LIBRELA

How to Evaluate New Pharmaceuticals and Medical Products

In our current times of accelerated technological and scientific innovation, alongside the effect of regulatory agency capture, the need to be discerning is more vital than ever.

Now that we have stepped out of the heightened flight-or-fight-or-freeze response brought on by the outbreak of a “novel” virus, we can slow down, gather our thoughts, and do some critical thinking regarding medical options that are becoming available for humans and for animals.

Many people are surprised that many of the same drugs that are used in human medicine are also used in veterinary medicine. What they do not understand is that most pharmaceuticals are tested for safety and efficacy on nonhuman animal species before they even make it to human drug trials. There are many instances of drugs working better, with fewer side effects, in one species of mammal over another; sometimes humans are the benefactors, sometimes another species, like canines.

What I have noticed over the past few decades, is that drugs having problems on the human medical side will be repurposed to veterinary medicine if at all possible. An example is gabapentin. The same year that Pfizer settled a lawsuit on the side effects of gabapentin, it suddenly appeared in an op-ed in the veterinary journals claiming it was the answer to neuropathic pain. And on top of that, it was a drug without side effects! That is quite the claim when even simple things in life, like water and oxygen, can have side effects if not used appropriately. It soon became, and probably still is, the most prescribed drug in veterinary medicine, even though its pain-relieving qualities have failed to be proven in any scientific studies.

But one may say, the pharmaceutical company has to recoup its money spent on research and development somewhere. Why not veterinary medicine?

When we can no longer trust the pharmaceutical companies or their representatives, or, (and with a heavy heart I say this because I have dedicated my life to this profession) our local veterinarian…

How do we go about evaluating new drugs and treatments for our animals?

We have an amazing tool at our fingertips but we need to learn how to use it with a critical eye: the INTERNET.

I am going to walk you through the steps I performed when researching the new product LIBRELA.

The following is not an all-inclusive or exhaustive search about this product. The depth and reach of the rabbit hole is determined by how much time one has available, but this should get you started and give you some basic guidelines to follow when questioning certain medical treatments.

My commentary and opinion will be in italics to differentiate it from other types of gathered information.

LIBRELA

STEP 1: Visit the pharmaceutical company’s website on the product: LIBRELA

“The first and only monthly injectable anti-nerve growth factor (NGF) monoclonal antibody (mAb) therapy for dogs with osteoarthritis (OA) pain.”

- ZOETIS, the animal health division of Pfizer

STEP 2: Here you will also find “Prescribing information”, or the PACKAGE INSERT for the product.

This will be fairly long, in small print, but contains vital information including safety and efficacy studies along with WARNINGS - not always marked as warnings but with phrases such as: “has not been established”, “was not able to be determined”, “has not been evaluated”. These phrases should serve as red flags to investigate or at least think about.

A few notes on evaluating Safety and Efficacy studies:

1. The “N” Value: indicates the sample size or the number of individuals in the study. The total N is the experimental group that was given the product plus the control group, usually given a placebo, i.e. saline injection.

2. What were the ages, breeds, and comorbidities of the subjects? Were they typical of the types of patients that will most likely be receiving the product?

   For example, most dogs with severe arthritis are senior or geriatric and may have a variety of comorbidities.

3. What is the length of the study? Is it comparable to the length of time the medication will be used in patients?

I lean on my knowledge of statistics, looking at how the drug is going to be used in the “real world” - the patient cohort, duration of use, comorbidities, and potential interaction with other meds these patients are likely to be on.

STEP 3: Next stop is the FDA Center for Veterinary Medicine: FDA Summary of Approval of Librela

This gives you their summary of the product and the following CYA statement:

“Veterinarians should advise owners about the possible adverse events and side effects before using the drug. The FDA encourages dog owners to work with their veterinarian to report any adverse events or side effects potentially related to the use of any drug, including Librela.”

STEP 4: At the bottom of the FDA announcement is a link to the FREEDOM OF INFORMATION SUMMARY:

This is a 24-page application with all the details of the studies and the findings given to the FDA to obtain their approval.

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STEP 5: Additional information and questions to ask and investigate

• How is it metabolized or cleared from the body?

• Physiological mechanism of action in the body

• Is it binding to certain receptors, or substances?

• What do those receptors or substances do physiologically in the body?

• What tissues and organs may be affected?

• History of the science behind the product and the product itself.

• Has this medication, or similar versions, been used in other parts of the world?

• Has it been used in human medicine? Has it been used for other conditions?

Let’s dive into the information we have on LIBRELA.

SAFETY AND EFFICACY STUDIES

1. EFFICACY: how well does it work for the condition for which it is labeled?

“Two field studies were conducted to evaluate the effectiveness of Librela – one in the United States (84 days, N=272 total: 135 Librela, 137 control, at least 1 years of age, various breeds, received at least 3 injections) and one in the European Union (84 days, N=284 total, 138 Librela, 143 control, various breeds, 3 injections). Both studies enrolled client-owned dogs diagnosed with OA. Half the dogs received Librela and half the dogs received a sterile saline injection every 28 days for a total of three doses. Before treatment and on various days throughout the study, owners used the Canine Brief Pain Inventory (CBPI) assessment tool to measure the severity of the dog’s pain and the degree to which the pain interfered with the dog’s daily activities. The weight of evidence from the two field studies demonstrated that Librela is effective at controlling pain associated with OA in dogs when at least two doses are given 28 days apart.” - FDA Summary of Approval

2. SAFETY:

From the FDA Summary of Approval:

“The most common side effects seen in dogs treated with Librela (in the above efficacy studies) included increased blood urea nitrogen (an indicator of kidney function), urinary tract infection, bacterial skin infection, skin irritation (dermatitis), rash (erythema) or pain at the injection site, vomiting (emesis), and weight loss (anorexia).

Veterinarians should advise owners about the possible adverse events and side effects before using the drug. The FDA encourages dog owners to work with their veterinarian to report any adverse events or side effects potentially related to the use of any drug, including Librela.”

Studies to determine long-term effects from the FREEDOM OF INFORMATION SUMMARY:

“Bedinvetmab is a canine recombinant monoclonal antibody that binds to and inhibits the biological activity of canine nerve growth factor (NGF), which has been found to be elevated in dogs with osteoarthritis (OA).

Some dogs from the EU field study were enrolled in a continuation phase to evaluate the safety of 6 additional monthly SC injections of Librela™ (there was no control group in this phase of the study). The adverse reactions were similar to those reported in the two field studies.

“The sponsor conducted a 6-month laboratory safety study in young, healthy, intact Beagles. (32 dogs, 8 per treatment group)The dogs were administered Librela™ by SC injection every 28 days for a total of 7 doses at 0X (0 mg/kg), 1X (1 mg/kg), 3X (3 mg/kg), or 10X (10 mg/kg) the high end of the inherent dose band. Dogs in the 3X and 10X treatment groups had scabbing lesions of the head and neck. Boney changes, including boney remodeling and cartilage degeneration, were seen in one dog in the 3X treatment group. The dog may have had an underlying musculoskeletal condition that caused the boney changes; however, a relationship to treatment cannot be ruled out.”

Study to determine interaction with NSAIDS:

“In a 2-week laboratory safety study, young, healthy Beagles concurrently received one SC injection of Librela™ at the high end of the inherent dose band and 14 days of an injectable non-steroidal anti-inflammatory drug (NSAID). Although there were no significant findings, this limited laboratory study did not provide sufficient data to support the safety of concurrent use of Librela™ and NSAIDs.”

“In a 3-month exploratory laboratory safety study, dogs were administered a nonfinal formulation of bedinvetmab by SC injection every 28 days for a total of 4 doses at 0X (0 mg/kg), 1X (1 mg/kg), 4X (4 mg/kg), and 12X (12 mg/kg) the high end of the inherent dose band. Both gross and microscopic skin lesions were observed at the injection site in all treatment groups.”

“Conclusion: Based on the data submitted by the sponsor for the approval of Librela™, FDA determined that the drug is safe and effective when used according to the labeling.”

IMMUNOGENICITY:

From Wikipedia:

“the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:

• Wanted immunogenicity typically relates to vaccines, where the injection of an antigen (the vaccine) provokes an immune response against the pathogen, protecting the organism from future exposure. Immunogenicity is a central aspect of vaccine development.

• Unwanted immunogenicity is an immune response by an organism against a therapeutic antigen. This reaction leads to the production of anti-drug-antibodies (ADAs), inactivating the therapeutic effects of the treatment and potentially inducing adverse effects.”

From FDA: Vaccines, blood, biologics

“A major problem with protein-based therapeutics is their immunogenicity, that is, their tendency to trigger an unwanted immune response against themselves. One form of immune response is the activation of B cells, which produce antibodies that bind to the proteins and reduce or eliminate their therapeutic effects. Such antibodies can also cause complications that can be life-threatening. Therefore, a critical part of determining the clinical safety and efficacy of protein-based therapeutic products is measuring their tendency to trigger antibody formation.”

From Freedom of Information Summary for Librela:

“All therapeutic protein products have the potential for inducing an immune response (immunogenicity) following administration to a host, like a humoral immune response and the production of antibodies in the host. These host-derived antibodies may bind to the therapeutic protein (drug product) and may result in decreased effectiveness or increased risk for an adverse reaction. Such host-derived antibodies specific for the therapeutic protein are also termed antidrug antibodies (ADA).

Due to limitations of the assay methods performed to evaluate immunogenicity (confirmatory and titration), clinically relevant conclusions or correlations were not determined from the immunogenicity data reported.”

Librela Package Insert

“Treatment with LIBRELA may result in the formation of anti-bedinvetmab antibodies and potentially the loss of product effectiveness” (with no mention of adverse effects).

My summary: there are very real possibilities that antidrug antibodies could form but we have no information if or when this may happen. We also do not know the ramifications of this occurring, although in other cases it has led to severe immune reactions, e.g.

fatal anaphylaxis, chronic autoimmune conditions, or the activation of the complement system leading to reactions and potential fatalities.

SAFETY AND DRUG INTERACTIONS

From the Package Insert

“The safe use of this product with other monoclonal antibodies has not been evaluated.”

Another commonly used monoclonal antibody in veterinary medicine is Cytopoint. I would NOT use both products together as it may risk an immunogenic adverse event - see above. The more circulating antibodies in the bloodstream, the higher the likelihood of an adverse reaction.

“Evaluations were not made to determine if interactions occurred between LIBRELA and veterinary vaccines.”

“The safe use of anti-NGF monoclonal antibodies with concurrent non-steroidal anti-inflammatory drugs (NSAIDs) has not been established in dogs. “

Nearly all arthritic dogs have been vaccinated and have circulating antibodies to multiple vaccines, sometimes at high levels. And many arthritic dogs are on some kind of NSAID or other pain medication. It is unknown whether there are any adverse interactions to be concerned about.

LONG-TERM EFFECTS:

From the Package Insert

“Long-term effects which may occur more than 9 months after the use of LIBRELA have not been evaluated.”

We have no information past 9 months.

METABOLISM OF PRODUCT:

“The metabolic pathway of bedinvetmab has not been characterized. As a canine IgG monoclonal antibody, bedinvetmab is expected to be (but not proven?) degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.”

Here it is ; “expected to be” but not really unknown. They may as well say “we assume” and we all know where that gets us.

MECHANISM OF ACTION:

From Package Insert

“Bedinvetmab is a recombinant canine monoclonal antibody that binds to nerve growth factor (NGF), reduces NGF binding to the tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) receptors, and decreases TrkA signal transduction in cell types involved in pain.

In vitro binding studies suggest that bedinvetmab binds with high affinity to NGF but does not bind to other neurotrophins including human neurotrophin-3 (NT-3), canine and human NT-4, and human brain-derived neurotrophic factor (BDNF).

NGF has been found to be elevated in the osteoarthritic joints of dogs. Following a noxious stimulus, inflammatory cytokines and NGF are released by tissues of the joint. NGF binds to TrkA/p75NTR receptors found on peripheral nerves, immune cells, endothelial cells, synoviocytes, and chondrocytes to induce peripheral sensitization, neurogenic inflammation, and increased pain perception. Bedinvetmab binds to NGF and prevents NGF/TrkA/p75NTR cellular signaling. In in vitro studies, bedinvetmab potently inhibits NGF-mediated signaling as measured by a reduction in TF-1 cell proliferation and functionally blocks NGF-induced neurite outgrowth in rat PC-12 neuronal cells. NGF binds to TrkA receptors located on immune cells to elicit the release of additional proinflammatory mediators, including NGF itself. These inflammatory mediators lead to further peripheral sensitization involved in pain perception. Bedinvetmab reduces the expression of these inflammatory mediators in rat PC-12 neuronal cells.”

What else does NGF do in the body?

NERVE GROWTH FACTOR: History of its discovery and role in the body

Here are some excerpts from a paper published in 2012 looking at the discovery and research done on NGF, and foreshadowing its possible use to treat pain. It points out the major places in the body where it has an effect, which is pretty much globally:

• “Nerve growth factor (NGF) is the first discovered member of the neurotrophin family. NGF is essential for the development and phenotypic maintenance of neurons in the peripheral nervous system (PNS) and for the functional integrity of cholinergic neurons in the central nervous system (CNS).”

• “NGF dynamically controls neurotransmitters and neuropeptides synthesis, ie norepinephrine, substance P.”

• “NGF supply from the innervation field influences the neuronal plasticity that allows the adult nervous system to modify its structure and functions in response to stimuli.”

“The huge amount of research data produced since its discovery in the 1950s first characterized the physiological role of the neurotrophin NGF in the regulation of development and phenotypic maintenance of peripheral nervous system (PNS). A similar role for central cholinergic neurons was described starting from the 1980s, while more recently NGF has been characterized as a survival, differentiative and trophic factor also for cells belonging to the immune system and the epithelial lineage. Basic and translational research based on such described NGF activities have then explored the possibility of developing NGF-based pharmacotherapies for peripheral neuropathies, brain degenerative and traumatic diseases, and several kinds of epithelial derangements. A possible, yet unexplored field for clinical development of NGF as a drug, is based on its activity as an immune-regulator, possibly involved in autoimmune and chronic inflammatory pathologies.”

Aloe, L., Rocco, M.L., Bianchi, P. et al. Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 10, 239 (2012). https://doi.org/10.1186/1479-5876-10-239

From Package Insert:

“NGF is expressed within the heart and vasculature, and the long-term effects of reduced NGF in dogs with cardiac disease are unknown.”

Cardiac effects are unknown even though we know NGF is expressed in heart and vascular tissue.

What about all the other tissues and organs in the body where it is expressed?

Central nervous system, brain: Cognitive decline?

Skin issues - already showing symptoms in the efficacy study?

Peripheral neuropathies, eg GOLPP (Geriatric onset laryngeal paralysis polyneuropathy), degenerative myelopathy?

Immune system: Autoimmune, chronic inflammation?

History of Monoclonal Antibody Use in Human Medicine

Monoclonal antibodies have been used to treat a variety of conditions in human medicine: autoimmune, cardiovascular, musculoskeletal, cancer, and COVID-19, as noted in this summary article, which also lists the wide-ranging side effects:

“Pharmacological monoclonal antibodies (mAbs) are genetically engineered versions of antibodies. As more mAb agents become available for clinical use, they can interfere with natural immunity which may predispose for both common and unusual infections, such as tuberculosis (TB), among treated patients. It should be noted here that all patients are screened for TB before they are prescribed any mAb.”

Puthenpurail A, Rathi H, Nauli SM, Ally A. A BRIEF SYNOPSIS OF MONOCLONAL ANTIBODY FOR THE TREATMENT OF VARIOUS GROUPS OF DISEASES. World J Pharm Pharm Sci. 2021 Nov;10(11):14-22. PMID: 35071113; PMCID: PMC8775886.

NGF Monoclonal Antibodies in Humans:

Several drug companies have attempted to develop and bring to market an NGF mAB for humans.

In 2010, Johnson & Johnson had a drug placed on hold over FDA concerns that it could be linked to a serious bone disorder.

In 2016, the FDA put Teva and Regeneron's NGF inhibitor fasinumab on hold after one trial participant developed arthropathy, which is the rapid destruction of a joint. Fasinumab was being developed for the treatment of chronic lower back pain.

In 2021, Eli Lilly and Pfizer”s product, Tanezumab, was not approved by the FDA:

“Despite showing definitively positive results in Phase III clinical trials, the FDA had raised critical safety concerns over tanezumab. Prime among them was the development of rapidly progressing osteoarthritis (RPOA), a condition both companies observed during clinical research.

Lilly and Pfizer had sought to evaluate and monitor the drug and the associated safety issues under the FDA's Risk Evaluation and Mitigation Strategy (REMS). However, the agency stated in March that the "proposed REMS is not sufficient to mitigate the risk of RPOA and would not ensure that the benefits of tanezumab outweigh the risks of RPOA." The FDA's Joint Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee voted 19-1 that the REMS would not ensure the drug's benefits outweigh its risks”.

https://www.biospace.com/article/eli-lilly-and-pfizer-put-once-promising-osteoarthritis-pain-drug-out-of-its-misery-/

The RPOA was so severe it led to joint replacement surgery in all cases.

Yu Y, Lu ST, Sun JP, Zhou W. Safety of Low-Dose Tanezumab in the Treatment of Hip or Knee Osteoarthritis: A Systemic Review and Meta-analysis of Randomized Phase III Clinical Trials. Pain Med. 2021 Mar 18;22(3):585-595. doi: 10.1093/pm/pnaa260. PMID: 33141224.

This safety issue is mentioned in the package insert of Librela:

“In human clinical trials, rapidly progressing osteoarthritis (RPOA) has been reported in a small number of patients receiving humanized anti-NGF monoclonal antibody therapy. The incidence of these events increased in human patients receiving NSAID treatment long-term in combination with an anti-NGF monoclonal antibody. RPOA has not been characterized or reported in dogs.”

My conclusions as a clinician:

Monoclonal antibodies are a potent targeted modality. The fact that they can trigger an immune response, in and of themselves, that can create a variety of side effects, some predictable, most not, means they need to be used responsibly with full informed consent of the patient, or patient’s guardian. The cases in which to use them need to be carefully chosen considering co-morbidities, length of time it will be administered, other viable treatment options, and quality of life of the patient.

This particular product should not be used in an animal who is currently taking Cytopoint, that has been vaccinated, (recently or ever??), or on NSAIDS.

We do not know if there will be any side effects or long-term issues after the third injection or after 9 months of receiving the injections. No studies have been performed.

And it is being marketed for repeat monthly injections.

Due to the fact it binds to and blocks NGF, regardless of organ or tissue location, particular concern should be given to senior animals at risk of cognitive decline, peripheral neuropathies, cardiac disease, allergies, compromised immune systems and/or cancer.

Will I be recommending Librela? Or giving it to my own 85 lb German shepherd mix with severe hip arthritis?

No, not when I have so many other modalities available for arthritis management that do not cause harm to my patients.

If you would like to see more informative articles like this one, please consider a paid subscription, amount at your discretion. This will free up some time from seeing patients so that I can do the research involved in bringing you this information. Then you, as a pet parent, may make a truly informed decision.

ADDENDUM December 17, 2023

On November 20, 2023, the US FDA CVM issued an Untitled Letter to Zoetis for making false or misleading claims and representations about the efficacy of Librela.

"What is an Untitled Letter? According to the FDA website, “An Untitled Letter cites violations that do not meet the threshold of regulatory significance for a Warning Letter. However, Untitled Letters serve as an initial notification to firms that FDA is aware of their violations of federal law, and they document formal notification by FDA to the person or firm. They also allow the firm to come into compliance without further FDA action." (From Joeys Legacy FB group)

https://www.fda.gov/media/174818/download?attachment

ADDENDUM 2: December 17. 2023

In the EU they reported the adverse event “increased BUN”. Blood Urea Nitrogen (BUN) is one measurement of kidney function performed on routine blood analysis.

The pathophysiology behind this finding could be as straight forward as the monoclonal antibody binding to nerve growth factor, creating large antibody-antigen complexes. These complexes can deposit in the glomeruli of the kidney creating glomerulonephritis, leading to increased BUN and eventually kidney failure.

“immune-complex–mediated proliferative glomerulonephritis is caused by the deposition of immune complexes in the glomeruli”