KNOWLEDGE SUMMARY
Keywords: CANINE; OSTEOARTHRITIS; BEDINVETMAB; MONOCLONAL ANTIBODY; CANINE NERVE GROWTH FACTOR; ANALGESIA; CHRONIC OSTEOARTHRITIS ASSOCIATED PAIN; SAFETY; EFFECTIVENESS
In dogs diagnosed with osteoarthritis, how safe and effective is long-term treatment with bedinvetmab in providing analgesia?
Katrin Kronenberger, PhD1*
1 University of Edinburgh, Royal (Dick) School of Veterinary Studies, Easter Bush Campus, Midlothian EH25 9RG
* Corresponding author email: k.kronenberger@sms.ed.ac.uk
Vol 8, Issue 1 (2023)
Submitted 15 Feb 2022; Published: 01 Feb 2023; next review: 25 Aug 2024
DOI: https://doi.org/10.18849/ve.v8i1.598
PICO question
In dogs diagnosed with osteoarthritis (OA), how safe is treatment with bedinvetmab, when compared to a placebo and how effective in long-term reduction of the severity of the clinical signs associated with OA-related pain?
Clinical bottom line
Category of research
Treatment.
Number and type of study designs reviewed
Two papers were critically reviewed. One was a randomised, blinded, multi-arm laboratory safety study; the other a multi-center field trial consisting of a block-randomised, double blind, placebo-controlled phase, followed by a non-comparative, open-label case series study.
Strength of evidence
Weak.
Outcomes reported
One study rated the reduction of the severity of clinical signs associated with OA pain using owner Canine Brief Pain Inventory (CBPI) ratings and non-validated veterinary clinical assessments (VCAs). Safety was addressed by evaluating adverse health effects (AHEs), concentration of antidrug antibodies (ADAs), and clinical pathology. Significant improvements in pain scores and VCAs were reported in this treatment study. The second safety-only study used clinical observation to evaluate AHEs. Both studies reported AHEs.
Conclusion
A single study suggests that treatment with bedinvetmab is effective. Two studies support the drug having few AHEs. Both studies have significant design limitations preventing the evaluation of bedinvetmab effectiveness. There is weak / inconclusive evidence for long-term efficacy and short-term safety of OA treatment with bedinvetmab. The decision to use bedinvetmab remains dependent on the judgement and experience of the clinician.
How to apply this evidence in practice
The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.
Clinical scenario
A 12-year-old Laika-cross has been diagnosed with canine osteoarthritis (OA), affecting his coxofemoral and stifle joints. Meloxicam helped manage the dog’s pain for over 12 months successfully. However, the owner is concerned about the risk of adverse effects and asks for alternative treatment options not involving non-steroidal anti-inflammatory drugs (NSAIDs). You are considering bedinvetmab (Librela, Zoetis), which has only recently become available. You want an understanding of efficacy, effectiveness, and safety evidence before deciding whether this is an alternative treatment option to suggest to the owner.
The evidence
The Krautmann et al. (2021) pre-clinical laboratory study addressed the safety effects of bedinvetmab in healthy, mature laboratory beagles. The authors neither describe the process of random assignment to the three study groups, nor further assignment to the smaller subgroups within these separate studies. In this study, dogs were stratified by sex. The small cell sizes (n = 8) within each study condition raise concerns of overall potential sample bias or cell-specific sample bias. Generalising from mature laboratory beagles to an older target OA population may be a concern, although this is how most other analgesics are tested.
The Corral et al. (2021) ‘change from baseline’ study assessed both efficacy and safety of bedinvetmab in client-owned dogs with OA. Pretreatment Canine Brief Inventory (CBPI) pain scores were used as baseline comparison and included in the efficacy analysis of bedinvetmab. Standardisation instructions on using the CBPI explicitly indicate that the first CBPI score should be discarded due to potential regression to the mean (RTM) (Brown et al., 2008). Corral et al. (2021) did not follow this guidance to use the second pain score as baseline, which may have resulted in treatment and control groups being significantly different. Interpretation of this difference was confounded by 7 days of bedinvetmab treatment preceding this second score. This multi-site, multi-national trial spanned several countries with different numbers of sites in each country and different numbers of dogs at each site. The CBPI was not translated into the target languages, potentially impacting its reliability / validity. Loss to follow-up affected placebo and treatment groups differentially, which may increase the risk of bias. 22/146 (15.1%) of the dogs randomised to the placebo group, and 9/141 (6.4%) of the dogs randomised to the bedinvetmab group were excluded from the efficacy analysis. Loss to follow-up and blinding was incomplete.
Limitations of study design and execution of both studies suggest there currently is only weak evidence for long-term efficacy and short-term safety of bedinvetmab for the alleviation of OA-related pain in dogs.
Summary of the evidence
Corral et al. (2021)
Population: |
Client–owned dogs of any breed, sex, and body weight. Eligibility criteria for inclusion:
Criteria for exclusion:
|
---|---|
Sample size: |
287 dogs.
|
Intervention details: |
Intervention
Control
Initial 3 month randomised, controlled, blinded, comparative phase:
6 month single–armed, open–label, uncontrolled continuation phase:
|
Study design: |
A randomised, double-blind, placebo-controlled, parallel-arm, multi-site experimental field study, followed by a 6 month single-arm, open-label case series study. |
Outcome Studied: |
Primary efficacy outcome measure (subjective)
Secondary efficacy outcome measures (subjective)
Safety outcome measures (objective)
|
Main Findings |
Efficacy of bedinvetmab
Safety of bedinvetmab
*These values were generated by the Knowledge Summary author and based on the back transformed mean proportions reported. |
Limitations: |
|
Krautmann et al. (2021)
Population: |
Criteria for inclusion
Criteria for exclusion
|
---|---|
Sample size: |
n = 96 dogs. |
Intervention details: |
Overall intervention
Control
Three sub-studies Study 1 (dose-dependent pre-clinical safety evaluation)
Study 2 (evaluation of T-lymphocyte-dependent immune response of bedinvetmab to keyhole limpet hemocyanin (KLH))
Study 3 (evaluation of adverse effects of concurrent administration of bedinvetmab and NSAID carprofen)
For each separate study
Study 1
Study 2
Study 3
For each study
|
Study design: |
Randomised (stratified by sex), blinded, multi-arm, parallel-group safety study. |
Outcome Studied: |
Study 1
Study 2
Study 3
Objective safety endpoints (studies 1 and 3)
|
Main Findings |
Study 1
Study 2
Study 3
Studies 1 & 3
|
Limitations: |
|
Appraisal, application and reflection
Bedinvetmab (Librela, Zoetis) is a canine immunoglobulin G2 (IgG2) monoclonal antibody (mAb) intended for the alleviation of osteoarthritis-related pain. Its mode of action differs from cyclooxygenase inhibiting NSAIDs, that block the production of prostaglandins. Bedinvetmab modulates nociceptive and neuropathic pathways by targeting and binding to canine nerve growth factor (NGF), blocking NGF / tropomyosin receptor kinase A receptor (TrkA) signaling (Enomoto et al., 2019). Species-specific anti-NGF mAb treatments may have fewer adverse health events than NSAIDs due to their high binding specificity and, unlike opiates, may not block protective nociceptive sensation (Enomoto et al., 2019).
The Corral et al. (2021) multi-centre field trial examined the efficacy and safety of 9 monthly subcutaneous injections (SC) of bedinvetmab (0.5–1.0 mg/kg Librela, Zoetis) in client-owned dogs diagnosed with osteoarthritis (OA). The initial 3 month study was randomised, blinded, and had a placebo control group. The process of randomisation across multiple sites in different countries with different numbers of subjects is unclear. The authors do not describe individual site blinding methodology and do not discuss statistical management of missing data, particularly methods for handling the implementation of rescue medication (Donders et al., 2006). Furthermore, incomplete follow–up minimised data interpretability.
The 6 month, open-label, observational case series study following the 3 month randomised controlled trial (Corral et al., 2021) observed efficacy and safety outcome measures without a control group. The study cited ethical concerns with a 6 month placebo comparison group in a clinical sample. A case series study without control can provide suggestive information about treatment and safety outcomes (i.e., potential serious adverse events), but there is an inherent potential for various biases and confounds. The lack of blinding of outcome assessors was an additional issue with this follow-on. No information was provided about demographics, age or weight, or severity of condition for the dogs selected for follow-on (described as ‘responded positively’ previously to treatment with bedinvetmab). Corral et al. (2021) neither discuss the implications of selecting the second group on this basis, nor define what ‘responding positively’ means.
The study’s primary efficacy outcome measure was owner-assessed OA-related change of pain scores using the Canine Brief Pain Inventory (CBPI) (Corral et al., 2021). Standardisation of the CBPI reports robust statistical power and reliability for quantifying owner perception of pain severity and impact of chronic OA-associated pain on dogs’ quality of life (QoL) Brown et al., 2007; 2008; and 2013). Corral et al. (2021) did not adhere to scale administrative guidelines (Brown et al., 2008) by collecting data at enrolment and using these as the baseline for comparison with scores obtained at later time points, despite standardisation guidance to avoid using scores collected on the first appointment given concerns about regression (Brown et al., 2008; and Friedman et al., 2015). A measurable subject variable, like pain, varies over time. Pain scores that are 'extreme' by chance tend to 'regress towards the mean' when repeated. The natural variation in repeated in-subject measurements may erroneously infer clinically meaningful change after intervention and affect clinical decisions, while regression to the mean (RTM) confounded the change from baseline (Barnett et al., 2005). Beginning baseline data collection after the first appointment will allow dogs to be at their 'average' pain level, alternatively taking the mean of two or more baseline measurements before the intervention alleviates RTM effects (Brown et al., 2008; and Friedman et al., 2015). The study’s relatively small differences between treatment and control may be an artefact of the failure to follow scale guidelines or other test–retest reliability concerns. In addition, there is no discussion of language impacts on reliability and validity (Essner et al., 2020). The CBPI was scaled in English, but Corral et al. (2021) administered it to owners of various nationalities. Furthermore, no information was provided on the veterinary clinical assessments (VCAs) carried out by different veterinarians at different sites and across different countries, raising additional questions about the reliability and validity of the outcome measures of the VCAs. A final issue is that numbers reported in charts and in-text descriptions occasionally did not match. Due to these concerns, confidence in the results is low.
Krautmann et al. (2021) investigated the safety of 7 monthly subcutaneous injections with bedinvetmab at different dose levels in healthy, mature laboratory dogs compared to a placebo. This study was randomised, controlled, and blinded. The authors do not describe randomised allocation, and the blinding of outcome assessors was incomplete. Sample sizes were small and were further reduced in each of the three studies in this preclinical trial, limiting statistical power and potentially impacting the detection of adverse health effects (AHEs). The sample population consisted of healthy, young dogs, limiting generalisability to sensitive subpopulations, such as older dogs with OA. However, this is the statutory safety protocol for licensing new drugs (EMEA VICH Topic GL43, 2008). Six randomised dogs were removed from the study subgroups during the acclimation period and replaced with dogs of the same sex. Four of those dogs were ‘deemed unsuitable’ with no further explanation for their removal or why replacement dogs were ‘deemed eligible’. It is difficult to determine what effect this replacement had on randomisation or magnitude, or direction of effects.
Krautmann et al. (2021) state that the 2 week trial of short-term co-administration of bedinvetmab and carprofen (NSAID) suggests that (a) a washout period between carprofen and bedinvetmab administration is not needed and that (b) intermittent short-term supplemental pain control via NSAIDs is possible. Study limitations suggest this statement should be viewed with caution.
Although rapidly progressive OA (RPOA) has not been reported in dogs, evidence from human clinical trials suggests a dose-dependent risk for developing RPOA with humanised anti-NGF mAb tanezumab both as monotherapy and when co-administered with NSAIDs (Schnitzer et al., 2015; and Hochberg et al., 2021).
Notably, the Food and Drug Administration (FDA) concluded that 2.5 mg tanezumab is not superior to oral prescription strength NSAIDs for alleviating pain and that adverse events such as accelerated joint destruction and abnormal peripheral sensation are more prevalent with tanezumab than NSAIDs (FDA, 2020; Hochberg et al., 2021; and Neogi et al., 2022). Due to these safety concerns, tanezumab has not been authorised (FDA, 2020; and EMA, 2021).
NSAIDs are a cornerstone for pain management of inflammatory conditions such as canine OA and demonstrate short-term efficacy (Hunt et al., 2015; and Hochberg et al., 2021). NSAID therapy can be associated with gastrointestinal, renal, and hepatic complications; their exact incidence rate is, however, unknown and, considering the frequent use of NSAIDs in clinical practice, likely low (Monteiro-Steagall et al., 2013; Hunt et al., 2015; and Gruen et al., 2022).
Studies by Lascelles et al. (2015) and Webster et al. (2014) have shown good pain relief with anti-NGF mAbs in dogs, and anecdotal evidence reveals a largely positive response of clients and veterinarians to the use of bedinvetmab for pain relief in clinical practice since its launch. This is promising and suggests that anti–NGF mAbs may be an additional choice for OA-related pain relief in dogs not tolerating NSAID treatment.
However, significant trial design limitations of the two reviewed studies in this Knowledge Summary mean that they provide only weak / inconclusive evidence for short-term safety and long-term efficacy of bedinvetmab. Additional well-designed studies examining the efficacy, effectiveness, and safety of short- and long-term treatment with bedinvetmab for dogs diagnosed with OA and chronic pain are needed.
Methodology
Search Strategy
Databases searched and dates covered: |
CAB Abstracts on OVID Platform (1973–2022 week 33) Web of Science Core Collection (1900–25/08/2022) PubMed accessed via NCBI platform (1910–25/08/2022) |
---|---|
Search strategy: |
CAB Abstracts:
Web of Science: (dog OR dogs OR bitch* OR canine) AND (arthrit* OR osteoarthrit* OR osteo–arthrit* OR OA OR ‘degenerative joint disease’ OR DJD OR ‘joint disease’) AND (bedinvetmab OR 'monoclonal antibody' OR 'nerve growth factor' OR NGF) AND (pain OR analgesia) PubMed: (dog OR dogs OR bitch* OR canine) AND (arthrit* OR osteoarthrit* OR osteo–arthrit* OR OA OR ‘degenerative joint disease’ OR DJD OR ‘joint disease’) AND (bedinvetmab OR 'monoclonal antibody' OR 'nerve growth factor' OR NGF) AND (pain OR analgesia) |
Dates searches performed: |
25 Aug 2022 |
Exclusion / Inclusion Criteria
Exclusion: |
|
---|---|
Inclusion: |
Clinical trials in which the safety or efficacy of bedinvetmab for the treatment of canine osteoarthritis was studied. |
Search Outcome
Database |
Number of results |
Excluded – Not answering PICO question |
Excluded – Conference articles, review articles, editorial materials, letters |
Total relevant papers |
---|---|---|---|---|
CAB Abstracts |
7 |
4 |
2 |
1 |
Web of Science |
30 |
22 |
6 |
2 |
PubMed |
18 |
16 |
0 |
2 |
Total relevant papers when duplicates removed |
2 |
Acknowledgements
The author would like to extend thanks to Louise Buckley for the introduction to evidence-based veterinary medicine, and to Maureen O’Mara for her guidance.
ORCID
Katrin Kronenberger: https://orcid.org/0000-0003-2717-6009
Conflict of Interest
The author declares no conflicts of interest.
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