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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.

Background:Symptomatic osteoarthritis (OA) leads to functional limitations and loss of independence. OA management focuses on pain relief and preserving physical function using non-pharmacologic and pharmacologic therapy. Additionally, patients commonly manage OA pain by avoiding activities that exacerbate their pain. Informal care, i.e. assistance from an unpaid caregiver, plays a major role in the total care provided to patients with chronic diseases like OA.Objectives:To evaluate how OA pain severity affects physical functioning and the subsequent need for assistance with mobility and daily activities in 5 EU countries: France, Germany, Italy, Spain and UK.Methods:Data were drawn from the Adelphi OA Disease Specific Programme (2017-18), a point-in-time study of physicians and their OA patients. Patients rated their average pain intensity over the last week on a 0-10 scale (0 = no pain; 10 = worst possible pain) and were then categorised into mild (0-3), moderate (4-6) and severe (7-10) pain groups. Patients also provided an assessment of their physical function (0-10 WOMAC scale where higher scores indicated greater functional impairment), impact on mobility, whether caregiver assistance was required, daily activities requiring caregiver assistance and home modifications made due to their OA. Physicians also rated patients’ functioning on a 0 to 10 scale (0 = fully functional; 10 = completely impaired). Comparisons among pain severity groups were made using chi-squared tests and analysis of variance.Results:The analysis included 1750 OA patients: 24% mild pain (n=413); 47% moderate pain (n=822); 29% severe pain (n=515). The patients were predominantly women (58%) and had a mean (SD) age of 65.6 (11.5).Increased pain severity was associated with greater functional impairment scores as reported by patients (WOMAC scores: mild pain=2.1; moderate pain=4.1; severe pain=5.9) and physician-rated functional impairment (mild pain=3.5; moderate pain=4.3; severe pain=5.6). Mobility was impacted for 78% of patients with severe pain (vs. 41% mild; 63% moderate) and the need for a walking aid such as a walking stick or walking frame increased with worsening severity; wheelchair assistance was needed for 7% of severe patients (compared with The need for assistance from a caregiver to help with daily activities was associated with an increase in patients’ pain (9% mild; 20% moderate; 42% severe [pConclusion:In this study of European patients, increased pain severity was associated with greater functional impairment and impact on mobility as expected; however, this study highlights the substantial need for assistance with daily activities as well as modifications to the home. The unseen costs to the patient with moderate to severe OA pain are significant.Disclosure of Interests:Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Lucy Abraham Shareholder of: Pfizer, Employee of: Pfizer, Peita Graham-Clarke Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Beck Shareholder of: Pfizer, Employee of: Pfizer, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Niall Hatchell: None declared, Emily Clayton: None declared, James Jackson: None declared

Background:Joint pain is the most prevalent symptom for sufferers of osteoarthritis (OA). Pharmacological management of OA is restricted by limited efficacy and considerable toxicity, with growing fears about opioid use.Objectives:To understand the current real-world prescribed drug treatment paradigm related to OA disease severity for patients in 5 EU countries; France, Germany, Italy, Spain and the UK.Methods:Data were drawn from the Adelphi OA Disease Specific Programme (2017-18), a point-in-time study of physicians and their patients. Physicians classified their patients as currently having mild, moderate or severe disease severity, and provided details on currently prescribed OA therapy and physician satisfaction with therapy, rated from very satisfied to very dissatisfied. Patients were excluded from these analyses if they suffered from back and neck OA only, and shoulder OA that had not been diagnosed by X-ray. Comparisons among disease severity groups were made using analysis of variance and chi-squared tests.Results:The study included 489 physicians (primary care physicians, rheumatologists, orthopaedists) reporting on 3596 of their OA patients: 24% mild (n=874), 53% moderate (n=1904), and 23% severe (n=818). Overall, 73% patients were prescribed at least one drug for their OA (65% of mild; 76% of moderate; 77% of severe patients [Table 1.Prescribed treatment by physician-reported OA severityMild(n=874)Moderate(n=1904)Severe(n=818)Current class of medication prescribed for OA, n (%)Paracetamol186 (21.3)663 (34.8)313 (38.3)NSAIDs267 (30.5)605 (31.8)237 (29.0)Any opioid93 (10.6)501 (26.3)386 (47.2)Weak opioid82 (9.4)407 (21.4)255 (31.2)Strong opioid11 (1.3)99 (5.2)146 (17.8)Opioid + analgesic (combined)6 (0.7)15 (0.8)7 (0.9)Corticosteroid31 (3.5)150 (7.9)92 (11.2)Glycosaminoglycan50 (5.7)149 (7.8)62 (7.6)Viscosupplement12 (1.4)93 (4.9)42 (5.1)Number of currently prescribed drug classes, mean (SD)0.9 (0.8)1.4 (1.1)1.6 (1.2)Conclusion:Physicians reported decreasing satisfaction with treatment for their OA patients as disease severity increased, despite increasing use of opioids and numbers of classes of prescribed drugs.Disclosure of Interests:Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Lucy Abraham Shareholder of: Pfizer, Employee of: Pfizer, Peita Graham-Clarke Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Beck Shareholder of: Pfizer, Employee of: Pfizer, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Niall Hatchell: None declared, Emily Clayton: None declared, James Jackson: None declared

Background:Osteoarthritis (OA) is a chronic joint disease associated with pain and impaired activity. With increasing obesity trends and an ageing population, the prevalence of OA is expected to rise in the future. This represents an increasing societal problem which will lead to an increased burden on healthcare services.Objectives:To understand the pattern of healthcare resource utilisation (HCRU) across France, Germany, Italy, Spain and the UK, as OA disease severity increases.Methods:Data were drawn from the Adelphi OA Disease Specific Programme (2017-18), a point-in-time study of physicians and their OA patients. OA disease severity was reported by physicians, who categorised patients’ OA severity as mild, moderate or severe. Patients were excluded from the analyses if they suffered from back and neck OA only, and shoulder OA that had not been diagnosed by X-ray. Physicians provided information, on a patient record form, about OA-related visits to healthcare professionals (HCPs), tests/scans conducted, emergency room (ER) visits and surgeries. Statistical comparisons among disease severity groups were made by analysis of variance and chi-squared tests.Results:The study included 489 physicians (primary care physicians, rheumatologists, orthopaedists) reporting on 3596 of their patients with OA: 24% mild (n=874), 53% moderate (n=1904) and 23% severe (n=818). Over the last 12 months, the mean number of consultations with HCPs increased with disease severity (3.7 mild, 4.2 moderate and 5.7 severe [Table 1.Physician-reported healthcare burden by OA disease severityMild(n=874)Moderate(n=1904)Severe(n=818)Number of patient visits to ER in the last 12 months, mean (SD)0.1 (0.4)0.1 (0.6)0.5 (1.0)Patients with ≥1 emergency visit in the last 12 months, n (%)13 (1.5)43 (2.3)79 (9.7)Patients with ≥1 hospitalisation in the last 12 months, n (%)11 (0.1)9 (0.5)26 (3.2)Number of patient outpatient hospital visits in the last 12 months, mean (SD)0.5 (1.4)0.6 (1.1)1.2 (1.4)Conclusion:This real-world data demonstrated an increase in visits to HCPs, monitoring tests and scans, hospitalisations, ER visits and surgery as OA disease severity worsened.Disclosure of Interests:Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Lucy Abraham Shareholder of: Pfizer, Employee of: Pfizer, Peita Graham-Clarke Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Craig Beck Shareholder of: Pfizer, Employee of: Pfizer, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Niall Hatchell: None declared, Emily Clayton: None declared, James Jackson: None declared

Background:Tanezumab, a monoclonal antibody against nerve growth factor, was recently evaluated in an 80 week placebo and tramadol-controlled trial in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics (NSAIDs, opioids, etc). Primary endpoint was change in Low Back Pain Intensity (LBPI) at week 16 vs placebo. Key secondary endpoints were the proportion of patients with ≥50% improvement in LBPI at week 16, change in Roland Morris Disability Questionnaire score at week 16, and change in LBPI at week 2 (all vs placebo). Tanezumab 10mg met the primary and all key secondary endpoints. Tanezumab 5mg did not meet the primary endpoint, but improved 2 of 3 key secondary endpoints. Due to the primary endpoint result and the statistical gate-keeping approach to control for multiple comparisons, a conclusion of superiority over placebo could not be made for the 5mg dose.Objectives:To further characterize tanezumab’s effects on pain and function in this trial through analysis of Brief Pain Inventory-short form (BPI-sf) scores.Methods:Patients received placebo (n=406), subcutaneous (SC) tanezumab 5mg (every 8 weeks; n=407), SC tanezumab 10mg (every 8 weeks; n=407) or oral tramadol prolonged-release (100-300mg/day; n=605). Pre-specified secondary endpoints included BPI-sf worst pain, average pain, the overall pain interference index, and selected individual domains of the index (general activity, walking ability, sleep, and normal work). Least squares (LS) mean (standard error [SE]) changes from baseline in BPI-sf scores were compared between groups (unadjusted for multiplicity) at week 16 using an analysis of covariance model. Scores range from 0-10 with higher scores indicating greater pain severity or functional impairment.Results:LS mean (SE) differences from placebo for worst pain were -0.52 (0.19) for tanezumab 5mg (p≤0.01), -0.54 (0.19) for tanezumab 10mg (≤0.01), and -0.24 (0.17) for tramadol (p=0.17). LS mean (SE) differences from placebo for average pain were -0.37 (0.18) for tanezumab 5mg (p=0.04), -0.46 (0.18) for tanezumab 10mg (≤0.01), and -0.17 (0.16) for tramadol (p=0.29). LS mean (SE) differences from placebo for the pain interference index were -0.41 (0.18) for tanezumab 5mg (p=0.03), -0.58 (0.18) for tanezumab 10mg (≤0.01), and -0.15 (0.17) for tramadol (p=0.39). Effects of tanezumab were not statistically different (p>0.05) from tramadol for worst pain, average pain, and the pain interference index, with exception of the pain interference index for tanezumab 10mg (p=0.01). Mean dose of tramadol was 203mg/day at week 16.Tanezumab 10mg significantly (pConclusion:Tanezumab 5mg and 10mg significantly improved worst pain, average pain, and overall pain interference index scores vs placebo in patients with CLBP. Tanezumab 10mg also significantly improved the overall pain interference index vs tramadol. Tanezumab 5mg significantly improved most individual domains of the pain interference index vs placebo, while tanezumab 10mg significantly improved all domains assessed vs placebo and vs tramadol.Disclosure of Interests:John Markman Consultant of: Consultant: Trigemina, Editas Medicine, and Plasma Surgical; Advisory board: Clexio Biosciences, Flexion Therapeutics, Quark Pharmaceuticals, Quartet Medicine, Collegium Pharmaceutical, Purdue Pharma, Biogen, Novartis, Aptinyx, Nektar, Allergan, Grünenthal, Eli Lilly and Company, Depomed, Janssen Pharmaceuticals, Teva Pharmaceutical Industries, KemPharm, Abbott Laboratories, Plasma Surgical, Chromocell, Convergence Pharmaceuticals, Inspirion, Pfizer, Sanofi, Daiichi Sankyo, and Trevena; Data safety monitoring boards for Novartis and Allergan, Serge Perrot Consultant of: Grunenthal, Pfizer, Lilly, MSD, Sanofi, Menarini, Seiji Ohtori: None declared, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Said Beydoun Grant/research support from: Argenx, Catalyst Pharma, Mallinckrodt, Pfizer, UCB, Consultant of: Alexion, Akcea, Alnylam, CSL, Takeda, Mitsubishi Tanabe, Speakers bureau: Alexion, Akcea, Alnylam, CSL, Takeda, Mitsubishi Tanabe, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ruoyong Yang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Candace Bramson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background:Tanezumab, a monoclonal antibody against nerve growth factor (NGF), is in development for the treatment of osteoarthritis (OA).Objectives:To assess the effects of gender, age and body mass index (BMI) on the incidence of adverse events (AEs) in patients (pts) treated with subcutaneous (SC) tanezumab in pooled data from three phase 3 OA studies. Anti-NGF therapy has been associated with joint safety events1. Here we focus on treatment emergent AEs, including abnormalities of peripheral sensation (APS).Methods:All three randomised, double-blind, placebo-controlled studies enrolled pts with radiographically-confirmed OA of the hip or knee, who had inadequate response or could not tolerate standard of care analgesics. In the 16-week (wk) Study 1 (NCT01089725), pts received placebo, tanezumab 2.5 mg, 5 mg or 10 mg at baseline and wk 82. Due to a clinical hold on NGF antibodies, nddose at wk 8. Pts in the 16-wk Study 2 (NCT02697773), received placebo or tanezumab 2.5 mg at baseline and wk 8 or tanezumab 2.5mg at baseline and 5mg at wk 81. Pts in the 24-wk Study 3 (NCT02709486), received placebo, tanezumab 2.5 mg or 5 mg at baseline, wks 8 and 16. All treatments were given SC. AE data from the treatment period of each study were pooled for placebo, tanezumab 2.5 mg and 5 mg groups and examined by subgroups of gender, age and BMI. Data from the 10 mg group of Study 1 were not included due to the low sample size.Results:The incidence of any AE was numerically higher in females across treatment groups and in pts with a BMI ≥30 kg/m2in the tanezumab 5mg, but not 2.5 mg group, vs the overall population (Table 1). SAEs were infrequent but numerically higher across all tanezumab 5 mg subgroups vs placebo (Table 2). Paraesthesia and hypoaesthesia were the most common AEs of APS and were increased in all tanezumab groups in the overall population vs placebo. In any of the subgroups, the incidence of paraesthesia or hypoaesthesia was ≤7.8% and ≤3.9%, respectively. The difference within a patient subgroup for paraesthesia or hypoaesthesia was typically comparable with that of the overall population across treatments.Table 1.Incidence of AEs during the treatment period% of pts with an AE in each subgroupPlacebon=586Tanezumab2.5 mgn=602Tanezumab2.5 mg/5 mg n=219Tanezumab5 mgn=347Overall population51.752.347.054.8Gender Male51.149.741.346.6 Female52.053.650.459.0Age (years) 55.054.044.054.5 ≥6547.250.052.654.9BMI (kg/m2) 58.146.651.945.5 25–51.455.943.750.0 30–49.251.543.258.9 ≥3552.752.355.360.9BMI, body mass index; kg/m2, kilogram per square metreTable 2.Incidence of SAEs during the treatment period% of pts with a SAE in each subgroupPlacebon=586Tanezumab2.5 mgn=602Tanezumab2.5 mg/5 mg n=219Tanezumab5 mgn=347Overall population1.52.21.42.6Gender Male1.63.01.32.5 Female1.51.71.42.6Age (years) 1.22.61.41.9 ≥652.01.61.33.1BMI (kg/m2) 1.61.102.3 25–1.62.702.7 30–1.62.01.43.1 ≥351.32.34.31.6BMI, body mass index; kg/m2, kilogram per square metreConclusion:This pooled analysis showed that the safety profile of tanezumab in the subgroups studied is broadly similar to that of the overall study population.References:[1]Schnitzer, T. J.et al. JAMA(2019)[2]Birbara, C.et al. J Pain Res(2018)Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, 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, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sean Donevan Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer

Background:Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the treatment of signs and symptoms of osteoarthritis (OA).Objectives:To assess the safety and tolerability of subcutaneous (SC) tanezumab in patients with OA.Methods:Data were derived from 3 randomized placebo-controlled OA trials. SC treatment (every 8 weeks for 16–24 weeks with 8–24 week follow-up) included placebo, tanezumab 2.5 mg, tanezumab 2.5/5 mg (2.5 mg at day 1 and 5 mg at week 8), and tanezumab 5 mg. Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation were pooled from all 3 trials (placebo N = 586; tanezumab: 2.5 mg N = 602, 2.5/5 mg N = 219, 5 mg N = 347). Pre-specified TEAEs potentially associated with sympathetic neuropathy (anhidrosis, bradycardia, hypohidrosis, orthostatic hypotension, or syncope) and pre-specified joint events (primary osteonecrosis, rapidly progressive OA [RPOA] type 1 or type 2, subchondral insufficiency fracture, or pathological fracture; adjudicated by an independent committee of experts) were pooled from the 2 trials that included prospective evaluation of sympathetic and joint safety (placebo N = 514; tanezumab: 2.5 mg N = 528, 2.5/5 mg N = 219, 5 mg N = 284). TEAEs are presented for the treatment period; joint safety is presented for the full study (treatment plus follow up) period.Results:Patient demographics (80.7% white, 66.8% female, mean age ≈ 63 years) and clinical characteristics were similar across groups. TEAE rates were: placebo = 51.7%, tanezumab 2.5 mg = 52.3%, tanezumab 2.5/5 mg = 47.0%, and tanezumab 5 mg = 54.8%. Of TEAEs occurring in ≥2% of patients in any group, only oedema peripheral, joint stiffness, and paraesthesia had a higher incidence (95% confidence interval excluded 0) in any tanezumab group relative to placebo. Serious TEAE rates were: placebo = 1.5%, tanezumab 2.5 mg = 2.2%, tanezumab 2.5/5 mg = 1.4%, and tanezumab 5 mg = 2.6%. Rates of treatment and/or study discontinuation due to TEAEs were: placebo = 2.2%, tanezumab 2.5 mg = 1.8%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 1.4%. Only arthralgia and OA led to discontinuation in >1 patient in any group. TEAEs of abnormal peripheral sensation rates were: placebo = 2.2%, tanezumab 2.5 mg = 5.1%, tanezumab 2.5/5 mg = 3.2%, and tanezumab 5 mg = 6.1%. Paraesthesia and hypoaesthesia were the most common events. Potential sympathetic neuropathy TEAE rates were: placebo = 0.8%, tanezumab 2.5 mg = 1.5%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 2.8%; exposure-adjusted rates were not statistically different between any tanezumab group and placebo. Bradycardia and orthostatic hypotension were the most common events. No patient was considered to have a sympathetic neuropathy. TEAEs of abnormal peripheral sensation and potential sympathetic neuropathy were mostly mild and resolved. Joint safety event rates were statistically different for tanezumab 5mg (3.2%), but not 2.5mg (1.9%) or 2.5/5mg (0.5%), compared to placebo (0%). RPOA type-1 was the most common event. Total joint replacement rates were: placebo = 4.5%, tanezumab 2.5 mg = 5.9%, tanezumab 2.5/5 mg = 6.8%, and tanezumab 5 mg = 7.0%; rates were not statistically different between any tanezumab group and placebo.Conclusion:Tanezumab was generally safe and well tolerated in most patients, with rates of overall TEAEs and treatment/study discontinuations similar to placebo and no evidence of a sympathetic safety signal. TEAEs of abnormal peripheral sensation and joint safety events were infrequent but more common with tanezumab than placebo.Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, 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, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Glenn Pixton Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Isabelle Davignon Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

We thank Riddle and Perera1 for their interest in our publication.2 In our article, we adhered to recognised statistical methods and appropriate association with meaningfulness. We agree with the American Statistical Association guidance that a statistically significant effect does not inform its size or importance,3 and therefore, a change needs to be associated with clinical impact. In this study (ClinicalTrials.gov: NCT02709486), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale and Physical Function subscale were measured using an 11-point numeric rating scale (specifically, the WOMAC NRS3.1 V5 US). As specified in the WOMAC User Guide, each WOMAC subscale is to be summed and can be normalised on a 0–10 scale for the numeric rating scale. Therefore, in this study, the five questions for the Pain subscale and the 17 questions for the Physical Function subscale were summed and averaged, respectively, to determine each mean subscale score. This differs from subscale scores that are not normalised …