Sofosbuvir

Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (2013) Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 368 34-44... 

Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ et al (2014) Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 370 211-221... 

Sofosbuvir (Sovaldi) The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor... 

Currently, three categories of anti-HCV DAAs have been approved, and the nomenclature is based on which viral function is inhibited or affected. The categories are NS3/NS4A protease inhibitors [PI, e.g., boceprevir (2), telaprevir (3), and simeprevir (4)], NS5A protein inhibitors [e.g., ledipasvir (5)], and NS5B RNA-dependent RNA polymerase (RdRp) inhibitors (e.g., sofosbuvir). The last category can be divided further into two subclasses nucleoside/nucleotide polymerase inhibitors (NPI) and nonnucleoside polymerase inhibitors (NNPI). 

The oral bioavailability of sofosbuvir was estimated as 10% in dogs. Oral T , values for sofosbuvir in dogs varied from approximately 0.3 to 3 h but could not be measured in mice and rats dne to blood instability of sofosbuvir. GS-9851 (PSl-7851) was stable in simulated gastric and intestinal flnid, whole blood from dogs and monkeys, and whole blood and plasma from hnmans bnt was nnstable (6/2 < 0.25 h) in rat and mouse blood and in human liver S9 fractions (6/2 < 0.4 h). ... 

In hnmans, following a single 400 mg dose, the PK profile of sofosbuvir showed rapid turnover with a tmax of 0.5 h and a short half-Ufe of approximately 0.5 h. The bioavailability of drng-related material was moderate to high, at least 50%.Dosefinding studies identified optimal inhibition of HCV replication with a once-daily dose of 400 mg. ... 

Sofosbuvir is not a substrate, inhibitor, or inducer of CYP450 enzymes, therefore eliminating a major source of drug-drug interaction. However, sofosbuvir is a substrate (but not an inhibitor) of P-glycoprotein and breast cancer resistance protein. Thus, absorption of sofosbuvir may be affected by coadministration of inducers or inhibitors of these transporters. ... 

Sofosbuvir is the fu-st specific inhibitor of the HCV NS5B polymerase to come to the market. On December 6, 2013, the FDA approved SOF as a component of an antiviral combination regimen for the treatment of HCV genotypes 1, 2, 3, and 4. This was followed by approvals in Canada and the European Union (EU). Treatment was also approved for HCV persons co-infected with HIV-1, using SOF and RBV. In the EU, SOF is also approved for use in genotypes 5 and 6 in a 12-week regimen of SOF with PegIFN and RBV. 

The safety and efficacy of sofosbuvir were evaluated in five phase 3 trials (NEUTRINO, FISSION, POSITRON, FUSION, and VALENCE) including a total of 1724 HCV mono-infected subjects with genotypes 1-6 CHC and one phase 3 trial (PHOTON-1) with 223 HCV/HIV-1 co-infected subjects with genotype 1, 2, or 3 CHC. The primary endpoint in these studies was sustained virologic response 12 weeks after completion of therapy (SVR12). 

Sofosbuvir was also studied with other oral DAA that have a different mechanism of action, with the ultimate goal of elimination of PeglFN and RBV, increased efficacy, decreased duration of treatment, and minimized drug toxicity. These DAA include NS5A inhibitors (daclatasvir, ledipasvir, GS-5816, and ACH-3102), NS3/4A protease inhibitors (simeprevir and GS-9451), and the non-nucleoside polymerase inhibitor (GS-9669). Among them, a fixed dose combination study of SOF and ledipasvir, Harvoni, was the first approved interferon-free DAA combination for the treatment of HCV infection. 

The combination of sofosbuvir with simeprevir (SMV) was studied in a phase 2a trial (COSMOS) on genotype 1 subjects ( = 167). The enrolled persons were either null responders with a METAVIR score of FO to F2 (cohort 1) or treatment-naive and previous null responder with a METAVIR score of E3 to E4 (cohort 2). Subjects received SOE and SMV with or without RBV for 12 or 24 weeks. SVR12 rates were 90% overall (154/167), 90% (72/80) in cohort 1, and 94% (82/87) in cohort 2. The SVR12 rates were not significantly altered by use of ribavirin, duration of treatment, or previous treatment history. 

Sofosbuvir was also studied in combination with non-nucleoside inhibitor GS-9669 and protease inhibitor GS-9451 in genotype 1 persons in phase 2 trials. In the ELECTRON trial, SVR12 rates were 92% (23/25) in treatment-naive persons with 12... 

The synthesis of sofosbuvir was based on the convergent condensation of nucleoside PSI-6206 (10) and a phosphoramidating reagent. The discovery synthesis of PSI-6206 started from cytidine in a linear approach (Scheme 1). Cytidine (29) was selectively benzoylated and silylated to 30, which underwent Swem oxidation and MeLi addition, giving exclusively 2 -a-methyl compound 32. Desilylation and benzoylation of 32 yielded benzoylated 2 -a-methyl compound 33, which was converted to 2 -p-methyl-2 -fluorocytidine 34 by DAST fluorination. Deamination of 34 followed by deprotection provided PSI-6206 (10). 

The discovery synthesis of sofosbuvir (Scheme 3) employed the couphng reaction of PSI-6206 (10) and phosphoramidating reagent 46 which was prepared freshly from phenyl dichlorophosphate 45 and isopropyl L-alanate 44. This couphng resulted in a 1 1 mixture of diastereomers (1 and 28). From this mixture, sofosbuvir (1) was isolated either by HPLC or recrystallization. ... 

Hebner, C. M. Lee, Y. J. Han, B. In vitro pangenotypic and combination activity of sofosbuvir in stable replicon cell lines, The 63th Annual Meeting of the American Association for the Study of Liver Diseases (Boston, MA, 2012), Abstract 1875. 

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