PX578, a potentially disease-modifying, first-in-class investigational medicine cleared to start clinical trials in patients.

Pretzel Therapeutics, Inc., a clinical-stage biotechnology company advancing a new class of medicines designed to restore mitochondrial function, improve cellular energetics and impede disease progression across a range of neurological and rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application to initiate a first-in-patient  clinical trial of PX578, the Company’s lead therapeutic candidate. The Phase 2 study, POLARIS (POLg Activation and Recovery In Subjects), will evaluate PX578 in adult patients with POLG-mediated primary mitochondrial disease (POLG disease), a rare, progressive genetic disorder caused by mutations in the POLG gene causing a depletion of mitochondrial DNA. This mitochondrial DNA depletion syndrome results in mitochondrial dysfunction and a range of debilitating neurological and systemic manifestations. There are currently no approved disease-modifying treatments for this condition.  POLARIS will build on recent success with a Phase 1 healthy volunteer study with PX578 conducted in New Zealand.

“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 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. “We have worked closely with regulators, the patient community and key opinion leaders to thoughtfully design POLARIS.  We are eager to begin evaluating PX578 in patients with POLG disease, where there remains a profound unmet need for therapies that can meaningfully alter the course of disease.”

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. Given the central role of impaired mitochondrial DNA replication in POLG disease, PX578’s ability to enhance POLy processivity during mtDNA synthesis provides a strong mechanistic rationale for its evaluation in this patient population.

“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. 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. We look forward to seeing this program advance into the clinic and to the insights that clinical research may bring to the POLG community,” said Kristen Clifford, United Mitochondrial Disease Foundation, President and Chief Executive Officer.

The advancement of PX578 into Phase 2 represents an important opportunity to test a therapeutic approach specifically designed to address the mitochondrial DNA depletion that lies at the heart of POLG disease. Supported by encouraging preclinical findings and successful completion of a Phase 1 study, PX578 is being developed on a strong scientific foundation that directly targets disease biology. While much work remains, the initiation of POLARIS marks a meaningful step forward and offers renewed hope for patients, families and clinicians seeking treatments capable of changing the course of this devastating disease.