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.

About POLG-mediated Primary Mitochondrial Disease

POLG-mediated primary mitochondrial disease (POLG disease) is a progressive, multisystem disorder caused by impaired cellular energy production due to mitochondrial DNA (mtDNA) depletion. It represents one of the most common forms of mitochondrial DNA depletion syndromes (MDDS) yet remains considerably underdiagnosed or misdiagnosed. The disease affects individuals across all ages, with presentation and prognosis largely determined by age of onset: childhood-onset (prior to age 12) is severe and rapidly progressive, characterized by liver involvement, seizures, and cognitive regression; 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. Across all forms, POLG disease is highly debilitating and associated with substantial morbidity and early mortality. There are currently no disease-modifying therapies, underscoring a critical and urgent need for treatments that address the underlying mitochondrial dysfunction.

About PX578

PX578 is a first-in-class, CNS penetrant small molecule activator of the mitochondrial polymerase POLG designed to increase mitochondrial DNA (mtDNA) levels, enhance mitochondrial function and improve quality of life by halting or reversing disease progression across mitochondrial disorders, including POLG-mediated primary mitochondrial disease, a rare and often devastating condition for which no approved disease-modifying therapies currently exist. 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.

About Pretzel Therapeutics

Pretzel Therapeutics, a clinical-stage biotechnology company building a deep, first-in-class pipeline of novel medicines designed to restore mitochondrial function, improve cellular energetics and impede disease progression across a range of neurological and rare diseases. The Company’s lead therapeutic candidate, PX578, is expected to enter Phase 2 clinical study for individuals with POLG disease in late 2026. The company is headquartered in Waltham, MA, and has research facilities in Mölndal, Sweden. For more information, visit www.pretzeltx.com.

Forward-Looking Statements

This press release contains “forward-looking statements” that involve substantial risks, assumptions, and uncertainties. Forward-looking statements are often identified by the use of words such as, but not limited to, “believe,” “estimate,” “intend,” “may,” “plan,” “potentially,” “will,” “expect,” “enable,” “likely” or the negative of these terms or other similar expressions. All statements, other than statements of historical facts, regarding management’s expectations, beliefs, goals, plans or Pretzel’s prospects should be considered forward-looking statements. Readers are cautioned that actual results may differ materially from projections or estimates due to a variety of important factors. These forward-looking statements are made as of the date of this presentation, and Pretzel assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law.

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