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Background: This phase III, randomized, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy. Methods: Subjects were randomized (stratified by (1) tumor aggressiveness and (2) presence/absence of concomitant anticancer treatment) to placebo or tanezumab 20 mg. Treatment was administered by subcutaneous injection every 8 weeks for 24 weeks (3 doses) followed by a 24-week safety follow-up period. The primary outcome was change in daily average pain in the index bone metastasis cancer pain site (from 0 = no pain to 10 = worst possible pain) from baseline to week 8. Results: LS mean (SE) change in pain at week 8 was −1.25 (0.35) for placebo (n = 73) and –2.03 (0.35) for tanezumab 20 mg (n = 72). LS mean (SE) [95% CI] difference from placebo was –0.78 (0.37) [–1.52, –0.04]; P =.0381 with α = 0.0478. The number of subjects with a treatment-emergent adverse event during the treatment period was 50 (68.5%) for placebo and 53 (73.6%) for tanezumab 20 mg. The number of subjects with a prespecified joint safety event was 0 for placebo and 2 (2.8%) for tanezumab 20 mg (pathologic fracture; n = 2). Conclusion: Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828. Bone metastasis is a common cause of cancer-related pain. This article reports on the potential of anti-nerve growth factor therapies, such as tanezumab, to reduce pain caused by bone metastases. [ABSTRACT FROM AUTHOR]

The pain threshold determines the extent of pain perception, and in some cases, its manifestation. Therefore, it is important in certain situations to increase the pain threshold. Measuring the pain threshold is challenging due to its approximate nature. The threshold depends on the number and function of Nav1.7 sodium channels and nerve growth factor (NGF). Unfortunately, we lack therapeutic tools to selectively act on these sodium channels. The clinical use of tanezumab, a drug that can counteract NGF, has not been approved. It is potentially dangerous to misuse drugs that can increase the pain threshold as it may divert attention from treating the underlying cause of pain or even dangerously limit its protective function. However, they can be particularly useful in pathologies where the main pathogenetic mechanism is a reduced pain threshold, such as migraine, musculotensive headache, trigeminal neuropathy, phantom limb pain, fibromyalgia, and others. They are also helpful in situations where pain is no longer useful for diagnostic purposes and when it is due to an incurable condition like cancer.

Introduction: We sought to predict analgesic response to daily oral nonsteroidal anti-inflammatory drugs (NSAIDs) or subcutaneous tanezumab 2.5 mg (every 8 weeks) at week 16 in patients with moderate-to-severe osteoarthritis, based on initial treatment response over 8 weeks. Methods: Data were derived from three randomized controlled trials of osteoarthritis. A two-step, trajectory-focused, analytics approach was used to predict patients as responders or non-responders at week 16. Step 1 identified patients using a data-element combination method (based on pain score at baseline, pain score at week 8, pain score monotonicity at week 8, pain score path length at week 8, and body site [knee or hip]). Patients who could not be identified in step 1 were predicted in step 2 using a k-nearest neighbor method based on pain score and pain response level at week 8. Results: Our approach predicted response with high accuracy in NSAID-treated (83.2–90.2%, n = 931) and tanezumab-treated (84.6–91.0%, n = 1430) patients regardless of the efficacy measure used to assess pain, or the threshold used to define response (20%, 30%, or 50% improvement from baseline). Accuracy remained high using 50% or 20% response thresholds, with 50% and 20% yielding generally slightly better negative and positive predictive value, respectively, relative to 30%. Accuracy was slightly better in patients aged ≥ 65 years relative to younger patients across most efficacy measure/response threshold combinations. Conclusions: Analyzing initial 8-week analgesic responses using a two-step, trajectory-based approach can predict future response in patients with moderate-to-severe osteoarthritis treated with NSAIDs or 2.5 mg tanezumab. These findings demonstrate that prediction of treatment response based on a single dose of a novel therapeutic is possible and that predicting future outcomes based on initial response offers a way to potentially advance the approach to clinical management of patients with osteoarthritis. ClinicalTrials.gov Identifiers: NCT02528188, NCT02709486, NCT02697773. [ABSTRACT FROM AUTHOR]

Introduction: A recent phase 3, randomized, placebo- and tramadol-controlled trial (56-week treatment/24-week safety follow-up) demonstrated efficacy of tanezumab 10 mg in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics. Here, we report on the clinical meaningfulness of treatment response in this study, focused on secondary measures of pain, interference with daily functions, overall disease status, and satisfaction with treatment. Methods: Patients received placebo (up to week 16; n = 406), subcutaneously administered (SC) tanezumab 5 mg (every 8 weeks; n = 407), SC tanezumab 10 mg (every 8 weeks; n = 407), or orally administered tramadol prolonged-release (100–300 mg/day; n = 605) for 56 weeks. Patient's global assessment of low back pain (PGA-LBP), Brief Pain Inventory-short form (BPI-sf), Treatment Satisfaction Questionnaire for Medication (TSQM), and modified Patient-Reported Treatment Impact (mPRTI) were assessed at weeks 16 and 56. Results: At week 16, significant (p < 0.05) improvements over placebo were evident with tanezumab for the PGA-LBP (10 mg) and most BPI-sf (both doses), TSQM (both doses), and mPRTI (both doses) items assessed. Improvements over baseline persisted for the PGA-LBP and BPI-sf at week 56. However, the magnitude of improvements was modestly lower at week 56 relative to week 16. Tramadol did not improve PGA-LBP or BPI-sf scores versus placebo at week 16. Most differences between tanezumab and tramadol at week 56 did not reach the level of statistical significance for all endpoints. Conclusions: The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo. ClinicalTrials.gov: NCT02528253. [ABSTRACT FROM AUTHOR]

Abstract Background A recent phase 3 study demonstrated that treatment with tanezumab, a nerve growth factor inhibitor, or nonsteroidal anti-inflammatory drugs (NSAIDs) improves pain and physical function in participants with moderate-to-severe osteoarthritis (OA) of the hip or knee. Here, we evaluated the time course and clinical importance of these initial efficacy findings using a mixture of primary, secondary, and post hoc endpoints. Methods Participants on stable NSAID therapy and with a history of inadequate response to other standard OA analgesics were enrolled in an 80-week (56-week treatment/24-week safety follow-up), randomized, NSAID-controlled, phase 3 study primarily designed to assess the safety of tanezumab for moderate-to-severe OA of the knee or hip. Participants received oral NSAID (twice daily naproxen, celecoxib, or diclofenac) or subcutaneous tanezumab (2.5mg or 5mg every 8 weeks). Non-responders were discontinued at week 16. Changes from baseline in WOMAC Pain and Physical Function, Patient’s Global Assessment of Osteoarthritis (PGA-OA), and average pain in the index joint were compared between tanezumab and NSAID groups over the 56-week treatment period. Clinically meaningful response (e.g., ≥30% and ≥50% improvement in WOMAC Pain and Physical Function), rescue medication use, and safety were also assessed. Results All groups improved WOMAC Pain, WOMAC Physical Function, PGA-OA, and average pain in the index joint over the 56-week treatment period relative to baseline. Across all groups, improvements generally occurred from the time of first assessment (week 1 or 2) to week 16 and then slightly decreased from week 16 to 24 before stabilizing from weeks 24 to 56. The magnitude of improvement and the proportion of participants achieving ≥30% and ≥50% improvement in these measures was greater (unadjusted p≤0.05) with tanezumab than with NSAID at some timepoints on or before week 16. Adverse events of abnormal peripheral sensation, prespecified joint safety events, and total joint replacement surgery occurred more frequently with tanezumab than with NSAID. Conclusions Tanezumab and NSAID both provided early and sustained (up to 56 weeks) efficacy relative to baseline. Improvements in pain and function were clinically meaningful in a substantial proportion of participants. Adverse events of abnormal peripheral sensation and joint safety events occurred more frequently with tanezumab than with NSAID. Trial registration ClinicalTrials.gov NCT02528188 . Registered on 19 July 2015.

Introduction: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo.Methods: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression.Results: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments.Conclusions: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188). [ABSTRACT FROM AUTHOR]

Introduction: Tanezumab is a monoclonal antibody against nerve growth factor that is under investigation for the treatment of osteoarthritis (OA) pain. We conducted subgroup analyses of two randomized phase 3 studies to summarize efficacy, general safety, and adjudicated joint safety of tanezumab in Japanese patients with moderate-to-severe OA. Methods: In Study 1 (NCT02528188), patients received subcutaneous tanezumab 2.5 mg or 5 mg every 8 weeks or daily oral nonsteroidal anti-inflammatory drugs (NSAID) for 56 weeks. The co-primary efficacy endpoints were change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale score and WOMAC Physical Function subscale score at Week 16 (overall study and Japan-specific endpoints) as well as Patient Global Assessment (PGA)-OA score at Week 16 (overall study endpoint only). In Study 2 (NCT02709486), patients received subcutaneous tanezumab 2.5 mg, 5 mg, or placebo every 8 weeks for 24 weeks. Safety monitoring included adjudicated composite joint safety endpoint (CJSE) including rapidly progressive osteoarthritis type 1 (RPOA1), RPOA2, primary osteonecrosis, pathological fracture, or subchondral insufficiency fracture. Results: For Study 1, Japanese patients (n = 200) treated with tanezumab 2.5 mg and 5 mg showed numerically greater improvements in WOMAC Pain, WOMAC Physical Function, and PGA-OA scores versus NSAID at Week 16. Incidences of treatment-emergent adverse events were generally similar between tanezumab 2.5 mg, 5 mg, and NSAID groups. In the integrated safety analysis (Studies 1 + 2; n = 306), ten patients were adjudicated to have a component of CJSE: RPOA1 [tanezumab 2.5 mg (n = 2), tanezumab 5 mg (n = 5)], RPOA2 [tanezumab 2.5 mg (n = 1), tanezumab 5 mg (n = 1)], or primary osteonecrosis [tanezumab 2.5 mg (n = 1)]. Time-adjusted adjudicated rates of RPOA1 and RPOA2 were higher with tanezumab than NSAID or placebo and increased with dose of tanezumab. Conclusion: Observations from the Japanese subgroup were generally consistent with the overall study populations. [ABSTRACT FROM AUTHOR]

Objective: To assess onset of effect in three placebo- or nonsteroidal anti-inflammatory drug (NSAID)-controlled trials of tanezumab in patients with moderate-to-severe osteoarthritis. Methods: Post-hoc nonparametric Kaplan–Meier analyses were used to estimate median time to first improvement and to sustained improvement in Western Ontario and McMaster Universities Osteoarthritis Index domain (Pain, Physical Function, Stiffness) scores across a range of improvement thresholds (0–100%, in 5% increments). Time to first improvement was defined as the first week scores met the pre-specified threshold. Time to sustained improvement was defined as the first week scores met the pre-specified threshold and were sustained (on average) for the remainder of the treatment period. Results: Across all domains, tanezumab-treated patients had shorter median times to first improvement (at most thresholds) and reached higher levels of improvement than placebo-treated patients. No substantial differences were observed between tanezumab doses (2.5 and 5 ​mg), or between tanezumab and NSAIDs. Most patients experiencing an event of first improvement went on to experience a sustained event. At low thresholds, sustained improvement occurred simultaneously with, or shortly after, first improvement. At higher thresholds, median time to sustained improvement was longer than median time to first improvement. Conclusions: Following initiation of tanezumab treatment, first improvement of osteoarthritis symptoms of 30% was evident within 2–4 weeks and sustained improvement was evident within 2–8 weeks. Time to improvement of 50% was more variable, with first and sustained events expected within 4–16 and 8–24 weeks, respectively. ClinicalTrials.gov identifiers: NCT02697773; NCT02709486; NCT02528188.

Aims: Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. Methods: Data from 10 studies of IV or SC tanezumab (2.5–20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2‐compartment model with linear and nonlinear elimination (based on prior analysis of pre‐2015 IV osteoarthritis studies) was expanded to include other pre‐2015 studies. In Step 2, post‐2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment‐emergent anti‐drug antibodies (TE ADA). Results: SC bioavailability was estimated at 62–76%. The key disposition parameters CL, Vc, Vp and KM were estimated to be 0.133 L d−1, 2.6 L, 1.77 L and 31.2 μg L−1, respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9–11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5–10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4–8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6–7%). Conclusion: Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK. [ABSTRACT FROM AUTHOR]

The problem of chronic musculoskeletal pain, the cause of severe suffering and disability of hundreds of millions of people on our planet, is far from being solved. Pain control is particularly difficult in patients with severe forms of osteoarthritis (OA) and chronic non-specific low back pain (CLBP). Popular analgesics – nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, demonstrate moderate effectiveness and a high risk of adverse events (AE). This leads to the search for new approaches for analgesic therapy. Tanezumab is a monoclonal antibody that specifically blocks nerve growth factor, which plays a key role in the development of chronic pain. A series of phase II and III studies showed that tanezumab was administered intravenously or subcutaneously at a dose of 2.5 mg to 20 mg once every 8 weeks. In patients with OA or CNSLBP, it has a pronounced and persistent analgesic effect that exceeds the effect of placebo, and is equal to or superior to the effect of many months of daily intake of naproxen, celecoxib, diclofenac, oxycodone and tramadol. Tanezumab can cause various AE, primarily rapid progression of OA (in 2.6–6.0%) and neurological disorders (paresthesia and hyposthesia, in ≈5%). At the same time, the progression of OA was significantly more often observed with the combined use of tanezumab and NSAIDs. Nevertheless, taking into account the characteristics of patients who used tanezumab (patients with pain refractory to standard treatment; severe forms of OA), the good analgesic potential of tanezumab allows us to consider it as a promising tool for the control of chronic musculoskeletal pain, which will be widely used in real clinical practice.

ObjectiveStudies suggest nerve growth factor inhibitors (NGFi) relieve pain but may accelerate disease progression in some patients with osteoarthritis (OA). We sought cost and toxicity thresholds that would make NGFi a cost-effective treatment for moderate-to-severe knee OA.DesignWe used the Osteoarthritis Policy (OAPol) model to estimate the cost-effectiveness of NGFi compared to standard of care (SOC) in OA, using Tanezumab as an example. Efficacy and rates of accelerated OA progression were based on published studies. We varied the price/dose from $200 to $1000. We considered self-administered subcutaneous (SC) injections (no administration cost) vs provider-administered intravenous (IV) infusion ($69-$433/dose). Strategies were defined as cost-effective if their incremental cost-effectiveness ratio (ICER) was less than $100,000/quality-adjusted life year (QALY). In sensitivity analyses we varied efficacy, toxicity, and costs.ResultsSOC in patients with high levels of pain led to an average discounted quality-adjusted life expectancy of 11.15 QALYs, a lifetime risk of total knee replacement surgery (TKR) of 74%, and cumulative discounted direct medical costs of $148,700. Adding Tanezumab increased QALYs to 11.42, reduced primary TKR utilization to 63%, and increased costs to between $155,400 and $199,500. In the base-case analysis, Tanezumab at $600/dose was cost-effective when delivered outside of a hospital. At $1000/dose, Tanezumab was not cost-effective in all but the most optimistic scenario. Only at rates of accelerated OA progression of 10% or more (10-fold higher than reported values) did Tanezumab decrease QALYs and fail to represent a viable option.ConclusionsAt $100,000/QALY, Tanezumab would be cost effective if priced ≤$400/dose in all settings except IV hospital delivery.

Background: Tanezumab is a nerve growth factor monoclonal antibody that may regulate pain in hip or knee osteoarthritis (OA). This meta-analysis was performed to evaluate the efficacy and safety of low and moderate doses of tanezumab in treating hip or knee OA. Methods: PubMed, EMBASE, the Cochrane Library, and Web of Science were comprehensively searched for clinical trials published before 1 May 2021. Patients were assessed via efficacy and safety outcomes. Results: Twelve randomized controlled trials including 6022 patients were identified. Both low and moderate doses of tanezumab significantly improved efficacy outcomes. However, only the point estimates (mean difference, MD) of moderate-dose tanezumab significantly exceeded the minimal clinically important differences (MCIDs). There were no significant differences in the incidence of treatment-related adverse events (AEs), withdrawals due to AEs, serious AEs, and total joint replacement between the tanezumab and placebo groups, whereas the incidence of AEs was higher in the tanezumab group (relative risk, RR = 1.10; 95% confidence interval, 95% CI = 1.04–1.17). The incidence of rapidly progressive OA was significantly higher in the combined low- and moderate-dose tanezumab groups than in the placebo group (RR = 5.01; 95% CI = 1.17–21.33). Furthermore, both low and moderate doses of tanezumab significantly increased the incidence of abnormal peripheral sensation (RR = 1.99, 95% CI = 1.21–3.28; RR = 2.64, 95% CI = 1.91–3.67, respectively). Compared with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, tanezumab showed significantly improved efficacy outcomes (p < 0.05). However, the point estimates (MD) of tanezumab were not greater than the MCID. Pooled analysis showed no significant differences between tanezumab and NSAIDs and opioids in safety outcomes (p > 0.05). Conclusion: Tanezumab is efficacious in patients with hip or knee OA. Tanezumab is relatively well tolerated and safe but increases the incidence of AEs and reversible abnormal peripheral sensation. Additional studies on the occurrence of rapidly progressive OA are needed. A moderate dose of tanezumab may maximize the benefits for hip or knee OA. [ABSTRACT FROM AUTHOR]

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 (≥ 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. Results: Pooled 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. Conclusion: Responders 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. [ABSTRACT FROM AUTHOR]