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Introduction Zuranolone (ZRN) is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the US and under investigation for adults with major depressive disorder (MDD). The randomised, double-blind, placebo-controlled, Phase 3 CORAL Study assessed the efficacy and safety of ZRN 50 mg vs placebo, each co-initiated with an open-label standard-of-care antidepressant (ADT). Patients who completed CORAL could roll over into open-label SHORELINE, which assessed the safety and tolerability of ZRN 50 mg and need for repeat treatment courses in adults with MDD. Objectives To assess the safety and tolerability (primary endpoint) and need for repeat ZRN 50 mg treatment courses (secondary endpoint) in adults with MDD who previously enrolled in CORAL. Methods CORAL enrolled adults (18–64 years) with MDD and 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥24. After completing the 6-week CORAL Study, patients who enrolled in SHORELINE could enter a 46-week observation period to assess the safety and need for 14-day repeat ZRN treatment course(s), with a total of ≤4 repeat treatment courses permitted. Patients were screened every 2 weeks with the 9-item Patient Health Questionnaire, and scores ≥10 prompted a HAMD-17 assessment within 1 week. Patients with HAMD-17 total score ≥20 were eligible for repeat ZRN course(s) ≥8 weeks after completing the prior ZRN treatment course. Results Among the 190 patients from CORAL who rolled over into SHORELINE and received ≥1 ZRN treatment course in either study, 133 (70.0%) had received ZRN+ADT and 57 (30.0%) received placebo+ADT in CORAL. Overall, 118 rollover patients received ≥1 open-label ZRN treatment course in SHORELINE. For patients who received ≥1 ZRN treatment course in either study, 76.8% received 1 (54.2%; 103/190) or 2 (22.6%; 43/190) total ZRN treatment courses across both studies in up to 1 year in study. The most common (>5%) treatment-emergent adverse events (TEAEs) during treatment and 14 days following the last ZRN dose were somnolence (16.1% of patients), dizziness (8.5%), headache (8.5%), fatigue (7.6%), sedation (5.9%), and nausea (5.1%); study-period TEAEs (73.7%; 87/118) for the majority of patients were mild/moderate (69.5%; 82/118) in severity and occurred primarily during the treatment period (58.5%; 69/118). No signals for increased suicidal ideation/behaviour were observed. Conclusions Safety and tolerability among rollover patients were consistent with previous studies; most of the TEAEs reported by adults with MDD who received ZRN were mild/moderate in severity. Most patients who rolled over from CORAL to SHORELINE received ≤2 total treatment courses in up to 1 year in study. Disclosure of Interest G. Mattingly Grant / Research support from: Akili, Alkermes, Allergan (now AbbVie), Axsome, Boehringer, Janssen, Lundbeck, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, Takeda, and Teva, Consultant of: Akili, Alkermes, Allergan (now AbbVie), Axsome, Ironshore, Intra-Cellular Therapies, Janssen, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Rhodes, Sage, Sunovion, Takeda, and Teva, Speakers bureau of: Alkermes, Allergan (now AbbVie), Ironshore, Janssen, Lundbeck, Otsuka, Sunovion, and Takeda, S. Mathew Grant / Research support from: Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, Inc., and VistaGen Therapeutics, Consultant of: Allergan (now AbbVie), Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Inc., Seelos Therapeutics, Signant Health, and Sunovion, S. Parikh Grant / Research support from: Aifred, Assurex, Janssen, Mensante, Sage Therapeutics, Inc., and Takeda, S. Aaronson Grant / Research support from: COMPASS Pathways and Neuronetics; has served as a consultant to Genomind, Inc., Janssen, LivaNova PLC, Neuronetics; and Sage Therapeutics, Inc., Speakers bureau of: Janssen and Sunovion Pharmaceuticals, Inc., B. Baune Speakers bureau of: Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, LivaNova, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sumitomo Pharma, Wyeth, and Boehringer-Ingelheim, A. Czysz Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., I. Nandy Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., V. Ona Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., C. Brown Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., S. Kyaga Employee of: Biogen Inc., F. Forrestal Employee of: Biogen Inc., S. Levin Employee of: Biogen Inc., J. Doherty Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., G. Mattingly: None Declared

Rationale: Zuranolone is an oral positive allosteric modulator of GABA A receptors. Due to its central nervous system (CNS) activity, zuranolone may impact activities requiring complex cognition, including driving., Objective: Evaluate the effect of zuranolone on simulated driving performance., Methods: In this randomized, double-blind, active- and placebo-controlled, four-period crossover study, treatments included once-nightly zuranolone 50 mg on days 1-7, zuranolone 50 mg on days 1-6 and zuranolone 100 mg on day 7, zopiclone 7.5 mg on days 1 and 7, and placebo on days 1-7. Driving was assessed using a validated simulator. Primary endpoint was standard deviation of lateral position (SDLP), evaluated 9 h post-dose on days 2 and 8. Secondary endpoints included additional driving assessments, cognitive tests, pharmacokinetics, and safety., Results: Healthy adults (N = 67) enrolled and received ≥ 1 dose. Zuranolone 50 mg increased SDLP versus placebo on days 2 (least squares mean difference [LSMD]: 7.4 cm; p < 0.0001) and 8 (LSMD: 4.6 cm; p = 0.0106). Zuranolone 100 mg evoked a larger increase in SDLP versus placebo on day 8 (LSMD 18.9 cm; p < 0.0001). Reduced performance in other driving assessments and cognition were observed with zuranolone 50 mg on day 2; many resolved by day 8. Despite the SDLP observations, most participants judged themselves capable of driving. Frequent adverse events (≥ 20%) were CNS-related; most were mild/moderate., Conclusion: Zuranolone impaired simulated driving and reduced cognitive function versus placebo 9 h after administration. Although many impairments resolved after 7 days of dosing, driving remained impaired. These results may inform prescriber decision-making., Competing Interests: Declarations. Ethical approval: This study was performed in accordance with the Declaration of Helsinki and is consistent with Good Clinical Practice guidelines according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Harmonized Tripartite Guideline, as well as all applicable regulatory requirements. Consent to participate: All participants provided written informed consent. Competing interests: Joi Dunbar, Carrie Vaudreuil, Indrani Nandy, and Victor Ona are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options. Gaetano Morelli has no conflicts of interest to disclose. Rakesh Jain reports research funding from AbbVie, Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda and participation on advisory boards for Adamas Pharmaceuticals; Alkermes; Corium; Eisai; Janssen; Lilly; Lundbeck; Merck; Neos Therapeutics; Neurocrine Biosciences; Otsuka; Pamlab; Pfizer; Sage Therapeutics, Inc.; Shire; Sunovion; Supernus; Takeda; Teva Pharmaceuticals; and Usona. Rakesh Jain also reports honoraria for speakers’ bureaus from AbbVie, Alkermes, Almatica, Axsome, Corium, Eisai, Intra-Cellular Therapies, Ironshore, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shire, Sumitomo Pharma, Sunovion, Takeda, Tris Pharma, and Viatris and consulting fees from AbbVie; Acadia; Adamas Pharmaceuticals; Alfasigma; Alkermes; Almatica; Axsome; Biogen Inc.; Boehringer Ingelheim; Cingulate; Corium; Eisai; Evidera; Impel Pharmaceuticals; Janssen; Lilly; Lundbeck; Merck; Neos Therapeutics; Neurocrine Biosciences; Osmotica Pharmaceuticals; Otsuka; Pamlab; Pfizer; Sage Therapeutics, Inc.; Shire; Sumitomo Pharma; Sunovion; Supernus; Takeda; Teva Pharmaceuticals; Transcend Therapeutics; and Viatris. Margaret K. Moseley and Seth Levin are employees of Biogen Inc. and may hold stock. Gary Kay is an employee of Cognitive Research Corporation and may hold stock., (© 2024. The Author(s).)

Background: Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States., Aims: To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol., Methods: This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated., Results: All participants (Part A, N  = 24; Part B, N  = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's | d | = 0.126-0.76); effects were larger with alprazolam (Cohen's | d | = 0.523-0.93) and ethanol (Cohen's | d | = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's | d | = 0.6-1.227) or ethanol (Cohen's | d | = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity., Conclusion: A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: David P Walling has received grants or contracts from Acadia, Alkermes, Allergan, Avanir, Biogen, Boehringer Ingelheim, Cerevel, Indivior, IntraCellular, Janssen, J&J PRD, Karuna, Lundbeck, Lupin, Lyndra, Merck, Neurocrine, Novartis, Noven, Otsuka, Pfizer, Roche, Sage, Sunovion, Takeda; and consulting fees from Biogen, Boehringer Ingelheim, Janssen, Lyndra, Merck, and Otsuka.Howard A Hassman is a current employee of CenExel Hassman Research Institute, an independent research site that conducts investigator-initiated and industry-sponsored pharmaceutical trials. He has no conflicts of interest or bias in the conclusions of the current investigation or promotion of the current study results.Paul Maruff is an employee of Cogstate Ltd. and may hold stock and/or stock options.Rakesh Jain reports research funding from AbbVie, Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda; participation on advisory boards for Adamas, Alkermes, Corium, Eisai, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Sage, Shire, Sunovion, Supernus, Takeda, Teva, and Usona; honoraria for speakers’ bureaus from AbbVie, Alkermes, Almatica, Axsome, Corium, Eisai, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shire, Sumitomo, Sunovion, Takeda, Tris Pharmaceuticals, and Viatris; and consulting fees from AbbVie, Acadia, Adamas, Alfasigma, Alkermes, Almatica, Axsome, Biogen, Boehringer Ingleheim, Cingulate Therapeutics, Corium, Eisai, Evidera, Impel, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Osmotica, Otsuka, Pamlab, Pfizer, Sage, Shire, Sumitomo, Sunovion, Supernus, Takeda, Teva, Transcend Therapeutics, and Viatris.Andy Czysz was an employee of Sage Therapeutics, Inc., at the time that the study was completed, and may hold stock and/or stock options.Indrani Nandy, Victor Ona, and Joi Dunbar are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options.Margaret K Moseley and Seth Levin are employees of Biogen Inc. and may hold stock.

Background/Objectives : Radical cystectomy (RC) represents one of the most complex and morbid surgical procedures in the field of Urology. Extraperitoneal open RC has emerged as an alternative to the traditional transperitoneal approach for the treatment of muscle-invasive bladder cancer. Frailty is one of the most important risk factors for perioperative morbidity and mortality, and this category of patients can benefit the most from the extraperitoneal approach. The purpose of this study was to evaluate the feasibility and the safety of extraperitoneal open RC in our experience; Methods : We retrospectively collected the data of 75 frail patients who underwent an extraperitoneal open RC, performed by a single experienced surgeon. We assessed their frailty status using the simplified frailty index (sFI). We recorded data regarding general characteristics, intraoperative, pathological, and postoperative complications, and mortality (within 90 days); Results: We analyzed 61 males and 14 females with an sFI equal to or higher than 3. The median age was 77 years. Fifty-one patients had an ASA score of 3 or more. Sixty procedures were with radical intention, while fifteen were palliative. Cutaneous ureterostomy was performed in 70 cases and extraperitonized ileal conduit in five cases. The median operative time was 150 min. The median blood loss was 400 mL. The median time to flatus was 2 days. The median postoperative stay was 7 days. Thirteen patients had Clavien-Dindo III or IV complications. Two patients died in first 90 days postoperatively; Conclusions : The extraperitoneal open RC in frail patients was demonstrated to be a feasible and safe alternative approach in definitive treatment or a palliative setting in our experience.

Extensive literature probes labor market discrimination through correspondence studies in which researchers send pairs of resumes to employers, which are closely matched except for social signals such as gender or ethnicity. Upon perceiving these signals, individuals quickly activate associated stereotypes. The Stereotype Content Model (SCM; Fiske 2002) categorizes these stereotypes into two dimensions: warmth and competence. Our research integrates findings from correspondence studies with theories of social psychology, asking: Can discrimination between social groups, measured through employer callback disparities, be predicted by warmth and competence perceptions of social signals? We collect callback rates from 21 published correspondence studies, varying for 592 social signals. On those social signals, we collected warmth and competence perceptions from an independent group of online raters. We found that social perception predicts callback disparities for studies varying race and gender, which are indirectly signaled by names on these resumes. Yet, for studies adjusting other categories like sexuality and disability, the influence of social perception on callbacks is inconsistent. For instance, a more favorable perception of signals like parenthood does not consistently lead to increased callbacks, underscoring the necessity for further research. Our research offers pivotal strategies to address labor market discrimination in practice. Leveraging the warmth and competence framework allows for the predictive identification of bias against specific groups without extensive correspondence studies. By distilling hiring discrimination into these two dimensions, we not only facilitate the development of decision support systems for hiring managers but also equip computer scientists with a foundational framework for debiasing Large Language Models and other methods that are increasingly employed in hiring processes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gallo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple injections of M6495, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5)  nanobody, in healthy volunteers and patients with osteoarthritis., Methods: Two randomized, placebo-controlled, double-blind studies were performed. Study 1 enrolled 54 healthy male volunteers who received one subcutaneous (s.c.) injection of M6495 (1-300 mg) or placebo (ratio 2:1), evaluating safety, PK, and PD as changes in the serum aggrecan fragment alanine-arginine-glycine-serine (ARGS). Study 2 enrolled 32 patients with osteoarthritis with Kellgren-Lawrence grades 2 to 4 and pain greater than or equal to 40 on the Western Ontario and McMaster Universities Arthritis Index pain subscale at screening and evaluated the safety, PK, and PD of three doses every two weeks (75-300 mg per dose) or six once-weekly M6495 s.c. doses (300 mg) or placebo (ratio 3:1) over 106 days' follow-up., Results: M6495 in single and multiple doses of less than or equal to 300 mg s.c. weekly was well tolerated with no clinically significant changes in any safety parameter. Adverse events more frequently reported in the M6495 groups were mostly mild cases of injection site reactions, myalgia, and nausea, which resolved after treatment cessation. The elimination half-life of single s.c. doses of M6495 ranged from 79 to 267 hours. M6495 administration substantially reduced serum ARGS levels, indicative of target engagement and indicating disease-modifying potential of M6495., Conclusion: Treatment with M6495 in single and multiple doses up to and including 300 mg s.c. was found to be well tolerated and adequately safe for further clinical evaluation of potential disease-modifying effects., (© 2024 Nordic Bioscience A/S, DanTrials ApS, Merck Healthcare KGaA and The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II., Methods: In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares., Results: In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4-93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo., Conclusion: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll-like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double-blind, placebo-controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single-dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple-dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo-stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open-label, one-way crossover study in the 25 mg single-dose cohort. Single- and multiple-oral doses of enpatoran up to 200 mg were well tolerated and no significant dose-limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose-proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure-dependent inhibition of ex vivo-stimulated interleukin-6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID-19 pneumonia., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Objective: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results., Methods: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression., Results: 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53)., Conclusion: In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR., Trial Registration Number: NCT01919164., Competing Interests: Competing interests: FE is an employee and co-owner of Chondrometrics GmbH and reported receiving grants and consulting fees from Merck KGaA, Darmstadt, Germany, Samumed LLC, AbbVie, Bioclinica, Orthotrophix, Kolon TissueGene, Servier, Roche, Galapagos, Novartis, ICM and Healthlink. MH reports being the president of Rheumcon and receiving consulting fees from Bone Therapeutics, Bristol-Myers Squibb, Eli Lilly, Galapagos, IBSA Insititut Biotechniq SA, Novartis Pharma AG, Pfizer, Samumed LLC, Theralogix LLC and Kolon TissueGene. HG, BD, OG, CL and MM are employees of Merck KGaA, Darmstadt, Germany. FM and VO are employees of EMD Serono (a business of Merck KGaA, Darmstadt, Germany). ARB, IB and JRA are employees and shareholders in Nordic Bioscience. PGC has received consultancy or speaker’s bureau fees from AbbVie, AstraZeneca, BMS, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Flexion Therapeutics, Galapagos, Kolon Tissue-Gene, Novartis, Pfizer, Samumed and Stryker., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)