Anti-nerve Growth Factor Monoclonal Antibodies Research Articles

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

In their letter to the editor, Farrell et al., (2024) presented questions related to canine joint health after treatment with the anti-Nerve Growth Factor (NGF) monoclonal antibody (mAb) bedinvetmab, which was presented as a component of a non-clinical laboratory safety assessment published in Krautmann et al., (2021). Their questions appear to have stemmed from an anti-NGF mAb developed for the treatment of osteoarthritis in humans (tanezumab; FDA, 2021) which in 2021 failed to achieve marketing approval due to an unfavorable benefit: risk profile, primarily due to a syndrome called Rapidly Progressive Osteoarthritis (RPOA) which occurred more commonly in treatment groups when compared to controls. Farrell et. al. (2024) have posed questions on radiographic and histopathologic bone findings from studies included in Krautmann, et al., (2021) and communicated in the FDA’s Freedom of Information summary for Librela (FDA, 2023). These findings have previously been determined to be incidental and not bedinvetmab-associated. To address the questions posed, it is important to briefly define RPOA and summarize the syndrome in humans, review why the bone/joint findings in bedinvetmab safety studies in dogs are not indicative of RPOA or an RPOA-like condition, provide an update on joint health after use of bedinvetmab since market approval (>3 years in some markets), and summarize why Zoetis, the manufacturer of Librela, has confidence in joint safety after use of bedinvetmab in dogs.

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

We are writing to express our interest in the article entitled “Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs”, published in the October, 2021 issue of The Veterinary Journal, Volume 276, 105733, by Krautmann and others.

Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1mg/kg IV or 0.1-0.3mg/kg SC)/fixed dose (9-12mg IV or 1-12mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1mg SCdose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Cutaneous lesions and clinical outcomes in five cats after frunevetmab injections.

This case series describes five cats with cutaneous adverse events after subcutaneous administration of frunevetmab, a felinised anti-nerve growth factor monoclonal antibody, including histopathological findings in one case. All cats displayed moderate to severe pruritus resulting in self-trauma to the neck and/or head, causing lesions ranging from superficial dermatitis to alopecia and ulcerations. There were no reactions at the injection sites. In one cat, clinical signs developed after the second frunevetmab dose the cat received, with no reaction noted after the first dose. For the remaining cats, clinical signs were observed after their first dose of frunevetmab. The onset of the first episode of pruritus and self-trauma was 3-18 days after the most recent frunevetmab injection. Three cats had one or more additional frunevetmab injections after the original adverse event and all had subsequent reactions. Subsequent reactions were either similar in time frame or occurred more rapidly, with similar or more severe pruritus compared with the original reactions. Treatments and outcomes varied between cases. Frunevetmab is a novel, monthly injectable monoclonal antibody for the management of pain associated with osteoarthritis in cats. This is the first published report detailing the nature of cutaneous adverse events associated with this treatment, and the first report of the histopathological findings.

The effect of anti-nerve growth factor monoclonal antibodies on the clinical signs of degenerative joint disease in cats

PICO Question Are felinised anti-nerve growth factor monoclonal antibodies (frunevetmab) effective at reducing the clinical signs of pain and immobility in cats with degenerative joint disease when compared with no treatment? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed Three peer-reviewed randomised controlled trial treatment studies, two of which were pilot studies. Strength of evidence Moderate. Outcomes reported All three studies concluded that there was a statistical reduction in pain and an improvement in mobility in the groups administered frunevetmab, when compared to the groups administered the placebo. Conclusion There is moderate evidence suggesting that the administration of frunevetmab by injection led to a reduction in pain and an increase in mobility. Injections were given at day 0; day 0 and 28, or day 0, 28 and 56 depending on the study. Further research should be conducted to ensure repeatability, involving more objectively measured outcomes to reduce the reliance on subjective measures which are more likely to have associated bias. 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.

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

ObjectiveBedinvetmab, a fully canine anti-nerve growth factor monoclonal antibody, was evaluated in dogs for control of osteoarthritis-related pain in a study conducted to support registration in the USA. Study designRandomized, double-blind, placebo-controlled, multicenter, parallel-group study. AnimalsGeneral practice client-owned dogs with osteoarthritis (n = 272). MethodsDogs were block randomized 1:1 to placebo (saline, n = 137) or bedinvetmab (n = 135; 0.5–1.0 mg kg–1) administered subcutaneously, once monthly. The primary end point, day 28 Canine Brief Pain Inventory (CBPI) treatment success (TS), required pain severity score (PSS; 0–10) decrease ≥1 and pain interference score (PIS; 0–10) decrease ≥ 2. CBPI TS rates [and number needed to treat (NNT)], change in scores [and standardized effect size (ES)], change in quality of life (QoL) and bedinvetmab half-life were calculated. ResultsSignificant (p < 0.05) improvement with bedinvetmab over placebo occurred (days 28, 42, 56, 84) for CBPI TS. Of cases evaluable for day 28 CBPI TS (placebo, n = 131; bedinvetmab, n = 128), success rates were 36.6% and 47.4%, respectively (p = 0.0410) (NNT, 9.3; PSS and PIS ES, 0.3). CBPI TS increased after the second dose in both groups, plateaued for bedinvetmab at day 42 and decreased for placebo beginning day 84. Day 84 NNT (4.3), PSS (0.4) and PIS (0.5) showed continued improvement with monthly dosing. After the first dose, mean (± standard deviation) bedinvetmab half-life was 19.1 (8.3) days. Adverse events were similar between groups and not considered treatment-related. There was a significant effect of bedinvetmab versus placebo on all CBPI components (PIS, PSS, QoL). Conclusions and clinical relevanceThese results corroborated those previously reported and provide further support of safety and effectiveness of bedinvetmab (0.5–1.0 mg kg–1) administered subcutaneously at monthly intervals to dogs for control of osteoarthritis-related pain.

First-in-human study to assess the safety, tolerability, pharmacokinetics and immunogenicity of DS002, an anti-nerve growth factor monoclonal antibody.

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 0.5mg, 1.0mg, 2.0mg, 4.0mg, 7.0mg, 12.0mg and 20.0mg, respectively. The drug was administered by single subcutaneous injection. Four subjects were enrolled in the first dose group (0.5mg) 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 0.5-20.0mg. Adverse event rates were generally similar across treatments. After a single subcutaneous injection, the median Tmax in different dose groups ranged 167.77-337.38h; mean t1/2 ranged 176.80-294.23h, the volume of distribution (Vz) ranged 5265.42-7212.00ml, and the clearance rate (CL) ranged 12.69-24.75ml/h. In the dose range of 0.5-20.0mg, Cmax ranged from 51.83 ± 22.74ng/ml to 2048.86 ± 564.78ng/ml, AUC0-t ranged from 20615.16 ± 5698.28h·ng/mL to 1669608.11 ± 387246.36h·ng/mL, and AUC0-inf ranged from 21852.45 ± 5920.21h·ng/mL to 1673504.66 ± 389106.13h·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 0.5mg-20.0mg. 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.

Does anti-nerve growth factor monoclonal antibody treatment have the potential to replace nonsteroidal anti-inflammatory drugs and opioids in treating hip or knee osteoarthritis? A systematic review of randomized controlled trials.

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.

Articular Cartilage Regeneration in Veterinary Medicine.

Cartilage is an avascular tissue with a limited rate of oxygen and nutrient diffusion, resulting in its inability to heal spontaneously. Articular cartilage defects eventually lead to osteoarthritis (OA), the endpoint of progressive destruction of cartilage. In companion animals, OA is the most common joint disease, and many pain management and surgical attempts have been made to find an appropriate treatment. Pain management of OA is usually the first choice of OA therapy, which is often managed with nonsteroidal anti-inflammatory drugs (NSAIDs). To avoid known negative side effects of NSAIDs, other approaches are being considered, such as the use of anti-nerve growth factor monoclonal antibodies (anti-NGF mAB), hyaluronic acid (HA), platelet-rich plasma (PRP), and mesenchymal stem cells (MSCs). The latter is increasingly being recognized as effective in reducing or even eliminating pain and lameness associated with OA. However, the in vivo mechanisms of MSC action do not relate to their differentiation potential, but rather to their immunomodulatory functions. Achieving actual regeneration of cartilage to prevent OA from developing or even revert already existing OA condition has not yet been achieved. Several techniques have been tried to overcome cartilage's inability to regenerate, from osteochondral transplantation, autologous chondrocyte implantation (ACI), and matrix-induced ACI (MACI). Combinatory use of MSCs unique features and biomaterials is also being investigated with the aim to as much as possible recapitulate the native microenvironment of the cartilage, yet so far none of the methods have produced reliable and truly effective results. Although OA, for now, remains an incurable disease, novel techniques are being developed, rendering hope for the future accomplishment of actual cartilage regeneration. The aim of this chapter is firstly to summarize known and developing pain management options for OA, secondly to present surgical attempts to regenerate articular cartilage, and finally to present the attempts to improve existing regenerative treatment options using mesenchymal stem cells, with the vision for the possible use of developing strategies in veterinary medicine.

Frunevetmab, a felinized anti-nerve growth factor monoclonal antibody, for the treatment of pain from osteoarthritis in cats.

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.

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

Nerve growth factor (NGF), a critical mediator of nociception, is a novel analgesic therapeutic target. Bedinvetmab, a canine monoclonal antibody (mAb), binds NGF and inhibits its interaction with tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR) receptors. The objective of three integrated laboratory studies was to demonstrate the safety of bedinvetmab in adult laboratory Beagle dogs. Daily health, veterinary, clinical pathology, systemic exposure, and anti-drug antibody evaluations were performed. Study 1 additionally included electrocardiography, neurologic, and ophthalmic assessments, and radiographic monitoring of joints of the appendicular skeleton. Study 2 evaluated T-lymphocyte-dependent immune function. Study 3 evaluated the safety of short-term concurrent administration of carprofen, a nonsteroidal anti-inflammatory drug (NSAID), with bedinvetmab. Studies 1 and 3 included terminal pathology and histopathology evaluations. Study designs and procedures included directed complementary morphologic and functional evaluations of a literature- and in vitro-based list of potential safety issues related to the NGF signaling pathway and characteristics engineered into this mAb. Screening-level general procedures evaluated effects associated with mAbs that target and inhibit soluble agonist cytokines.There were no treatment-related adverse changes in clinical evaluations, clinical neurological and ophthalmic examinations, joints, immune morphology or function, and no effects of short-term concurrent NSAID usage. Treatment-emergent immunogenicity was not observed. Bedinvetmab (1 mg/kg SC monthly; 3× and 10× dose multiples) was well tolerated in normal laboratory Beagle dogs for 6 months and with 2 weeks’ concurrent NSAID administration.

The Role of Anti-Nerve Growth Factor Monoclonal Antibodies in the Control of Chronic Cancer and Non-Cancer Pain.

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.

Efficacy and Safety of an Anti-nerve Growth Factor Antibody (Frunevetmab) for the Treatment of Degenerative Joint Disease-Associated Chronic Pain in Cats: A Multisite Pilot Field Study.

Background: Pain management for cats with degenerative joint disease (DJD) remains a critical unmet need. Recent work has shown promise for a feline-specific anti-nerve growth factor monoclonal antibody (frunevetmab) to deliver safe and effective pain management. Our objectives were to evaluate the efficacy and safety of frunevetmab administered twice using two administration routes (subcutaneous and intravenous) compared to placebo.Methods: This was a randomized placebo-controlled, double-masked study. After a week-long pain and activity baseline, 126 cats were randomized to receive injections of frunevetmab (IV then SC; n = 42 or SC then SC; n = 43) or placebo (IV then SC; n = 41) on Days 0 and 28. Owners completed questionnaires on Days 14, 28, 42, and 56. Accelerometry data were collected continuously throughout.Results: Owner questionnaire results showed significant improvement in frunevetmab-treated cats [compared to placebo; (p < 0.05)] at Days 42 and 56; no difference was found between routes of administration for frunevetmab. All groups had decreased objectively measured weekly activity from baseline; frunevetmab-treated cats had a mean decrease of 0.9%, while placebo-treated cats had a mean decrease of 9.3%. Treatments were generally well-tolerated. The majority of adverse events included dermatitis/alopecia related to activity-monitor collars; these occurred in a higher percentage of frunevetmab, compared to placebo, treated cats.Conclusions and Clinical Relevance: Treatment with frunevetmab provided improvements in owner ratings of mobility over treatment with placebo; these results were supported by objectively measured accelerometry. Frunevetmab has the potential to address a critical gap in the treatment of chronic pain in cats.

The Effectiveness of Anti-Nerve Growth Factor Monoclonal Antibodies in the Management of Pain in Osteoarthritis of the Hip and Knee: A PRISMA Systematic Review and Meta-Analysis.

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.

Pharmacological Treatment of Pain in Osteoarthritis: A Descriptive Review.

Osteoarthritis (OA) is the most common form of arthritis that is characterized by loss of articular cartilage and new formation of bone. Pain and functional disability are common features that lead to disability and poor quality of life. This review discusses the current state of knowledge concerning the treatment of pain in OA, with a focus on pharmacological treatments. This includes the use of non-steroidal anti-inflammatory drugs, acetaminophen, and other disease-modifying agents. An updated review of the role of anti-nerve growth factor monoclonal antibodies and other novel agents in the treatment of OA is also presented. In addition, a discussion of current research on biological agents such as small molecules targeting ion channels and G protein-coupled receptors is included. These new pharmacological interventions expand the frontier for treatment of patients with OA. The purpose of the review is to provide clinicians with information about the effectiveness of different pharmacological modalities in order to enable them to make the best choices for the treatment of their patients.

First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain.

The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology. Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti-nerve growth factor monoclonal antibody, in chronic or acute pain. In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3-1000 μg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design. The second study (CL002) was a placebo-controlled dose-escalation (tanezumab 10-1000 μg/kg; N = 50) study in patients undergoing bunionectomy surgery. Adverse event rates were generally similar across treatments. Most adverse events were generally mild to moderate in severity and no patients discontinued as a result of adverse events. Adverse events of abnormal peripheral sensation were more common with higher doses of tanezumab (≥100 μg/kg) than with placebo. These were generally mild to moderate in severity. Tanezumab provided up to 12 weeks of effective analgesia for OA knee pain, with statistically significant improvements at doses ≥100 μg/kg (P < 0.05). By contrast, no trend for analgesic activity was found when tanezumab was administered 8 to 16 hours before bunionectomy. The demonstration of a favorable safety profile and clinical efficacy in OA pain supports clinical development of tanezumab as a potential treatment for chronic pain conditions.

Nerve Growth Factor Antagonists: Is the Future of Monoclonal Antibodies Becoming Clearer?

Although there is an unmet need for pain medications that are both effective and safe, virtually no novel analgesics have been approved over the past two decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the clinical development of humanised anti-nerve growth factor monoclonal antibodies (anti-NGF mAbs) aroused particular interest. However, the US Food and Drug Administration (FDA) placed a clinical hold on anti-NGF mAb clinical studies in late 2010, first because of reports of serious joint-related adverse events, and afterwards because of sympathetic nervous system safety concerns. The development programmes of tanezumab and fasinumab resumed after the FDA lifted its hold in March 2015, whereas other anti-NGF mAbs were dropped by their sponsors. This article provides an updated review on the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies and public information from websites, and discusses the possible future role of these agents in managing chronic pain. The efficacy of anti-NGF mAbs was highly variable depending on the chronic pain condition studied. The most consistent and convincing results were obtained in patients with symptomatic osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain and peripheral neuropathic pain generated mixed results. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in cancer pain and urological chronic pelvic pain syndromes. Treatment-emergent adverse events were similar across anti-NGF mAbs, thus being suggestive of 'class-specific effects'. Although most patients tolerated anti-NGF agents well, neurosensory symptoms occurred frequently, and some patients developed new or worsened peripheral neuropathies. However, the most problematic safety issue was rapidly destructive arthropathies, leading to joint replacement surgery. To date, the aetiologies of joint-related side effects and their pathophysiology have not been clearly elucidated. However, some risk factors have been identified, such as higher doses of anti-NGF mAbs and longer drug exposure, concurrent nonsteroidal anti-inflammatory drug use and pre-existing subchondral insufficiency fractures. Taken together, the present data suggest that low-dose anti-NGF mABs may exhibit a favourable risk-benefit ratio in selected patients with certain chronic pain conditions, especially symptomatic osteoarthritis.

In Vitro and In Vivo Characterization of a Fully Felinized Therapeutic Anti-Nerve Growth Factor Monoclonal Antibody for the Treatment of Pain in Cats

In Vitro and In Vivo Characterization of a Fully Felinized Therapeutic Anti-Nerve Growth Factor Monoclonal Antibody for the Treatment of Pain in Cats

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

Reports of serious joint adverse events (AEs) due to osteonecrosis were noted during randomized placebo-controlled clinical trials of monoclonal antibodies to nerve growth factor (NGF), including tanezumab and fulranumab. All available medical records from subjects with reported cases of osteonecrosis, as well as records of subjects who underwent joint replacement during these studies, were reviewed by an independent adjudication committee that was established by each company; the committees were different for each company and included distinct individual experts. Cases were categorized as having definite osteonecrosis, normal or rapid progression of osteoarthritis (OA), another diagnosis or unable to determine the underlying diagnosis. The vast majority of investigator reported cases of osteonecrosis were adjudicated as either normal or rapid progression of OA. Indeed, the syndrome of rapid progression of OA associated with chondrolysis and bone destruction appears to be a safety signal that is associated with not only increasing doses of anti-NGF antibodies but also concomitant therapy with nonsteroidal anti-inflammatory drugs. These results have implications for future clinical trials of anti-NGF agents in OA and other painful conditions.

Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (Macaca fascicularis).

Two intravenous studies with tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. Study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (GD) 20 through parturition. Study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20-21 per group) from GD 20 through 48. In the absence of maternal toxicity, tanezumab increased stillbirth and post-birth infant mortality/morbidity, decreased infant growth and resulted in microscopic changes in the peripheral sympathetic and sensory nervous system of the infants at all doses. Decreased primary antibody responses and increased incidences in skin changes in infants were also observed. The no-observed-adverse-effect-level for maternal toxicity was 30 mg/kg and <0.5 mg/kg for developmental toxicity.