Pretzel Therapeutics has presented new preclinical data on the lead therapeutic in its bioenergetics restoration franchise, PX578, at the 2026 MDA Clinical & Scientific Conference in Orlando, Florida.
PX578, a first-in-class small molecule activator of the mitochondrial DNA polymerase POLG, is currently in phase 1 clinical development for the treatment of mitochondrial DNA depletion syndromes (MDDS), including POLG disease, a rare and often devastating condition for which no approved disease-modifying therapies currently exist.
Reduced mitochondrial DNA (mtDNA) levels are a central driver of MDDS, a group of rare disorders caused by mutations in genes responsible for mtDNA production and maintenance, including POLG. PX578 is designed to directly activate mutant POLG enzyme to increase mtDNA levels and address the underlying cause of disease. The therapy has demonstrated activity across all POLG mutations tested to date, including the four most common mutations found in approximately 70% of patients.
Preclinical studies across multiple in vitro and in vivo models have generated supportive evidence for the advancement of PX578, demonstrating improved cellular respiration and energy production, increased survival and mtDNA levels, and improved markers of liver health. Collectively, these findings support the disease-modifying potential of PX578 and its continued clinical advancement.
“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, chief scientific officer and co-founder of Pretzel Therapeutics.
Pretzel initiated a phase 1 healthy volunteer study of PX578 in 2025 and is on track to complete phase 1 in the first half of 2026. The company plans to initiate a phase 2 clinical trial in the second half of 2026, designed to generate robust pharmacokinetic and safety data, as well as proof-of-concept data in relevant clinical and patient-reported outcomes.
“The data presented at MDA 2026 highlight the potential of PX578 as a meaningful treatment strategy in POLG disease,” said Jay Parrish, 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.”