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https://pmc.ncbi.nlm.nih.gov/articles/PMC12315950/pdf/sciadv.adw2286.pdf

Ultra-long-acting Tenofovir Phosphonate Prodrug

Developer(s)

University of Nebraska Medical Center

Originator
https://www.unmc.edu/

United States of America

The University of Nebraska Medical Centre (UNMC) is a premier public academic health science centre located in Omaha, Nebraska. Established in 1869 as the Omaha Medical College, it became part of the University of Nebraska system in 1902 and operates as the state's only publicly supported health sciences centre.

Drug structure

Structure of amino acid–free hydrophobic and lipophilic crystalline TFV phosphonate prodrug

Structure of amino acid–free hydrophobic and lipophilic crystalline TFV phosphonate prodrug

https://pmc.ncbi.nlm.nih.gov/articles/PMC12315950/pdf/sciadv.adw2286.pdf

Drug information

Associated long-acting platforms

phosphonate prodrug nanosuspension

Administration route

Intramuscular

Therapeutic area(s)

HIV
HBV

Use case(s)

Pre-Exposure Prophylaxis (PrEP)
Treatment

Use of drug

Ease of administration

Administered by a community health worker
Administered by a nurse
Administered by a specialty health worker

Frequency of administration

Other/Variable/Unknown : Frequency is unknown but the formulation sustained suppression of viral replication for >10 weeks

User acceptance

Not provided

Dosage

Available dose and strength

Preclinical doses: 200 mg/kg & 400 mg/kg. Strength: 303 mg/ml via Intramuscular (IM) route

Maximum dose

400 mg/kg

Recommended dosing regimen

Not provided

Format

Not provided

Additional comments

Not provided

Dosage link(s)

https://pmc.ncbi.nlm.nih.gov/articles/PMC12315950/pdf/sciadv.adw2286.pdf

Drug information

Drug's link(s)

https://go.drugbank.com/drugs/DB14126

Generic name

Nanoformulated Myristoylated Monophenyl Tenofovir Phosphonate Prodrug

Brand name

Tenofover Phosphate

Compound type

Small molecule

Drug class/category

Protease Inhibitor (PI)

Lifecycle status

Preclinical / IND

Summary

NM5TFV (nanoformulated myristoylated monophenyl tenofovir ) is an ultra-long-acting intramuscular prodrug formulation designed to provide sustained delivery of tenofovir after a single administration. Following injection, nanocrystal depots formed at the injection site gradually release M5TFV into systemic circulation. The prodrug undergoes hydrolysis to tenofovir, which is subsequently phosphorylated intracellularly to the active metabolite, tenofovir diphosphate, responsible for antiviral activity. This approach aims to overcome adherence limitations associated with daily oral therapy by maintaining prolonged systemic drug exposure. Pharmacokinetic studies demonstrated slow and sustained release of tenofovir from the depot formulation. In rats, a single intramuscular dose maintained detectable plasma tenofovir concentrations for up to 365 days, with prolonged distribution to liver, spleen, lymph nodes, kidney and muscle tissues. The extended exposure was attributed to slow nanocrystal dissolution and gradual prodrug conversion. In HBV-transgenic mice, sustained drug levels following a single dose produced durable suppression of HBV DNA, HBsAg, HBeAg and intrahepatic viral markers

Approval status

Under preclinical investigation

Regulatory authorities

Under preclinical investigation

Safety

Based on preclinical studies: 1) No drug-related systemic toxicity was observed, with normal hematology, serum chemistry, liver, kidney and spleen histology. 2) Mild-to-moderate transient granulomatous inflammatory reactions occurred at the injection site and resolved over time without muscle degeneration, edema, or erythema. 3) No adverse effects on body weight were detected.

Efficacy

1) A single dose of TFV phosphonate prodrug caused >2.5 log10 reduction in blood HBV DNA for >2 months in transgenic mouse models 2) At weeks 6 and 8 post-injection, a significant 0.7 log10 difference in HBV DNA reduction

Evidence Summary

Preclinical studies demonstrated a favorable safety profile for ultra long-acting tenofovir phosphonate for HBV infections. No drug-related systemic toxicity was observed, and hematology, serum chemistry, and histopathology of the liver, kidney, and spleen remained normal. Mild-to-moderate transient granulomatous inflammatory reactions occurred at the injection site but resolved over time without muscle degeneration, edema, or erythema. No adverse effects on body weight were detected, supporting good overall tolerability. Efficacy studies showed sustained antiviral activity, with a >2.5 log10 reduction in blood HBV DNA maintained beyond two months after a single administration. Significant antiviral effects persisted through weeks 6 and 8 post-injection, achieving approximately 0.7 log10 greater HBV DNA reduction than comparator treatment. These findings support the potential of long-acting tenofovir phosphate as a durable and well-tolerated therapy for chronic hepatitis B.

Delivery device(s)

Not provided

Scale-up and manufacturing prospects

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Not provided

Manufacturing

1. Manufacturing formulation: Scalable-milling-compatible high-pressure homogenization process 2. Synthesis: Tenofovir monophenyl was chemically modified through esterification with octadecanol via a cleavable phosphoester bond to generate M5TFV, a lipophilic, amino acid-free crystalline phosphonate prodrug of tenofovir. The reaction requires: - PPh₃: Triphenylphosphine. - 2,2′-Dithiopyridine: Reaction-promoting reagent. - Et₃N: Triethylamine. - Pyridine: Reaction medium. - Temperature: 65°C.

Specific analytical instrument required for characterization of formulation

1. Fourier transform infrared (FT-IR) spectroscopy, 2. Nuclear magnetic resonance (NMR) 3. Matrix-assisted laser desorption/ionization–time-of-flight (MALDI-TOF) mass spectrometry

Clinical trials

Not provided

Excipients

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

1. Tween 20 2. PEG 3350

Residual solvents used

Not provided

Patent info

Description

Prodrugs and formulations thereof

Brief description

The present invention provides prodrugs and methods of use thereof.

Representative patent

US20220288037A1

Category

Prodrug formulation design

Patent holder

University of Nebraska System

Exclusivity

Not provided

Expiration date

August 20, 2030

Status

Abandoned

Supporting material

Publications

Raut SS, Das S, Bybee G, et al. A scalable ultra-long-acting tenofovir phosphonate prodrug sustains HBV suppression. Sci Adv. 2025;11(31):eadw2286. doi: 10.1126/sciadv.adw2286

Samiksha S Raut — Science Advances — 2025-08-11

Link: https://pubmed.ncbi.nlm.nih.gov/40749058/

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 log10 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.

Additional documents

Useful links

There are no additional links

Additional information

Not provided