Epigenome Editing Therapy Raises Hopes for a Functional Cure for Chronic Hepatitis B

For the estimated 300 million people living with chronic hepatitis B (CHB), a liver infection caused by the hepatitis B virus (HBV), life-threatening complications such as cirrhosis of the liver or hepatocellular carcinoma are a constant and serious concern.¹ While nucleoside therapy can suppress viral replication and lower the risk of cirrhosis and HCC, this standard-of-care treatment cannot eradicate HBV, leaving patients in need of a functional cure.²

Speaking at the European Association for the Study of Liver (EASL) Congress this month, epigenome editing startup Tune Therapeutics reported data from a Phase I clinical trial of their TUNE-401 candidate, demonstrating durable repression of four key HBV biomarkers in all treated CHB patients. “We have proof of concept that we've durably silenced genes of interest in humans with a common disease by 95 to 100 percent,” said John McHutchison, chief executive officer of Tune Therapeutics.

A First-in-Class Therapy That Mimics Biology

HBV is a small, partially double-stranded DNA virus that infects hepatocytes. Although unrelated, HBV shares some common characteristics with retroviruses that make it difficult to eradicate; it replicates through an RNA intermediate and is known to integrate into the host cell genome, contributing to the development of CHB.¹

Once it enters the nucleus of the host cell, the single-stranded region of the HBV genome is repaired, forming a circular, double-stranded mini-chromosome known as covalently closed circular DNA (cccDNA). This stable form of the virus serves as a template for transcription and a reservoir of viral particles, resisting both the host immune system and antiviral drugs.¹ A functional cure for CHB would need to repress both the cccDNA and the integrated form of the HBV virus (intDNA).

McHutchison, a former physician-scientist and researcher, previously led the research and development team at Gilead Biosciences. Back then, he and his team screened millions of small-molecule compounds to identify a drug that could transcriptionally silence the virus, but to no avail. “We couldn't do it safely, potently, or specifically without toxicity,” he said. “That's what TUNE-401 can do. It is quite remarkable.”

Tune Therapeutics approach to treating HBV is based on a very rare natural phenomenon in which chronic HBV patients can silence the virus through repressive epigenetic marks. TUNE-401 consists of a catalytically dead CRISPR nuclease fused to two epigenetic effector domains, directed by a single guide RNA. Packaged in a liver-targeting lipid nanoparticle, the therapy targets a conserved HBV sequence that controls transcription, aiming to place the same kind of repressive epigenetic marks that suppress replication in those rare patients.

When McHutchison first joined the scientific advisory board at Tune Therapeutics about three years ago, he wasn’t sure if epigenome editing could be successfully translated to humans, but he was impressed by the powerful effects of TUNE-401 in preclinical models. “Nobody's ever shown that before,” he explained. “So I knew they had the inherently important backbone mechanism that we had failed to be able to do for at least a decade, which was to silence the transcriptional reservoir of cccDNA.”

McHutchison’s doubts were eliminated when he saw the data. “Then it was a matter of determining how effective and potent and safe it could be in the clinic,” he recalled.

Epigenome Editing Silences Both Forms of HBV

Beginning in late 2024, the first-in-human trial of TUNE-401 aimed to explore dosage requirements and determine if the therapy is safe in patients with CHB. So far, the data show that the therapy is well-tolerated and has a favorable safety profile, with no major adverse events in the treated patients.

However, McHutchison was most impressed with the stark and durable reductions in the four HBV biomarkers, which indicates strong, long-term antiviral activity. “One [of the slides in that presentation] is the most dramatic slide I've seen in 20 years, where all the biomarkers go way, way, way down in parallel, which means you are really silencing the [viral] reservoir,” he remarked.

According to McHutchison, the biomarkers were reduced by up to 98 percent in one patient, and those figures remained consistent over the 250 days of the initial study. “We have had four people who have become biomarker negative,” he added.

Ed Gane, a medical scientist and HBV expert at the University of Auckland, is the principal investigator of the New Zealand arm of the trial. “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 Gane in a press release from Tune Therapeutics. “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.”

With the success of the initial study, Tune scientists are ramping up for a larger Phase II trial that will explore the maximum effective dose of the therapy. They will also determine whether patients can come off their background nucleoside therapy by monitoring the presence or absence of cccDNA in blood samples over several months. “If cccDNA is really silenced, then pre-genomic RNA should remain undetectable, and if you don't have pre-genomic RNA, then you can't reverse transcribe and make DNA, so then people should remain DNA negative in that situation,” said McHutchison. “We'd like to do that carefully with a couple of select patients over the next few months.”