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Minimum costs to produce Hepatitis C Direct Acting Antivirals for access programs in developing countries
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Reported by Jules Levin
64th Annual Meeting of AASLD, Washington DC, United States of America, November 2013 [Poster 1097]
Andrew Hill and Saye Khoo, Department of Pharmacology and Therapeutics, Liverpool University, UK
Bryony Simmons, Imperial College, London, UK
Nathan Ford, University of Cape Town, South Africa
Ribavirin (generic) is a nucleoside analogue, with a relatively simple chemical synthesis (conversion factor (CF) x1). The daily dose is 1000-1200mg, with an overall dose of 84-100g for 12 weeks of treatment. Production costs were estimated at $0.25 to $0.75 per gram, giving an estimated cost of $21 to $76 for a 12 week course of treatment.
Daclatasvir (patent expiry 2027) is an NS5A inhibitor, and has a straightforward synthesis given its symmetry and the availability of cheap starting materials to synthesise the side-chains (CF x1-3). The daily dose is 60mg, with a total dose of 5g for 12 weeks of treatment. Production costs were estimated conservatively at $2 to $6 per gram, giving an estimated cost of $10 to $30 for a 12 week course of treatment.
Sofosbuvir (patent expiry 2029) is a nucleotide which requires a 2'-fluro-2'-methylfuranose intermediate. This cost-limiting material complicates synthesis (CF x4). The daily dose is 400mg, with a total dose of 34g for 12 weeks of treatment. Production costs were estimated at $2 to $4 per gram, giving an estimated cost of $68 to $136 for 12 weeks of treatment.
Faldaprevir (patent expiry 2025) is a protease inhibitor which requires a tetra-substituted quinoline and a vinyl-cyclopropane amino acid : this complicates the chemical synthesis (CF x10). The daily dose is 120mg, with a total dose of 10g for 12 weeks of treatment. Production costs were estimated at $10 to $21 per gram, giving an estimated cost of $100 to $210 for 12 weeks of treatment.
Simeprevir (patent expiry 2026) , a protease inhibitor, is a medium-ring macrocycle that utilises a novel, ring-closing metathesis reaction in the late stages of API manufacturing. Novel raw material include a tetra-substituted quinoline and a vinyl-cyclopropane amino acid: this significantly complicates synthesis (CF x10). The daily dose is 150mg, with a total dose of 13g for 12 weeks of treatment. Production costs were estimated at $10 to $21 per gram, giving an estimated cost of $130 to $270 for 12 weeks of treatment.
REFERENCES
HCV epidemiology: Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17(2):107-15 doi: 10.111/j.1469-0691.2010.03432.x. http://www.ncbi.nlm.nih.gov/pubmed/21091831
Income classification: The World Bank income classifications, 2013. http://data.worldbank.org/about/country-classifications/country-and-lending-groups
Genotype prevalence: Alberti A, Negro F. The global health burden of hepatitis C virus infection. Liver International 2011;31(2) doi:
10.1111/j.1478-3231.2011.02537.x. http://www.ncbi.nlm.nih.gov/pubmed/21651699
Costs of HIV drugs: Medecins Sans Frontières. Untangling the web of antiretroviral price reductions. 15th Edition - July 2012. http://utw.msfaccess.org/
Patent expiry dates of HCV drugs (all patents are subject to potential patent life extensions):
Ribavirin: WHO, Application for inclusion of ribavirin in the WHO model list of essential medicines. Nov. 2006, page 2. http://archives.who.int/eml/expcom/expcom15/applications/newmed/ribaravin/ribavirin.pdf
Daclatasvir: Bristol-Myers Squibb Company, Form 10-K, year ending 2011, page 9. http://www.sec.gov/Archives/edgar/data/14272/000119312512066416/d302058d10k.htm
Sofosuvir: Pharmasset, Inc, Form 10-K, year ending 2011, page 26; Patent US7,429,572; composition of matter patent US7,964,580. http://quote.morningstar.com/stock-filing/Annual-Report/2011/9/30/t.aspx?t=:VRUS&ft=10-K&d=9038796906580b2535f464bf081028c1
Faldaprevir: Patents US7,585,845 (http://www.google.com/patents/US7585845
) and US7,514,557 (http://www.google.com/patents/US7514557)
Simeprevir: Medivir annual report, 2012, page 18; Patent WO07/014926 http://www.medivir.se/v4/images/pdf/2013/Medivir-ENG-web_0403.pdf
Retro-synthesis and identification of cost limiting materials
Witkowski JT, et al. Design, synthesis, and broad spectrum antiviral activity of 1-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem. 1972; 15(11): 1150-4
Gao M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465(7294): 96-100.
Peng G, et al.; Bristol-Myers Squibb Company. Process for synthesising compounds useful for treating hepatitis C. Patent Application WO2009/020825 A1. Feb 12, 2009.
Chun BK, Wang P.; Pharmasset, Inc. Preparation of 2'fluro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. Patent Application WO2006/031725 A3. Apr 16, 2009.
Chun BK, et al.; Pharmasset, Inc. Nucleoside phosphoramidates. Patent Appliation US2011/0251152 A1. Oct 13, 2011.
White PW, et al. Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. Antimicrob Agents Chemother. 2010; 54(11): 4611-8.
Llinas-Brunet M, et al. Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). J Med Chem. 2010; 53(17): 6466-76.
Horvath A, et al.; Janssen Pharmaceuticals, Inc. Improved process for preparing an intermediate of the macrocyclic protease inhibitor TMC435. Patent Application WO2013/061285 A1. May 2, 2013.
DAA combinations (interferon-free): i-Base/Treatment Action Group. 2012
Pipeline Report: HIV, HCV, and TB drugs, diagnostics, vaccines, and preventative technologies in development. July 2012. http://www.pipelinereport.org/toc
SOUND-C2: Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor faldaprevir (BI 201335) and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin: final results of SOUND-C2 and predictors of response (Abstract 232). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_20.htm
AI444-040: Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.; AI444040 Study Group. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5a inhibitor) plus sofosbuvir (nucleotide NS5b inhibitor) with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3 (Abstract LB-2). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_06.htm
AI443-014: Everson GT, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection (Abstract LB-3). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_07.htm
AI447-011: Lok AS, Gardiner DF, Hezode C, et al. Sustained virologic response in chronic HCV genotype (GT) 1-infected null responders with combination of daclatasvir (DCV; NS5a inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV) (Abstract 79). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_15.htm
ELECTRON: Gane EJ, Stedman CJ, Hyland RH, et al. Once daily sofosbuvir (GS-7977) regimens in HCV genotype 1-3: The ELECTRON trial (Abstract 229). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_31.htm
SPARE: Osinusi A, Heytens L, Lee JY, et al. High Efficacy of GS-7977 in Combination with Low or Full dose Ribavirin for 24 weeks in Difficult to Treat HCV Infected Genotype 1 Patients: Interim Analysis from the SPARE Trial (Abstract LB-4). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, MA. http://www.natap.org/2012/AASLD/AASLD_08.htm
POSITRON: Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med;
2013;368:1867-1877. http://www.nejm.org/doi/full/10.1056/NEJMoa1214854
COSMOS: Lawitz E, Ghalib R, Rodriguez-Torres M, et al. SVR4 results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 null responders. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3-6; Atlanta, GA. http://www.natap.org/2013/CROI/croi_34.htm
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