Why Do Some Dogs Appear to Develop Neurologic Problems after Anti-Nerve Growth Factor Monoclonal Antibody Injections?

Nov 23, 2023 | Blog

This dog looks concerned

What are anti-NGF monoclonal antibodies doing to my nervous system?

Why It’s Unwise to Inhibit Nerve Growth Factor

by Narda G. Robinson, DO, DVM, MS, FAAMA

On social media, stories of starkly different reactions to bedinvetmab are mounting by the day.  Bedinvetmab, a caninized anti-nerve growth factor monoclonal antibody (antiNGF mABs) biologic, received FDA approval in May, 2023 for the treatment of osteoarthritis in dogs.  Already, we’re hearing reports that range from “game-changing relief” to a host of unexpected downturns, some severe, that clients are connecting to the monthly injection.  Reeling from heartbreak and desperate for answers, these pet parents are gathering (along with veterinarians in academia / private practice and industry executives) in Facebook groups such as the US-based LIBRELA REVIEWS & FEEDBACK and the UK-based Librela Experiences.  They share stories, seek solace, and wonder, “Why weren’t we warned?” and “What do I do now?” Another Facebook group, VETLESSONS ON LIBRELA®, led by Dr. Michael Farrell, links to published research they may not have heard about otherwise.  Thus far, the veterinary response has been mixed.  Some maintain that they’ve witnessed only benefits.  Others aren’t sure how to guide clients and are now recommending the biologic only after exhausting other options for pain control, or not at all.

Neurobiologic Consequences: Following one or more injections, adverse effects described online include the following: lethargy, drooling, shaking, behavior changes, hiding, urinary incontinence, inappetence, increased or decreased thirst, ataxia, hind-end weakness, inability to walk, new or worsened seizures, and organ damage.(1)  What we’re left to sort out is whether these effects stem from the antibodies or something else.  Neurobiologically, several of these signs make sense. Throughout an individual’s lifespan, NGF has endless protective, supportive, and reparative roles to fulfill throughout the body, affecting the eye, the gut, and the entire nervous system.(2)  We block it at our peril or, more specifically, perhaps at our patients’ peril.  How do we know which dogs will probably do fine and which ones won’t?  We can’t, at least not yet.  There’s not enough research.

The Blood-Brain Barrier

Those who promote bedinvetmab may dispute the idea that antibodies could damage the central nervous system (CNS).  They argue that the large molecular size of mABs would prohibit their passage through the blood-brain barrier (BBB). However, the BBB is not infallible and omnipresent.  It can weaken with illness or naturally not exist in parts of the brain. Pathologic reasons for increased permeability include inflammation, brain cancer, brain infection, traumatic brain injury, hypercapnia, hypoxia, stroke, seizures, and a host of other chronic conditions, such as amyotrophic lateral sclerosis (like degenerative myelopathy in dogs), epilepsy, high blood pressure, and diabetes mellitus.(3) Patients with these problems could conceivably become more susceptible to side effects from NGF inhibition.  Medications (e.g., cyclosporin A and tacrolimus) may also weaken the BBB through apoptosis of endothelial cells.(4)  Neurodegenerative diseases (e.g., Alzheimer’s) can compromise the BBB and  reduce its ability to defend against toxins and engage in self-repair. 

Brain areas that form without a BBB have open access to the general circulation.  The median eminence of the hypothalamus serves as one example.  This brain center regulates thirst and relies on NGF to function normally.(5) Could bedinvetmab have impaired its ability to appropriately regulate water intake in those dogs that experience uncontrollable thirst or who refuse water altogether after injection? The pineal gland, the posterior pituitary, and the area postrema also have no BBB.  Might they be susceptible to injury, too, from bedinvetmab? If so, could dogs exhibit sequelae such as immune dysfunction from effects on the pineal gland (6), neuroendocrine dysregulation from impact in the posterior pituitary, and nausea and vomiting (7) from disturbance in the area postrema? Without further research, we can’t know if any of these potential connections make sense, but at this point, we don’t have much else to go on.

The Blood-Spinal Cord Barrier

Long-assumed to be the functional equivalent of the BBB, the blood-spinal cord barrier (BSCB) differs in its heightened vulnerability to injury by mechanical stress. (8)   That is, too much torque on the spinal cord from excessive vertebral movement can biomechanically strain the basement membrane.  Would having intervertebral disk disease (IVDD) and the anatomic degradation that accompanies it, put dogs at greater risk of negative outcomes after antiNGF mABs injection?  Miniature Dachshunds show a lifetime prevalence of 20% for IVDD.(9)  What happens when these dogs receive bedinvetmab, month after month, especially as they advance in years?

According to a study on the association of IVDD-related diseases with age and breed, “The hazard… of IVD degeneration-related diseases increased with age.  Evaluation of combined veterinary healthcare and life insurance claims revealed that the 3 breeds at highest risk of developing these diseases before the age of 12 years were (in decreasing order) Miniature Dachshund, Doberman Pinscher, and Standard Dachshund.  According to these calculations, of dogs that lived up to 12 years of age, 20% of Miniature Dachshunds, 17.5% of Doberman Pinschers, and 15% of Standard Dachshunds were at risk for greater than or equal to 1 occurrence of IVD degeneration-related disease…German Shepherd Dogs had the highest risk of lumbosacral IVD degeneration-related disease in this study and had a 7% lifetime prevalence of any IVD degeneration-related disease before the age of 12 years.”(10)  The authors noted that their research likely underestimated the true incidence of IVDD due to strict selection constraints.. Should IVDD be considered a contraindication to bedinvetmab administration for these breeds?

Peripheral nerve injury also has the capacity to weaken the BSCB.  BSCB leakage leads to recruitment of spinal blood-borne monocytes and macrophages.   Chemokine release triggers microglial activation and initiates neuropathic pain. (11) Aging, infections, and auto-immune conditions contribute to BCBS pathology as does exposure to environmental pollution – especially traffic-related. What percentage of dogs who become paretic after bedinvetmab already had subclinical neurologic compromise that the biologic exposed and worsened?  Moreover, what can be done to restore function, when “tincture of time” fails to do so?  

Was the FDA too quick to sign off on antiNGF mABs? As of this writing, a literature search on PubMed.gov for “bedinvetmab” found only three studies on dogs, all with close ties to the manufacturer.  The two prospective, randomized, placebo-controlled trials it turned up claimed that the product was safe and effective.(12, 13)

We need more clinical trials, and those should be performed by researchers without financial or other conflicts of interest related to the manufacturer.  And, what do we do to help dogs who have developed serious negative reactions after injections?  That’s the problem.  We don’t know.

REFERENCES

  1. Bassingthwaighte E.  Librela (Beransa) – Wonder drug or disasterin the making?  Dogs Naturally.  October 31, 2023.  Accessed on November 3, 2023 at https://www.dogsnaturallymagazine.com/librela-berensa-wonder-drug-or-disaster-in-the-making/.
  2. Aloe L, Rocco ML, Balzamino BO, et al.  Nerve growth factor: a focus on neuroscience and therapy.  Current Neuropharmacology.  2015;13:294-303.
  3. Cleveland Clinic Website.  Blood-Brain Barrier.  Accessed on November 3, 2023 at https://my.clevelandclinic.org/health/body/24931-blood-brain-barrier-bbb .
  4. Zheng W.  Neurotoxicology of the brain barrier system: New implications.  J Toxicol Clin Toxicol.  2001;39(7):711-719.
  5. McNulty JA, Fox LM, and Silberman S. Immunocytochemical demonstration of nerve growth factor (NGF) receptor in the pineal gland: effect of NGF on pinealocyte neurite formation.  Brain Res.  1993;610(1):108-114.
  6. Miller AD and Leslie RA.  The area postrema and vomiting.  Front Neuroendocrinol.  1994;15(4):301-320.
  7. Chopra N, Menounos S, Choi JP, et al.  Blood-spinal cord barrier: its role in spinal disorders and emerging therapeutic strategies.  NeuroSci.  2022;3(1):1-27; https://doi.org/10.3390/neurosci3010001.
  8. Bergknut N, Egenvall A, Hagman R, et al.  Incidence of intervertebral disk degeneration-related diseases and associated mortality rates in dogs.  JAVMA.  2012; 240(11): 1300-1309.
  9. Ibid.
  10. Ibid.
  11. Corral MJ, Moyaert H, Fernandes T, et al.  A prospective, randomized, blinded, placebo-controlled multisite clinical study of bedinvetmab, a canine monoclonal antibody targeting nerve growth factor, in dogs with osteoarthritis.  Vet Anaesth Analg.  2021; 48(6):943-955.
  12. Michels GM, Honsberger NA, Walters RR, et al.  A prospective, randomized, double-blind, placebo-controlled multisite, parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab, a canine anti-nerve growth factor monoclonal antibody.  Vet Anaesth Analg. 2023;50(5):446-458.