Identification and validation of nerve growth factor as a peripheral pain mediator
Submitting Institution
King's College LondonUnit of Assessment
Biological SciencesSummary Impact Type
TechnologicalResearch Subject Area(s)
Medical and Health Sciences: Neurosciences, Pharmacology and Pharmaceutical Sciences
Summary of the impact
There a great need to develop novel drugs to treat pain and in particular
chronic pain. Scientists at King's College London (KCL) identified nerve
growth factor (NGF) as an important mediator of persistent pain and
validated it as a therapeutic target by demonstrating the beneficial
effects of neutralising its activity using biological reagents in a number
of animal models. The KCL team collaborated closely with the scientists at
Genentech who went on to develop a neutralising antibody to NGF for the
treatment of pain. This drug has been found to exhibit unprecedented
efficacy in phase III trials in man and is currently being considered for
registration. Their discovery has also led to several other major
pharmaceutical companies initiating drug discovery programs in this area
and has contributed to the subject area of pain management.
Underpinning research
Chronic pain remains a major unmet medical need affecting around 20% of
Europeans with a considerable socio-economic burden due to both cost of
therapy and loss of working hours. Pharmacological treatment of chronic
pain is focussed around two major classes of drug — opiates and
non-steroid anti-inflammatory agents — both of which have significant side
effects and limited long-term efficacy. Research into new pain-relieving
compounds has been led at King's College London (KCL) by Prof Steve
McMahon (1984-present, Sherrington Professor of Physiology) supported by
several colleagues including Dr Dave Bennett (2006-12, Wellcome Trust
Fellow) and Dr John Priestley (at KCL until 1999).
Following early work on the influences of peripheral tissues on the
properties of their sensory innervation, KCL scientists hypothesised that
nerve growth factor (NGF), which at this point was largely viewed as a
molecule with only beneficial properties, acted as a peripheral pain
mediator in a number of chronic pain states. This ground-breaking
hypothesis was rigorously tested by the KCL team with the key results
published in a number of high impact papers.
Following development by the biotechnology company Genentech in 1994 of a
NGF knockout mouse, KCL scientists demonstrated that these animals failed
to respond to noxious mechanical stimuli. This provided the first clue
that NGF might be a pain mediator (Crowley C, et al. Cell. 1994). This
could have been interpreted as reflecting a role for NGF solely in the
development of pain sensing neurons, especially as in-utero up to
80% of dorsal root ganglion (DRG) cells are dependent on NGF for their
survival. However, a number of breakthrough studies by KCL showed that the
high-affinity NGF receptor TrkA was expressed on pain sensing neurons in
adult animals. For instance, in the rat, TrkA was found to be expressed by
a very high percentage of visceral afferents of DRG neurons (McMahon S, et
al. Neuron, 1994; Bennett, DL et al. Eur J Neurosci, 1996) and in cells in
the dorsal horn of the spinal cord (Averil S, et al. Eur J Neurosci,
1995). This indicated an ongoing function for NGF as opposed to a role
restricted to development.
The next major breakthrough came when KCL scientists showed that
administration of NGF can induce pain. Studies with adult rats found that
single intradermal injections of doses over 250 ng of human recombinant
NGF into the hindpaw led to a prolonged thermal hyperalgesia to radiant
heat, suggesting activation and sensitization of cutaneous nociceptors
(Andreev N, et al. Eur J Neurosci, 1995). Together with collaborators at
Genentech these observations led to seminal studies demonstrating that
endogenous NGF could be neutralised by administration of a TrkA-IgG fusion
molecule (a biological molecule that directly binds NGF and prevents its
action). They also found that neutralisation of endogenous NGF reduced
abnormal pain sensitivity in a variety of models of pain, particularly
those associated with peripheral inflammation. For instance, in one study,
administration of TrkA-IgG to cultured sensory neurons produced a
sustained thermal and chemical hypoalgesia and led to a downregulation of
the sensory neuropeptide calcitonin gene-related peptide. Acute
administration of TrkA-IgG also blocked the hyperalgesia that normally
develops with carrageenan-induced inflammation (McMahon S, et al. Nature
Med, 1995). Another study used an in vitro rat skin nerve
preparation in which carrageenan administration produced a marked increase
in the proportion of nociceptors displaying ongoing activity and
spontaneously active fibres were sensitized to heat. Here, when TrkA-IgG
was coadministered with carrageenan at the onset of inflammation, primary
afferent nociceptors did not sensitize and displayed essentially normal
response properties (Koltzenburg M, et al. Eur J Neurosci, 1999).
References to the research
• Andreev N, Dimitrieva N, Koltzenburg M, McMahon SB. Peripheral
administration of nerve growth factor in the adult rat produces a thermal
hyperalgesia that requires the presence of sympathetic post-ganglionic
neurones. Pain 1995;63:109-15. http://dx.doi.org/10.1016/0304-3959
(95)00024-M(137 Scopus citations)
• Averill S, McMahon SB, Clary DO, Reichardt LF, Priestley JV.
Immunocytochemical localization of trkA receptors in chemically identified
subgroups of adult rat sensory neurons. Eur J Neurosci 1995;7:1484-94.
Doi: 10.1111/j.1460-9568.1995.tb01143.x (422 Scopus citations)
• Bennett DL, Averill S, Clary DO, Priestley JV, McMahon SB. Postnatal
changes in the expression of the trkA high-affinity NGF receptor in
primary sensory neurons. Eur J Neurosci 1996;8:2204-8. Doi:
10.1111/j.1460-9568.1996.tb00742.x (106 Scopus citations)
• Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts-Meek S, Armanini
MP, Ling LH, McMahon SB, Shelton DL, Levinson AD, et al. Mice lacking
nerve growth factor display perinatal loss of sensory and sympathetic
neurons yet develop basal forebrain cholinergic neurons. Cell 1994;
76:1001-11. Doi: 10.1016/0092-8674(94)90378-6 (Scopus citations 614)
• Koltzenburg M, Bennett DL, Shelton DL, McMahon SB. Neutralization of
endogenous NGF prevents the sensitization of nociceptors supplying
inflamed skin. Eur J Neurosci 1999;11:1698-704. Doi:
10.1046/j.1460-9568.1999.00590.x (122 Scopus citations)
• McMahon SB, Armanini MP, Ling LH, Phillips HS. Expression and
co-expression of Trk receptors in subpopulations of adult primary sensory
neurons projecting to identified peripheral targets. Neuron
1994;12:1161-71. Doi: 10.1016/0896-6273(94)90323-9 (385 Scopus citations)
• McMahon SB, Bennett DL, Priestley JV, Shelton DL. The biological
effects of endogenous nerve growth factor on adult sensory neurons
revealed by a trkA-IgG fusion molecule. Nature Med 1995;1:774-80. Doi:
doi:10.1038/nm0895-774 (Scopus citations 285)
Grants supporting this work
• 1993-1998. PIs: SB McMahon, J Priestley, M Rattray. Neurotrophins and
the maintenance and repair of sensory neurones: normal role and
therapeutic implications. Medical Research Council, £728,500.
• 1999-2003. PIs: SB McMahon, M Malcangio. Trophic factor regulation of
synaptic efficacy of primary sensory neurons' Wellcome Trust, £381,900
• 1999-2004. PIs: SB McMahon, J Priestley. Trophic regulation of pain
signalling systems in the adult. Wellcome Trust Ref, £794,900
• 2001-2004. PI: SB McMahon. Mechanisms of neuropathic sensory disorders
and their regulation by neurotrophic factors. Wellcome Trust, £79,300
Details of the impact
KCL research leads to the development of tanezumab
King's College London (KCL) scientists contributed to the identification
and validation of nerve growth factor (NGF) as a peripheral pain mediator.
Collaborative work with Genentech led to this San Francisco-based
biotechnology company developing a neutralising antibody to NGF for the
treatment of pain: tanezumab (RN-624). Genentech established as spinout
company — Rinat — to take tanezumab forward and in 2006 the drug was
acquired by the pharmaceutical company Pfizer. Pfizer have invested
heavily in tanezumab and sponsored a large number of Phase II and III
clinical trials involving over 10,000 patients for a variety of conditions
including osteoarthritis (OA) pain, low back pain and visceral pain. The
successful results of these trials have been published in a number of
peer-reviewed journals. For example, Phase II and III trials using
tanezumab to reduce joint pain and improve function in people with OA of
the knee, involving 450 and 690 people respectively, have shown superior
analgesic efficacy of tanezumab compared to a placebo. These studies also
showed that tanezumab was well tolerated, something essential in pain
management therapy as current treatment options can be limited by their
adverse event profiles (1a,b). Both of these papers draw on KCL research
when discussing the background to the discovery of the role of NGF in
causing or augmenting pain, including McMahon 1995 and a 1996 review of
NGF by McMahon that includes the early studies detailed above (1c).
More recently tanezumab has been shown to be an effective treatment for
OA hip pain in a trial involving over 600 patients that used McMahon's
2006 review to paint the background of tanezumab's development (1d). Other
studies, involving over 1500 patients in total and citing Andreev 1995
when discussing how NGF administration results in hyperalgesia, have shown
tanezumab to be safe and efficacious in the treatment of chronic low back
pain (1e,f). The contribution of KCL work to the development of tanezumab
is also reflected in the inclusion of this research in a number of
patents. For instance, Crowley 1994 is one of the first references cited
in two of Pfizer's patents for anti-NGF antibodies, published in 2009 (1g)
and 2010 (1h). The second of these also cites Andreev 1995, McMahon 1995
and McMahon's 1996 review.
KCL research spurs development of other NGF-blocking compounds
Since the trials of tanezumab established the translatability of the
preclinical work pioneered at KCL several other companies have invested
heavily in clinical trials for compounds blocking NGF's actions. For
instance, PG110 (ABT-110) a humanized mAb developed by the company
PanGenetics, was acquired in 2009 by Abbott Labs for $190 million (2a).
The patent for this product cites the majority of the above-discussed KCL
studies as well as McMahon's 1996 review (2b). Other NGF products in
development include fulranumab, a fully human mAb by Amgen for OA pain
(2c); fasinumab, a fully human mAb by Regeneron/Sanofi-Aventis (2d) and
MEDI-578, a monoclonal single chain variable fragment for OA of the knee
by Medimmune/AstraZenica (2e). This reflects considerable investment by
each company in the first important new class of drugs for general pain
for around 100 years.
Following reports that a small number of OA patients in these trials
needed early joint replacement, the FDA recently halted all trials of NGF
blockers and reviewed the data to assess potential side effects of the
treatments. Subsequently their Arthritis Drugs Advisory Committee voted
21-0 that anti-NGF agents should continue to be developed to treat OA
pain. The panel also voted 20-1 that anti-NGFs should be studied in
indications for which there are no products with demonstrated analgesic
efficacy, such as interstitial cystitis or chronic pancreatitis. The green
light was given based on the fact that this is an entirely new and very
effective treatment for pain and many studies have resumed (2f).
KCL studies impact knowledge of pain therapy
NGF blocking agents have been heralded as the `next big thing' in pain
management in several recent reviews that cite KCL research when
discussing the background to their development (e.g. 3a,b). Research from
KCL is also highly cited in the book `The Senses: A Comprehensive
Reference' in chapters about `Pharmacological Modulation of Pain' (citing
Andreev 1995) and `Neurotrophins and Pain' (citing the majority of studies
discussed above), among others (3c) and in `The Human Nervous System,' the
standard reference book for the anatomy of the central and peripheral
nervous system, in the chapter on `Pain Systems' (citing Averill 1995,
Bennett 1996, McMahon 1994) (3d).
Sources to corroborate the impact
1. KCL research leads to the development of tanezumab
a. Lane NE, et al. Tanezumab for the treatment of pain from
osteoarthritis of the knee. N Engl J Med 2010:363:1521-531. Doi:
10.1056/NEJMoa0901510
b. Brown MT, et al. Tanezumab reduces osteoarthritic knee pain: results
of a randomized, double-blind, placebo-controlled phase III trial. J Pain
2012;13(8):790-98. Doi: 10.1016/j.jpain.2012.05.006
c. McMahon SB. NGF as a mediator of inflammatory pain. Philos Trans R Soc
Lond B Biol Sci 1996;351:431-40: http://rstb.royalsocietypublishing.org/content/351/1338/431.long
d. Brown MT, et al. Tanezumab reduces osteoarthritic hip pain: results of
a randomized, double-blind, placebo-controlled phase III trial. Arthritis
Rheum 2013; 7:1795-1803. Doi: 10.1002/art.37950
e. Kivitz AJ, et al. Efficacy and safety of tanezumab versus naproxen in
the treatment of chronic low back pain. Pain 2013;154:1009-21. Doi.
10.1016/j.pain.2013.03.006
f. Katz N, et al. Efficacy and safety of tanezumab in the treatment of
chronic low back pain. Pain 2011; 152:2248-2258. Doi.
10.1016/j.pain.2011.05.003
g. Patent: Anti-NGF antibodies and methods using same. US 7569364 B2.
Original Assignee: Pfizer Inc. Publication date: 4.8.2009: http://www.google.com/patents/US7569364
h. Patent: Anti-NGF antibodies and methods using same US 7655232 B2.
Original Assignee: Pfizer Inc. Publication date: 2.2.2010: https://www.google.com/patents/US7655232
2. KCL research spurs development of other NGF-blocking compounds
a. ABT-110:
http://www.streetinsider.com/Corporate+News/Abbott+Labs+(ABT)+PanGenetics+BVs+PG110+F
ully+Humanized+Antibody+for+$170M+Plus+Milestones/5100451.html
b. Patent. Method for the treatment of pain with humanized anti-nerve
growth factor antibodies. US 8257710 B2. Original Assignee: Abbot Research
B.B. Publication date: 4.9.2012:
https://www.google.com/patents/US8257710?dq=US08257710&hl=en&sa=X&ei=MJdzUpqTBtGq
hQfnzoHYBQ&ved=0CDkQ6AEwAA
c. Fulranumab: Sanga P, et al. Efficacy, safety, and tolerability of
fulranumab, an anti-nerve growth factor antibody, in the treatment of
patients with moderate to severe osteoarthritis pain. Pain
2013;154(10):1910-9. Epub 2013 Jun 5. Doi: 10.1016/j.pain.2013.05.051.
d. Fasinumab: http://www.regeneron.com/regn475
e. MEDI-578:
http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D2460C00001_C
f. FDA decision:
http://www.painresearchforum.org/news/14439-fda-gives-green-light-restart-ngf-antibody-trials
3. KCL studies impact knowledge of pain therapy
a. Kumar V, Mahal BA. NGF — the TrkA to successful pain treatment. J Pain
Res 2012;5:279- 87. Doi: 10.2147/JPR.S33408.
b. Chessell IP, et al. Biologics: the next generation of analgesic drugs?
Drug Discov Today 2012;17(15-16):875-9. Doi: 10.1016/j.drudis.2012.03.005
c. The Senses: A Comprehensive Reference, Six-Volume Set. Bushnell CM, et
al (Eds).
- Dray A. Pharmacological Modulation of Pain. Volume 5;2010;795-819.
Doi: 10.1016/B978-012370880-9.00196-1
- Mendell LM. Neurotrophins and Pain. Volume 5;2010;259-278.
10.1016/B978-012370880-9.00161-4
d. The Human Nervous System. Third edition. Mai JK, Paxinos G (Eds). Chpt
32. Westlund KN, Willis WD. Pain System. Academic Press. (November 28,
2011) ISBN-10: 0123742366