Kosh Agarwal1, Scott K Fung2, Tuan T Nguyen3, Wendy Cheng4, Eric Sicard5, Stephen D Ryder6, John F Flaherty7, Eileen Lawson7, Sally Zhao7, G Mani Subramanian7, John G McHutchison7, Edward J Gane8, Graham R Foster9. 1. Institute of Liver Studies, King's College Hospital, London, UK. Electronic address: kosh.agarwal@nhs.net. 2. Toronto General Hospital, Toronto, Ontario, Canada. 3. T. Nguyen Research and Education, San Diego, CA, USA. 4. Royal Perth Hospital, Perth, Western Australia, Australia. 5. Algorithme Pharma, Montreal, Quebec, Canada. 6. Nottingham University Hospitals NHS Trust and Biomedical Research Unit, Nottingham, UK. 7. Gilead Sciences, Inc., Foster City, CA, USA. 8. Auckland Clinical Studies, Auckland, New Zealand. 9. Queen Mary's University of London, Barts Health, UK.
Abstract
BACKGROUND & AIMS:Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. METHODS:Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. RESULTS:51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses⩽25 mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. CONCLUSIONS:Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.
RCT Entities:
BACKGROUND & AIMS:Tenofovir alafenamide, a phosphonate prodrug of tenofovir with greater plasma stability than tenofovir disoproxil fumarate, provides efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures. METHODS: Non-cirrhotic, treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive tenofovir alafenamide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and assessed for safety, antiviral response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. RESULTS: 51 subjects were randomized and all completed study treatment. Groups were generally well matched (67% male, 57% Asian, 53% HBeAg-negative, mean HBV DNA approximately 6.0 log10 IU/ml) with HBV genotypes reflective of the population. No subject experienced an adverse event that was serious or severe (grade 3/4). Across the tenofovir alafenamide groups, similar mean changes in serum HBV DNA were found at Week 4 (-2.81, -2.55, -2.19, and -2.76 log10 IU/ml for the 8, 25, 40, and 120 mg groups, respectively) which were also comparable to the control (-2.68 log10 IU/ml for tenofovir disoproxil fumarate 300 mg). Kinetics of viral decline were also similar among groups. Tenofovir alafenamide pharmacokinetics were linear and proportional to the dose; doses⩽25 mg were associated with ⩾92% reductions in mean tenofovir area under the curve relative to tenofovir disoproxil fumarate 300 mg. CONCLUSIONS:Tenofovir alafenamide was safe and well tolerated; declines in HBV DNA were similar to tenofovir disoproxil fumarate at all doses evaluated. Tenofovir alafenamide 25 mg has been selected for further hepatitis B clinical development.
Authors: S K Sarin; M Kumar; G K Lau; Z Abbas; H L Y Chan; C J Chen; D S Chen; H L Chen; P J Chen; R N Chien; A K Dokmeci; Ed Gane; J L Hou; W Jafri; J Jia; J H Kim; C L Lai; H C Lee; S G Lim; C J Liu; S Locarnini; M Al Mahtab; R Mohamed; M Omata; J Park; T Piratvisuth; B C Sharma; J Sollano; F S Wang; L Wei; M F Yuen; S S Zheng; J H Kao Journal: Hepatol Int Date: 2015-11-13 Impact factor: 6.047