{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T15:37:10Z","timestamp":1772638630202,"version":"3.50.1"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"pharmacia GENERIUM"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Patients with cystic fibrosis (CF) need costly medical care and adequate therapy with expensive medicinal products. Tigerase<jats:sup>\u00ae<\/jats:sup> is the first biosimilar of dornase alfa, developed by the lead Russian biotechnology company GENERIUM. The aim of the manuscript to present post hoc sub-analysis of patients\u2019 data with cystic fibrosis and severe pulmonary impairment of a larger comparative study (phase III open label, prospective, multi-centre, randomized study (NCT04468100)) of a generic version of recombinant human DNase Tigerase<jats:sup>\u00ae<\/jats:sup> to the only comparable drug, Pulmozyme<jats:sup>\u00ae<\/jats:sup><\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>In the analyses included subgroup of 46 severe pulmonary impairment patients with baseline FEV<jats:sub>1<\/jats:sub> level 40\u201360% of predicted (23 patients in each treatment group) out of 100 patients registered in the study phase III open label, prospective, multi-center, randomized study (NCT04468100), and compared efficacy endpoints (FEV<jats:sub>1<\/jats:sub>, FVC, number and time of exacerbations, body weight, St.George\u2019s Respiratory Questionnaire) as well as safety parameters (AEs, SAEs, anti-drug antibody) within 24 treatment weeks.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>All outcomes were comparable among the studied groups. In the efficacy dataset, the similar mean FEV<jats:sub>1<\/jats:sub> and mean FVC changes for 24 weeks of both treatment groups were observed. The groups were also comparable in safety, all the secondary efficacy parameters and immunogenicity.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The findings from this study support the clinical Tigerase<jats:sup>\u00ae<\/jats:sup> biosimilarity to Pulmozyme<jats:sup>\u00ae<\/jats:sup> administered in CF patients with severe impairment of pulmonary function.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0261410","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T18:34:48Z","timestamp":1640284488000},"page":"e0261410","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comparison of biosimilar Tigerase and Pulmozyme in long-term symptomatic therapy of patients with cystic fibrosis and severe pulmonary impairment (subgroup analysis of a Phase III randomized open-label clinical trial (NCT04468100))"],"prefix":"10.1371","volume":"16","author":[{"given":"Elena L.","family":"Amelina","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislav A.","family":"Krasovsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4548-7532","authenticated-orcid":true,"given":"Nina E.","family":"Akhtyamova-Givirovskaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nataliya Yu.","family":"Kashirskaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana I.","family":"Abdulganieva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina K.","family":"Asherova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilya E.","family":"Zilber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liliya S.","family":"Kozyreva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lubov M.","family":"Kudelya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalya D.","family":"Ponomareva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nataliya P.","family":"Revel-Muroz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena M.","family":"Reutskaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana A.","family":"Stepanenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gulnara N.","family":"Seitova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga P.","family":"Ukhanova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga V.","family":"Magnitskaya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry A.","family":"Kudlay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oksana A.","family":"Markova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Gapchenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"issue":"1","key":"pone.0261410.ref001","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1053\/srin.2002.31690","article-title":"Pulmonary infections in patients with cystic fibrosis","volume":"17","author":"S. Rajan","year":"2002","journal-title":"Semin Respir Infect."},{"key":"pone.0261410.ref002","first-page":"672","volume-title":"Cystic Fibrosis","author":"N. Kapranov","year":"2014"},{"issue":"61","key":"pone.0261410.ref003","first-page":"54","article-title":"Potekhina, Analysis of the clinical and genetic features and incidence of genetic diseases in Kirov and the Kirov Region","volume":"1","author":"E. Koledaeva","year":"2019","journal-title":"Vyatka Medical Bulletin"},{"issue":"2","key":"pone.0261410.ref004","doi-asserted-by":"crossref","first-page":"115","DOI":"10.15690\/pf.v14i2.1726","article-title":"Davydovskaya, Cystic fibrosis patient registries: national and foreign practice","volume":"14","author":"D. Andreev","year":"2017","journal-title":"Paediatric Pharmacology"},{"key":"pone.0261410.ref005","unstructured":"Clinical Guidelines Cystic Fibrosis in Children, Russian Paediatric Association, 2016. Available: http:\/\/www.pediatr-russia.ru\/sites\/default\/files\/file\/kr_mv.pdf. [\u0414\u0430\u0442\u0430 \u043e\u0431\u0440\u0430\u0449\u0435\u043d\u0438\u044f: 15 Jan 2020] (in Russian)."},{"key":"pone.0261410.ref006","volume-title":"Voronkova, Registry of Cystic Fibrosis Patient in the Russian Federation 2018","author":"E. Amelina","year":"2020"},{"issue":"6","key":"pone.0261410.ref007","first-page":"77","article-title":"Petrova, Clinical and genetic characteristics and outcomes of meconium ileus in cystic fibrosis","volume":"61","author":"E. Kondratieva","year":"2016","journal-title":"Russian Bulletin of Perinatology and Pediatrics"},{"key":"pone.0261410.ref008","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1136\/thx.52.10.900","article-title":"Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis","author":"M. Robinson","year":"1997","journal-title":"Thorax"},{"issue":"14","key":"pone.0261410.ref009","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1034\/j.1399-3003.1999.14b35.x","article-title":"Effects of drugs on mucus clearance","author":"E. Houtmeyers","year":"1999","journal-title":"Eur Respir J"},{"issue":"39","key":"pone.0261410.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ppul.20134","article-title":"DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: Influence of treatment with dornase alpha","author":"F. Ratjen","year":"2005","journal-title":"Pediatr Pulmonol"},{"issue":"4","key":"pone.0261410.ref011","first-page":"611","article-title":"Review of recombinant human deoxyribonuclease (rhDNase) in the management of patients with cystic fibrosis","volume":"2","author":"\u0422. Pressler","year":"2008","journal-title":"Biologics"},{"issue":"6","key":"pone.0261410.ref012","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1097\/MCP.0b013e328358d51f","article-title":"Dornase alfa (Pulmozyme)","volume":"18","author":"J. Wagener","year":"2012","journal-title":"Curr Opin Pulm Med"},{"issue":"6","key":"pone.0261410.ref013","doi-asserted-by":"crossref","first-page":"111","DOI":"10.24110\/0031-403X-2019-98-6-111-117","article-title":"Dornasum alfa in treatment of patients with cystic fibrosis","volume":"98","author":"E. K. A. Voronkova","year":"2019","journal-title":"Pediatria"},{"issue":"9","key":"pone.0261410.ref014","first-page":"CD001127","article-title":"Montgomery, Dornase alfa for cystic fibrosis,","author":"C. Yang \u0438 M","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"issue":"11","key":"pone.0261410.ref015","first-page":"CD007923","article-title":"Timing of dornase alfa inhalation for cystic fibrosis","author":"R. Dentice","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"issue":"4","key":"pone.0261410.ref016","first-page":"889","article-title":"Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease","volume":"110","author":"K. McCoy","year":"1996","journal-title":"Pulmozyme Study Group, Chest"},{"issue":"6","key":"pone.0261410.ref017","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1067\/mpd.2001.118570","article-title":"A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities","volume":"139","author":"J. Quan","year":"2001","journal-title":"J Pediatr"},{"issue":"1","key":"pone.0261410.ref018","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/ppul.23897","article-title":"Cystic fibrosis clinical characteristics associated with dornase alfa treatment regimen change","volume":"53","author":"D. VanDevanter","year":"2018","journal-title":"Pediatr Pulmonol"},{"issue":"6","key":"pone.0261410.ref019","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.jcf.2015.04.003","article-title":"Randomized trial of efficacy and safety of dornase alfa delivered by eRapid nebulizer in cystic fibrosis patients","volume":"14","author":"G. Sawicki","year":"2015","journal-title":"J Cyst Fibros"},{"issue":"6","key":"pone.0261410.ref020","first-page":"894","article-title":"A review of its pharmacological properties and therapeutic potential in cystic fibrosis","volume":"48","author":"H. Bryson","year":"1994","journal-title":"Drugs"},{"issue":"6","key":"pone.0261410.ref021","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1177\/106002809603000614","article-title":"The role of dornase alfa in the treatment of cystic fibrosis","volume":"30","author":"G. Cramer","year":"1996","journal-title":"Ann Pharmacother"},{"issue":"12","key":"pone.0261410.ref022","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1056\/NEJM199203193261207","article-title":"preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis","volume":"326","author":"R. Hubbard","year":"1992","journal-title":"N Engl J Med"},{"key":"pone.0261410.ref023","unstructured":"Hoffmann-La Roche Limited, Product monograph \"Pulmozyme\u00ae\", 2015. [Online]. Available: https:\/\/www.rochecanada.com\/PMs\/Pulmozyme\/Pulmozyme_PM_E.pdf. [Accessed 15 Jan 2020]."},{"key":"pone.0261410.ref024","unstructured":"Protocol KI-39\/14, Single-centre, open-label, randomized study to assess safety, tolerability and pharmacokinetics of Tigerase (GENERIUM JSC, Russia) in comparison with Pulmozyme\u00ae (F. Hoffmann-La Roche, Switzerland) following repeated dose inhalation, 2016 (in Russian)."},{"issue":"6","key":"pone.0261410.ref025","doi-asserted-by":"crossref","first-page":"695","DOI":"10.18093\/0869-0189-2019-29-6-695-706","article-title":"Efficacy and safety of the biosimilar medicinal product Tigerase\u00ae (dornase alfa) in long-term symptomatic treatment of patients with cystic fibrosis: results of a phase III clinical trial","volume":"29","author":"E. Amelina","year":"2019","journal-title":"Pulmonology"},{"key":"pone.0261410.ref026","unstructured":"St. George\u2019s London University, St. George\u2019s Respiratory Questionnaire, [Online]. Available: http:\/\/www.healthstatus.sgul.ac.uk\/sgrq. [Accessed 23 Jan 2020]."},{"key":"pone.0261410.ref027","unstructured":"Common Terminology Criteria for Adverse Events (CTCAE), National Cancer Institute, [Online]. Available: https:\/\/ctep.cancer.gov\/protocolDevelopment\/electronic_applications\/ctc.htm. [Accessed 03 09 2020]."},{"key":"pone.0261410.ref028","unstructured":"Stata Statistical Software: Release 14. StataCorp LP, College Station, 2015."},{"issue":"18","key":"pone.0261410.ref029","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1056\/NEJM199204303261804","article-title":"Prediction of mortality in patients with cystic fibrosis","volume":"326","author":"E. Kerem","year":"1992","journal-title":"N Engl J Med"},{"issue":"3","key":"pone.0261410.ref030","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1378\/chest.12-1404","article-title":"Longitudinal trends in health-related quality of life in adults with cystic fibrosis","volume":"144","author":"E. Dill","year":"2013","journal-title":"Chest"},{"issue":"5","key":"pone.0261410.ref031","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1164\/rccm.200909-1421OC","article-title":"Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation","volume":"182","author":"D. Sanders","year":"2010","journal-title":"American Journal of Respiratory and Critical Care Medicine"},{"issue":"5","key":"pone.0261410.ref032","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1183\/09031936.05.00035205","article-title":"Interpretative strategies for lung function tests","volume":"26","author":"R. Pellegrino","year":"2005","journal-title":"Eur Respir J"},{"issue":"4","key":"pone.0261410.ref033","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.jcf.2016.05.014","article-title":"Physiologic endpoints for clinical studies for cystic fibrosis","volume":"15","author":"S. Stanojevic","year":"2016","journal-title":"Journal of Cystic fibrosis"},{"issue":"267","key":"pone.0261410.ref034","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1001\/jama.1992.03480140073036","article-title":"Recombinant human DNase inhalation in normal subjects and patients with cystic fibrosis. A phase 1 study.","author":"M. Aitken","year":"1992","journal-title":"JAMA"},{"issue":"148","key":"pone.0261410.ref035","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1164\/ajrccm\/148.1.145","article-title":"Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis.","author":"B. Ramsey","year":"1993","journal-title":"Am Rev Respir Dis"},{"issue":"342","key":"pone.0261410.ref036","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0140-6736(93)92297-7","article-title":"Efficacy and safety of short-term administration of aerosolised recombinant human DNase I in adults with stable stage cystic fibrosis","author":"C. Ranasinha","year":"1993","journal-title":"Lancet"},{"issue":"331","key":"pone.0261410.ref037","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1056\/NEJM199409083311003","article-title":"Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group","author":"H. Fuchs","year":"1994","journal-title":"N Engl J Med"},{"issue":"131","key":"pone.0261410.ref038","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/S0022-3476(97)70134-3","article-title":"Safety of repeated intermittent courses of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis","author":"J. Eisenberg","year":"1997","journal-title":"J Pediatr"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261410","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T18:35:25Z","timestamp":1640284525000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261410"}},"subtitle":[],"editor":[{"given":"Davor","family":"Plavec","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,12,23]]},"references-count":38,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0261410","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,23]]}}}