Managing OA with anti-NGF therapyIn adult mammals, nerve growth factor and its interaction with its receptors plays an important role in nociception November 22, 2019 By B. Duncan X. Lascelles, BSc, BVSC, PhD, FRCVS, CertVA, DSAS (ST), Diplomate ECVS, Diplomate ACVSFigure 1: Osteoarthritis-associated pain is extremely common in cats and yet, in the U.S., there are no approved therapeutics to treat it. It is clear to any practicing veterinarian there is a very limited toolbox when it comes to effective treatments for osteoarthritis (OA) pain in dogs and cats. The need, however, is quite apparent. In dogs, osteoarthritis (OA) is most commonly caused by developmental disease, meaning the disease process begins at a very young age and is lifelong, with at least 30 to 40 percent of dogs affected clinically.1,2 Although the etiology in cats is less well understood, recent clinical data indicates approximately 90 percent have radiographic signs of OA,3 and about half of these have clinical signs of pain associated with this joint disease.4 In the U.S., the only drugs approved for the alleviation of clinical signs associated with OA pain in dogs are nonsteroidal anti-inflammatory drugs (NSAIDs), which traditionally comprise cyclooxygenase- (COX-) inhibiting and non-COX inhibiting prostaglandin E2 (PGE2) receptor antagonists and an injectable that is approved for the mitigation of clinical signs of OA. For cats, there are no drugs approved for the alleviation of OA pain. Compounding the problem of this sparse toolbox is very limited clinical evidence for efficacy of other drugs or therapies. For example, anti-epileptic drugs are widely used to treat OA pain in dogs, yet there are no published studies evaluating their efficacy, let alone any demonstrating they are an effective analgesic. Searching for effective pain control targets Despite the great need for new, safe, and effective therapeutics, finding a single target that makes an important difference to the pain experience is challenging because there is so much redundancy in the pain transmission system. However, over the last 25 years, researchers have identified nerve growth factor (NGF) as such a target, concluding it plays a critically important role in the generation of pain signals in disease states. As a result, inhibiting NGF’s action has been shown to produce a dramatic reduction in pain. What is NGF? Nerve growth factor was originally discovered as a neurotrophic factor (NTF) essential for the survival of sensory and sympathetic neurons during development.5 However, in the adult mammal, NGF and its interaction with its receptors (tropomyosin receptor kinase A receptor [TrkA], and the p75 neurotrophin receptor [p75NTR]) has been found to play a very important role in nociception (i.e. the sensory nervous system’s response to harmful or potentially harmful stimuli). Preclinical and clinical research over the past several decades has demonstrated clearly the important role of NGF in nociceptor sensitization in a wide variety of both acute and chronic pain states, including postoperative and OA pain.5-8 NGF appears to play a particularly important role in OA pain,5 as it is released from damaged joint tissues, as well as inflammatory/immune cells. NGF is a key molecule in the sensitization of primary afferent nociceptors (pain-sensing fibers). In this respect, NGF can be considered to be similar to PGE2, which also produces nociceptor sensitization. Both play a role in the sensitization of nerves following injury, which is the fundamental protective effect of pain. However, NGF not only sensitizes nerve fibers, it also changes the number of “pain receptors” and the amount of “pain neurotransmitters” primary afferent fibers express (Figure 1). Through these effects, NGF produces pain and contributes to inflammation. Preventing the actions of NGF Locally produced NGF contributes to pain and inflammation in arthritic joints. Capturing free nerve growth factor by using monoclonal antibodies against NGF (anti-NGF mAbs) has emerged as an effective way of preventing the actions of NGF and decreasing pain. Across multiple species, and both preclinical and clinical research, there is strong evidence of robust analgesic effects resulting from using anti-NGF mAbs. Interestingly, in both rodent studies9 and clinical studies in humans,10 the analgesic effects of anti-NGF mAbs has been repeatedly found to be greater than that of comparator NSAIDs. Monoclonal antibodies are biologics (i.e. proteins). As such, they need to be species-specific to prevent a neutralizing immune response. These antibodies are very specific in their actions, reducing off-target side effects. They are catabolized within cells into amino acids and peptides and, therefore, are not metabolized in the liver or kidneys, converted into reactive or toxic metabolites, or excreted in urine. Thus, monoclonal antibodies are highly unlikely to induce liver or kidney toxicity. Clinical evidence for efficacy of anti-NGF mAbs Anti-NGF mAbs have recently been developed for the management of OA-associated pain in dogs and cats, and the first clinical trials have been conducted. The studies show these anti-NGF mAbs produce a dramatic reduction in pain and are very well-tolerated.11-15 Given as a single injection, the efficacy of anti-NGF mAbs appears to last approximately four to six weeks and the magnitude of effect appears equal to, or greater than, that of NSAIDs. Keep in mind these clinical trials have been relatively small and are simply proof of concept studies. More in-depth studies are in the works, but no information is available at this time. Figure 2: Using activity-monitoring devices attached to the collar of dogs and cats, researchers can monitor the effects of an analgesic therapeutic on normal activity in the home environment. Recent work has shown elevated levels of NGF in synovial fluid in dogs with naturally occurring OA compared to healthy joints.16 The first clinical work published that explored the analgesic effect of an anti-NGF mAb was a randomized and double-blind study where all dogs received a canine-specific anti-NGF mAb (ranevetmab).15 In an innovative trial, nine dogs with OA received a single injection of ranevetmab during the 10 weeks of study period (either at the start, two weeks, or four weeks into the study), with owners blinded to the time of injection. The dogs were evaluated every two weeks for six weeks following injection, with significantly lower owner-assessed pain and disability seen compared with baseline scores until four weeks after treatment. The following year, a randomized, double-blind, placebo-controlled clinical proof of concept study in 26 dogs evaluating the efficacy of a single IV injection was published.14 This study found the dogs that received the single IV injection had significant improvement based on owners’ assessments. Further, their activity had significantly increased as measured by an activity monitor attached to their collar (Figure 2) compared to a placebo over a four-week period. The data suggested the positive effects were greater than what would have been expected with an NSAID. Clinical trials for chronic pain in cats have been hampered by the large caregiver placebo effect,17 making it very difficult to see beneficial outcomes of putative analgesics. However, a clinical proof of concept trial of a feline-specific version of an anti-NGF mAb (frunevetmab), showed dramatically positive results.13 One subcutaneous injection of frunevetmab produced positive treatment effects lasting up to six weeks in cats with OA-associated pain. The positive effects, measured by owner assessments and activity monitors, were greater than has been seen with NSAIDs. Further, this work was the first published clinical study where owners had been able to distinguish the difference between a therapeutic and placebo in a parallel group design. Side effects of anti-NGF therapy No significant adverse events associated with treatment have been reported in dogs and cats in the published research; however, the studies so far have been relatively small. The development programs for anti-NGF mAbs in humans have shown that approximately 1.3 percent of humans taking anti-NGF mAbs experience rapidly progressing osteoarthritis (RPOA) in one joint. This effect is more pronounced following higher doses and concomitant use with NSAIDs. RPOA is not described in the veterinary literature, and it has not been seen in the clinical studies performed to date. Figure 3: Clinical studies are a vital part of improving patient care in practice. Here, the author is “gaiting” a dog across a force plate to measure limb use precisely. NGF is important for the phenotypic maintenance of neurons in the peripheral nervous system (PNS) and for the functional integrity of cholinergic neurons in the central nervous system (CNS).18 A specific role of NGF has been proposed for the cholinergic neuron population of the CNS.19 However, with respect to potential side effects of anti-NGF mAbs, it is important to remember anti-NGF monoclonal antibodies are confined to the periphery because of the blood–brain barrier (BBB). NGF is produced and utilized by several cell types, including structural (e.g. epithelial cells and endothelial cells), accessory (e.g. glial cells and astrocytes), and immune cells (e.g. lymphocytes and mast cells).18 During the last two decades, evidence has been accumulated supporting the hypothesis that NGF possesses potential therapeutic properties on tissue healing (cutaneous and corneal ulcers), cardiomyopathy, and myocardial ischemia.18 Conclusion Anti-NGF mAb therapy is considered one of the most important advances in several decades in the pain therapeutics field in human medicine, even though they are not yet available for this use. Single injections of species-specific anti-NGF mAbs have produced four to six weeks of significant and clinically meaningful reductions in pain and disability in cats and dogs. Anti-NGF mAb therapy appears a very promising pharmacological pain management option, with a single injection potentially providing several weeks of pain relief. Further work (Figure 3) will help define the therapeutic profile of this new class of analgesic, and also shed light on potential adverse effects. Hopefully, the next few years will see this new therapeutic class of analgesic enter clinical practice, and clinical data be generated to guide clinicians on how to most effectively and safely use it. Duncan X. Lascelles, BSc, BVSC, PhD, FRCVS, CertVA, DSAS (ST), Diplomate ECVS, Diplomate ACVS, is professor in small animal surgery and pain management at North Carolina State University. His research program, Translational Research in Pain (TRiP), develops methods to measure pain associated with spontaneous disease in animals, and seeks to understand the underlying neurobiology. Dr. Lascelles’ work improves pain control in companion animals and facilitates analgesic development in human medicine. He is director of the Comparative Pain Research and Education Centre (CPREC). 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