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In this study, researchers looked at the safety of tanezumab (a medication that blocks nerve growth factor) in Japanese people with chronic low back pain (CLBP). Researchers also looked at how well tanezumab improves the symptoms (pain and difficulty doing activities) of CLBP. People in the study were given oral (taken by mouth) celecoxib (a medication commonly used to treat CLBP) or injections of tanezumab (5 or 10 mg doses) under the skin of the belly or upper leg every 8 weeks for a total of 56 weeks. Side effects (something expected or unexpected that people experienced during the study that may or may not be due to the medication they received) occurred in 63.0% of people receiving tanezumab 5 mg, 54.8% of people receiving tanezumab 10 mg and 67.4% of patients receiving celecoxib. More people receiving tanezumab 5 mg (9.8% of people) had a side effect related to abnormal peripheral sensation (tingling, burning, numbness or sensitivity to heat or cold hands or feet) than people receiving tanezumab 10 mg (4.3% of people) or celecoxib (4.3% of people). More people receiving tanezumab (5 mg = 1.1% of people, 10 mg = 2.2% of people) had a problem with one of their joints (knees or hips) during the study than people receiving celecoxib (0% of people). All treatments improved pain and the ability to do activities. Overall, the researchers concluded that tanezumab was well tolerated in most people and may improve the symptoms of CLBP.

Introduction: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. Methods: Endpoints at week 16 included proportions of responders (C 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, IntroductionCombining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo.MethodsEndpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders.ResultsPooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints.ConclusionResponders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

OBJECTIVES The aim of this meta-analysis was to evaluate the efficacy and safety of tanezumab for the treatment of patients with knee or hip osteoarthritis (OA). METHODS PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to July 2020. Randomized-controlled trials comparing tanezumab with placebo or nonsteroidal anti-inflammatory drugs in patients with OA. Two investigators identified studies and independently extracted data, and conventional meta-analyses were conducted with Review Manager 5.3. The outcomes were pain relief, functional improvement, and risk of adverse events (AEs). RESULTS A total of 8 articles, comprising 9 randomized-controlled trials, were included. Overall, tanezumab was superior to placebo for relieving pain and improving function, as well as in the patient's global assessment. Tanezumab also had significant advantages over nonsteroidal anti-inflammatory drugs for relieving pain and improving function, as well as in the patient's global assessment. Significantly more patients discontinued treatment because of AEs after treatment with tanezumab. However, the differences in serious AEs and total joint replacement were not significant. Moreover, tanezumab-treated patients experienced significantly more rapid progression of osteoarthritis. DISCUSSION Tanezumab can alleviate pain and improve function for patients with OA of the hip or knee. Although tanezumab does not cause serious AEs, rapid progression of OA occurred in a small number of participants, so more clinical trials are needed to explore its safety.

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.

This study aims to evaluate the efficacy and safety of tanezumab administered as a fixed dosing regimen in patients with knee or hip osteoarthritis. Randomized controlled phase III trials (RCTs) that evaluated the efficacy and safety associated with tanezumab for knee or hip OA were systematically identified by searching electronic databases, including Cochrane Library, PubMed, and Embase, for 30 years from December 1990 up to July 2020. Ten relevant studies were included in our meta-analysis. The research was reported based on the preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure the reliability and verity of results. Our study showed that the tanezumab groups were more effective than the placebo groups in terms of mean change from the baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (P < .00001), WOMAC physical functional (P < .00001), and patient's global assessment (PGA) (P < .00001). Discontinued due to adverse events (AEs) (P < .00001), serious AEs (P = .02), abnormal peripheral sensations (both P < .00001), and peripheral neuropathy (P < .002) in tanezumab groups were significantly higher than that in control groups. Compared with placebo, tanezumab can effectively relieve pain and improve WOMAC physical function and patient's global assessment (PGA) in knee and hip osteoarthritis. Meanwhile, adverse events are transient in nature and generally well-tolerated. However, we still need large-sample, high-quality studies to investigate the long-term safety of tanezumab to give the conclusion.

Objectives To evaluate the safety of low-dose tanezumab in the treatment of knee or hip osteoarthritis (OA). Methods Databases were searched up to September 2019 for phase III randomized controlled trials (RCTs). Eleven phase III RCTs comprising 11,455 patients were eligible. The pooled estimates of safety outcomes were assessed and expressed using relative risks (RRs) and 95% confidence intervals with a random-effects model. Results Tanezumab significantly increased the incidence of rapidly progressive OA (RPOA; RR = 9.07, 95% CI = 1.21–67.90, P = 0.03) and abnormal peripheral sensation (APS; RR = 2.68, 95% CI = 1.64–4.37, P Conclusions These results demonstrate that RPOA and APS should be the most concerning AEs when using tanezumab in OA patients. Additional data are needed to define the optimal dose to minimize risk and to determine the optimal subjects to receive this treatment.

The treatment of chronic low back pain (cLBP) often involves multimodal pharmacologic and non-pharmacologic strategies. There remain shortcomings with these tools with regards to both effect size and side effects.In an effort to better address cLBP, anti-nerve growth factor (NGF) monoclonal antibodies (mAbs) are nearing marketing approval. This class of medications has been primarily evaluated for osteoarthritis, but are being examined at higher doses for use in cLBP. We review the efficacy of this class in treating LBP as well as their potential side effects based on nine phase II or III published clinical trials. Five trials evaluated Tanezumab and four trials evaluated Fasinumab, with seven trials evaluating nonspecific LBP, one evaluating sciatica related cLBP, and one evaluating vertebral fracture related cLBP.The results of available clinical trials indicate modest effectiveness with regard to reduction of pain in the low back, and improved functionality, compared to placebo in keeping with the effect size of other pharmacologic treatment modalities. Rapidly progressive osteoarthritis was infrequently reported. However, the continued observation of this serious side effects warrants careful patient selection and balancing the risks and benefits of anti-NGF mAbs in treating cLBP.

Supplemental Digital Content is Available in the Text. Placebo and tramadol-controlled study assessing long-term safety and efficacy of tanezumab in patients with chronic low back pain and inadequate response to standard analgesics., This randomized, double-blind, phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5 or 10 mg every 8 weeks), or oral tramadol prolonged-release (100-300 mg/day). Primary endpoint was change in low back pain intensity (LBPI) at week 16 for tanezumab vs placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire at week 16, and change in LBPI at week 2 for tanezumab vs placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10 mg met the primary endpoint by significantly improving LBPI at week 16 vs placebo; least squares (LS) mean (95% CI) difference = −0.40 (−0.76 to −0.04; P = 0.0281). Tanezumab 10 mg significantly improved all key secondary endpoints. Tanezumab 5 mg did not meet the primary endpoint (LS mean [95% CI] treatment difference vs placebo = −0.30 [−0.66 to 0.07; P = 0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5 mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97 to 1.70; P = 0.0846]), and 46.3% in the tanezumab 10 mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09 to 1.91; P = 0.0101]). Prespecified joint safety events were more frequent with tanezumab 10 mg (2.6%) than tanezumab 5 mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10 mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10 mg significantly improved pain and function vs placebo in patients with difficult-to-treat chronic low back pain. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement.

a). PURPOSE OF REVIEW: Osteoarthritis (OA) is the most common form of arthritis, and pain is the primary symptom of the disease, yet analgesic options for treating OA pain remain limited. In this review, we aimed to give an update on the current clinical and preclinical studies targeting two pathways that are being investigated for treating OA pain: the nerve growth factor (NGF) pathway and the transient receptor potential vanilloid-1 (TRPV1) pathway. b). RECENT FINDINGS: Antibodies against NGF, small molecule inhibitors of TrkA, TRPV1 agonists, and TRPV1 antagonists are all in different stages of clinical and pre-clinical testing for the treatment of OA pain. NGF antibodies have shown efficacy in the primary endpoints tested compared to placebo, however, rapidly progressive OA has been consistently observed in a subset of patients and the cause remains unclear. TRPV1 agonists have also demonstrated reduced pain with no serious adverse events – the most common adverse events include a burning or warming sensation upon administration. c). SUMMARY: Targeting the NGF and TRPV1 pathways appear effective for reducing OA pain, but further work is needed to better understand which patients may benefit most from these treatments. The anti-NGF antibody tanezumab and the TRPV1 agonist CNTX-4975 have both received fast-track designation from the FDA for the treatment of OA pain.

Objective: To systematically evaluate the effects of different drugs for the treatment of painful diabetic peripheral neuropathy.Methods: All literature from PubMed, Embase, and Cochrane Central Register of Controlled Trials published over the past 12 years (from January 1, 2008 to June 1, 2020) was searched, and two reviewers independently assessed study eligibility, continuous data extraction, independent assessment of bias risk, and graded strength of evidence. The pain score was used as the main result, and 30 and 50% pain reduction and adverse events were used as secondary results.Results: A total of 37 studies were included. Pregabalin, duloxetine, tapentadol, lacosamide, mirogabalin, and capsaicin were all more effective than placebo in alleviating the pain associated with diabetic peripheral neuropathy, while ABT-894 and gabapentin showed no significant effect. In addition, the efficacy of buprenorphine, tanezumab, fulranumab and others could not be concluded due to insufficient studies.Conclusion: Pregabalin and duloxetine showed good therapeutic effects on painful DPN, but adverse events were also significant. The analgesic effects of ABT-894 and gabapentin need to be further studied with longer and larger RCTs. As an opioid drug, tapentadol has a good analgesic effect, but due to its addiction, it needs to be very cautious in clinical use. Although lacosamide, mirogabalin, and capsaicin are more effective than placebo, the therapeutic effect is weaker than pregabalin. For the results of our meta-analysis, long-term studies are still needed to verify their efficacy and safety in the future.Systematic Review Registration: PROSPERO, identifier: CRD42020197397.

Musculoskeletal pain such as osteoarthritis (OA) and low back pain (LBP) are very common and contribute to enormous burden and societal costs, despite dramatic therapeutic advances over recent decades. Novel approaches and targeted therapies are required to satisfy the urgent unmet medical need of musculoskeletal pain relief in both conditions. Nerve growth factor (NGF) inhibitors have utilized novel mechanisms different from conventional drugs, which have a variety of gastrointestinal, cardiac, or renal adverse effects. Several phase 2/3 studies have been accomplished for these drugs, such as tanezumab, fasinumab, and tyrosine receptor kinase A (TrkA) inhibitors. We searched the literature using the PubMed database and clinical trials using ClinicalTrials.gov to identify original papers, meta-analyses as well as ongoing clinical trials assessing the efficacy and safety profile of these drugs. In this narrative review, we briefly overview the disease burden of musculoskeletal pain, the role of NGF signaling and its receptors in the genesis of pain, and the mechanisms of action of inhibitors of NGF signaling and downstream pathways, and then discuss the efficacy and safety of each investigational drug in OA and LBP. Finally, we briefly review two serious adverse effects of NGF inhibitors, namely rapidly progressive OA and sympathetic system effects, and conclude with possible barriers and potential research directions to overcome these.

AIM To assess the impact of pre-specified patient characteristics on efficacy and safety of subcutaneous tanezumab in patients with osteoarthritis (OA). METHODS Data were pooled from two (efficacy; N = 1545) or three (safety; N = 1754) phase 3 placebo-controlled trials. Change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and patient global assessment of OA (PGA-OA) scores was compared between tanezumab (2.5 and 5 mg) and placebo groups via analysis of covariance. Treatment-emergent adverse events (TEAEs) were summarised descriptively. Analyses were done in patient subgroups (men or women; age

Background Previous meta-analyses have reported the superiority of tanezumab versus placebo in the treatment of osteoarthritis (OA). However, they did not compare different injection methods (intravenous or subcutaneous), doses of injection. Objective The goal of this network meta-analysis (NMA) was to evaluate the therapeutic effects of different dosages and methods of injection of tanezumab on relieving pain in patients with OA. Methods An online systematic search was performed by using the PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov databases from inception to November 9, 2019. The goal was to identify randomized controlled trials (RCTs) that concentrated on the therapeutic effects of different dosages and methods of injection of tanezumab in patients with OA. The pairwise meta-analyses with the fixed effects model were undertaken with the “meta” package using R 3.6.0 programming language. In addition, an NMA with fixed effects was assessed using a gemtc software. The surface under the cumulative ranking curve value of each intervention was calculated to obtain a hierarchy of treatments. Results Of the 328 RCTs identified through the literature search, 12 RCTs were included in the current NMA. In terms of the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales, the most effective treatment was intravenous injection of tanezumab (10 mg; surface under the cumulative ranking curve values of 90% and 88%, respectively), and the least effective therapy was subcutaneous injection of tanezumab (2.5 mg; 20% and 19%). Conclusions To achieve high therapeutic efficacy and avoid treatment failure, an intravenous injection of tanezumab (10 mg) is recommended as an efficacious therapy, facilitating pain relief in patients with OA. However, this conclusion may also be affected by the limitations of this study owing to the small sample size and data heterogeneity, and further research should therefore be conducted to eliminate these limitations and to confirm the findings.

Background: Osteoarthritis (OA) high disability rate will increase as people getting older, and is the most prevalent form of arthritis in the future. This study identified the clinical effects of optimum doses of tanezumab for patients with OA.Method: Three electronic databases were searched up until January 15, 2021. The mean difference (MD) or odds ratio (OR) was considered an effect measure. The design-by-treatment interaction model was adopted for network meta-analyses. Analyses were conducted using WinBUGS 1.4.3 and R 4.0.5 software.Results: nine publications with 10 studies were included. Compared with placebo in network meta-analysis, except the outcomes of Western Ontario and McMaster Universities Osteoarthritis (WOMAC) stiffness subscale and joints replaced, all dosages of tanezumab in the other effectiveness outcome were superior to placebo, and the difference was statistically significant. However, there was no statistical difference among all different doses of tanezumab. Compared with placebo, except the outcomes of adverse events (AEs) and AEs of abnormal peripheral sensation, all different dosages of tanezumab weren’t superior to placebo in the other effectiveness outcome, and the difference was statistically significant. The 10 mg of tanezumab with highest SUCRA had the best effect, but it was associated with a higher safety event. Compared with placebo, except the outcomes of WOMAC stiffness subscale and joints replaced, all dosages of tanezumab in the other effectiveness outcome were superior to placebo, and the difference was statistically significant. Compared with placebo, except for the outcomes of AEs and AEs of abnormal peripheral sensation, all dosages of tanezumab in the other effectiveness outcome were superior to placebo, and the difference was statistically significant. Other direct comparisons showed no statistical difference.Conclusion: This study recommended that clinicians should give priority to the treatment of OA patients with a low dose of 2.5 mg according to the patient’s condition and actual situation. If the effect using tanezumab with 2.5 mg is not satisfactory, the increase up to 10 mg should be carefully pondered, because of a more unbalanced risk/benefit ratio.

Leslie Tive,1 Alfonso E Bello,2 David Radin,3 Thomas J Schnitzer,4 Ha Nguyen,1 Mark T Brown,5 Christine R West5 1Pfizer Inc, New York, NY, USA; 2Illinois Bone and Joint Institute, Glenview, IL, USA; 3Stamford Therapeutics Consortium, Stamford, CT, USA; 4Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 5Pfizer Inc, Groton, CT, USA Purpose: A pooled analysis was conducted to evaluate tanezumab efficacy and safety in patients with osteoarthritis (OA), including subgroup analyses of at-risk patients with diabetes, severe OA symptoms, and those aged ≥65 years.Patients and methods: Data from phase III placebo-controlled clinical trials of patients with moderate-to-severe OA of the knee or hip were pooled to evaluate tanezumab efficacy (four trials) and safety (nine trials). Patients received intravenous tanezumab, tanezumab plus an oral NSAID (naproxen, celecoxib, or diclofenac), active comparator (naproxen, celecoxib, diclofenac, or oxycodone), or placebo. Efficacy assessments included change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores, Patient’s Global Assessment (PGA) of OA, and percentage of patients with ≥30%, ≥50%, ≥70%, and ≥90% improvement in WOMAC pain. Safety assessments included adverse event (AE) documentation and physical and neurologic examinations.Results: Tanezumab significantly improved all efficacy end points in the overall population. Efficacy in at-risk patient subgroups was similar to the overall population. Incidence of AEs was highest in the tanezumab plus NSAID group and lowest in the placebo group. Incidence of AEs in the tanezumab monotherapy and active comparator groups was similar. Overall incidence of AEs was similar across subgroups. AEs of abnormal peripheral sensation were more frequently reported in tanezumab-treated patients compared with placebo or active comparator. Patients receiving active comparator had a slightly higher incidence of AEs suggestive of postganglionic sympathetic dysfunction.Conclusion: Tanezumab consistently provided significant improvement of pain, physical function, and PGA in individuals with OA, including patients with diabetes, severe OA symptoms, or aged ≥65 years. No increased safety risk was observed in at-risk patient subgroups.Trial registration: NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00809354, NCT00864097, NCT00863772, NCT01089725, NCT00985621. Keywords: tanezumab, efficacy, safety, osteoarthritis, nerve growth factor

Introduction: This prospective cohort study (ClinicalTrials.gov identifier: NCT02674386) evaluated the postoperative outcomes of patients who had undergone total joint replacement (TJR) while participating in one of three tanezumab (a nerve growth factor inhibitor) randomized phase 3 osteoarthritis (OA) studies. Materials and Methods: Eligible patients were those who underwent TJR (knee, hip, or shoulder) at any time during any of three tanezumab randomized phase 3 OA studies. Consenting patients were followed for 24 weeks post-surgery. Patients undergoing sub-total arthroplasty procedures were not eligible; there were no further protocol-defined exclusion criteria. Outcomes assessed in relation to joint adjudication outcome and prior tanezumab treatment included: 1) surgeon’s assessment of procedural difficulty (uneventful, minor complications, major complications) at the time of the TJR; 2) postsurgical complications (clinically significant events attributable to the TJR, derived from adverse events) up to week 24; and 3) additional/corrective procedures (procedures or investigations related to the TJR) up to week 24. Results: The 150 patients had received placebo (n=20), tanezumab 2.5mg (n=52), tanezumab 2.5mg titrated to 5mg (tanezumab 2.5/5mg, n=8), tanezumab 5mg (n=53), or a nonsteroidal anti-inflammatory drug (n=17) in the parent studies. The 150 patients were adjudicated to have primary osteonecrosis (n=1), rapidly progressive OA (RPOA) type 2 (n=8), RPOA type 1 (n=3), other joint outcome (n=6), normal progression of OA (NPOA) (n=130), or insufficient information to determine RPOA versus NPOA (n=2). Surgeon’s assessment of procedural difficulty was uneventful for 95.1% (116/122) of patients. Through the 24-week study, there were no postsurgical complications for 96.0% (144/150) of patients; the 6 patients who had complications were all adjudicated as NPOA (tanezumab 2.5mg, n=2; tanezumab 5mg, n=4). There were no additional/corrective procedures for 93.3% (140/150) of patients. Conclusion: Procedural difficulty of minor complications during surgery, postsurgical complications, and additional/corrective procedures were infrequent, although more common with tanezumab 5mg, typically occurring in patients adjudicated as NPOA. Adjudication outcome (RPOA/primary osteonecrosis vs. NPOA) was not associated with postoperative outcome.

Aims To assess the relative efficacy and tolerability of tanezumab (2.5, 5, and 10 mg) in osteoarthritis (OA) patients. Materials and methods Six randomized controlled trials (RCTs) including 3,813 patients and examining the efficacy and tolerability of tanezumab (2.5, 5, 10 mg), naproxen (1,000 mg), and placebo, based on the number of withdrawals among osteoarthritis patients, were included in this Bayesian random-effects network meta-analysis, which combined direct and indirect evidence. Results Tanezumab (5, 2.5, 10 mg) and 1,000 mg naproxen were more efficacious than placebo (odds ratio (OR): 0.34, 95% credible interval (CrI): 0.26 - 0.43; OR: 0.35, 95% CrI: 0.24 - 0.48; OR: 0.364, 95% CrI: 0.28 - 0.45; and OR: 0.44, 95% CrI: 0.32 - 0.61, respectively). The number of withdrawals due to lack of efficacy were lower in the tanezumab groups than in the naproxen group, and the difference was not significant. Ranking probability based on the cumulative ranking curve (SUCRA) indicated that 5 mg tanezumab had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy, followed by 2.5 mg tanezumab, 10 mg tanezumab, 1,000 mg naproxen, and placebo. Ranking probability based on SUCRA indicated that 2.5 mg tanezumab and placebo had the highest probability of being the most tolerable treatment, followed by 5 mg tanezumab, 1,000 mg naproxen, and 10 mg tanezumab. Conclusion Tanezumab (5 mg) had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy among the medications, while 2.5 mg tanezumab and placebo had the highest probability of being the most tolerable treatment.

[Abstract] Background: To evaluate if early improvements in pain and function with subcuta-neous tanezumab are meaningful and sustained over 24 weeks. Methods: Patients with moderate- to- severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within- patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT- OARSI) responders (within- patient) and Patient- reported Treatment Impact Assessment- Modified questionnaire. Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tan-ezumab group versus placebo from Week 2 through Week 12 (LS mean, unad-justed p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT- OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The propor-tions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. Significance: This exploratory analysis of data from a placebo- controlled, Phase 3 study of patients with moderate- to- severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24- week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

In this 12th annual installment of the Antibodies to Watch article series, we discuss key events in antibody therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency. Of these 16 mAbs, 11 are possible treatments for non-cancer indications and 5 are potential treatments for cancer. Based on the information publicly available as of November 2020, 44 antibody therapeutics are in late-stage clinical studies for non-cancer indications, including 6 for COVID-19, and marketing applications for at least 6 (leronlimab, tezepelumab, faricimab, ligelizumab, garetosmab, and fasinumab) are planned in 2021. In addition, 44 antibody therapeutics are in late-stage clinical studies for cancer indications. Of these 44, marketing application submissions for 13 may be submitted by the end of 2021. *Note added in proof on key events announced during December 1-21, 2020: margetuximab-cmkb and ansuvimab-zykl were approved by FDA on December 16 and 21, 2020, respectively; biologics license applications were submitted for ublituximab and amivantamab.

OBJECTIVE To assess the long-term safety and 16-week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA). METHODS This was a phase III randomized, double-blind, active treatment-controlled (using nonsteroidal antiinflammatory drugs [NSAIDs] as the active treatment control) safety trial of tanezumab (56-week treatment/24-week posttreatment follow-up) in adults who were receiving stable-dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.5 mg (n = 1,002) or 5 mg (n = 998) subcutaneously every 8 weeks. Coprimary efficacy end points at week 16 were changes in WOMAC pain and physical function scores and changes in PtGA. The primary joint safety end point over 80 weeks comprised adjudicated rapidly progressive OA type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture. Mean values, least squares mean values, and least squares mean differences between groups (with 95% confidence intervals [95% CIs]) were calculated. RESULTS Of 3,021 randomized patients, 2,996 received ≥1 treatment dose. Adverse events (AEs) were similar between patients treated with tanezumab 2.5 mg and those treated with NSAIDs, and were more prevalent in those treated with tanezumab 5 mg. Composite joint safety events were significantly more prevalent with tanezumab 2.5 mg and tanezumab 5 mg than with NSAIDs (observation time-adjusted rate/1,000 patient-years 38.3 [95% CI 28.0, 52.5] and 71.5 [95% CI 56.7, 90.2], respectively, versus 14.8 [95% CI 8.9, 24.6]; P = 0.001 for tanezumab 2.5 mg versus NSAIDs; P < 0.001 for tanezumab 5 mg versus NSAIDs). Tanezumab 5 mg significantly improved pain and physical function but did not improve PtGA at week 16 when compared to NSAIDs; corresponding differences between the tanezumab 2.5 mg and NSAID groups were not statistically significant. CONCLUSION In patients previously receiving a stable dose of NSAIDs, tanezumab administered subcutaneously resulted in more joint safety events than continued NSAIDs, with differences being dose dependent. Pain and physical function improved with both doses of tanezumab compared to NSAIDs, reaching statistical significance with tanezumab 5 mg at 16 weeks.

Publication spin, in the context of randomised clinical trials, is defined as ‘use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results’ (p. 2059).1 In our view, a secondary but clinically important alternative type of publication spin is reliance on statistically significant findings without regard to potential clinical implications of the estimated effects. The American Statistical Association (ASA) has commented on this issue, stating a statistically significant effect does not inform its size or importance.2 A later editorial more explicitly states that conclusions not be based solely on statistical significance.3 We believe the recently published trial by Berenbaum and colleagues4 meets our secondary definition of publication spin and does not meet the recommendation endorsed by the ASA. Berenbaum and colleagues conducted a three-arm phase III randomised …

Background Osteoarthritis (OA) causes pain, disability and impaired quality of life. Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the management of OA pain. Two randomised, placebo-controlled studies with a primary aim of assessing the efficacy and safety of subcutaneously administered tanezumab were recently completed as part of a phase 3 OA programme, and the data reported, separately. Here we report pooled analyses of secondary efficacy outcomes from these two trials: Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) treatment response and EuroQol 5 Dimension (EQ-5D-5L) questionnaire. Methods Both studies enrolled patients with moderate-to-severe OA of the hip or knee, for whom standard care was inadequate or unsuitable. In study one (NCT02709486) with primary endpoint at Week 24, patients received three doses of placebo, tanezumab 2.5 mg or tanezumab 5 mg (at baseline/Week 8/Week 16). Study two was a dose-titration study (NCT02697773) with primary endpoint at Week 16, where patients received two doses of: placebo at baseline/Week 8 (pooled with study one placebo group), tanezumab 2.5 mg at baseline/Week 8 (pooled with study one tanezumab 2.5 mg group) or tanezumab 2.5 mg at baseline/tanezumab 5 mg at Week 8 (pooled with study one tanezumab 5 mg group). The current analysis assessed differences between pooled groups in OMERACT-OARSI treatment response, and EQ-5D-5L questionnaire responses and overall utility scores, at Week 16. Results A total of 1,545 patients were evaluated. At Week 16 in the pooled analyses, more patients in the tanezumab 2.5 mg (76.0%, 390/513) or tanezumab 5 mg (77.4%, 400/517) groups than the placebo group (64.7%, 332/513) met the criteria for OMERACT-OARSI response (each p < 0.0001 versus placebo). Patients in the pooled placebo, tanezumab 2.5 mg and 5 mg groups, respectively, recorded their baseline pain/discomfort (EQ-5D-5L) as none (1.8%, 1.0%, 0.6%), slight (7.6%, 9.7%, 8.9%), moderate (52.6%, 50.7%, 50.7%), severe (35.1%, 36.3%, 36.4%) or extreme (2.9%, 2.3%, 3.5%). At Week 16, patients recorded their pain/discomfort as none (12.8%, 15.4%, 15.8%), slight (37.3%, 44.3%, 44.8%), moderate (40.6%, 33.9%, 32.0%), severe (8.8%, 6.4%, 6.4%) or extreme (0.4%, 0.0%, 1.0%). Improvements in mobility, self-care, usual activities and anxiety/depression were also seen. At Week 16, the change from baseline in EQ-5D-5L utility score was greater for the pooled tanezumab 2.5 mg group (difference in least squares means [95% confidence interval], 0.03 [0.01, 0.05], p = 0.0083) or tanezumab 5 mg group (0.04 [0.01, 0.06], p = 0.0015) compared with placebo. Conclusion Together, pooled analyses from these studies show that significant improvements in the composite measure OMERACT-OARSI response are accompanied by significant improvements in overall health status as assessed by the EQ-5D-5L utility score at Week 16 for tanezumab-treated patients compared with placebo. These studies were sponsored by Pfizer and Eli Lilly and Company. Disclosures D. Walsh: Consultancies; consulting fees (non-personal, pecuniary interest) from Pfizer, Lilly, GlaxoSmithKline, AbbVie, Medscape Education, Love Productions. T.J. Schnitzer: Consultancies; TJS has received consulting fees from Pfizer, Lilly, AbbVie, Aptinyx, Genzyme, Regeneron, and Vertex. Grants/research support; TJS has engaged in clinical research for AbbVie, Grünenthal, and Radius. F. Berenbaum: Consultancies; Consulting fees/remuneration from AbbVie, Merck, Regulaxis, 4P Pharma, Bone Therapeutics, Galapagos, Peptinov, Expanscience, Flexion, Janssen, MerckSerono, Novartis, Roche, Gilead, Sanofi, GlaxoSm. S. Howland: Corporate appointments; SH is an employee of Pfizer Ltd. Shareholder/stock ownership; SH holds Pfizer stock options. S. Wilhelm: Corporate appointments; SW is a Lilly employee. Shareholder/stock ownership; SW holds Lilly stock and/or stock options. R. Junor: Corporate appointments; RJ is an employee of Pfizer Ltd. Shareholder/stock ownership; RJ holds Pfizer stock and/or stock options.

Background Patients with mild-to-moderate carpal tunnel syndrome (CTS) are commonly treated with night splints and/or local corticosteroid injection. In the INSTINCTS (INjection versus SplinTing in Carpal Tunnel Syndrome) trial, we previously reported that a single corticosteroid injection is more effective than night splinting at 6 weeks but not at 6 months. The aims of follow-up at 12 and 24 months were to examine whether corticosteroid injection is clinically and cost-effective in reducing symptoms in the longer-term compared to night splinting and to compare rates of CTS surgery. Methods INSTINCTS was a pragmatic clinical trial in adults ≥18 years with mild-to-moderate CTS diagnosed using standardised clinical criteria. Participants were recruited from primary care or musculoskeletal interface services and randomised 1:1 to receive either a single carpal tunnel injection of 20mg methylprednisolone acetate or a night splint. Follow-up questionnaires were mailed at 6 weeks and 6, 12 and 24 months. Key clinical outcomes at 12 and 24 months were the Boston Carpal Tunnel Questionnaire (BCTQ), hand/wrist pain intensity (0-10 numeric rating scale (NRS)) and the number of patients referred for and receiving CTS surgery. Longitudinal mixed effect models were fitted to estimate overall treatment effect at each time point by including interaction terms between treatment and time, adjusted for age, gender, symptom duration and baseline score. The cumulative number (%) of participants i) referred or ii) undergoing CTS surgery were examined by treatment group. Cost-utility analysis was conducted from an NHS perspective to determine the cost-effectiveness of injection versus night splinting. Results 118 participants were randomised to night splinting and 116 to corticosteroid injection. In the splint group, 88 (78%) and 81 (74%) completed follow-up at 12 and 24 months respectively compared to 87 (77%) and 78 (72%) in the injection group. There were no statistically significant differences between splint and injection groups in BCTQ score at 12 (adjusted mean difference -0.09; 95%CI -0.30, 0.12) or 24 months (0.06; -0.16, 0.28) or hand pain NRS (12 months 0.03; -0.79, 0.85. 24 months 0.41; -0.45, 1.26). By 24-month follow-up, a greater proportion of the injection group had been referred for (28% vs 20%) and undergone (22% vs 16%) CTS surgery than the splint group. Injection was more costly (mean difference £68.59 (-120.84, 291.24)) with lower quality-adjusted life-years (QALYs) than splinting over 24 months (mean difference -0.022 (-0.074, 0.024)). Conclusion To our knowledge, this is the longest-reported follow-up of a randomised trial investigating the conservative management of CTS, with the largest sample size. Over 24-months, there were no differences in symptoms between groups and injection was not cost-effective compared with splinting. Surgical referral and intervention rates were low overall, but slightly more frequent in the injection group. Disclosures C.L. Burton None. T. Rathod-Mistry None. M. Blagojevic-Bucknall None. L.S. Chesterton None. G. Davenport None. K.S. Dziedzic None. S.M. Jowett Consultancies; Sue Jowett received payment as an independent advisor for a Pfizer chronic pain advisory board meeting in November 2018. H.L. Myers None. R.A. Oppong Consultancies; Raymond Oppong received payment as an independent advisor for a Pfizer Tanezumab HEOR Advisory Board Meeting in October 2018. D.A. Van der Windt None. E.M. Hay None. E. Roddy None.

ObjectiveTanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up.MethodsThis double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study.ResultsFrom March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, pConclusionTanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups.Trial registration numberNCT02709486.

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article–related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

Chronic lower back pain is a significant disease that affects nearly 20% of the worldwide population. Along with hindering patients' quality of life, chronic lower back pain is considered to be the second most common cause of disability among Americans. Treating chronic lower back pain is often a challenge for providers, especially in light of our current opioid epidemic. With this epidemic and an increased aging population, there is an imminent need for development of new pharmacologic therapeutic options, which are not only effective but also pose minimal adverse effects to the patient. With these considerations, a novel therapeutic agent called tanezumab has been developed and studied. Tanezumab is a humanized monoclonal immunoglobulin G2 antibody that works by inhibiting the binding of NGF to its receptors. NGF is involved in the function of sensory neurons and fibers involved in nociceptive transduction. It is commonly seen in excess in inflammatory joint conditions and in chronic pain patients. Nociceptors are dependent on NGF for growth and ongoing function. The inhibition of NGF binding to its receptors is a mechanism by which pain pathways can be interrupted. In this article, a number of recent randomized controlled trials are examined relating to the efficacy and safety of tanezumab in the treatment of chronic lower back pain. Although tanezumab was shown to be an effective pain modulator in major trials, several adverse effects were seen among different doses of the medication, one of which led to a clinical hold placed by the US Food and Drug Administration. In summary, tanezumab is a promising agent that warrants further investigation into its analgesic properties and safety profile.

Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety.

Tanezumab, a humanized monoclonal anti-NGF antibody, has demonstrated efficacy and safety profiles in Phase III clinical trials of chronic pain. In a 24-week study in non-human primates, morphological observations of sympathetic ganglia showed decreased ganglia volume, decreased neuronal size, and increased glial cell density compared with controls after 3 tanezumab treatments. Using stereological techniques to quantify glial cells, the present 26-week study found no significant difference after weekly treatments in total cervicothoracic ganglia satellite glial cell number between placebo- or tanezumab-treated cynomolgus monkeys. These findings suggest that tanezumab treatment does not result in a true gliosis in sympathetic ganglia.

Background:Tanezumab is a monoclonal antibody directed against nerve growth factor. It is in development for the treatment of moderate to severe chronic pain associated with osteoarthritis (OA) in adult patients for whom other treatments are ineffective or not appropriate. Phase 3 clinical trials have demonstrated the efficacy of subcutaneous tanezumab versus placebo for pain and function outcomes over various timepoints. Largely similar change from baseline was demonstrated in an oral nonsteroidal anti-inflammatory drug (NSAID)-controlled study.1,2,3,4 The efficacy of some other OA therapies can be dampened in patients with depression, anxiety, or insomnia.5,6,7Objectives:A post-hoc analysis to explore the efficacy of subcutaneous tanezumab after 16 weeks treatment, as compared to oral NSAID, in patients with OA and a history of depression, anxiety, or insomnia at baseline.Methods:Subgroup analysis of data from a randomized, double-blind, double-dummy, active-controlled phase 3 study of subcutaneous tanezumab (2.5 mg or 5 mg every 8 weeks) vs twice daily oral NSAID in patients (≥18 years) with radiographically-confirmed moderate to severe hip or knee OA (Kellgren-Lawrence grade ≥2; NCT02528188).4 Co-primary efficacy endpoints were change from baseline to week 16 in Western Ontario and McMaster Universities OA Index (WOMAC*) Pain and Physical Function subscale scores (both ≥5/10 at randomisation; increasing score indicates increasing pain/disability), and Patient’s Global Assessment of OA (PGA-OA, ≥3/5 at randomisation; increasing score indicates poorer condition). Enrolled patients had a history of inadequate pain relief with acetaminophen; inadequate pain relief with/intolerance to/contraindication to tramadol or opioids; or an unwillingness to take opioids. Patients were on a stable dose of NSAID for ≥30 days before screening. Data are presented as least squares (LS) mean change from baseline to week 16 for the whole population and for subgroups of patients with/without a history of depression, anxiety, or insomnia at baseline. Exploratory statistical analysis was conducted by analysis of covariance. P values were not adjusted for multiplicity. This exploratory post-hoc analysis was not part of the pre-specified hypothesis testing plan or included in any sample size calculations; therefore, comparisons between treatment arms or patient subgroups should be interpreted with caution.Results:Overall, 2996 patients were randomized and received at least one dose of study treatment (subcutaneous tanezumab 2.5 mg: n=1002; subcutaneous tanezumab 5 mg: n=998; oral NSAID: n=996). In this population (comprising patients with or without a history of anxiety, depression or insomnia), all treatments were associated with notable and largely similar magnitude improvements in WOMAC Pain, WOMAC Physical Function, and PGA-OA at week 16 (Figure 1). Across treatment groups, differences in LS mean change from baseline in patients with and without a history of depression, anxiety or insomnia ranged between 0 - 0.34 for WOMAC Pain and Physical Function and 0 - 0.19 for PGA-OA.Conclusion:Patients with a history of depression, anxiety, or insomnia did not appear to experience dampened improvements in pain or function with tanezumab or NSAID, as compared to those without.References:[1]Schnitzer T, et al. JAMA. 2019;322(1):37-48;[2]Berenbaum F, et al. Ann Rheum Dis. 2020;79(6):800-10;[3]Schnitzer T, et al. Semin Arthritis Rheum. 2020;50(3):387-93;[4]Hochberg M, et al. Arthritis Rheumatol. In Press;[5]Sharma A, et al. Open Access Rheumatol. 2016;31(8):103-13;[6]Mallen C, et al. PLoS Med. 2017;14(4):e1002273;[7]Campbell C, et al. Arthritis Care Res. 2015;67(10):1387-96.Acknowledgements:Study sponsored by Pfizer and Eli Lilly and Company. Editorial support was provided by Jennifer Bodkin of Engage Scientific Solutions and funded by Pfizer and Eli Lilly and Company.Disclosure of Interests:Philip J Mease Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly and Company, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly and Company, Novartis, Pfizer, Sun, UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly and Company, Novartis, Pfizer, Sun, UCB, Theresa Mallick-Searle Speakers bureau: Allergan, Abbvie, Eli Lilly and Company, Salix, Consultant of: Pfizer, Eli Lilly and Company, Elizabeth Johnston Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Dominique Menuet Employee of: Pfizer, Ruoyong Yang Employee of: Pfizer, Robert J Fountaine Shareholder of: Pfizer, Employee of: Pfizer.

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.

Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs).Serum samples from patients enrolled in phase III trials of tanezumab who experienced TJR (n = 174) or matched patients who did not (n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR.At baseline, biomarker combinations for patients who did not use NSAIDs before starting tanezumab and used NSAIDs during tanezumab treatment90 days ("nonNSAID"), identified 77% (95% confidence interval [CI]: 71-84%) of patients who experienced TJR and 77% (95% CI: 65-86%) who did not over a 6-month study period (on average). These biomarker combinations increased odds of identifying patients to remain free of a TJR by 3.3-fold. In patients who used NSAIDs continuously (during screening and ≥90 days during tanezumab treatment), 64% (95% CI: 54-73%) who had TJR and 75% (95% CI: 68-83%) who did not were identified by biomarker combinations different from nonNSAID patients, with an increase in odds of identifying patients to remain free of a TJR by two-fold.Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.

Back pain is the second leading cause of disability among American adults and is currently treated either with conservative therapy or interventional pain procedures. However, the question that remains is whether we, as physicians, have adequate therapeutic options to offer to the patients who suffer from chronic low back pain but fail both conservative therapy and interventional pain procedures before they consider surgical options such as discectomy, disc arthroplasty, or spinal fusion. The purpose of this article is to review the potential novel therapies that are on the horizon for the treatment of chronic low back pain. We discuss medications that are currently in use through different phases of clinical trials (I-III) for the treatment of low back pain. In this review, we discuss revisiting the concept of chemonucleolysis using chymopapain, as the first drug in an intradiscal injection to reduce herniated disc size, and newer intradiscal therapies, including collagenase, chondroitinase, matrix metalloproteinases, and ethanol gel. We also review an intravenous glial cell-derived neurotrophic growth factor called artemin, which may repair sensory nerves compressed by herniated discs. Another new drug in development for low back pain without radiculopathy is a subcutaneous monoclonal antibody acting as nerve growth factor called tanezumab. Finally, we discuss how platelet-rich plasma and stem cells are being studied for the treatment of low back pain. We believe that with these new therapeutic options, we can bridge the current gap between conservative/interventional procedures and surgeries in patients with chronic back pain.

Purpose of review Anti-nerve growth factor (NGF) antibodies hold tremendous potential for the management of osteoarthritis pain, but clinical trials have revealed serious adverse effects that are incompletely understood. This review discusses clinical trial results along with preclinical studies that have assessed NGF blockade in experimental osteoarthritis, in order to provide insight for future studies. Recent findings Systematic reviews have revealed that anti-NGF therapy, including tanezumab, is efficacious in improving pain and function, but serious adverse events, including rapidly progressive osteoarthritis and osteonecrosis, resulted in a moratorium on trials that was only recently lifted. Within the past year, preclinical testing has revealed effects of NGF blockade on both pain behaviors and joint structure in experimental models of osteoarthritis. Similar to clinical trial results, these studies in laboratory animals demonstrated analgesic efficacy of NGF blockade. Interestingly, several animal studies have suggested detrimental effects on joint integrity as a result of treatment, particularly when treatment is started early in the disease, when joint damage is mild to moderate. Summary NGF blockade continues to represent a promising new approach for the treatment of osteoarthritis pain, but the actual benefits and risks remain to be fully elucidated. Preclinical models may suggest patient populations that could be best served while limiting side-effects, but future work should further investigate the mechanisms of benefits and unwanted side-effects.

Objective To examine the onset and maintenance of efficacy of subcutaneous tanezumab for pain relief and functional improvement in difficult-to-treat patients with moderate-to-severe osteoarthritis (OA) in a 16-week dose-titration study (NCT02697773). Methods Patients were randomized to placebo (placebo group) or tanezumab 2.5 mg at baseline and week 8 (tanezumab 2.5 mg group), or tanezumab 2.5 mg at baseline and tanezumab 5 mg at week 8 (tanezumab 2.5/5 mg group). Analyses included change from baseline in average daily index joint pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and treatment responses (WOMAC Pain improvement criteria and Outcome Measures in Rheumatology-Osteoarthritis Research Society International [OMERACT-OARSI] criteria). Results The 696 patients received placebo (n = 232), tanezumab 2.5 mg (n = 231), or tanezumab 2.5/5 mg (n = 233). Average daily index joint pain was statistically significantly improved within the first week (day 3–5) with tanezumab 2.5 mg compared with placebo. On first post-randomization WOMAC measurement (week 2), both tanezumab groups had statistically significant improvements compared with placebo in WOMAC Pain and Physical Function, and more tanezumab-treated patients achieved treatment response criteria (≥30%, ≥50%, or ≥70% reduction in WOMAC Pain or OMERACT-OARSI response). Efficacy was generally maintained throughout the 16-week treatment period. Conclusion Subcutaneous tanezumab provided statistically significant improvements compared with placebo in average daily index joint pain within the first week and WOMAC Pain and Physical Function (week 2) that were generally maintained throughout the 16-week treatment period. Tanezumab 5 mg provided only modest additional efficacy over tanezumab 2.5 mg.

IMPORTANCE: Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments. OBJECTIVE: To assess 2 subcutaneous tanezumab dosing regimens for OA. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions. INTERVENTIONS: Patients received by subcutaneous administration either tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232). MAIN OUTCOMES AND MEASURES: Co–primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores. RESULTS: Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the tanezumab, 2.5 mg, group; 7.3 to 3.6 in the tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were −0.60 [−1.07 to −0.13; P = .01] for tanezumab, 2.5 mg, and −0.73 [−1.20 to −0.26; P = .002] for tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, −0.66 [−1.14 to −0.19; P = .007] for tanezumab, 2.5 mg, and −0.89 [−1.37 to −0.42; P

Bioanalytical challenges were encountered during developmental and reproductive toxicity studies of tanezumab in cynomolgus monkeys. Possible changes in breast milk composition over the postpartum period potentially complicated assessment of tanezumab concentration in this matrix, requiring validation of the quantification assay across different time intervals. Immunogenicity assessment in maternal serum was complicated by apparent increases in the incidence of antidrug antibody-positive results in treatment-naive samples as pregnancy progressed that were due to changes in the concentration of nerve growth factor, tanezumab’s target protein. This was overcome by employing gestational day-specific cut points throughout pregnancy. Researchers should recognize potential challenges associated with dynamic matrices/physiological conditions and anticipate that assays developed under normal conditions may require adaptation for specialized situations.

Background Increased nerve growth factor (NGF) levels are associated with chronic pain conditions, including low back pain and osteoarthritis (OA). NGF signalling through its receptor TrkA regulates pro-inflammatory neurotransmitters such as substance P (SP). Inhibition of NGF has shown therapeutic efficacy in knee OA [1] and chronic back pain [2], but trials have revealed rare cases of rapidly progressive OA of peripheral joints. Objectives To describe the tissue distribution of NGF, TrkA, SP and macrophages in facet joint osteoarthritis (FJOA) of the lumbar spine and their association with FJOA grade. Methods FJOA specimens were obtained by facetectomy from patients undergoing intervertebral fusion (n=10, average age 69 years, 5 males). FJOA severity and presence of synovial hypertrophy was graded using preoperative magnetic resonance imaging (MRI). Relative abundance of NGF, CD68 (macrophages), TrkA and SP in capsular synovium (SY), cartilage (CL), subchondral bone (SB) and subchondral bone marrow (BM) was evaluated semi-quantitatively on a scale ranging from 0-3 using immunohistochemistry. Association between imaging parameters and tissue expression was determined using Pearson correlation analysis. Results Synovial hypertrophy as determined by MRI was present in six cases (60%) and median Weishaupt grade of FJOA was 2 (1.5-3) corresponding with moderate to severe OA. NGF was abundantly expressed in SY (3 [0.5-3]) and to a lesser extent in BM tissues (2 [1-3]), whereas TrkA expression was detected in BM exclusively. NGF abundance in SY and BM showed a strong correlation (r=0.94), but did not associate with synovial hypertrophy or FJOA severity. CD68+ macrophages were highly abundant in BM (3 [1.5-3]) and sparse in SY tissues (0.5 [0-1]). The relative abundance of macrophages and NGF was strongly correlated in SY tissue only (r = 0.78). SP as a downstream mediator of NGF signalling was also abundantly expressed in SY, CL and BM tissues. Tissue distributions of CD68, NGF and SP are summarized in the figure. Conclusion NGF expression and signalling is evident in lumbar spine FJOA specimens, but not strongly associated with synovial hypertrophy or disease severity. These results are in agreement with recent studies of human knee OA, which have shown osteochondral NGF expression as a hallmark of symptomatic OA independently of chondropathy or synovitis [3]. References [1] Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, Brown MT.(2010) Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 363:1521. [2] Katz N, Borenstein DG, Birbara CA, Bramson C, Nemeth MA, Smith MD, Brown MT. (2011) Efficacy and safety of tanezumab in the treatment of chronic low back pain. Pain. 152(10):2248 [3] Aso K, Shahtaheri SM, Hill R, Wilson D, McWilliams DF, Walsh DA. (2019) Associations of symptomatic knee OA with histopathologic features in subchondral bone. Arthritis Rheumatol. ePub Disclosure of Interests Matthias Seidel Grant/research support from: Pfizer, Actelion, Consultant for: Pfizer, Lilly, Nathalie Busso: None declared, Veronique Chobaz: None declared, Cordula Netzer: None declared, Thomas Huegle Grant/research support from: AbbVie, Lilly, Novartis and Pfizer, Speakers bureau: AbbVie, Lilly, Novartis and Pfizer, Jeroen Geurts: None declared

Background Tanezumab, a monoclonal antibody against nerve growth factor, is in development for treatment of osteoarthritis (OA) pain. Objectives To assess efficacy and safety of tanezumab in patients with moderate to severe OA pain who have not responded to or cannot tolerate standard of care analgesics. Methods A randomized, double-blind, placebo-controlled study (24 week treatment; 24 week follow-up) was conducted in patients in Europe and Japan with moderate to severe OA pain of the knee or hip and history of insufficient pain relief or intolerance to acetaminophen, oral nonsteroidal anti-inflammatory drug, and either tramadol or opioids (or unwilling to take opioids). Patients received subcutaneous tanezumab (2.5 or 5 mg) or placebo at baseline, week 8, and week 16. Co-primary endpoints were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and Patient Global Assessment of OA (PGA-OA) scores at week 24. Safety, including independent adjudication of joint safety events, was assessed. Results Tanezumab 5 mg met all co-primary endpoints (Fig. 1). Tanezumab 2.5 mg met WOMAC Pain and Physical Function endpoints but not the PGA-OA endpoint; thus, this dose did not meet pre-specified efficacy criteria. The occurrence of adverse events (AEs) and discontinuations due to AEs were similar across groups, though serious AEs occurred more frequently in both tanezumab groups relative to placebo. Two deaths in the 5 mg tanezumab group were deemed unrelated to treatment. The only AE occurring in =3% of patients in any group, and more frequently (>1% difference) in both tanezumab groups relative to placebo, was OA. Total joint replacements (TJR) occurred in 6.7%, 7.8%, and 7.0% of patients in the placebo, tanezumab 2.5 mg, and tanezumab 5 mg groups, respectively. Joint safety events, including TJRs, were mostly adjudicated as normal progression of OA (58/79; 73.4%). Pre-specified joint safety events occurred in 0% and 2.5% (n = 14) of patients in the placebo and tanezumab (2.5 mg = 1.8%; 5 mg = 3.2%) groups, respectively. These 14 events in the tanezumab groups included rapidly progressive OA (2.5 mg n = 4; 5 mg n = 8), subchondral insufficiency fracture (2.5 mg n = 1), and primary osteonecrosis (5 mg n = 1). Conclusion Tanezumab 5 mg significantly improved all co-primary endpoints of pain, physical function, and PGA-OA. Tanezumab 2.5 mg significantly improved pain and physical function, but did not reach significance on PGA-OA. AEs are consistent with previous studies of tanezumab in OA. A similar number of TJRs were reported across groups, though overall joint safety events were more frequent with tanezumab than placebo. Disclosure of Interests Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (throughinstitution), Consultant for: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Francisco J. Blanco Grant/research support from: Galapagos NV, Abbvie, Sanofi, Bristol MS, UCB, Novartis, Genentech Inc., Regeneron, Lilly, Celgene, Amgen, Janssen, kiniksa Pharmaceuticals, Ltd., Tedec Meiji., Consultant for: Pfizer, Gebro, Bioiberica, Sanofi., Ali Guermazi Consultant for: AstraZeneca, Pfizer, TissueGene, Galapagos, Roche and MerckSerono., Eric Vignon Consultant for: Pfizer/Eli Lilly, Kenji Miki Speakers bureau: Pfizer, Janssen, Ayumi, Hisamitsu, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer, Lars Viktrup Shareholder of: Eli Lilly & Company, Grant/research support from: Astella, Lundbeck, Coloplast, Employee of: Ciba Geigy, Eli Lilly and Company (currently), Rod Junor Shareholder of: Pfizer, Employee of: Pfizer, William Carey Shareholder of: Pfizer, Employee of: J&J, Pfizer (currently), Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer, Employee of: Pfizer

The neurotrophin and cytokine families of proteins regulate neuronal functions that affect survival, growth, and differentiation. Because of their extensive expression throughout the nervous system, some neurotrophins and cytokines are widely accepted to modulate synaptic plasticity and nociceptive processing. Among the neurotrophin family are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), which all bind to the tyrosine receptor kinases. The potential for BDNF as a therapeutic target is supported by a large body of evidence demonstrating its role in driving plastic changes in nociceptive pathways to initiate and maintain chronic pain. On the other hand, NGF has already proved fruitful as an analgesic target, with efficacy shown for NGF-neutralizing antibodies for pain relief in rheumatic diseases. The cytokine family includes the interleukins, tumor necrosis factors (TNFs), chemokines, interferons (IFNs), and transforming growth factor ß (TGF-ß) family. These bind, often promiscuously, to the heterogeneous group of cytokine receptors, and this cytokine signaling is essential for normal responses of the innate and adaptive immune systems. In pathophysiological states, chronic inflammation enhances the expression of pro-inflammatory cytokines, and many studies support a modulatory role of cytokines in nociceptive processes. At the forefront of anticytokine therapy for analgesia are TNF and IL6 monoclonal antibodies, which are licensed treatments for pain relief in rheumatoid arthritis. This article reviews the pro- and antinociceptive roles of key members of the neurotrophin and cytokine families in the context of chronic pain mechanisms and therapeutic approaches.

ObjectiveTo investigate whether the effects of nerve growth factor (NGF) inhibition with tanezumab on rats with medial meniscal tear (MMT) effectively model rapidly progressive osteoarthritis (RPOA) observed in clinical trials.MethodsMale Lewis rats underwent MMT surgery and were treated weekly with tanezumab (0.1, 1 or 10 mg/kg), isotype control or vehicle for 7, 14 or 28 days. Gait deficiency was measured to assess weight-bearing on the operated limb. Joint damage was assessed via histopathology. A second arm, delayed onset of treatment (starting 3–8 weeks after MMT surgery) was used to control for analgesia early in the disease process. A third arm, mid-tibial amputation, evaluated the dependency of the model on weight-bearing.ResultsGait deficiency in untreated rats was present 3–7 days after MMT surgery, with a return to normal weight-bearing by days 14–28. Prophylactic treatment with tanezumab prevented gait deficiency and resulted in more severe cartilage damage. When onset of treatment with tanezumab was delayed to 3–8 weeks after MMT surgery, there was no increase in cartilage damage. Mid-tibial amputation completely prevented cartilage damage in untreated MMT rats.ConclusionsThese data suggest that analgesia due to NGF inhibition during the acute injury phase is responsible for increased voluntary weight-bearing and subsequent cartilage damage in the rat MMT model. This model failed to replicate the hypotrophic bone response observed in tanezumab-treated patients with RPOA.