Tune Therapeutics, a leading epigenetic therapy company, has received approval from the Hong Kong Department of Health to initiate a Phase 1b clinical trial for TUNE-401, an investigational epigenetic silencing therapy for chronic hepatitis B (CHB). This follows a previous approval in New Zealand, marking a significant step in the development of a novel treatment approach for this widespread infectious disease.
The Hong Kong trial will be led by Professor Man-Fung Yuen from The University of Hong Kong and Queen Mary Hospital, a renowned hepatologist with extensive experience in hepatitis B research and treatment. Professor Yuen's expertise will be crucial in evaluating the potential of TUNE-401 to address the unique challenges of treating HBV in Asian populations, where the disease is often acquired early in life.
Targeting cccDNA for Functional Cure
TUNE-401 employs a novel mechanism of action, utilizing a catalytically-dead Cas9 (dCas9) fused to epigenetic repressor domains to target and silence the HBV genome. This approach aims to address the limitations of current standard-of-care treatments, which rarely achieve a complete cure due to the persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes. By targeting both integrated viral DNA and cccDNA, TUNE-401 seeks to induce long-term epigenetic silencing, potentially leading to a functional cure for HBV infection.
Derek Jantz, Chief Scientific Officer at Tune Therapeutics, expressed optimism about the potential of TUNE-401 to transform the treatment landscape for chronic HBV, stating, "Our hope is that this could be a 'one-and-done' functional cure for HBV infection," and that the therapy might permanently inactivate the virus, freeing patients from daily antiviral regimens.
Strategic Focus on High-Prevalence Regions
The decision to conduct clinical trials in Hong Kong and New Zealand reflects a strategic focus on regions with a high prevalence of HBV. According to the World Health Organization, the Western Pacific Region carries the highest burden of hepatitis B infection globally. By initiating trials in these regions, Tune Therapeutics aims to accelerate the development of TUNE-401 and bring a new treatment option to the patients who need it most.
Professor Yuen highlighted the importance of this new therapeutic approach, stating, "This therapy is expected to address the gap of the existing treatment which does not have high efficacy against immune-suppressive viral antigen, i.e., hepatitis B surface antigen," and that the aim is to allow host immune restoration, removing the need for lifelong therapy.
Preclinical Data and Future Outlook
In November 2024, Tune Therapeutics presented preclinical data demonstrating TUNE-401's ability to repress both cccDNA and integrated DNA in target cells and animal models. These encouraging results provide a strong foundation for the ongoing clinical development program. The Phase 1b trial in Hong Kong will evaluate the safety, tolerability, and preliminary efficacy of TUNE-401 in patients with chronic hepatitis B, paving the way for future studies and potential regulatory approval.
TUNE-401 comprises a catalytically-dead Cas9 (dCas9) fused to two effector domains – a methyltransferase and another epigenetic repressor; these work together to exploit a weakness in the epigenetic regulation of HBV. Delivered via lipid nanoparticles, TUNE-401 contains an mRNA sequence encoding the epigenetic repressors and a guide RNA sequence targeting HBV. The target is a master controller sequence that is conserved between the integrated viral DNA and cccDNA of the virus across all known genotypes. Data presented at AASLD in November 2024, demonstrated near-complete (99.99%) repression of HBV RNA from cccDNA of infected primary human hepatocytes and in a ‘true infection’ FRG mouse model, after treatment with TUNE-401.
