey et al. 2006). TRPV1 is a non-selective ligand-gated cation channel that responds to mechanical, thermal and chemical (i.e. acid, lipids) stimuli derived from extra- and intracellular sources. Stimulus-induced opening of TRPV1 results in Ca2+ influx and the generation of an action potential (and thus transmission of pain signals) by the nociceptive neuron (Moran et al. 2004; Ramsey et al. 2006). An increase in NGF expression following injury or inflammation affects the function of TRPV1 in two main ways: (i) NGF binding to its TrkA receptor on nociceptive neurons activates phospholipase C which leads to TRPV1 sensitization by decreasing the threshold at which it opens (Chuang et al. 2001) (ii) NGF increases TRPV1 expression (Winston et al. 2001; Ji et al. 2002) and its trafficking to the plasma membrane (Ji et al. 2002; Stein et al. 2006). Both effects tend to decrease the threshold for action potential generation in nociceptive neurons. NGF also up-regulates a number of genes (substance-P, Nav1.8, BDNF) in nociceptive neurons that further sensitize these neurons and facilitate activation of second-order neurons in the CNS (Hefti et al. 2006; Mantyh et al. 2011). NGF indirectly contributes to the facilitation of pain by inducing the release of pain mediators such as histamine, prostaglandins and NGF itself from mast cells all of which results in the formation of a positive-feedback loop that sensitizes adjacent nociceptive neurons (Kawamoto et al. 2002) (Fig. 1).

image

Figure 1. Mechanisms through which nerve growth factor (NGF) facilitates pain transmission. (a) Photomicrograph of a β-III tubulin-stained nocieptive neuron grown in culture from the dorsal root ganglion. NGF acts locally on the axonal terminals of these neurons and is also internalized and retrogradely transported to the neuronal soma where it induces a signalling cascade that modifies gene transcription. (b) The main way NGF promotes pain and hyperalgesia following tissue damage or inflammation. An increase in NGF expression following injury or inflammation, binds to TrkA and activates phospholipase C (PLC) which leads to transient receptor potential cation channel subfamily V member 1 (TRPV1) sensitization. NGF also increases TRPV1 expression and its trafficking to the plasma membrane, which decrease the threshold for action potential generation in nociceptive neurons. NGF also induces the release of pain mediators such as histamine, prostaglandins and NGF itself from mast cells which result in a positive-feedback loop that sensitizes nociceptive neurons.

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Genetic mutations in the NGF and TrkA genes result in a loss of pain perception

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

The key role that NGF signalling plays in perception of pain is illustrated by studies showing that genetic mutation in NGF or the TrkA receptor leads to a congenital insensitivity or a decreased ability of humans to perceive pain. These genetic conditions are part of the hereditary sensory autonomic neuropathies (HSANs) which encompass a spectrum of disorders that affect one's ability to perceive sensation. There are five types of HSAN's (type I–V) that predominantly affect the peripheral nervous system. Of the five types, HSAN IV and HSAN V are relevant to this review as they are caused by mutations in TrkA and NGF respectively (Rotthier et al. 2012).

HSAN IV and TrkA mutation

HSAN IV, also known as ‘Congenital Insensitivity to Pain with Anhidrosis’ (CIPA), ‘Familial dysautonomia type II’ or ‘congenital sensory neuropathy with anhidrosis’ is a rare autosomal recessive disorder (Toscano and Andria 2001). It was first reported in 1963 when two siblings presented with an inability to feel pain and to sense temperature (Swanson 1963). The most common clinical presentations of HSAN IV are insensitivity to noxious (painful or temperature-associated) stimuli and anhidrosis (the inability to sweat). Other clinical characteristics, which illustrate the diverse roles of NGF in the peripheral and central nervous systems, are episodic fevers, self-mutilation and mental retardation. HSAN IV patients may be prone to bone fractures and slow healing; joint dislocations and deformities; skin infections; impaired immune responses and renal failure (Indo et al. 1996) or rarely facial dysmorphism, swallowing disorders and myasthenic EMG patterns (Raspall-Chaure et al. 2005).

The condition results from mutations in the TrkA gene located on chromosome 1q21-q22 (Indo et al. 1996). Mutations occur in the extracellular (NGF binding) and intracellular (signal transduction) domains of TrkA (Mardy et al. 1999). TrkA mutations have been reported in HSAN IV patients from different ethnic groups, including families of Ecuadorian and Japanese descent (Mardy et al. 1999), Israeli-Bedouin Tribes (Shatzky et al. 2000) and a patient of Spanish origin (Sarasola et al. 2011). These mutations result in impairment of NGF binding to TrkA or of signal transduction following NGF binding. As a result, in this condition, subsets of sensory and sympathetic neurons do not develop normally. As a consequence, neuropathological findings include an absence of small unmyelinated fibres, a decrease in number of myelinated fibres in peripheral nerves, an absence of nociceptive innervation of the epidermis and diminished sympathetic innervation of eccrine sweat glands. These anatomical findings explain the physiological basis to pain insensitivity and inability to sweat in HSAN IV patients (Swanson et al. 1965; Langer et al. 1981). The mutations in TrkA have also been found to result in defective lymphocyte signalling which may explain why patients have a greater incidence of infection than age-matched controls. Specifically, B cells have defective TrkA phosphorylation and consequently display defects in cytoskeleton assembly and MAP kinase activation (Melamed et al. 2004). One TrkA mutation (1926-ins-T) is associated with impaired neutrophil chemotaxis, which may contribute to the greater incidence of infection and in patients with HSAN IV (Beigelman et al. 2009). Although, the mutations in TrkA are directly responsible for the congenital insensitivity to pain and anhidrosis, in a 25 year follow-up study, two of three HSAN IV patients died of renal failure, aged 15–25 years (Barone et al. 2005). As of 2005, the third patient suffered from renal impairment and severe deep vein thrombosis (Barone et al. 2005). Given that the kidney is incompletely innervated in NGF−/− mice (Glebova and Ginty 2004), it is possible that this contributes to a pre-disposition to developing renal disease in individuals with HSAN IV.

HSAN V and NGF mutation

Rarer than HSAN IV, the autosomal recessive disorder HSAN V is also known as ‘Congenital insensitivity to pain without anhidrosis’. As the name suggests, it differs from HSAN IV, in that, although there are selective deficiencies in pain perception, affected individuals do not present with anhidrosis and are otherwise neurologically normal (Minde et al. 2004). HSAN V patients demonstrate decreased numbers of unmyelinated fibres and of thin, myelinated fibres. As a result, the condition is characterized by a selective loss of deep pain perception, but normal perception of touch, pressure and vibration. Given that affected individuals cannot feel deep pain, they often present with fractures, bone necrosis, osteochondritis and neuropathic joint destruction (Minde et al. 2004).

HSAN V results from a mutation on the NGFβ gene which encodes NGF, on chromosome 1p13.2-p11.2. These mutations in NGF are caused by an amino acid R to W substitution at position 100 of mature NGF (R100W mutation) that disrupts its binding to the p75NTR, whereas it can bind normally to TrkA (Covaceuszach et al. 2010). Furthermore, this mutation results in decreased processing of pro NGF into mature NGF in cultured cells (Larsson et al. 2009). As NGF binding to TrkA is normal in patients with HSAN V, the resulting phenotype is less severe than that of HSAN IV (in which NGF-TrkA binding is defective). This clinical finding is consistent with the observations that (i) in mice defective in TrkA signalling (Smeyne et al. 1994) (a model of HSAN IV), both sensory and sympathetic neurons are absent, and (ii) in p75 knock-out mice (a model of HSAN V), only sensory neurons are absent.

Lessons from the HSAN studies

The HSAN conditions highlight the key role that NGF plays in the development and survival of primary nociceptors (Swanson et al. 1965; Langer et al. 1981; Ritter et al. 1991; Smeyne et al. 1994; Indo et al. 1996; Mardy et al. 1999; Glebova and Ginty 2004; Covaceuszach et al. 2010; Rotthier et al. 2012). The role NGF plays in nocieption changes in the adult in whom it becomes a key effector in the generation of pain. This switch in the role of NGF has been identified in the post-natal development period, during which NGF can acutely (within minutes) sensitize responses of nociceptors to noxious stimuli during post-natal days 4 and 10 (P4–P10) (Zhu et al. 2004). Given the switch in the function of NGF from survival in developing animal to sensitization in the adult, it is not clear that ‘developmental HSAN’ can enable us to understand or predict the effects of intermittent NGF/TrkA blockade in the adult. However, a number of issues arising from studies of HSAN can inform the experimental approach to NGF antagonism. For example, patients suffering from HSAN V (resulting from a mutation in NGF) have a less severe phenotype than that of patients with HSAN IV (resulting from TrkA mutation) as described above. Patients with NGF mutations, lose the ability to perceive pain, whereas those with TrkA mutations suffer from loss of pain sensation, anhidrosis and mental retardation. This suggests that pharmacological approaches that block NGF rather than TrkA may be the safer option in terms of predicting adverse effects. For example, K252a is a kinase inhibitor, known to inhibit TrkA resulting in a subsequent attenuation of pain in an animal model of pancreatic pain (Winston et al. 2003). However, this kinase inhibitor can also inhibit all kinase receptors i.e. not selective for TrkA. Given the other neurological and sympathetic problems seen in the patients with TrkA mutation, one might predict that blockade of TrkA using kinase inhibitors would cause adverse effects that are unrelated to nociception. Therefore, scrutiny of the clinical histories of patients with developmental HSAN IV and HSAN V may be useful in identifying potential adverse effects. These studies also suggests that antagonism of NGF as a therapeutic approach for the treatment of chronic pain may be the safer option that antagonism of TrkA.

Potential intervention strategies: NGF versus TrKA versus p75

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

A number of intervention strategies exist for the inhibition of NGF signalling in vivo. Although to date, significant efforts have been undertaken to develop NGF-sequestering or function blocking antibodies, alternative approaches include blocking the NGF receptors TrkA and/or p75 have been proposed (McMahon et al. 1995; Owolabi et al. 1999; Winston et al. 2003; Obata et al. 2006; Ugolini et al. 2007; Fukui et al. 2010; Ghilardi et al. 2010, 2011; Orita et al. 2010).

Administration of an anti-TrkA monoclonal antibody has induced analgesia in both inflammatory and neuropathic pain models (Ugolini et al. 2007). Similarly, in a mouse model of bone pain associated with cancer, a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA kinase activity), was found to significantly attenuate cancer-induced pain behaviour (Ghilardi et al. 2010); in a related study, fracture pain-related behaviours (Ghilardi et al. 2011). ALE0540 is a non-peptidic molecule which affects binding of NGF to both TrkA and p75NTR and was also effective in neuropathic and inflammatory pain models (Owolabi et al. 1999).

In relation to blocking p75NTR, studies have shown that specifically inhibiting p75NTR alleviated neuropathic pain in the rat (Obata et al. 2006). This effect was associated with a decrease in TrkA and p38 mitogen-activated protein kinase phosphorylation, and the induction of transient receptor potential channels in dorsal root ganglion neurons (Obata et al. 2006). When compared with treatment with anti-NGF and anti-TrkA antibodies, direct single intradiscal application of an anti-p75NTR agent produced the most profound suppression of neuropeptide calcitonin gene-related peptide (CGRP) in injured rat IVD (Orita et al. 2010). Given that CGRP produces hyperalgesia (Sun et al. 2004), CGRP may be an indirect measure of pain experienced. However, the effect of anti-NGF, anti-TrkA and anti-p75NTR administration on pain behaviours was not conducted in this study (Orita et al. 2010). More direct evidence for the efficacy of p75NTR inhibition has come from studies showing that p75NTR function blocking suppressed CGRP and p75NTR expression and significantly decreased pain behaviour in the form of mechanical allodynia in a mouse sciatic nerve crush model (Fukui et al. 2010) and mechanical hyperalgesia in a wrist joint inflammatory pain model without adverse effects (Iwakura et al. 2010).

Despite the success of molecules targeting TrkA and p75NTR for the control of pain in animal models, clinical trials are not yet underway. If drug development is to proceed, investigators will need to take account of the lack of selectivity associated with the Trk inhibitors and ARRY-470. ARRY-470 blocks TrkA, as well as with TrkB and TrkC (Ghilardi et al. 2010). This lack of selectivity for TrkA suggests possible adverse effects related to the inhibition of other kinases (Winston et al. 2003). These include hyperphagia and a large dose-dependent increase in weight in the animals and ataxia (in greater doses) that has been attributed to inhibition of BDNF/TrkB signalling (Unger et al. 2007). However, the non-selectivity of Trk inhibitor ARRY-470 was found to have no obvious effect on the density or function of sensory and sympathetic nerve fibres (Ghilardi et al. 2011). Although the antagonism of the NGF receptors may serve as future therapeutic options in the treatment of painful conditions, it will be important to develop strategies and compounds that target these receptors selectively. A cautious approach is advisable based on the clinical presentation of patients in HSAN type IV and type V; clearly disruption of TrkA signalling has more profound consequences for neurological function than disruption of NGF signalling.

NGF antagonism as a novel approach to clinical pain management

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

Substantial evidence that NGF is important in the mediation and potentiation of pain has led to the development of NGF antagonists as potential analgesics and anti-hyperalgesics (Watson et al. 2008). One form of NGF antagonism is through the use of anti-NGF antibodies. Anti-NGF antibodies act to sequester NGF and thus block NGF signalling in pain states. Administration of anti-NGF antibodies has been shown to provide effective analgesia in a number of animal models of human disease. These include arthritic joint pain (Ghilardi et al. 2012), femoral fracture pain (Koewler et al. 2007), cancer pain (Mantyh et al. 2010) and pancreatic pain (Zhu et al. 2011). To date, there have been a number of clinical trials focusing on the use of anti-NGF antibodies (or variants of them) run by Pfizer (NYSE: PFE) for RN624 (Tanezumab); Johnson and Johnson for JNJ-42160443, AMG-403 (Fulranumab); Regeneron Pharmaceuticals (Nasdaq: REGN) together with Sanofi-Aventis (Euronext: SAN) SNY) for REGN475/SAR164877 and AstraZeneca (LSE: AZN) for medi578 (Watson et al. 2008; Lane et al. 2010; Carey 2012; Garber 2012) (Table 1).

Table 1. Summary of the clinical trials involving anti-NGF therapy in human disease
ConditionAuthorNumber of patientsInclusion criteriaDeliveryDoseTime pointsPain reliefAdverse effects
Efficacy assessmentTrial endPercentage [DOWNWARDS ARROW] from baseline
OALane et al. (2010)444Knee OA according to ACRi.v. on day 1 & day 56Placebo or TNZ: 10, 25, 50, 100, 200 μg/kg16/5226/52

TNZ: 45–62%

Placebo: 22%

68% TNZ vs. 55% Placebo

- Headache

- URTI

- Paresthesia

Dose dependent

Mild-moderate

OASchnitzer et al. (2011)281Knee OA according to ACRi.v. on day 1 & day 56 + subsequent up to eight doses at 8-week intervalsTNZ: 50 μg/kg8/5256/52TNZ: 18%

7.5% of patients

- Hypoesthesia

- Paresthesia

- Hyperesthesia

- Peripheral neuropathy & sensory disturbance

Mild and resolved before completion of study

OANagashima et al. (2011)81Knee OA according to ACRi.v. on day 1Placebo or TNZ: 10, 25, 50, 100, 200 μg/kg8/52120/7

TNZ: 53–68%

Placebo: 33–38%

53.7% TNZ vs. 81.3% Placebo

- Allodynia

- Paresthesia

- Dysesthesia

-Thermohypoesthesia

Dose dependent

Mild-moderate and resolved without treatment

OABrown et al. (2012)690Knee OA according to ACRi.v. on day 1, 57 and 113Placebo or TNZ: 2.5, 5, 10 mg16/5232/52

TNZ: 51–62%

Placebo: 39%

60% TNZ vs. 48% Placebo

- Headache

- Paresthesia

Four joint replacements required for one person in each treatment group

LBPKatz et al. (2011)217Chronic LBP between T12 and gluteal fold requiring regular analgesic medicationi.v. on day 1Placebo or Naproxen 500 mg or TNZ: 200 μg/kg6/5212/52 Follow up: 16/52

TNZ: 52%

Naproxen: 37.3%

Placebo: 29%

30.7% TNZ vs. 18.2% Naproxen vs. 22.0% Placebo

- Headache

- Myalgia

- Dyesthesia

- Hyperesthesia

- Neuralgia

- Paresthesia

Resolved by completion of study

Interstital cystitis (IC)Evans et al. (2011)64Moderate – severe ≥ 13 on pelvic pain and urgency/frequency symptom questionnairei.v. on day 1Placebo or TNZ: 200 μg/kg6/5216/52

TNZ: 57%

Placebo: 35%

displayed a ≥ 30% reduction in pain score

TNZ: 36%

Placebo: 9%

displayed a ≥ 50% reduction in pain score

47% TNZ vs 40% Placebo

- Headache

- Paresthesia

Anti-NGF therapy: Tanezumab

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

Of the pharmacological agents developed to date, antibody therapeutics that block the interaction of NGF with its receptors have shown the most promise. Tanzeumab (formerly RN624) is a humanized IgG2 monoclonal antibody directed against NGF to which it binds with high affinity and specificity. As a result, Tanezumab blocks the interaction of NGF with its receptors TrkA and p75NTR (Abdiche et al. 2008).

Osteoarthritis

In 2005, NGF antagonism by Tanezumab was shown to provide effective anti-hyperalgesia in a model of chronic arthritis (Shelton et al. 1995). Pfizer Inc. adopted Tanezumab in 2006 and clinical trials followed. In a small phase I clinical trial, a single intravenous (i.v.) dose of Tanezumab decreased pain and improved function in patients with osteoarthritis (OA) of the knee (Lane et al. 2010). In 2010, Lane et al. subsequently performed a ‘proof of concept’ study in which the safety, adverse effects and analgesic efficacy of repeat treatments and various doses of Tanezumab for patients with moderate to severe OA knee were investigated. Tanezumab was administered at a dose of 10, 25, 50, 100, or 200 μg per kilogram (μg/kg) of body weight or placebo on days 1 and 56. Pain was assessed using a visual-analogue scale (VAS) that ranged from 0 to 100. Improvements in knee pain (45–62%), stiffness and limitations in physical function were reported over 16 weeks following treatment. Although this was not a formal ‘dose response’ study, greater improvements were associated with the greater doses administered of Tanezumab (100 or 200 μg/kg) than among those taking lower doses (25 μg/kg), with no clear benefit of the 200 μg dose over the 100 μg dose. Tanezemub therapy did not result in a significant increase in the proportion of patients who experienced adverse effects (68% and 55% in the Tanezumab and placebo groups respectively). However, the incidence of treatment related adverse events was greater among patients receiving greater doses (100 or 200 μg/kg) of Tanezumab (78% in those receiving 200 μg/kg) compared with patients receiving lesser doses (59% in those receiving 50 μg/kg). The most common adverse effects included headache 9% versus 3% (at greater doses), upper respiratory tract infection 7% versus 5% (URTI), paresthesia 7% versus 3% (Lane et al. 2010) (NCT00394563).

The study by Lane et al. (2010) was extended to evaluate the long-term safety and effectiveness of repeated doses of Tanezumab on OA knee pain. A phase II open-label clinical trial was performed over a 56-week period in 2011 (NCT00399490). All patients (n = 281) received infusions of Tanezumab at a dose of 50 μg/kg on day 1 and 56 with subsequent doses administered at 8-week intervals (up to a total of eight infusions). Pain intensity was assessed using a VAS scale. Patients demonstrated continued pain relief and improved function over 56 weeks as overall knee pain decreased from baseline by a mean (± standard error) of −12.8 (± 1.78) or by 18%. Repeated administration of Tanezumab resulted in a low incidence of treatment-related adverse effects (7.5%) and low severe adverse effects (2.8%). A few cases of abnormal peripheral sensation were reported. These included hypoesthesia (3.2%), paresthesia, (2.5%) and hyperesthesia, peripheral neuropathy and sensory disturbance (0.4% for each). Reports of abnormal peripheral sensation were rated as ‘mild’ by 95% of the patients and the majority (65%) resolved before study completion (Schnitzer et al. 2011).

Importantly, this study demonstrated the efficacy of Tanezumab therapy in maintaining pain relief over longer periods of time, without an increase in the incidence of adverse effects (although no active or placebo comparator was used). Furthermore, as this is a continuation of the earlier controlled study by Lane et al. 2010 and excluded any patients who experienced adverse effects during the earlier study, it is likely Schnitzer et al. 2011 under-represents the true incidence of adverse effects associated with longer term Tanezumab therapy.

In another study, a 32 week randomized double blind, placebo-controlled phase III clinical trial was conducted to compare the analgesic efficacy of Tanezemab versus placebo in patients (n = 690) with knee OA. Patients received 2.5, 5 or 10 mg of Tanezumab or placebo, and pain response was assessed using the Western Ontario and McMaster Osteoarthritis Index (WOMAC)/numerical rating scale (NRS) (1–10) scale. Compared with placebo, each Tanezumab dose produced significant improvements in pain from baseline to week 16 (p ≤ 0.015); treatment with Tanezumab 10 mg resulting in the largest differential (p < 0.001 vs. placebo). The incidence of adverse effects was greater in the Tanezumab groups; patients who received Tanezumab 10 mg experienced more adverse effects relative to those in other groups. Abnormal sensation was the most common adverse effect reported, in particular paresthesia (2–5%) and hypoesthesia (1–4%) in patients receiving Tanezumab. Finally, patients involved in the treatment groups of this study (n = 4) reported a total of five joint replacements of both the knee and hip. As the completion of this study, patients participating in phase III studies of OA of the hip and knee developed osteonecrosis, some of which resulted in the need for total joint replacement (discussed below) (Brown et al. 2012) (NCT00733902).

Chronic low back pain

Chronic low back pain (LBP) is designated as pain persisting in the lower back for greater than 3 months. A phase II, randomized, double-blind, placebo- and active (naproxen)-controlled trial was performed to evaluate the safety and efficacy of Tanezumab in patients suffering with LBP. In this trial, patients received a single i.v. dose of Tanezumab 200 μg/kg plus oral placebo (n = 88), i.v. placebo plus oral naproxen 500 mg twice a day (n = 88) or i.v. placebo plus oral placebo (n = 41). This study demonstrated that after week 6 of therapy, Tanezumab treatment resulted in a greater mean change in patients average LBP intensity (aLBPI) (−3.37) (52%) that was statistically significant compared with those in naproxen (−2.54; p = 0.004) (37.3%) and placebo groups (−1.96; p < 0.001) (29%). Tanezumab treated patients also had greater improvement in function, based on Roland Morris Disability Questionnaire results (Katz et al. 2011).

The incidence of treatment-related adverse events reported was greater in the Tanezumab group (30.7%) compared with the other treatment groups (18.2% and 22.0% for Naproxen and Placebo groups respectively). More than 5% of patients receiving Tanezumab reported arthralgia, headache, myalgia and hyperesthesia. Serious adverse effects were reported only in the naproxen group (2.3%) and included vasovagal and atrial fibrillation, but these were not believed to be related to the drug (Katz et al. 2011) (NCT00584870).

Interstitial cystitis

In Phase II proof of concept clinical trial of patients (n = 64) with interstitial cystitis (long-term, chronic inflammation of the bladder wall), patients in the treatment group (n = 34) received a single i.v. dose of 200 μg/kg Tanezumab. All patients were assessed over a 6-week period. Findings indicate an analgesic effect of Tanezumab superior to placebo with average daily pain score versus placebo [treatment difference (LS mean, 90% CI) was −1.4 (−2.2, −0.5)] estimated using a NRS (0–11) scale. Overall, 57% of patients on Tanezumab versus 25% of those on placebo had a 30% or greater reduction in pain score from baseline and 36% (Tanezumab) versus 9% (placebo) had a 50% or greater reduction. Not surprisingly, the other symptoms of cystitis were not affected. The commonest associated adverse effects were headache (20.6% vs. 16.7% in the placebo group) and paraesthesia (17.6% vs. 3.3% in the placebo group) (Evans et al. 2011) (NCT00999518). However, this was a small sample size and administration of treatment was via a single i.v. injection. Long-term safety, efficacy and possibly repeated dose studies are needed.

Chronic prostatitis and cancer

A phase II, 16 week, proof of concept study evaluating the efficacy and safety of Tanezumab for the treatment of pain associated with chronic prostatitis (infection of the prostate gland) has also been completed (NCT00826514). In addition, a Phase II trial to test the efficacy and safety of Tanezumab as add-on therapy to opioid medication in patients with pain because of bone metastases over a 16-week period was conducted (NCT00545129). No results have been officially reported for either of these trials. However, in spite of this, there is a study currently recruiting for a phase II open-label safety extension study of Tanezumab in cancer patients with pain because of bone metastases (NCT00830180).

Efficacy of Tanezumab therapy: the clinical trial evidence

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

All trials discussed demonstrate that Tanezumab treatment results in alleviation of pain (Lane et al. 2010; Evans et al. 2011; Katz et al. 2011; Schnitzer et al. 2011; Brown et al. 2012). A number of doses of Tanezumab have been investigated for both efficacy and safety. These include 10, 25, 50, 100 and 200 μg/kg. Although, not a formal ‘dose response’ study, Lane et al. 2010 found that greater improvements were associated with the greater doses administered (100 or 200 μg/kg) than among those taking lower doses (25 μg/kg), with no clear benefit of the 200 μg dose over the 100 μg dose. All trials demonstrated that the efficacy of Tanezumab treatment was superior to that of placebo treatment in all conditions. Administration of Tanezumab was effective in alleviating pain amongst OA patients to a greater extent than in patients with Interstitial Cystitis and LBP (Lane et al. 2010; Evans et al. 2011; Katz et al. 2011) (see Table 1.). Not surprisingly, outcome measures used varies amongst conditions, however, the outcome measure for pain as a primary end point is generally represented by a form of subjective scale and this scale maybe incorporated into a larger evaluation measure. For example, the Western Ontario and McMaster Osteoarthritis Index (WOMAC) measures pain, stiffness and functional limitation and is commonly used for evaluating patient conditions such as arthritis, back pain and fibromyalgia (Quintana et al. 2006). In the discussed studies, pain has been evaluated using either VAS (Schnitzer et al. 2011) or NRS (Brown et al. 2012). For both VAS and NRS, the greater the value reported indicates greater pain intensity. These subjective measures are more likely to accurately reflect within patient change over time (as applied in each of these trials) rather than point in time estimates across different patients.

It is not clear why Tanezumab is more effective in some pain conditions than in others, and any attempt to explain these differences is speculative. One interesting possibility is that nociceptive neurons innervating different regions may be differentially responsive to NGF. If this were the case, it might account for different degrees of pain relief achieved by Tanezumab administration in different conditions. The differential response to NGF is highlighted by studies examining peripheral innervation in NGF−/− mice (Glebova and Ginty 2004). These mice were also Bax−/− to ensure the survival of neurons and to study the direct effect of NGF on target innervation. Interestingly, the NGF−/−/Bax−/− mice displayed a heterogeneous requirement for NGF to establish of normal target innervation. Elimination of NGF results in complete absence of innervation in the submaxillary salivary gland, the parotid gland and the eye; drastically decreased innervation of the heart and lungs; decreased innervation of the spleen, stomach and kidney and only slightly decreased innervation of the trachea when compared with control (Glebova and Ginty 2004). These data suggest that in vivo, there are regional differences amongst neuronal populations in their responsiveness to NGF. If this situation existed in the pool of adult nociceptive neurons, it might explain the differing efficacy of NGF antagonism in different pain states.

With regard to duration of pain relief, following open label extension (Schnitzer et al. 2011) of the initial proof of concept study (Lane et al. 2010), pain relief was maintained for patients who retained equivalent treatment doses from the initial study. This indicates that pain relief with continued Tanezumab treatment can be maintained.

The efficacy of Tanezumab has been compared with active comparators in OA trials, including NSAIDS (Yazici et al. 2011) and controlled release oxycodone (Fidelholtz et al. 2011). In a phase III randomized, double blind, placebo and active controlled study, Tanezumab (two doses 10/5 mg in 8-week intervals) was compared with oxycodone (10–40 mg every hour). The primary endpoint was WOMAC pain subscale and the primary endpoint timing was 8 weeks (reduced from 16 weeks because of clinical hold by FDA, see later section). Tanezumab treated patients demonstrated improvement in pain (p < 0.001) compared with control and (p < 0.018) compared with those who received oxycodone. The efficacy of Tanezumab in alleviating hip OA pain was compared with that of combined NSAID and Tanezumab treatment or NSAID treatment alone in a Phase III study (Yazici et al. 2011). Patients received oral naproxen (500 mg twice per day), oral celecoxib (100 mg twice per day), Tanezumab (5/10 mg) every 8 weeks or Tanezumab (5/10 mg) every 8 weeks combined with naproxen (500 mg twice per day) or celecoxin (100 mg twice per day). The WOMAC Pain subscale was applied at week 16 and effects were evaluated up to week 56. Tanezumab alone resulted in greater improvement in pain relief compared with that achieved by either naproxen or celecoxin alone (p < 0.015).

Comparison of the adverse effects between the different trials

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

In all of the clinical trials to date, a number of adverse effects have been associated with the administration of Tanezumab. The incidence of these reported adverse effects were 55–68% in OA (Lane et al. 2010; Brown et al. 2012), 30% in LBP (Katz et al. 2011) and 47% in Interstitial Cystits (Evans et al. 2011). Of these adverse effects, ‘abnormal sensation’ appears to be the most commonly reported adverse effect in patients receiving Tanezumab in all the clinical trials to date (Lane et al. 2010; Evans et al. 2011; Katz et al. 2011; Schnitzer et al. 2011). The most commonly documented abnormal sensation is paresthesia which has been reported in 17.6% of patients in the Interstitial Cystitis trial, 4% in the LBP trial and between 1 and 7% of OA patients (Lane et al. 2010; Evans et al. 2011; Katz et al. 2011; Schnitzer et al. 2011). NGF is thought to act on small-diameter sensory afferent neurons; the occurrence of abnormal sensations such as paresthesia is associated with large-fibres sensory function suggesting a transient change in the sensitivity of different afferent fibre populations as discussed in detail elsewhere (Lane et al. 2010). The adverse effects associated with Tanezumab administration have been deemed to be mild to moderate in severity (Lane et al. 2010; Evans et al. 2011; Katz et al. 2011; Schnitzer et al. 2011). In a long-term study on the effect of Tanezumab treatment for OA pain with the primary focus on safety of Tanezumab administration in OA patients, only mild adverse effects were reported, all of which were resolved before the completion of the study (Schnitzer et al. 2011). An increase in adverse effects was associated with greater doses of Tanezumab dosage; however, this has only been assessed in OA trials (Lane et al. 2010; Brown et al. 2012). Adverse effects reported in Tanezumab treated groups in OA, Interstitial Cystitis and LBP trials have been comparable with those experienced by placebo groups in a number of trials (Lane et al. 2010; Evans et al. 2011; Katz et al. 2011) Adverse effects reported in a phase III trial were less frequent than those for a phase II trial in OA (Lane et al. 2010; Brown et al. 2012). In general, adverse effects reported were resolved by the completion of the studies (Katz et al. 2011; Schnitzer et al. 2011).

Compared with other treatments for pain, Tanezumab-associated adverse effects are similar or less in incidence than those associated with existing therapies. For example, a lesser proportion of patients treated with Tanezumab (40–44%) reported adverse effects compared with that of patients treated with clinically relevant doses of oxycodone (63%) (Fidelholtz et al. 2011). Adverse effects were reported by a greater proportion of patients who received Tanezumab alone (75%) or combined Tanezumab and NSAID (74%) compared with that of patients who received NSAID alone (68%). This has been attributed to longer treatment periods in the former groups. This contrasts with an earlier study that found no increase in AEs with longer treatment (Schnitzer et al. 2011).

Suspension of the clinical trials

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

Clinical trials have identified important limitations to the usefulness of NGF antagonism (or sequestration); its role is yet undefined. Following completion of the phase II clinical trial described above (Schnitzer et al. 2011), a number of Phase III clinical trials of Tanezumab in the management of pain in patients with OA of the knee was begun. In one of these trials, 16 patients developed progressively worse knee and hip osteoarthritis, with radiologic evidence of bone necrosis. A number of these patients required joint replacement. As a result, in December 2010, all Tanezumab clinical trials for the treatment of pain in knee osteoarthritis were suspended by the FDA (Schnitzer et al. 2011). Subsequently, clinical trials sponsored or supported by Regeneron/Sanofi Aventis and Johnson and Johnson investigating various anti-NGF antibodies in the treatment of pain were also halted (Garber 2012).

The cause of worsening osteoarthritis in some individuals during the Tanezumab trials is not fully elucidated. The sponsors all agree there is a signal linking the use of anti-NGF drugs and deterioration of the joints; they propose that this link is caused by patients using anti-NGF drugs in combination with NSAIDs and have recommended that patients not receive these categories of drugs in combination. In addition, lower doses and less frequent administration of anti-NGF agents as well as placebo were both associated with naturally progressing osteoarthritis; greater doses of anti-NGF drugs or concomitant use of an NSAID was linked to rapidly-progressing osteoarthritis as well as osteonecrosis (Carey 2012). One other possibility is that improved analgesia resulted in patients using the joints without the benefit of acute warning pain. Conceivably, this could lead to greater rate of degenerative change in the joint(s); it is not clear how this could cause bone necrosis. It has also been proposed that anti-NGF therapy may have had a direct affect on bone maintenance. This theory is not consistent with prior study which demonstrated that anti-NGF treatment (although not specifically Tanezumab) did not affect the biomechanical properties of the femur or histomorphometric indices of bone healing (Koewler et al. 2007).

Studies involving the use of Tanezumab in the treatment of OA knee pain have continued in Japan. Results of a preliminary phase II clinical trial of Tanezumab in the management of OA knee pain indicate that the incidence of adverse effects is low; these include allodynia; paresthesia; dysesthesia; thermohypoesthesia all of which were mild to moderate in severity and transient in nature (Nagashima et al. 2011). These findings are consistent with the earlier studies of Schnitzer et al. 2011.

Resumption of the clinical trials

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

In March, 2012, a panel of independent arthritis experts recommended that the FDA allow pharmaceutical companies to restart clinical trials of anti-NGF therapy provided safety measures are put in place. The Arthritis Advisory Committee stressed that anti-NGFs should not be taken with other drugs such as NSAIDs in subsequent trials. Clinical trial participants should be adequately informed of the potential risks. Throughout the studies, participants should be regularly monitored for bone health by imaging scans such as X-rays and MRIs. Recommendations also called for testing anti-NGF drugs in patients with no other options for analgesics, including patients with interstitial cystitis and chronic pancreatitis (Carey 2012).

Given the evidence to date, it appears that the principal determinant of the usefulness of Tanezumab in management of chronic painful conditions will be its long-term safety profile. Its promise as an effective analgesic in patients with OA may be realized through improved risk stratification for specific patient groups or identification of a regimen which is not associated with bone necrosis or disease acceleration. Overall, the development of monoclonal antibodies for therapeutic purposes offers great potential arising from their specificity, and often favourable, predictable pharmacokinetics. However, selective antagonism of a mediator in a complex biological system must be expected to reveal both redundancy and reactive responses which may limit its therapeutic potential.

Conclusions and future perspectives

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References

NGF antagonism offers the potential to improve on currently available analgesic therapies. The outcomes of clinical trials of Tanezumab which are currently underway, in particular those related progression of arthritis or osteonecrosis, are the next important determinant of whether and when that potential will be realized. In the event that Tanezumab is shown to have an acceptable long-term safety profile, certain standard ‘characterisation’ questions will be addressed: which patients and conditions will benefit and from which regimen? Which combinations of analgesic therapies should include an NGF (or NGF receptor) antagonist? One important question which could be overlooked is: What role will NGF antagonism have in non-inflamed or pain free humans (such as prior to elective surgery or in the very early pre-clinical stages of an inflammatory disease)? Harm can result when sensory thresholds are decreased below baseline; perhaps the neuroplastic changes associated with pain persistence are amenable to prevention through ‘pre-emptive’ NGF antagonism? The ultimate role of Tanezumab in pain management of patients with chronic conditions may depend on a greater understanding of its distinct effects on symptom control (i.e. analgesia) versus disease modification (pain chronicization or persistence) (Woolf 2000).

References

  1. Top of page
  2. Abstract
  3. NGF overview
  4. NGF and pain
  5. Genetic mutations in the NGF and TrkA genes result in a loss of pain perception
  6. Potential intervention strategies: NGF versus TrKA versus p75
  7. NGF antagonism as a novel approach to clinical pain management
  8. Anti-NGF therapy: Tanezumab
  9. Efficacy of Tanezumab therapy: the clinical trial evidence
  10. Comparison of the adverse effects between the different trials
  11. Suspension of the clinical trials
  12. Resumption of the clinical trials
  13. Conclusions and future perspectives
  14. Acknowledgements
  15. Authors contributions
  16. References
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