WALTHAM, Mass. — Pretzel Therapeutics reported new preclinical findings supporting the development of PX578, its lead therapeutic candidate for mitochondrial DNA depletion syndromes, including POLG disease, during the 2026 MDA Clinical & Scientific Conference in Orlando, Florida.
The company said the preclinical data demonstrate that PX578 increases mitochondrial DNA levels, improves cellular respiration and boosts energy production across multiple disease models. The therapy is currently being evaluated in a Phase 1 clinical trial involving healthy volunteers.
POLG disease is a rare and often severe mitochondrial disorder caused by mutations affecting mitochondrial DNA production and maintenance. Reduced mitochondrial DNA levels are a central driver of mitochondrial DNA depletion syndromes, a group of rare conditions that currently have no approved disease-modifying treatments.
PX578 is designed to activate the mitochondrial DNA polymerase POLG enzyme, helping restore mitochondrial DNA levels and address the underlying cause of disease. According to the company, the small-molecule therapy has demonstrated activity across all POLG mutations tested to date, including the four most common mutations that account for roughly 70 percent of cases.
“The data presented at MDA 2026 highlight the potential of PX578 as a meaningful treatment strategy in POLG disease,” said Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics. “With Phase 1 on track for completion in the first half of this year and a study planned for individuals living with POLG disease planned for the second half, we are advancing with momentum to bring this first-in-class medicine to the patients who need it.”
In preclinical studies using both in vitro and in vivo disease models, PX578 increased mitochondrial DNA levels and improved markers of cellular energy production. Researchers also observed improved survival and improved indicators of liver health, results the company said support the therapy’s potential to modify disease progression.
“These preclinical findings across multiple POLG mutation models and disease contexts give us strong confidence in PX578’s mechanism and its potential to address the underlying driver of disease for patients who currently have no treatment options,” said Gabriel Martinez, Ph.D., Chief Scientific Officer and Co-Founder of Pretzel Therapeutics.
Pretzel Therapeutics began its Phase 1 clinical trial of PX578 in 2025 and expects to complete the study in the first half of 2026. The company plans to launch a Phase 2 clinical trial in the second half of 2026 to evaluate pharmacokinetics, safety and proof-of-concept outcomes in individuals living with POLG disease.
