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Multiple information sources were used to: determine the status of eculizumab patents; examine the designation of orphan drug status by US, European, Japanese, and Brazilian regulatory authorities to determine registration status and approved clinical indications; estimate the prevalence of associated clinical conditions; investigate the history of the drug manufacturer, Alexion Pharmaceuticals, Inc., and its financialized business model; and examine global eculizumab sales revenues since its first marketing authorization.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Our search yielded 32 patent families divided into 98 applications. The first patent granted was filed in 1995 by Alexion Pharmaceuticals, Inc. in the US. Eculizumab has always been as an orphan drug, except in the Brazilian regulatory agency. All clinical indications approved thus far refer to rare diseases (e.g., paroxysmal nocturnal hemoglobinuria syndrome, atypical hemolytic-uremic syndrome, refractory and generalized myasthenia gravis, and neuromyelitis optica spectrum disorder). Alexion\u2019s revenues amounted to more than US$25 billion between 2007 and 2019, showing a growing trend. Eculizumab led sales from the beginning, being the only product in the company\u2019s portfolio until 2015. In 2019, the drug accounted for 79.1% of all revenues.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>Our findings show that a strategy focused on obtaining orphan drug designation, expanding therapeutic indications and the geographic range of marketing approvals, extending monopoly periods, and prioritizing public procurement niches has enhanced revenues and helped the company achieve leadership in a highly specific and profitable market.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0247853","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T18:37:07Z","timestamp":1614969427000},"page":"e0247853","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Dynamics of patents, orphan drug designation, licensing, and revenues from drugs for rare diseases: The market expansion of eculizumab"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1480-2453","authenticated-orcid":true,"given":"Ros\u00e2ngela","family":"Caetano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena","family":"Cordeiro Dias Villela Correa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Villardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo Henrique","family":"Almeida Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Garcia Serpa Osorio-de-Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,5]]},"reference":[{"key":"pone.0247853.ref001","unstructured":"Herper M. 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New York: Institute for New Economic Thinking (Working Paper N\u00b0 62, July 13, 2017, 27 p.). https:\/\/www.ineteconomics.org\/uploads\/papers\/WP_60-Lazonick-et-al-US-Pharma-Business-Model.pdf","DOI":"10.2139\/ssrn.3035529"},{"issue":"02","key":"pone.0247853.ref004","first-page":"39","article-title":"Dominant business models in the global pharmaceutical industry","volume":"04","author":"R Simonov","year":"2019","journal-title":"Economics & Education"},{"key":"pone.0247853.ref005","unstructured":"Orphanet: About Rare Diseases. 2014. https:\/\/www.orpha.net\/consor\/cgi-bin\/Education_AboutRareDiseases.php?lng = EN"},{"issue":"6","key":"pone.0247853.ref006","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/j.jval.2015.05.008","article-title":"Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group","volume":"18","author":"T Richter","year":"2015","journal-title":"Value Health"},{"issue":"1","key":"pone.0247853.ref007","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13023-018-0762-1","article-title":"Characteristics of drugs for ultra-rare diseases versus drugs for other rare diseases in HTA submissions made to the CADTH CDR","volume":"13","author":"T Richter","year":"2018","journal-title":"Orphanet J Rare Dis"},{"issue":"2","key":"pone.0247853.ref008","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s10198-014-0639-8","article-title":"Rare is frequent and frequent is costly: rare diseases as a challenge for health care systems","volume":"16","author":"JM Graf von der Schulenburg","year":"2015","journal-title":"Eur J Health Econ"},{"issue":"3","key":"pone.0247853.ref009","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/j.1365-2125.2006.02617.x","article-title":"Rare diseases and orphan drugs","volume":"61","author":"JK Aronson","year":"2006","journal-title":"Br J Clin Pharmacol"},{"issue":"10","key":"pone.0247853.ref010","doi-asserted-by":"crossref","first-page":"e0140002","DOI":"10.1371\/journal.pone.0140002","article-title":"Access to Orphan Drugs: A Comprehensive Review of Legislations, Regulations and Policies in 35 Countries","volume":"10","author":"T Gammie","year":"2015","journal-title":"PloS One"},{"issue":"1","key":"pone.0247853.ref011","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1006\/phrs.1999.0644","article-title":"A proposal to improve the supply of orphan drugs","volume":"42","author":"PM Minghetti","year":"2000","journal-title":"Pharmacol Res"},{"key":"pone.0247853.ref012","unstructured":"EvaluatePharma. 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Office of International Programs Pharmaceuticals and Medical Devices Agency (PMDA). 3rd IRDiRC Conference in February 2017. https:\/\/www.irdirc.org\/wp-content\/uploads\/2017\/12\/PAR3_TRA_02-Kondo.pdf"},{"key":"pone.0247853.ref017","unstructured":"Government of Brazil. Ag\u00eancia Nacional de Vigil\u00e2ncia Sanit\u00e1ria. RDC n\u00b0 205 de 28 de dezembro de 2017. Di\u00e1rio Oficial da Uni\u00e3o, se\u00e7\u00e3o 1 p. 28\u2013114. 29 de dezembro de 2015. https:\/\/www.in.gov.br\/materia\/-\/asset_publisher\/Kujrw0TZC2Mb\/content\/id\/1486126\/do1-2017-12-29-resolucao-rdc-n-205-de-28-de-dezembro-de-2017-1486122"},{"issue":"1","key":"pone.0247853.ref018","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ymgme.2008.10.003","article-title":"Clinical research for rare disease: opportunities, challenges, and solutions","volume":"96","author":"RC Griggs","year":"2009","journal-title":"Mol Genet Metab"},{"issue":"12","key":"pone.0247853.ref019","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1056\/NEJMoa061648","article-title":"The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria","volume":"355","author":"P Hillmen","year":"2006","journal-title":"N Engl J Med"},{"key":"pone.0247853.ref020","unstructured":"Bell, L. The Wall Street Transcript. https:\/\/www.twst.com\/bio\/leonard-bell-m-d-2\/"},{"key":"pone.0247853.ref021","unstructured":"Fierce Biotech. Stephen Squinto, Alexion. https:\/\/www.fiercebiotech.com\/special-report\/stephen-squinto-alexion"},{"issue":"2","key":"pone.0247853.ref022","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.clim.2015.08.009","article-title":"Applying complement therapeutics to rare diseases","volume":"161","author":"ES Reis","year":"2015","journal-title":"Clin Immunol"},{"issue":"1","key":"pone.0247853.ref023","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/nrneph.2017.156","article-title":"The renaissance of complement therapeutics","volume":"14","author":"D Ricklin","year":"2018","journal-title":"Nat Rev Nephrol"},{"issue":"9","key":"pone.0247853.ref024","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/s41573-019-0031-6","article-title":"Clinical promise of next-generation complement therapeutics","volume":"18","author":"DC Mastellos","year":"2019","journal-title":"Nat Rev Drug Discov"},{"issue":"1","key":"pone.0247853.ref025","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13023-018-0990-4","article-title":"Estimating the clinical cost of drug development for orphan versus non-orphan drugs","volume":"14","author":"K Jayasundara","year":"2019","journal-title":"Orphanet J Rare Dis"},{"issue":"10149","key":"pone.0247853.ref026","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/S0140-6736(18)31069-9","article-title":"Outrageous prices of orphan drugs: a call for collaboration","volume":"392","author":"L Luzzatto","year":"2018","journal-title":"Lancet"},{"key":"pone.0247853.ref027","doi-asserted-by":"crossref","unstructured":"Berdud M, Drummond M, Towse A. 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Orphan Drug Designations and Approvals. https:\/\/www.accessdata.fda.gov\/scripts\/opdlisting\/oopd\/index.cfm"},{"key":"pone.0247853.ref037","unstructured":"European Commission. Union Register of medicinal products. https:\/\/ec.europa.eu\/health\/documents\/community-register\/html\/index_en.htm"},{"key":"pone.0247853.ref038","unstructured":"Japan. Pharmaceuticals and Medical Devices Agency. Orphan Drugs WA. https:\/\/www.pmda.go.jp\/english\/rs-sb-std\/rs\/0008.html"},{"key":"pone.0247853.ref039","unstructured":"US Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm?event=BasicSearch.process"},{"key":"pone.0247853.ref040","unstructured":"European Medicines Agency. Medicines. https:\/\/www.ema.europa.eu\/en\/medicines"},{"key":"pone.0247853.ref041","unstructured":"Japan. Pharmaceuticals and Medical Devices Agency (PMDA). http:\/\/www.pmda.go.jp\/english\/review-services\/reviews\/approved-information\/drugs\/0001.html#select19"},{"key":"pone.0247853.ref042","unstructured":"Brasil. Ag\u00eancia Nacional de Vigil\u00e2ncia Sanit\u00e1ria\u2013ANVISA. Consulta a Produtos Registrados. Consulta a Medicamentos e Hemoderivados. http:\/\/portal.anvisa.gov.br\/medicamentos\/consultas"},{"key":"pone.0247853.ref043","unstructured":"Orphanet. https:\/\/www.orpha.net\/consor\/cgi-bin\/Disease_Search.php?lng=PT"},{"key":"pone.0247853.ref044","unstructured":"National Organization for Rare Diseases (NORD). https:\/\/rarediseases.org\/for-patients-and-families\/information-resources\/rare-disease-information\/"},{"key":"pone.0247853.ref045","unstructured":"Alexion Pharmaceuticals. Our History. http:\/\/alexion.com\/about-alexion-pharmaceuticals\/history"},{"key":"pone.0247853.ref046","unstructured":"MarketScreener Homepage. Equities. Nasdaq. 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Forbes, Sep 5, 2012. https:\/\/www.forbes.com\/sites\/matthewherper\/2012\/09\/05\/how-a-440000-drug-is-turning-alexion-into-biotechs-new-innovation-powerhouse\/#2771"},{"issue":"7","key":"pone.0247853.ref049","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cpa.2010.06.006","article-title":"Bio-pharma: A financialized business model","volume":"21","author":"T Andersson","year":"2010","journal-title":"Critical Perspectives on Accounting"},{"key":"pone.0247853.ref050","unstructured":"Alexion Pharmaceuticals Inc. News & Media. Press Release. https:\/\/alexionpharmaceuticalsinc.gcs-web.com\/news-media\/press-releases"},{"key":"pone.0247853.ref051","unstructured":"Alexion Pharmaceuticals Inc. Financials. Annual Reports. https:\/\/alexionpharmaceuticalsinc.gcs-web.com\/financial-information\/annual-reports"},{"key":"pone.0247853.ref052","unstructured":"Brasil. Portal de Compras Governo Federal. SIASG. O que \u00e9 o Sistema Integrado de Administra\u00e7\u00e3o de Servi\u00e7os Gerais. https:\/\/www.comprasgovernamentais.gov.br\/index.php\/sisg\/siasg"},{"key":"pone.0247853.ref053","unstructured":"Instituto de Pesquisa Econ\u00f4mica Aplicada. IPEAdata. Taxa de c\u00e2mbio comercial para venda: real (R$) \/ d\u00f3lar americano (US$)\u2013m\u00e9dia. http:\/\/www.ipeadata.gov.br\/ExibeSerie.aspx?serid=31924&module=M&chart=ChartsImage40417902344583176"},{"key":"pone.0247853.ref054","unstructured":"Government of Brazil. Lei n\u00b0 9.279, de 14 de maio de 1996. Regula direitos e obriga\u00e7\u00f5es relativos \u00e0 propriedade industrial http:\/\/www.planalto.gov.br\/ccivil_03\/leis\/l9279.htm"},{"key":"pone.0247853.ref055","unstructured":"Ducimeti\u00e8re C. Second Medical Use Patents -Legal Treatment and Public Health Issues. Research Paper 101. December 2019. South Centre. https:\/\/www.southcentre.int\/wp-content\/uploads\/2019\/12\/RP101_Second-Medical-Use-Patents-Legal-Treatment-and-Public-Health-Issues_EN.pdf"},{"issue":"10","key":"pone.0247853.ref056","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1377\/hlthaff.2012.0107","article-title":"Branded Pharmaceuticals: A Case Study of How Patents on Two HIV Drugs Could Be Extended for Decades","volume":"31","author":"T Amin","year":"2012","journal-title":"Health Aff"},{"issue":"1","key":"pone.0247853.ref057","doi-asserted-by":"crossref","first-page":"1743517","DOI":"10.1080\/19420862.2020.1743517","article-title":"An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry?","volume":"12","author":"E Moorkens","year":"2020","journal-title":"MAbs"},{"issue":"1","key":"pone.0247853.ref058","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/ejh.13411","article-title":"A randomized, double-blind, single-dose, three-arm, parallel group study to determine pharmacokinetic similarity of ABP 959 and eculizumab (Soliris\u00ae) in healthy male subjects","volume":"105","author":"V Chow","year":"2020","journal-title":"Eur J Haematol"},{"key":"pone.0247853.ref059","unstructured":"Mehr S. Amgen Settles with Alexion on Soliris Biosimilar, Dropping Litigation and Getting a Release Date. Biosimilar Review & Report. June 16 2020. https:\/\/biosimilarsrr.com\/2020\/06\/16\/amgen-settles-with-alexion-on-soliris-biosimilar-dropping-litigation-and-getting-a-release-date\/#:~:text=a%20Release%20Date-,Amgen%20Settles%20With%20Alexion%20on%20Soliris%20Biosimilar%2C%20Dropping,and%20Getting%20a%20Release%20Date&text=As%20reported%20by%20several%20sources,of%20Soliris%C2%AE%20in%202025"},{"key":"pone.0247853.ref060","unstructured":"Government of Brazil. Supremo Tribunal da Justi\u00e7a. RECURSO ESPECIAL N\u00b0 1.721.711\u2014RJ (2017\/0261991-0). 20 de abril de 2018. https:\/\/ww2.stj.jus.br\/websecstj\/cgi\/revista\/REJ.cgi\/ITA?seq=1699525&tipo=0&nreg=201702619910&SeqCgrmaSessao=&CodOrgaoJgdr=&dt=20180420&formato=PDF&salvar=false"},{"key":"pone.0247853.ref061","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3389\/fphar.2016.00193","article-title":"Overcoming Barriers to the Market Access of Biosimilars in the European Union: The Case of Biosimilar Monoclonal Antibodies","volume":"7","author":"E Moorkens","year":"2016","journal-title":"Front Pharmacol"},{"issue":"3","key":"pone.0247853.ref062","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1365-2125.2006.02654.x","article-title":"Are rare diseases still orphans or happily adopted? 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Di\u00e1rio Oficial da Uni\u00e3o n\u00b0 249, de 29 de dezembro de 2017."},{"issue":"2","key":"pone.0247853.ref064","first-page":"9","article-title":"Challenges and opportunities in the treatment of rare diseases","volume":"14","author":"PJ Vickers","year":"2012","journal-title":"Drug Discovery World"},{"issue":"2\u20133","key":"pone.0247853.ref065","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.healthpol.2009.12.001","article-title":"The US Orphan Drug Act: rare disease research stimulator or commercial opportunity?","volume":"95","author":"O Wellman-Labadie","year":"2010","journal-title":"Health Policy"},{"key":"pone.0247853.ref066","doi-asserted-by":"crossref","first-page":"c6471","DOI":"10.1136\/bmj.c6471","article-title":"Orphan drug pricing may warrant a competition law investigation","volume":"341","author":"JC Roos","year":"2010","journal-title":"BMJ"},{"issue":"5","key":"pone.0247853.ref067","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1377\/hlthaff.2017.1179","article-title":"Evaluating The Impact Of The Orphan Drug Act\u2019s Seven-Year Market Exclusivity Period","volume":"37","author":"A Sarpatwari","year":"2018","journal-title":"Health Aff"},{"key":"pone.0247853.ref068","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/1750-1172-6-59","article-title":"Does market exclusivity hinder the development of Follow-on Orphan Medicinal Products in Europe?","volume":"6","author":"AE Brabers","year":"2011","journal-title":"Orphanet J Rare Dis"},{"issue":"6","key":"pone.0247853.ref069","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.tips.2018.03.003","article-title":"Orphan Drugs and Their Impact on Pharmaceutical Development","volume":"39","author":"MM Attwood","year":"2018","journal-title":"Trends Pharmacol Sci"},{"issue":"13\u201314","key":"pone.0247853.ref070","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.drudis.2012.02.005","article-title":"Orphan drug development: an economically viable strategy for biopharma R&D","volume":"17","author":"KN Meekings","year":"2012","journal-title":"Drug Discov Today"},{"issue":"1","key":"pone.0247853.ref071","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13023-017-0617-1","article-title":"Orphan medicinal products in Europe and United States to cover needs of patients with rare diseases: an increased common effort is to be foreseen","volume":"12","author":"V Giannuzzi","year":"2017","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0247853.ref072","unstructured":"EvaluatePharma. Orphan drug report 2020. London: EvaluatePharma; 2020 April. https:\/\/www.evaluate.com\/orphan-drugs."},{"issue":"4","key":"pone.0247853.ref073","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2165\/11590170-000000000-00000","article-title":"Drugs for rare diseases: influence of orphan designation status on price.","volume":"9","author":"E Picavet","year":"2011","journal-title":"Appl Health Econ Health Policy"},{"key":"pone.0247853.ref074","unstructured":"Brooks M. Rare Disease Treatments Make Up Top 10 Most Costly Drugs. 2 May 2017. https:\/\/www.medscape.com\/viewarticle\/879422."},{"key":"pone.0247853.ref075","unstructured":"EvaluatePharma. Orphan drug report 2015. London: EvaluatePharma; 2015 Oct. http:\/\/info.evaluategroup.com\/rs\/607-YGS-364\/images\/EPOD15.pdf"},{"issue":"1","key":"pone.0247853.ref076","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ejh.13059","article-title":"Screening and diagnostic clinical algorithm for paroxysmal nocturnal hemoglobinuria: Expert consensus","volume":"101","author":"A R\u00f6th","year":"2018","journal-title":"Eur J Haematol"},{"issue":"17","key":"pone.0247853.ref077","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1056\/NEJMra0902814","article-title":"Atypical hemolytic-uremic syndrome","volume":"361","author":"M Noris","year":"2009","journal-title":"N Engl J Med"},{"issue":"43","key":"pone.0247853.ref078","doi-asserted-by":"crossref","first-page":"42","DOI":"10.7748\/ns.2017.e10434","article-title":"Diagnosis and management of myasthenia gravis","volume":"31","author":"C Barber","year":"2017","journal-title":"Nurs Stand"},{"key":"pone.0247853.ref079","first-page":"255","article-title":"Clinical characteristics of refractory myasthenia gravis patients","volume":"86","author":"J Suh","year":"2013","journal-title":"Yale J Biol Med"},{"issue":"2","key":"pone.0247853.ref080","doi-asserted-by":"crossref","first-page":"169","DOI":"10.7861\/clinmedicine.19-2-169","article-title":"Neuromyelitis optica spectrum disorders","volume":"19","author":"S Huda","year":"2019","journal-title":"Clin Med (Lond)"},{"issue":"5","key":"pone.0247853.ref081","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.jval.2018.03.002","article-title":"The Problem of Rarity: Estimation of Prevalence in Rare Disease","volume":"21","author":"S Auvin","year":"2018","journal-title":"Value Health"},{"key":"pone.0247853.ref082","first-page":"256","volume-title":"Predatory Value Extraction: How the Looting of the Business Corporation Became the US Norm and How Sustainable Prosperity Can be Restored","author":"W Lazonick","year":"2020"},{"key":"pone.0247853.ref083","unstructured":"Lazonick W, Tulum \u00d6, Hopkins M, Sakin\u00e7 ME, Jacobson K. Financialization of the U.S. Pharmaceutical industry, The Academic-Industry Research Network. December 2, 2019, 15 p. https:\/\/www.ineteconomics.org\/perspectives\/blog\/financialization-us-pharma-industry"},{"key":"pone.0247853.ref084","unstructured":"Alexion. History. November 17 2020. https:\/\/alexion.com\/our-company\/history."},{"key":"pone.0247853.ref085","unstructured":"Fierce Pharma. Leonard Bell, Alexion Pharmaceuticals. https:\/\/www.fiercepharma.com\/special-report\/leonard-bell-alexion-pharmaceuticals."},{"key":"pone.0247853.ref086","unstructured":"Alexion. Pipeline. October 29 2020. https:\/\/alexion.com\/our-research\/pipeline."},{"issue":"10","key":"pone.0247853.ref087","doi-asserted-by":"crossref","first-page":"e0164681","DOI":"10.1371\/journal.pone.0164681","article-title":"Profitability and Market Value of Orphan Drug Companies: A Retrospective, Propensity-Matched Case-Control Study","volume":"11","author":"DA Hughes","year":"2016","journal-title":"PloS One"},{"issue":"6","key":"pone.0247853.ref088","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1182\/blood-2018-09-876136","article-title":"Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study","volume":"133","author":"JW Lee","year":"2019","journal-title":"Blood"},{"issue":"6","key":"pone.0247853.ref089","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1182\/blood-2018-09-876805","article-title":"Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study","volume":"133","author":"AG Kulasekararaj","year":"2019","journal-title":"Blood"},{"key":"pone.0247853.ref090","first-page":"1","article-title":"Ravulizumab for the treatment of paroxysmal nocturnal hemoglobin","volume":"14","author":"JW Lee","year":"2020","journal-title":"Expert Opin Biol Ther"},{"key":"pone.0247853.ref091","unstructured":"Government of Brazil. Minist\u00e9rio da Sa\u00fade, Ag\u00eancia Nacional de Vigil\u00e2ncia Sanit\u00e1ria. Consulta ao registro do medicamento Soliris. Bras\u00edlia, DF: ANVISA; 2019. https:\/\/consultas.anvisa.gov.br\/#\/medicamentos\/25351199836201512\/?substancia=25890."},{"key":"pone.0247853.ref092","unstructured":"Government of Brazil. Minist\u00e9rio da Sa\u00fade. Portaria n\u00b0 77, de 14 de dezembro de 2018. Torna p\u00fablica a decis\u00e3o de incorporar o eculizumabe para tratamento de pacientes com hemoglobin\u00faria parox\u00edstica noturna (HPN) no \u00e2mbito do Sistema \u00danico de Sa\u00fade. Di\u00e1rio Oficial Uni\u00e3o. 17 dez 2018; Se\u00e7\u00e3o 1:76. http:\/\/www.in.gov.br\/web\/guest\/materia\/-\/asset_publisher\/Kujrw0TZC2Mb\/content\/id\/55443289\/do1-2018-12-17-portaria-n-77-de-14-de-dezembro-de-2018-55443067."},{"key":"pone.0247853.ref093","unstructured":"Government of Brazil. Minist\u00e9rio da Sa\u00fade. Portaria Conjunta SCTIE\/SAES\/MS n\u00b0 18\/2019. Protocolo Cl\u00ednico e Diretrizes Terap\u00eauticas Hemoglobin\u00faria Parox\u00edstica Noturna. Di\u00e1rio Oficial Uni\u00e3o. 22 nov 2019; Se\u00e7\u00e3o 1:153. http:\/\/conitec.gov.br\/images\/Relatorios\/Portaria\/2019\/PortariaConjunta_SCTIE_SAES_18_2019.pdf."},{"key":"pone.0247853.ref094","doi-asserted-by":"crossref","first-page":"22","DOI":"10.11606\/s1518-8787.2020054001693","article-title":"The case of eculizumab: litigation and purchases by the Brazilian Ministry of Health","volume":"54","author":"R Caetano","year":"2020","journal-title":"Rev Saude Publica"},{"key":"pone.0247853.ref095","unstructured":"Vieira MF, Chaves GC. The Patent Paradox in Brazil. implications for purchases of medicines by the public health system. March 2018. Rio de Janeiro: Fiocruz. https:\/\/accessibsa.org\/media\/2018\/03\/The-Patent-Paradox-In-Brazil.pdf"},{"key":"pone.0247853.ref096","unstructured":"Government of Brasil. Lei n\u00b0 9.782, de 26 de janeiro de 1999. Define o Sistema Nacional de Vigil\u00e2ncia Sanit\u00e1ria, cria a Ag\u00eancia Nacional de Vigil\u00e2ncia Sanit\u00e1ria, e d\u00e1 outras provid\u00eancias. http:\/\/www.planalto.gov.br\/ccivil_03\/leis\/l9782.htm."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247853","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T18:38:59Z","timestamp":1614969539000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247853"}},"subtitle":[],"editor":[{"given":"J E.","family":"Trinidad Segovia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,5]]},"references-count":96,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0247853","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,5]]}}}