Anti-nerve growth factor in pain management: current evidence

Figures & data

Figure 1 Schematic diagram of the NGF mechanisms involved in the initiation and maintenance of pain.

Note: Drawing courtesy of Caitlin Hottinger.
Abbreviations: 5-HT, 5-hydroxytryptamine; ASIC3, acid-sensing ion channel 3; BDNF, brain-derived neurotrophic factor; BR₂, bradykinin receptor 2; Ca_v, voltage-gated calcium channel; CGRP, calcitonin gene-related peptide; CGRP-R, calcitonin gene-related peptide receptor; DRG, dorsal root ganglia; IL-1, interleukin 1; K, delayed-rectifier potassium channel; Na_v, voltage-gated sodium channel; NGF, nerve growth factor; NK-1, neurokinin 1 receptor; p75, neurotrophin receptor; SP, substance P; TNF-α, tumor necrosis factor alpha; trkA, tropomyosin receptor kinase A; trkB, tropomyosin receptor kinase B; TRPV1, transient receptor potential cation channel subfamily V member 1 receptor.

Table 1 Summary of evidence: monoclonal anti-NGF antibodies

Compound	Summary of evidence
	OA	CLBP	DN and PHN	Visceral pain	Cancer pain
Tanezumab	Strong evidence of efficacy, shown to be superior to active controls (NSAID and opioids); long-term safety study in active recruitment phase	In patients with nonradiculopathic CLBP, higher dose range (10 mg and 20 mg) demonstrated efficacy and superiority to naproxen	Single study in DN demonstrated efficacy at 20 mg dose; single study in PHN failed to demonstrate efficacy	In patients with interstitial cystitis, single dose improved pain and reduced urgency; in patients with chronic prostatitis/chronic pelvic pain syndrome, neither pain nor urgency reached significance	Single 10 mg dose did not achieve significance, but treatment continued up to 40 weeks demonstrated pain below baseline levels; post hoc analysis suggested that lower baseline opioid use and/or greater baseline pain was predictive of benefit
Fulranumab	Strong evidence of efficacy; in need of long-term safety study due to concern for rapidly progressive OA	In patients with nonradiculopathic CLBP, it was not superior to placebo in single Phase II trial	Single study in DN demonstrated dose–response relationship and efficacy only at highest dose (10 mg)
Fasinumab	Strong evidence of efficacy; in need of long-term safety study due to concern for rapidly progressive OA	A single study in which patients with sciatic pain demonstrated no benefit

Abbreviations: CLBP, chronic low back pain; DN, diabetic neuropathy; NGF, nerve growth factor; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; PHN, postherpetic neuralgia.

Table 2 Summary of evidence: NGF–trkA binding inhibitors and trkA inhibitors

Compound	Mechanism of action	Summary of evidence
MNAC13	Monoclonal anti-trkA antibody	Analgesia in mouse models of inflammatory and neuropathic pain; possible synergistic effect with opioids; mouse antibody with no equivalent humanized antibody
ALE0540	NGF inhibitor, prevents NGF binding to both trkA and p75	Reduces pain behavior in animal models of neuropathic pain; deemed unsuitable for clinical trial due to lack of specificity
K252a	Protein kinase inhibitor, inhibits trkA, trkB, and trkC	Reverses mechanical hypersensitivity in model of acute necrotizing pancreatitis; deemed unsuitable for clinical trial due to lack of specificity

Abbreviations: NGF, nerve growth factor; p75, neurotrophin receptor; trkA, tropomyosin receptor kinase A; trkB, tropomyosin receptor kinase B; trkC, tropomyosin receptor kinase C.