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Subcutaneous Tanezumab for Osteoarthritis of the Hip Or Knee

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Subcutaneous Tanezumab for Osteoarthritis of the Hip Or Knee Osteoarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216296 on 31 March 2020. Downloaded from CLINICAL SCIENCE Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24- week randomised phase III study with a 24- week follow- up period Francis Berenbaum ,1 Francisco J Blanco ,2 Ali Guermazi,3 Kenji Miki,4 Takaharu Yamabe,5 Lars Viktrup,6 Rod Junor,7 William Carey,7 Mark T Brown,5 Christine R West,5 Kenneth M Verburg5 Handling editor Josef S ABSTRact Key messages Smolen Objective Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or ► Additional material is What is already known about this subject? published online only. To view, knee in a study with 24- week treatment and 24- week ► A systematic review and meta- analysis of please visit the journal online safety follow- up. the efficacy and safety of tanezumab for (http:// dx. doi. org/ 10. 1136/ Methods This double-blind, randomised, phase osteoarthritis (OA), published in 2015, was annrheumdis- 2019- 216296). III study enrolled adults in Europe and Japan with based on a search of PubMed and Embase moderate-to- severe OA who had not responded to or For numbered affiliations see using relevant keywords (tanezumab, could not tolerate standard-of- care analgesics. Patients end of article. fulranumab, fasinumab, anti- nerve growth were randomised to tanezumab 2.5 mg or 5 mg factor (NGF), NGF, osteoarthritis or OA) and lists Correspondence to subcutaneously or matching placebo every 8 weeks of studies obtained from the developers. Professor Francis Berenbaum, (three doses). Co- primary end points were change from The authors imposed no eligibility restrictions Department of Rheumatology, baseline to week 24 in Western Ontario and McMaster ► Sorbonne Université, INSERM on the age of participants, the duration of Universities Osteoarthritis Index (WOMAC) Pain and CRSA, AP-HP Hopital Saint disease or concomitant medication use (non- Physical Function, and Patient’s Global Assessment Antoine, 184 rue du faubourg steroidal anti-inflammatory drug or opioids), nor Saint-­Antoine, Paris 75012, of OA (PGA-O A). Joint safety and neurological language or publication date/status restrictions. France; assessments continued throughout the 48-week study. francis. berenbaum@ aphp. fr This systematic review showed that the Results From March 2016 to December 2017, 849 ► early tanezumab studies investigated mostly patients were randomised and evaluated (placebo n=282, Received 10 September 2019 intravenous administration with primary end Revised 28 January 2020 tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At points evaluated at 16 weeks. Accepted 29 January 2020 week 24, there was a statistically significant improvement Doses were body weight- adjusted or from baseline for tanezumab 5 mg compared with placebo ► administered as fixed doses (up to http://ard.bmj.com/ for WOMAC Pain (least squares mean difference±SE tanezumab 10 mg). –0.62±0.18, p=0.0006), WOMAC Physical Function The few studies performed using subcutaneous (–0.71±0.17, p<0.0001) and PGA-O A (–0.19±0.07, ► injection were impacted by temporary partial p=0.0051). For tanezumab 2.5 mg, there was a clinical holds placed on non- cancer pain studies statistically significant improvement in WOMAC Pain and of all NGF monoclonal antibodies following Physical Function, but not PGA-O A. Rapidly progressive joint safety findings in clinical trials, which were osteoarthritis (RPOA) was observed in 1.4% (4/283) and on September 23, 2021 by guest. Protected copyright. adjudicated as rapidly progressive osteoarthritis, 2.8% (8/284) of patients in the tanezumab 2.5 mg and and concerns regarding histomorphological tanezumab 5 mg groups, respectively and none receiving changes in the sympathetic nervous system placebo. Total joint replacements (TJRs) were similarly reported in preclinical studies. distributed across all three treatment groups (6.7%–7.8%). After a comprehensive assessment of the Tanezumab-treated patients experienced more paraesthesia ► clinical data related to joint safety and (5 mg) and hypoaesthesia (both doses) than placebo. neurological safety as well as additional Conclusion Tanezumab 5 mg statistically significantly preclinical studies of sympathetic nervous improved pain, physical function and PGA-O A, but system morphology and function, a risk tanezumab 2.5 mg only achieved two co-primary © Author(s) (or their minimisation plan including comprehensive end points. RPOA occurred more frequently with employer(s)) 2020. Re- use surveillance for joint safety and sympathetic permitted under CC BY-­NC- tanezumab 5 mg than tanezumab 2.5 mg. TJRs were neurological safety was implemented. ND. No commercial re- use. similarly distributed across all three groups. See rights and permissions. The phase III OA programme conducted post- Trial registration number NCT02709486. ► Published by BMJ. 2015 used only lower doses of tanezumab To cite: Berenbaum F, administered subcutaneously in difficult- to- Blanco FJ, Guermazi A, et al. treat patients, and incorporated extensive risk Ann Rheum Dis Epub ahead management procedures to maintain patient of print: [please include Day INTRODUCTION safety. Month Year]. doi:10.1136/ Globally, osteoarthritis (OA) is a leading cause of annrheumdis-2019-216296 disability1 with joint pain that often makes common Berenbaum F, et al. Ann Rheum Dis 2020;0:1–11. doi:10.1136/annrheumdis-2019-216296 1 Osteoarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216296 on 31 March 2020. Downloaded from some of these studies.10 Due to these joint safety concerns and Key messages histomorphological changes in the sympathetic nervous system observed in preclinical animal studies,11 the US Food and Drug What does this study add? Administration placed partial clinical holds on studies of NGF Of the phase III OA programme, this is the first study to ► antibodies in 2010 and 2012, respectively. Investigation of these assess the efficacy of tanezumab 2.5 mg and 5 mg every 8 events provided evidence that led to the subsequent lifting of weeks for 24 weeks with additional 24- week safety follow- the tanezumab clinical holds, and an overall risk minimisa- up in patients with moderate- to- severe OA and inadequate tion strategy including comprehensive monitoring of joint and response to standard- of- care analgesics. neurological safety was implemented in subsequent studies. The phase III OA programme conducted after the clinical holds How might this impact on clinical practice or future were removed (post-2015) used only lower doses of tanezumab developments? administered subcutaneously in difficult-to- treat patients, incor- This study demonstrates the efficacy of subcutaneous ► porated extensive risk mitigation and surveillance, excluded tanezumab in difficult- to- treat patients with OA. patients with evidence of or risk factors for RPOA or who were Adjudicated joint safety end points occurred only in ► unsuitable for joint replacement and restricted chronic concom- tanezumab- treated patients. itant use of NSAIDs while in the study. Total joint replacements were similarly distributed across all ► The current study was designed to assess the efficacy three treatment groups. (24 weeks) and safety (total 48 weeks, including a 24- week A longer- term active- controlled study (ClinicalTrials.gov, ► post- treatment safety follow- up period) of subcutaneous NCT02528188) will provide data to further characterise the tanezumab (2.5 mg or 5 mg vs placebo, every 8 weeks for a total risk- benefit of tanezumab in patients with A.O of three doses) in patients with moderate- to- severe OA with an inadequate response to, or who could not tolerate, standard- of- care analgesics including acetaminophen, NSAIDs and tramadol or opioids. daily activities difficult. Patients with knee or hip OA also have a higher risk of mortality than the general population due to increased cardiovascular events.2 METHODS To manage the pain associated with OA, guidelines recommend Study design a combination of non- pharmacological approaches and analge- This was a phase III, randomised, double- blind, placebo- sics3 4 including acetaminophen (paracetamol), non- steroidal controlled, parallel-group, multicentre trial conducted at 104 anti- inflammatory drugs (NSAIDs) and opioids. Limited efficacy hospital, clinical research or general practice sites in Europe in some patients and concerns about adverse effects5 6 mean that and Japan from March 2016 to November 2018. Patients were an alternative to current pharmacological treatment options is recruited directly by investigators, through referrals, and also by needed. advertising. Nerve growth factor (NGF) is involved in pain signalling7 and The study comprised a screening period (up to 37 days prior has been implicated in OA pain.8 Early clinical trials of the NGF to randomisation), a 24- week double-blind treatment period monoclonal antibody tanezumab investigated mostly intrave- and a 24- week safety follow- up period (figure 1). The screening nous administration of doses that were body weight-adjusted or period included a washout phase (lasting a minimum of 2 days http://ard.bmj.com/ administered as a fixed dose (up to 10 mg), and used primary for all prohibited pain medications), if required, and an initial efficacy end points measured at 16 weeks or earlier.9 Cases of pain assessment period (the 7 days prior to randomisation/base- rapidly progressive osteoarthritis (RPOA) were observed in line) to establish average pain levels in the index joint. on September 23, 2021 by guest. Protected copyright. Figure 1 Study design. Scheduled in- clinic visits occurred at screening, baseline and weeks 2, 4, 8, 12, 16, 24, 32 and 48, with telephone contact scheduled for weeks 20, 28, 36, 40 and 44. Patients who did not complete the double-blind treatment period were still followed through the 24-week safety follow-up period. 2 Berenbaum F, et al. Ann Rheum Dis 2020;0:1–11. doi:10.1136/annrheumdis-2019-216296 Osteoarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216296 on 31 March 2020.
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