WALTHAM, Mass. — Pretzel Therapeutics said the U.S. Food and Drug Administration has cleared its Investigational New Drug application for PX578, allowing the company to begin a Phase 2 study in adults with POLG-mediated primary mitochondrial disease.
PX578 is Pretzel’s lead therapeutic candidate and is being developed as a potentially disease-modifying treatment for mitochondrial disorders. The company plans to initiate the Phase 2 POLARIS trial in late 2026.
POLG-mediated primary mitochondrial disease, also known as POLG disease, is a rare genetic disorder caused by mutations in the POLG gene that can lead to depletion of mitochondrial DNA, impaired mitochondrial function and progressive neurological and systemic symptoms. There are currently no approved disease-modifying treatments for the condition.
“FDA clearance of our IND application for PX578 is a significant milestone for our company and, more importantly, for individuals living with POLG disease,” said Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics. “POLG disease is a devastating, progressive condition with no approved disease-modifying treatments. The clearance of our IND application reflects the strength of the scientific and clinical foundation supporting PX578 and brings us one step closer to advancing a potential therapy designed to address the underlying mitochondrial dysfunction that drives disease progression.”
The POLARIS study will be a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of PX578 in adults with POLG disease.
The Phase 2 program follows the successful completion of a Phase 1 study of PX578 in healthy volunteers in New Zealand. Pretzel said the study met all of its objectives.
“The successful completion of our Phase 1 study in healthy volunteers which met all of its objectives, together with compelling preclinical data demonstrating the ability to increase mitochondrial DNA levels and improve function, gives us confidence that PX578 has the potential to address the fundamental driver of disease,” said Ashish Dugar, Chief Development Officer of Pretzel Therapeutics.
Dugar said the company worked with regulators, patients and clinical experts in designing the POLARIS study.
PX578 is a CNS-penetrant small molecule designed to activate mitochondrial polymerase POLG. Pretzel said the drug is intended to increase mitochondrial DNA levels and improve mitochondrial function by enhancing POLG activity during mitochondrial DNA synthesis.
Preclinical studies in laboratory and animal models have shown increases in mitochondrial DNA levels and improvements in mitochondrial function, according to the company.
“Today, there are no approved disease-modifying treatments that address the underlying biology of POLG disease, leaving patients and their families with limited options as the disease progresses,” said Kristen Clifford, President and Chief Executive Officer of the United Mitochondrial Disease Foundation. “The opportunity to evaluate a therapy designed to potentially modify the course of disease – not simply manage its symptoms – offers a meaningful reason for hope.”
POLG disease can affect people at any age, with symptoms and progression varying depending on the age of onset. Childhood-onset disease can involve liver problems, seizures and cognitive regression, while juvenile and adult-onset cases may include ataxia, peripheral neuropathy and seizures. Later-onset disease is often associated with ophthalmoplegia, ptosis and muscle weakness.
Pretzel Therapeutics is a clinical-stage biotechnology company developing therapies intended to restore mitochondrial function and improve cellular energy production in neurological and rare diseases.
