Pretzel Therapeutics has received authorization from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) to move its lead candidate, PX578, into clinical testing for patients with POLG-mediated mitochondrial disorders. The decision follows the US Food and Drug Administration (FDA)’s clearance in August 2026, which also granted the treatment a Fast Track Designation in September of that year.
The company now prepares to launch the phase 2 POLARIS study by the end of 2026. This randomized, double-blind trial will examine PX578’s safety, tolerability, and ability to alter disease progression in adults with POLG disease. POLG disease is a progressive, multisystem disorder caused by impaired cellular energy production due to mitochondrial DNA (mtDNA) depletion.
POLG disease manifests differently depending on when symptoms appear. In children under 12, it often triggers severe liver failure, seizures, and cognitive decline. Juvenile and adult-onset (ages 12-40) often presents with ataxia, peripheral neuropathy, and seizures; and late-onset (ages 40+) is typically more slowly progressive, characterized by ophthalmoplegia, ptosis, and myopathy. Despite being one of the most common mitochondrial depletion syndromes, it remains frequently misdiagnosed and lacks approved treatments that modify disease progression.
The drug works by stimulating the POLG enzyme to restore mitochondrial DNA levels and improve energy production in affected cells. Preclinical studies across multiple in vitro and in vivo models, as well as a recently completed phase 1 healthy volunteers study, support the disease-modifying potential of PX578 and its advancement into phase 2 clinical evaluation in patients with POLG disease.
Regulatory approval in both the US and UK clears the way for patient enrollment. Ashish Dugar, Pretzel’s chief development officer, described the MHRA’s decision as a major achievement for the program. The team is now finalizing operational details, aiming to begin dosing before the year’s end.
The disorder’s broad systemic effects make it particularly difficult to manage. Early-onset cases carry the highest mortality risk, but adult-onset forms also severely diminish quality of life. Without approved therapies, patients depend entirely on symptom relief, highlighting the importance of trials like POLARIS.
