Durham’s Tune Therapeutics to conduct first epigenetic therapy trial

Tune Therapeutics, an epigenome-editing company based in Durham and Seattle, will be the first to initiate a human clinical trial for an epigenetic therapy for a common infectious disease.

The company has received approval from the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) to initiate a Phase 1b clinical trial for TUNE-401, an investigational epigenetic silencing therapy designed to treat chronic Hepatitis B (HBV).

With the approval, TUNE-401 is expected to be the first epigenetic therapy to enter the clinic to treat a common and infectious disease. Over 250 million people are living with chronic HBV infection, which is also the leading cause of hepatocellular carcinoma, or liver cancer, accounting for about 56% of cases worldwide.

“Tune-401 is designed to mimic and amplify a natural, innate immune response against HBV,” said Derek Jantz, chief scientific officer at Tune. “Despite the well-established role of epigenetics in virus control, Tune-401 is the first treatment to employ direct epigenetic silencing to inactivate a virus. We feel confident that this unique mechanism of action will deliver long-awaited benefits for HBV patients and create renewed interest and momentum in the broader field of genetic medicine.”

The clinical trial, expected to begin in December, will enroll up to 36 patients and run for two years.

The first-in-human study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TUNE-401 in adults with chronic HBV. The initial clinical trial site will be in Auckland, New Zealand, where the study will be led by Principal Investigator Ed Gane, M.D., a liver specialist and professor of Medicine at the University of Auckland.

The company told NCBiotech that two factors drove the decision to initiate the clinical trial in New Zealand: the ability to work with a global leader in HBV and close access to potential patients.

Gane, the lead investigator, is a recognized pioneer in the field. Through his groundbreaking work on novel antiviral therapies, he has significantly advanced HBV treatment.

“Moreover, government-supported foundations in New Zealand have perhaps the most comprehensive systems of outreach and support for those affected by HBV, making patient-centric trial design and recruitment far more straightforward relative to many other countries,” the company said.

Disabling ‘viral factories’

Tune-401 uses lipid nanoparticles to deliver RNA encoding the active, HBV-targeting construct directly to liver cells. Inside these cells, the construct is translated into an epi-silencing protein that targets both integrated HBV DNA and cccDNA episomes – free-floating loops of HBV DNA that generate new viral particles and sustain chronic infection for years on end.

Clinicians assert that shutting down these cccDNA “viral factories” is an essential prerequisite to achieving a functional cure for HBV.

Tune-401 is the first treatment to reach the clinic that aims to silence both integrated HBV and HBV cccDNA at the epigenetic level, without cutting or editing DNA. Its active, epi-silencing protein binds to DNA without cutting, adding methyl groups that repress or inactivate viral genes while leaving the human genome intact. The protein is also highly specific – targeting a DNA target sequence unique to HBV, and highly conserved among HBV genomes.

"Hepatitis B remains a significant global health threat, with millions of people affected and in need of durable treatment solutions,” Gane said. “Epigenetic silencing has the potential to achieve a long sought-after goal in the community: the promise of sustained disease remission after a finite course of treatment.”

Tune presented data supporting TUNE-401’s entry into clinical trials at the recent American Association for the Study of Liver Diseases Liver Meeting on Nov. 18.

Lipid nanoparticle technology for TUNE-401 has been provided by Acuitas Therapeutics of Vancouver, British Columbia, Canada.

Genetic tuning platform

With its genetic tuning platform TEMPO, Tune aims to bring gene, cell and regenerative therapies into a new era of human medicine, expanding their range of application to common, chronic and age-related diseases that are straining healthcare systems and limiting human healthspan.

Genetic tuning involves working with the epigenome, the chemical compounds that determine how, when and where a cell’s genes are expressed. Epigenomic changes drive the differences in cell types – such as nerve cells versus muscle cells –and the health status of cells.

“The structures and signals of the epigenome can keep a gene packed tight, inaccessible and silent or wide open, accessible and active within the cell,” the company explains on its website. “Our TEMPO genetic tuning platform works in concert with these master conductors of gene activity, allowing us to turn up the volume on genes required for healthy cells and tissues or turn down the volume on genes that cause or contribute to disease, ultimately rebalancing levels of gene expression – even in complex, multi-gene networks. Genetic tuning via the epigenome opens the door to a powerful new class of treatments for common and chronic diseases.”

Unlike genome editing, the tuning process does not generate double- or single-strand breaks in DNA and makes no permanent changes to the DNA sequence. This de-risks the precise targeting of entire gene networks, allowing Tune to simultaneously turn silenced genes on and dial over-expressed genes down, in a practical, therapeutic context.

Tune Therapeutics was launched in December 2021 by three co-founders: 

• Akira Matsuno, the company’s president and chief financial officer, a biotech executive formerly with Juno Therapeutics and Lyell Immunopharma.
• Fyodor Urnov, professor of genetics, genomics, and development at UC Berkeley and scientific director for technology and translation at the Innovative Genomics Institute.
• Charles Gersbach, a renowned academic and genome engineer, who is the John W. Strohbehn Distinguished Professor of Biomedical Engineering at Duke University and director of the Duke Center for Advanced Genomic Technologies.

Tune’s TEMPO epi-editing platform was initially based upon work done by Gersbach and his lab at Duke but continues to evolve with additional components developed internally or licensed from other sources, the company said.

Tune employs 78 people. The staff is about evenly split between the Durham and Seattle sites, with a few working remotely elsewhere in the country.

Investors in the company include two North Carolina venture capital firms: Hatteras Venture Partners and Pappas Capital, both of Durham.

NCBiotech profiled Tune Therapeutics in April 2024.