December 23, 2013

Minimum costs to produce Hepatitis C Direct Acting Antivirals for access programs in developing countries

Provided by NATAP

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

(Click on images to enlarge)

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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.

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REFERENCES

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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

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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
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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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