Waltham, Massachusetts-based Pretzel Therapeutics announced receipt of US FDA Fast Track Designation for PX578, a central nervous system-penetrant small molecule activator of mitochondrial DNA polymerase gamma (POLG), for the treatment of POLG-mediated primary mitochondrial disorders (POLG disease). No approved disease-modifying therapy currently exists for the condition.
The designation follows FDA clearance in August 2026 of Pretzel's Investigational New Drug (IND) application to begin the first-in-patient trial of PX578. That clearance was itself predicated on a completed Phase I healthy volunteer study — a randomized, double-blind, placebo-controlled single and multiple ascending dose trial conducted in New Zealand — which the company said met all pre-specified safety, tolerability, and pharmacokinetic objectives.
PX578 is designed to directly activate mutant POLG enzyme, increasing mitochondrial DNA (mtDNA) levels to address the underlying cause of disease. Preclinical studies across multiple in vitro and in vivo models demonstrated increased mtDNA levels, improved cellular respiration and energy production, increased survival, and improved markers of liver health. The mechanistic basis was further supported by a Nature publication (Valenzuela et al., DOI: 10.1038/s41586-025-08856-9) showing that small molecule POLG activators restore enzymatic function and increase mtDNA levels in patient-derived cells carrying POLG mutations. Pretzel said PX578 has demonstrated activity across all POLG mutations tested to date, including the four most common mutations found in approximately 70% of patients.
The Fast Track Designation enables more frequent interactions with FDA during development and potentially expedited review, supporting Pretzel's path toward the Phase II POLARIS (POLg Activation and Recovery In Subjects) study. POLARIS is a randomized, double-blind, placebo-controlled trial designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical efficacy of PX578 in adults with POLG disease. Pretzel said initiation is planned for late 2026.