A scalable ultra-long-acting tenofovir phosphonate prodrug sustains HBV suppression
- Samiksha S. Raut
- Srijanee Das
- Grace Bybee
- Haritha Chava
- Mojisola Ogunnaike
- Weimin Wang
- Anup S. Pathania
- Brandon W. Hanson
- Nam Thai Hoang Le
- Samuel M. Cohen
- Howard E. Gendelman
- Larisa Y. Poluektova
- Benson J. Edagwa
- Natalia A. Osna
2025-08-01
Long-acting (LA) extended-release formulations are revolutionizing treatment and prevention of HIV infection. However, none of the existing LA therapies are active against hepatitis B virus (HBV), a common coinfection with HIV. Managing coinfection requires therapy to be effective against both viruses. Notable candidates are tenofovir (TFV) prodrugs. We have previously developed an LA TFV through a modified lipophilic ProTide strategy. Given the process chemistry challenges presented by amino acid chiral centers in ProTides, a simplified lipophilic amino acid–free crystalline phosphonate prodrug of TFV (M5TFV) has been created. Intramuscular injections of M5TFV nanosuspension (NM5TFV) were well tolerated in Sprague-Dawley rats and HBV transgenic mice. Notably, single doses at 200 and 400 milligrams per kilogram TFV equivalents produced >2.5 log 10 reduction in HBV DNA beyond 2 months in transgenic mice. Reductions of covalently closed circular DNA were seen in hepatocyte-like cells. These promising findings support further development of NM5TFV as an ultra-LA formulation.