Project

Antiviral - HBV Polymerase Inhibitors (3rd generation)

Goal: Develop AIB-001, a new oral liver targeted HBV Polymerase inhibitor as the Backbone component of a combination therapy for HBV Functional Cure.

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Project log

Cyril B Dousson
added a research item
In worldwide clinical settings, several nucleos(t)ide analogues (NAs), including tenofovir disoproxil fumarate (TDF), entecavir (ETV), and tenofovir alafenamide fumarate (TAF) are used to treat patients chronically infected with HBV.1,2 NAs are easily administrated orally and have favorable pharmacologic profiles.3 Their use is generally preferred to that of the immune stimulator pegylated-interferon (Peg-IFN)-alpha, which induces more adverse effects (AEs) and less virological suppression (i.e. HBV DNA decline in serum), although it is associated with a higher rate of HBsAg loss.1,2,4 Treatment indications for these NAs have been clearly defined by international societies, including EASL.1 Their efficacy to suppress/reduce HBV viremia and overall safety have been properly assessed in randomized controlled phase III clinical trials (i.e. registration trials) and in long-term real-world studies.1,2,4 When “no virologic resistance” occurs, long-term treatments with 1 of the 3 most used NAs (TDF, ETV, TAF) are associated with a prolonged virologic responses (i.e. viremia below detection levels by qPCR) in most patients (>95%), normalized alanine aminotransferase levels, regression of fibrosis, and altogether with the prevention of disease progression, including hepatocellular carcinoma development.
Cyril B Dousson
added a research item
Chronic Hepatitis B Virus infections afflict >250 million people and kill nearly 1 million annually. Current non-curative therapies are dominated by nucleos(t)ide analogs (NAs) that profoundly but incompletely suppress DNA synthesis by the viral reverse transcriptase. Residual HBV replication during NA therapy contributes to maintenance of the critical nuclear reservoir of the HBV genome, the covalently-closed circular DNA, and to ongoing infection of naive cells. Identification of next-generation NAs with improved efficacy and safety profiles, often through novel prodrug approaches, is the primary thrust of ongoing efforts to improve HBV replication inhibitors. Inhibitors of the HBV ribonuclease H, the other viral enzymatic activity essential for viral genomic replication, are in preclinical development. The complexity of HBV’s reverse transcription pathway offers many other potential targets. HBV’s protein-priming of reverse transcription has been briefly explored as a potential target, as have the host chaperones necessary for function of the HBV reverse transcriptase. Improved inhibitors of HBV reverse transcription would reduce HBV’s replication-dependent persistence mechanisms and are therefore expected to become a backbone of future curative combination anti-HBV therapies.
Cyril B Dousson
added a project goal
Develop AIB-001, a new oral liver targeted HBV Polymerase inhibitor as the Backbone component of a combination therapy for HBV Functional Cure.