Tune Therapeutics, a leading epigenome editing company, presented new data today at the European Association for the Study of Liver (EASL) Congress in Barcelona, Spain, demonstrating the first clinical evidence of epigenetic silencing in hepatitis B virus (HBV).
The oral presentation was delivered by Dr. Ed Gane, Professor of Medicine at the University of Auckland and world-renowned authority on HBV. The phase 1b/2a clinical trial evaluated the safety and tolerability of TUNE-401 in patients with Chronic Hepatitis B (CHB).
CHB affects more than 240 million people globally, and current therapies rarely achieve a functional cure (≈1 per annum). The key barrier to cure remains the persistence of intranuclear covalently closed circular DNA (cccDNA) within liver cells that serves as the stable viral reservoir. Both current and investigational therapies have indirect mechanisms of action that do not directly silence cccDNA; therefore, when these regimens are discontinued, the virus almost universally comes back.
“The development of a finite HBV cure has long been stalled by a central challenge: how to safely and specifically target and permanently silence cccDNA,” said Dr. Gane. “The TUNE-401 study provides the first clinical evidence that direct epigenetic silencing of HBV cccDNA can achieve this goal, with the potential to meaningfully improve long-term health outcomes for all patients living with chronic hepatitis B.”
Using Tune’s proprietary ‘genetic tuning’ platform, TEMPO, TUNE-401 is an intravenously delivered LNP-RNA epigenetic silencing therapy that is translated in the liver into an HBV-targeting protein, which potently and selectively methylates both cccDNA and integrated HBV DNA.
The ongoing study includes a single-ascending-dose cohort, which consisted of four dose-escalation levels of TUNE-401 IV infusion (SAD1=0.2 mg/kg, SAD2=0.45 mg/kg, SAD3=0.65 mg/kg, SAD4=0.85 mg/kg). The multiple-dose cohort consisted of up to three IV infusions (MD3 = 0.65 mg/kg), administered at least four weeks apart.
When evaluating the safety and tolerability of TUNE-401 in patients with chronic hepatitis B, researchers across the three study sites in New Zealand, Hong Kong, and Moldova observed:
Anti-viral activity
- Durable and dose-dependent repression of all HBV biomarkers including Hepatitis B surface antigen (HBsAg), pregenomic RNA (pgRNA), Hepatitis B e-antigen (HBeAg), Hepatitis B core-related antigen (HBcrAg) and phosphorylated Hepatitis B core HBcAg (P-HBcAg), demonstrating and indicative of direct cccDNA silencing.
- HBV-associated biomarker repression was observed in 100% of participants treated at dose levels 2-4.
Biomarker Silencing and Loss
- Direct cccDNA biomarker loss of pgRNA was observed in 4 out of 7 HBeAg(-) participants treated at dose levels 3 or 4. Of this subset with pgRNA loss, the three participants with detectable HBcrAg at baseline lost HBcrAg as well, with all participants additionally negative for P-HBcAg.
- Direct cccDNA biomarker loss of HBeAg was observed in 3 out of 5 HBeAg(+) participants treated at dose levels 3 or 4.
Durability
- Durable repression of multiple HBV-associated biomarkers following a single dose has currently been observed out to 17 months.
Safety
- A favorable safety profile has been observed to date. Mild to moderate infusion-related reactions and transient asymptomatic transaminase elevations that return to normal within days have been observed in both single and multiple-dose cohorts.
- No additive toxicity from multiple doses has been observed to date.
“Over the prior 30 years in hepatology, I have rarely seen a clinical signal this clear,” said John McHutchison, AO, MD, CEO of Tune Therapeutics. “The deep, dose-dependent, durable reductions across multiple HBV biomarkers, together with the ability to silence the cccDNA reservoir directly, mark a fundamental step toward a possible cure for chronic hepatitis B. We are advancing TUNE-401 into a larger Phase 2 trial with the goal of delivering the first epigenetic backbone therapy for patients with HBV infection.”
Tune Therapeutics is now advancing TUNE-401 into a larger Phase 2 study, including continued dose optimization and expanded multi-dose cohorts. Phase 2 initiation is expected as early as late 2026.
About Ed Gane, MD, MBChB
Dr. Ed Gane is Professor of Medicine at the University of Auckland, New Zealand, and Chief Hepatologist, Transplant Physician, and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital.
About TUNE-401
TUNE-401 is a first-in-class investigational product candidate for the treatment of HBV infection. TUNE-401 utilizes Tune’s TEMPO platform to epigenetically silence the virus’s transcriptional reservoir, cccDNA, the “viral factories” necessary for sustained CHB infection. The lipid nanoparticle for TUNE-401 is licensed from Acuitas Therapeutics Inc.
About Tune Therapeutics
Armed with its powerful and innovative genetic tuning platform (TEMPO), Tune Therapeutics aims to bring gene, cell, and regenerative therapies into a new era of human medicine – expanding their range of application from rare disease to common, chronic, and age-related conditions.
Forward-Looking Statements
This press release contains forward-looking statements regarding Tune Therapeutics’ clinical development plans, including statements about the potential safety, efficacy, and therapeutic benefit of TUNE-401, the design, timing, and progression of clinical trials, the advancement of TUNE-401 into Phase 2, and the broader application of the TEMPO platform. These statements are based on current expectations and assumptions that are subject to risks and uncertainties, including risks related to early-stage clinical results, the inherent uncertainty of clinical trials, regulatory review, and the company’s ability to fund and execute its development programs. Actual results may differ materially. Tune Therapeutics undertakes no obligation to update any forward-looking statement except as required by law.
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