Earlier this year, veterinarians in the United States finally gained access to a synthetic, feline-specific, monoclonal antibody (mAB) drug designed to treat osteoarthritis pain in cats. Administered as a once-monthly injection, frunevetmab binds to a neurotrophin called nerve growth factor (NGF), a protein found in heightened amounts in painful, arthritic joints.¹ By keeping NGF from binding to its receptors, frunevetmab limits its ability to issue nociceptive signals to the spinal cord and brain.

For well over a decade, human pharmaceutical companies invested billions of dollars into drug development, engineering mABs to render NGF inactive. If successful, they would have brought a drug to market that treated pain and reduced reliance on nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids.² Ultimately, they failed, mainly because the risks of blocking NGF throughout the body seemed too high. However, in January 2022, the manufacturer of a feline version succeeded and now awaits approval for its canine counterpart.³

The suppressive approach to NGF may have consequences, unfortunately. NGF mediates crosstalk between the nervous system and immune function. In so doing, NGF serves to both initiate and resolve inflammation. Under normal conditions, the acute inflammatory phase shifts to an active resolution process in which NGF participates.⁴ By disturbing regulatory feedback mechanisms, antiNGF mAB drugs could hypothetically worsen chronic inflammatory states.

If causing pain was the only job NGF did, then stopping it sounds reasonable. But it is not that simple. NGF exists in every peripheral tissue and organ supplied by sensory afferent and/or sympathetic efferent fibers, as well as central and peripheral nervous system and immune cells.⁵ In the brain, NGF supports the survival and function of neurons in centers typically afflicted by neurodegenerative disorders, highlighting its potential therapeutic value for cognitive dysfunction. Along with insulin, NGF plays a vital, autoregulatory role in pancreatic beta-cell survival and function.⁶ NGF also regulates activity in the hypothalamus and brainstem – specifically assisting with modulating autonomic responses to stress and maintaining physiologic homeostasis.

NGF supports tissue healing in many types of cells, including epithelial cells, fibroblasts, myofibroblasts, endothelial cells, smooth muscle cells, glial cells, astrocytes, and hepatocytes.⁷ Therapeutically, NGF assists in treating human cutaneous and corneal ulcers, pressure sores, maculopathy, retinitis pigmentosa, and glaucoma. Potential future applications span the gamut from Alzheimer's disease and myocardial infarction to spinal cord injury. Given the physiologic impact and benefits of NGF, what downsides might arise from antagonizing its effects, in small animals and over time? We do not fully know.

Nevertheless, in 2022, the American Animal Hospital Association (AAHA) published Pain Management Guidelines for Dogs and Cats. Its authors highlighted antiNGF mAB drugs as one of the "go to" approaches for chronic pain.⁸ They produced a "tiered decision tree" that "prioritizes the use of the most efficacious therapeutic modalities."⁹ In their words, "The tiered or ranked approach is based upon review of evidence-based veterinary medicine, incorporation of pertinent literature from human medicine, practical considerations, and clinical experience of the advisory panel. Tier 1 treatments are those that are considered the mainstay of pain management in the respective categories."

When the guidelines first showed up, most veterinarians couldn't even access antiNGF mAB drugs. The feline version, frunevetmab, received Food and Drug Administration (FDA) approval on January 13, 2022, but it remained unavailable to most veterinarians well into the summer. We still do not know when, or if, the canine version will receive a green light from the FDA.

Possible questions

One might ask why the experts on the panel placed so much promise on drugs that had not even entered the marketplace. Was the evidence backing them so strong and undeniable that these products should replace established therapies as first-line care? Do antiNGF mABs offer such a higher degree of safety than more familiar medications that we should advocate for and administer them without worry about potential downsides?

Even now, in late 2022, a PubMed search for the term "frunevetmab" yields only four results:¹⁰ two pilot studies,^{11, 12}one laboratory assessment of pharmacokinetics and immunogencitiy,¹³ and a German-language summary of new animal drugs. Most of the authors in the three English-language papers have financial relationships with the drug manufacturer. In one study¹⁴, "The funder was involved in the study design, execution and data analysis and publication decision." Furthermore, overlap exists between some of the authors of the frunevetmab studies and the AAHA Pain Management Guidelines. Why might this matter?

Clinical research sponsored by pharmaceutical manufacturers influences how health care providers practice medicine.¹⁵Moreover, "When a pharmaceutical company funds research into drugs, studies are likely to produce results favourable (sic) to the sponsoring company's product." "Research funded by drug companies was more likely to have outcomes that favour (sic) the sponsor's product than research funded by other sources."¹⁶

As noted earlier, the FDA denied approval for human antiNGF mAB drugs due to risks of adverse effects prior to its Center for Veterinary Medicine approving a felinized version for cats.¹⁷ Should that concern us? Differences exist between human and veterinary drugs in terms of evidence required.¹⁸

The conclusion from the FDA's Freedom of Information Summary, Original New Animal Drug Application for frunevetmab, appears to indicate the FDA relied on the manufacturer to supply the evidence, stating, "Based on the data submitted by the sponsor … FDA determined that the drug is safe and effective when used according to the labeling."¹⁹

Veterinary-specific issues

What, exactly, caused the FDA to reject the human drug, and what should we look for in veterinary patients? 1) Sufficient improvement to warrant continuation, and 2) The onset of side effects, some of which might turn out to be serious. The FDA rejected the human drug, tanezumab, because even a risk mitigation proposal failed to convince overseers that benefits sufficiently outweighed risks.

Specifically, they determined, although the tanezumab development program "provides substantial evidence of effectiveness," "the treatment effect size is modest, and there is no convincing evidence of a superior efficacy of tanezumab over NSAIDs." The FDA pointed out, "[T]wo serious toxicities caused by tanezumab have been identified during the development program: joint destruction (described as Rapidly Progressing Osteoarthritis [RPOA], and neuropathy."²⁰

Could this happen to dogs and cats, as well? A paper connected to the manufacturer on the "laboratory safety evaluation of bedinvetmab," claimed RPOA "has not been recognized" in veterinary medicine.²¹ But, they wrote, "[S]imilarity in bone biology, OA pathophysiology, NGF signaling, and NSAID pharmacology across species suggest some inferred but unknown risk in dogs." "Unknown" risk does not equal "no" risk.

While the laboratory evaluation study indicated bedinvetmab "was well tolerated in dogs" and "anti-drug antibodies to bedinvetmab were not detected" the experiments involved purpose-bred adult laboratory beagles. These animals' physiology differs from the typical geriatric dog with advanced arthritis and comorbidities that requires long-term treatment.

Looking long-term and short-term

In humans, the onset of RPOA is associated with higher doses of antiNGF mAB as well as the combined use of antiNGF mAB drugs and NSAIDs.²² Could long-term co-administration of NSAIDs and antiNGF mAB drugs lead to RPOA in dogs? What types of drug-drug interactions may occur, and how might we safely limit the risk of RPOA, should patients require rescue medication on their "bad" days? How do antiNGF mABs interact, if at all, with anti-inflammatory botanical preparations, including cannabis derivatives? These and more questions remain unanswered and require research, ideally done by independent scientists free from pharmaceutical funding and influence.

In the meantime, let us remain vigilant about the pros and cons we see with these drugs in our patients. The FDA Freedom of Information Summary indicated more cats receiving frunevetmab, compared to control, experienced worsened renal insufficiency, anorexia, lethargy, dermatitis, dehydration, lameness, pruritus, scabbing on the head/neck, bacterial skin infection, gingival disorder, otitis externa, alopecia, vomiting, abnormal behavior or behavioral disorders, and diarrhea.²³Reflecting on the myriad impacts of NGF in immune regulation and nervous system function, how might antiNGF mAB drugs alter feline physiology over time, especially in patients with neurologic, endocrine, dermatologic, or renal disease?

Dr. Narda G. Robinson is a graduate from Harvard/Radcliffe (AB), the Texas College of Osteopathic Medicine (DO), and Colorado State University College of Veterinary Medicine and Biomedical Sciences (DVM, MS). She served on the faculty of the CSU-CVMBS for 20 years and headed the Center for Comparative and Integrative Pain Medicine. She is vice-chair of the American Board of Medical Acupuncture, the board-certifying organization for physician acupuncturists, and is a Fellow of the American Academy of Medical Acupuncture. Dr. Robinson is the CEO and president of CuraCore MED and CuraCore VET, which educate human and veterinary practitioners in science-based integrative medicine and rehabilitation/physical medicine approaches. Her website is CuraCore.org. Opinions do not necessarily reflect those of Veterinary Practice News or VPN Plus+.

References

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