Laboratory safety evaluations of izenivetmab, a caninized anti-nerve growth factor monoclonal antibody, for three-month alleviation of osteoarthritic pain in dogs.

Nerve growth factor (NGF) is essential for the survival of sensory and sympathetic neurons during development. However, in the adult, NGF and its interaction with tropomyosin receptor kinase A receptor (TrkA) has been found to play a critical role in nociception and nervous system plasticity in pain conditions. Thus, various monoclonal antibody (mAb) therapies targeting this pathway have been investigated in the development of new pharmacotherapies for chronic pain. Although none of the mAbs against NGF are yet approved for use in humans, they look very promising for the effective control of pain. Recently, species-specific anti-NGF mAbs for the management of osteoarthritis (OA)-associated pain in dogs and cats has been developed, and early clinical trials have been conducted. Anti-NGF therapy looks to be both very effective and very promising as a novel therapy against chronic pain in dogs and cats. This review outlines the mechanism of action of NGF, the role of NGF in osteoarthritis, research in rodent OA models and the current status of the development of anti-NGF mAbs in humans. Furthermore, we describe and discuss the recent development of species-specific anti-NGF mAbs for the treatment of OA-associated pain in veterinary medicine.

Canine osteoarthritis (OA) is a degenerative joint disease and is one of the most common chronic conditions in dogs and other species. The management of OA remains a longstanding focus in veterinary medicine. Traditionally, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first-line treatment option for canine OA. Recently, bedinvetmab, a canine-specific monoclonal antibody (mAb) targeting the nerve growth factor (NGF), has been added as a pain management option for canine OA. Is monthly bedinvetmab injection safe in dogs over 12 months old with OA compared with other interventions? Four articles met the inclusion criteria of a structured literature search and investigated adverse events (AEs) associated with bedinvetmab. Two studies investigated a 3-month treatment period and did not find an increase in AEs associated with bedinvetmab in comparison with the placebo control group. The third study compared the safety of bedinvetmab to meloxicam in a 2-month treatment period, where bedinvetmab was found to have fewer associated AEs. The fourth study conducted a disproportionality analysis, and the musculoskeletal AEs were reported significantly more frequently in bedinvetmab-treated dogs than other traditional therapeutics. There is conflicting evidence regarding the safety of bedinvetmab, though stronger evidence supported the safety of bedinvetmab when administered for under 3 months. Future research should investigate the long-term safety of bedinvetmab and incorporate radiographic imaging pre- and post-treatment to monitor unusual joint changes.

SP0098 What is New:Osteoarthritis

PurposeConsidering the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids for treating osteoarthritis (OA), development of drugs that are more effective and better tolerated than existing treatments is urgently needed. This systematic review aimed to evaluate the efficacy and safety of anti-nerve growth factor (NGF) monoclonal antibodies vs active comparator therapy, such as NSAIDs and oxycodone, in treating hip or knee OA.MethodsDatabases were comprehensively searched for randomized controlled trials (RCTs) published before January 2022. Efficacy and safety outcomes were assessed.ResultsSix RCTs that included 4325 patients were identified. Almost all the RCTs indicated that moderate doses of anti-NGF monoclonal antibody treatment significantly improved efficacy outcomes based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, the WOMAC physical function score and the Patient’s Global Assessment compared with those of the active comparator. At least half of the RCTs indicated that the incidence of severe adverse events, withdrawals due to adverse events (AEs) and total joint replacement were not significantly different between anti-NGF monoclonal antibody treatment and active comparator therapy, but the outcomes of some studies may have been limited by a short duration of follow-up. Most RCTs suggested that anti-NGF monoclonal antibody treatment had a lower incidence of gastrointestinal and cardiovascular AEs. However, the majority of RCTs reported a higher incidence of abnormal peripheral sensation with anti-NGF monoclonal antibody treatment. Furthermore, the higher incidence of rapidly progressive osteoarthritis (RPOA) with anti-NGF monoclonal antibody treatment should also not be overlooked, and the identification of patient characteristics that increase the risk of RPOA is critical in further studies.ConclusionBased on the current research evidence, anti-NGF monoclonal antibodies are not yet a replacement for analgesic drugs such as NSAIDs but might be a new treatment option for hip or knee OA patients who are intolerant or unresponsive to nonopioid or opioid treatment. Notably, however, considering the inconsistency and inconclusive evidence on the safety outcomes of recent studies, more research is needed, and long-term follow-up is required.

Nerve growth factor (NGF) belongs to the neurotrophin family and plays a fundamental role in the endurance of sensory and sympathetic neurons during embryogenesis. NGF, by interacting with tropomyosin receptor kinase A receptor (TrkA), modulates the pain pathway through the enhancement of the neurotrophic and nociceptor functions. Moreover, it has been demonstrated that NGF is upregulated in patients with chronic pain syndromes, which are difficult to treat. Thus, new non-pharmacological approaches, based on the use of different species-specific monoclonal antibodies (mAbs) targeting the NGF pathway, have been tested for the treatment of chronic pain in preclinical and clinical studies. With regard to preclinical investigations, anti-NGF mAbs have been used for the management of osteoarthritis (OA) and chronic low back pain animal models, with encouraging results. Moreover, anti-NGF mAb therapy is effective in animal models of neuropathic cancer pain. As regards patients with OA, although phase II and phase III clinical trials with tanezumab led to pain reduction, the safety was not observed in all these patients. Here, we review the preclinical and clinical studies on anti-NGF mAb therapy in chronic syndromes, dissect the role of NGF in pain transduction, and highlight the use of anti-NGF mAbs in humans.

IntroductionNerve growth factor plays a key role in the pathology of osteoarthritis (OA) related chronic pain. The aim of these studies was to evaluate the safety, tolerability, pharmacokinetics, and clinical response of AMG 403, a human anti-nerve growth factor monoclonal antibody, in healthy volunteers and subjects with knee OA.MethodsTwo phase I, randomized, placebo-controlled, double-blind studies were conducted. The single-ascending dose study randomized healthy volunteers (n = 48) 3:1 to receive AMG 403 (1, 3, 10, or 30 mg intravenously; or 10 or 30 mg subcutaneously; n = 8 per group) or placebo. The multiple-ascending dose study randomized knee OA subjects (n = 18) 3:1 to receive AMG 403 (3, 10, or 20 mg subcutaneously once monthly for four doses) or placebo. Safety, tolerability, and pharmacokinetics (PK) were assessed for both studies. Patient’s and physician’s disease assessments and total WOMAC score were determined in knee OA subjects.ResultsAMG 403 appeared to be well-tolerated after single and multiple doses, except for subject-reported hyperesthesia, pain, and paresthesia (mild to moderate severity). These treatment-emergent neurosensory events showed evidence of reversibility and a possible dose-dependence. Three serious adverse events were reported in AMG 403 treated subjects, but were not considered treatment related. AMG 403 PK was linear with an estimated half-life of 19.6 to 25.8 days. After multiple doses, AMG 403 PK showed modest accumulation (≤2.4-fold increase) in systemic exposure. Knee OA diagnosis, body weight, and anti-drug antibody development did not appear to affect AMG 403 PK. Patient’s and physician’s disease assessments and total WOMAC score showed improvement in AMG 403 treated knee OA subjects compared with placebo.ConclusionsAMG 403 was generally safe and well-tolerated in both healthy volunteers and knee OA patients, and exhibited linear pharmacokinetics. Preliminary clinical efficacy was observed in knee OA subjects.Trial registrationClinicalTrials.gov NCT02348879. Registered 23 December 2014. Clintrials.gov NCT02318407. Registered 2 December 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0797-9) contains supplementary material, which is available to authorized users.

To conduct a systematic review and meta-analysis of the efficacy of anti-nerve growth factor (NGF) monoclonal antibodies in osteoarthritis pain (hip and knee). Grade the evidence for anti-NGF use. An interdisciplinary work group conducted a literature search for anti-NGF use in osteoarthritis. The systematic review was performed in accordance with methods described by the Cochrane collaboration. General inclusion criteria included all osteoarthritis trials studying any monoclonal anti-NGF antibody at any dose/phase. Excluded studies were those where participants received NSAIDs or analgesics other than anti-NGF antibodies. The Jadad Scale score was used to assess the quality of the included studies. Thirteen studies were included in the analysis, involving 8145 participants with a diagnosis of hip and/or knee osteoarthritis. Anti-NGF antibody treatment was associated with a significant improvement in all Western Ontario and McMaster Universities Arthritis Index (WOMAC) indices when compared to placebo. These agents were not associated with a significantly increased incidence of serious adverse events but were associated with significant increases in therapy discontinuation due to adverse events or side effects (e.g., peripheral neuropathy). Future randomized clinical trials are needed to characterize the overall risk-to-benefit ratio of anti-NGF antibodies in managing pain associated with OA, particularly with long-term use, in order to verify their efficacy and safety in clinical practice.

Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs

Purpose: To evaluate the safety, tolerability, pharmacokinetics and immunogenicity of DS002 injection, an anti-nerve growth factor (anti-NGF) monoclonal antibody for treating pain conditions, in healthy Chinese subjects.Methods: This study was a single-center, randomized, double-blind, single-dose escalation, placebo-controlled design (CTR20210155). A total of 53 healthy subjects, 27 male and 26 female, were enrolled in this study, and one subject withdrew from the study before administration. Seven dose groups were set up, which were 0.5 mg, 1.0 mg, 2.0 mg, 4.0 mg, 7.0 mg, 12.0 mg and 20.0 mg, respectively. The drug was administered by single subcutaneous injection. Four subjects were enrolled in the first dose group (0.5 mg) received DS002. Other dose groups enrolled eight subjects each, six of whom received DS002 while the other two received a placebo. Safety, tolerability, pharmacokinetic parameters and immunogenicity of DS002 were assessed.Results: DS002 was well tolerated; all adverse events were Grade 1–2, and did not reach the termination standard of dose increment within the range of 0.5–20.0 mg. Adverse event rates were generally similar across treatments. After a single subcutaneous injection, the median Tmax in different dose groups ranged 167.77–337.38 h; mean t1/2 ranged 176.80–294.23 h, the volume of distribution (Vz) ranged 5265.42–7212.00 ml, and the clearance rate (CL) ranged 12.69–24.75 ml/h. In the dose range of 0.5–20.0 mg, Cmax ranged from 51.83 ± 22.74 ng/ml to 2048.86 ± 564.78 ng/ml, AUC0-t ranged from 20615.16 ± 5698.28 h·ng/mL to 1669608.11 ± 387246.36 h·ng/mL, and AUC0-inf ranged from 21852.45 ± 5920.21 h·ng/mL to 1673504.66 ± 389106.13 h·ng/mL. They all increased with dose escalation, and Cmax and AUC0-t did not have a significant dose-linear relationship, whilst AUC0-t was not dose-dependent at all. anti-drug antibody test results of each group of all subjects in this trial were negative.Conclusion: DS002 showed satisfactory safety within the dose range of 0.5 mg–20.0 mg. The absorption and metabolism of DS002 were slow, it exhibited a low volume of distribution and the clearance rate was low. These data suggest that DS002, by blocking nerve growth factor, is expected to become a novel, safe and non-addictive treatment for pain conditions.

Canine osteoarthritis (OA) is a prevalent, progressive, and debilitating joint disorder characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling. This multifactorial disease leads to chronic pain and significant impairment of quality of life. As OA remains incurable, therapeutic strategies have shifted toward comprehensive multimodal management aimed at addressing the disease’s complex pathophysiology. This review presents an evidence-based overview of current approaches, including weight management, rehabilitation, pharmacologic therapies (Non-Steroidal Anti-Inflammatory Drugs, anti-Nerve Growth Factor monoclonal antibodies), disease-modifying osteoarthritis drugs, regenerative treatments, and nutraceuticals. This study also highlights practical challenges and future directions, emphasizing individualized treatment plans to optimize outcomes in canine OA.

Frunevetmab is a felinized anti-nerve growth factor monoclonal antibody that alleviates osteoarthritis (OA) pain in cats by blocking nerve growth factor (NGF) signaling. While its efficacy is established, comprehensive real-world safety profiles remain limited. To analyze frunevetmab-associated adverse events (AEs) using real-world data from the United States Food and Drug Administration (FDA) Animal Drug Adverse Events (ADAE) database. Adverse event reports submitted for cats receiving frunevetmab, extracted from the FDA ADAE database (January 2022 - December 2024). Disproportionality in frunevetmab-associated AEs was assessed by calculating the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence-propagation neural network, and the multi-item gamma Poisson shrinker. From 33,378 feline AE reports, 5,248 frunevetmab-specific reports were analyzed. Frunevetmab-induced AEs spanned 24 system organ categories. Among the 19 significant preferred terms (PTs) identified, the most frequently reported AEs included pruritus, unspecified skin disorders, alopecia, dermatitis and eczema, and unspecified skin lesions. Notably, the AEs with the highest signal strength were skin ulceration, unspecified skin disorders, unspecified skin lesions, injection site pain, and dermatitis and eczema. In addition, unexpected significant AEs (e.g., abnormal cytology, arthritis, paresis) were detected, all of which were absent from the package insert. We identified new potential AE signals for frunevetmab, emphasizing the need for robust clinical monitoring. Although these hypothesis-generating findings from disproportionality analysis require validation, they offer immediate, valuable guidance for veterinarians to optimize the safe use of this treatment in cats with OA.

Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies

In order to reassess the role of nerve growth factor (NGF) on rat basal forebrain cholinergic neurons (BFCNs) survival and/or phenotype maturation during the early postnatal life, we immunoneutralized NGF in vivo. Hybridoma cells producing the neutralizing anti-NGF monoclonal antibody alphaD11 were implanted in the lateral ventricle of the rat at different postnatal ages (P2, P8 and P15) and the effects on the number and the soma size of cholinacetyltransferase (ChAT) positive neurons were analysed 1, 2 or 3 weeks after the injection. A marked decrease in the number and in the soma size of BFCNs was observed implanting hybridoma cells at P2 and performing the analysis 1 week later. These effects are reversed 3 weeks after the implant of hybridoma cells at P2. At this time point, the levels of alphaD11 antibodies in the brain parenchyma are still in a vast molar excess over endogenous NGF. No effects on BFCNs were observed implanting alphaD11 cells at P15 while LGN neurons showed marked shrinkage. Our results demonstrate that the reduction in the number of ChAT-positive neurons during the first two postnatal weeks of anti-NGF treatment is not due to cell death. We conclude that NGF is not a survival factor for BFCNs, and that the influence of NGF on BFCNs cell maturation during the first 2 postnatal weeks is transient and reversible. Our results on tyrosine kinase (Trk) coexpression, suggest that NGF may cooperate with other factors in the cholinergic phenotype differentiation and maintenance after the second postnatal week.

BackgroundFrunevetmab, a felinized antinerve growth factor monoclonal antibody, effectively decreases osteoarthritis (OA) pain in cats.ObjectiveTo evaluate the efficacy of frunevetmab given at monthly intervals in a randomized, placebo‐controlled, parallel‐group, double‐blind superiority study.AnimalsTwo hundred seventy‐five client‐owned cats with naturally‐occurring OA pain and associated mobility impairment and disability.MethodsRandomized, placebo‐controlled, parallel‐group, double‐blind, superiority study. Following screening, cats received frunevetmab (nominal dose of 1.0 mg/kg, SC [effective dose range of 1.0‐2.8 mg/kg]) or placebo on days 0, 28, and 56. Outcome measures were owner questionnaires and veterinary physical and orthopedic evaluations at days 28, 56, and 84. Success/failure rates (and numbers needed treat, NNT) and change in scores (and standardized effect size, ES) were analyzed.ResultsFrunevetmab (182) and placebo (93) treated cats were enrolled and received at least 1 treatment. Significant improvement with frunevetmab over placebo occurred at days 28 and 56 for the client specific outcome measures (CSOM) questionnaire (success rates and total scores [NNT of 9 and ES of 0.3 at day 56]); at days 28 and 56 for owner‐assessed global treatment response; and at days 56 and 84 for veterinarian‐assessed joint pain (ES of 0.18 at day 56). Adverse events did not differ between groups, except skin disorders which collectively occurred significantly more frequently in frunevetmab treated (32/182 cats) vs placebo (8/93 cats).Conclusions and Clinical ImportanceFrunevetmab has the potential to address a critical gap in the treatment of pain because of osteoarthritis in cats.

BackgroundNeutralizing antibodies against nerve growth factor (NGF) are analgesic in rodent models, naturally occurring degenerative joint disease (DJD) pain in dogs, and chronic pain in humans.ObjectivesTo evaluate the efficacy of a fully felinized anti‐NGF antibody (NV‐02) for the treatment of DJD pain and mobility impairment in cats.AnimalsThirty‐four client‐owned cats with DJD‐associated pain and mobility impairment.MethodsIn a placebo‐controlled, pilot, masked clinical study, cats were randomized to a single treatment with NV‐02 (0.4 mg/kg SC [n = 11] or 0.8 mg/kg SC [n = 12]) or placebo (saline, SC [n = 11]). Activity was measured objectively. Additionally, owners completed clinical metrology instruments (client‐specific outcome measures [CSOM] and feline musculoskeletal pain index [FMPI]) on days 0 (screening), 14 (baseline), 35, 56, and 77. A repeated‐measures model was used to evaluate the objective activity data.ResultsNV‐02 significantly increased objectively measured activity overall (P = .017) and at 2 (P = .035), 3 (P = .007), 4 (P = .006), 5 (P = .007), and 6 (P = .017) weeks after treatment. CSOM scores (P = .035) and pain (P = .024) showed a significant effect of treatment 3 weeks after administration. In the treatment group, 83% of the owners correctly identified the treatment administered compared with 45% of owners in the placebo group (P = .013). No treatment‐related adverse effects were identified.ConclusionsThese pilot data demonstrate a 6‐week duration positive analgesic effect of this fully felinized anti‐NGF antibody in cats suffering from DJD‐associated pain.