Ultra Long-Acting Tenofovir ProTide

Associated long-acting platforms

Aqueous drug particle suspension, Solid Drug Nanoparticles

Administration route

Intramuscular

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Production scale-up viability for NM1TFV solid drug nanoformulations by high-pressure homogenization and/or wet bead milling processes have been established.

Tentative equipment list for manufacturing

Not provided

Manufacturing

Lipophilic ProTides of TFV bearing phenylalanine and alanine amino acid esters were created by replacing optimal short chain alkyl ester groups utilised by conventional ProTide strategies. The docosanol masking ester motif was selected based on inherent lipophilicity and synergy with nucleoside analogs. NM1TFV was synthesised by coupling a phenylalanyl or alanyl docosyl ester to monophenyl TFV in the presence of Et3N. As the conjugation step is moisture sensitive, further improvements to the chemical yields could be achieved by either optimizing the coupling reagents or reaction vessels.

Specific analytical instrument required for characterization of formulation

Dynamic light scattering (DLS) and HPLC to measure nanoparticle size, Autoflex maX MALDI-TOF/TOF mass spectrometer to confirm molecular mass.

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

No novel excipient or existing excipient used

Residual solvents used

Not provided

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Srijanee Das et al., An ultralong-acting tenofovir ProTide nanoformulation achieves monthslong HBV suppression. Sci. Adv. 8, eade9582(2022). DOI:10.1126/sciadv.ade9582

Treatment of chronic hepatitis B virus (HBV) requires lifelong daily therapy. However, suboptimal adherence to the existing daily therapy has led to the need for ultralong-acting antivirals. A lipophilic and hydrophobic ProTide was made by replacing the alanyl isopropyl ester present in tenofovir alafenamide (TAF) with a docosyl phenyl alanyl ester, now referred to as M1TFV. NM1TFV and nanoformulated TAF (NTAF) nanocrystals were formulated by high-pressure homogenization. A single intramuscular injection of NM1TFV, but not NTAF, delivered at a dose of TFV equivalents (168 milligrams per kilogram) demonstrated monthslong antiviral activities in both HBV-transgenic and human hepatocyte transplanted TK-NOG mice. The suppression of HBV DNA in blood was maintained for 3 months. Laboratory experiments on HBV-transfected HepG2.2.15 cells affirmed the animal results and the critical role of docosanol in the sustained NM1TFV antiviral responses. These results provide clear “proof of concept” toward an emerging therapeutic paradigm for the treatment and prevention of HBV infection.

Cobb, D.A., Smith, N., Deodhar, S. et al. Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles. Nat Commun 12, 5458 (2021). DOI: https://doi.org/10.1038/s41467-021-25690-5

Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.

Additional documents

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Useful links

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