GS-7340 : Tenofovir Prodrug Requires Lower Doses, But Will It Be Friendlier on Kidney and Bones?
CROI 2012- Oral Presentation #103. GS-7340 25 mg and 40 mg Demonstrate Superior Efficacy to Tenofovir 300 mg in a 10-day Monotherapy Study of HIV-1+ Patients
GS-7340 is a novel prodrug of tenofovir (TVF) that has shown greater antiviral activity at lower doses than tenofovir disoproxil fumarate (TDF) 300 mg, achieving higher intracellular TFV-diphosphate (DP) concentration with lower systemic TFV exposure, in a prior proof-of-concept study.
This randomized, partially blinded, placebo and active-controlled, dose-finding, 10-day monotherapy study was conducted to compare 3 different doses of GS-7340 (8, 25, and 40 mg once daily), open-label TDF (300 mg once daily), and GS-7340 placebo in HIV-1-infected subjects with HIV-1 RNA ≥2000 copies/mL, no genotypic resistance to TDF, and CD4 cell count ≥200 cells/mm3. The primary endpoint was time-weighted average HIV-1 RNA change from baseline after 10 days of treatment. Plasma and intracellular peripheral blood mononuclear cell pharmacokinetics were also assessed.
The study found that GS-7340 at 25 mg and 40 mg demonstrated superior antiviral efficacy to TDF at 300 mg, achieving higher intracellular TFV-DP concentration with lower systemic TFV exposure. GS-7340 has the potential to be more efficacious with an improved safety margin, and to be easier to co-formulate, compared with TDF. A later presentation also showed that this prodrug has better penetration in different body compartments compared to tenofovir.
Let’s hope that this pro drug will show less of a negative effect on kidney function and bone density than tenofovir. Let’s also hope that its better tissue penetration is different body compartments will also result in better control of latent HIV infection in reservoirs.