Pretzel Therapeutics Receives UK MHRA Authorization for PX578 Phase 2 Trial in POLG-Mediated Mitochondrial Disease
Pretzel Therapeutics, Inc., a clinical-stage biotechnology company developing a new class of medicines intended to restore mitochondrial function, improve cellular energetics and slow disease progression across neurological and rare diseases, has received authorization from the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) for its clinical trial application for PX578. The company’s lead therapeutic candidate is being developed for patients with POLG-mediated mitochondrial disorders, a rare and progressive group of genetic diseases associated with mutations in the POLG gene and depletion of mitochondrial DNA.
The UK regulatory authorization represents another important step in Pretzel Therapeutics’ efforts to advance PX578 into clinical development for people living with POLG disease. The decision follows clearance of the candidate’s Investigational New Drug (IND) application by the US Food and Drug Administration (FDA) in August 2026. In September 2026, the FDA also granted Fast Track Designation to PX578 for the treatment of POLG-mediated primary mitochondrial disorders.
With the MHRA authorization, PX578 has reached its third major regulatory milestone, supporting the company’s plans to move forward with global clinical development. Pretzel Therapeutics is preparing to advance its Phase 2 POLARIS study, which will evaluate the candidate in adults with POLG disease. The company expects to initiate the clinical trial by the end of 2026.
The regulatory progress marks an important development for a disease area in which treatment options remain limited. POLG-mediated disorders can cause progressive and potentially life-threatening complications, and there are currently no approved disease-modifying therapies specifically designed to address the underlying cause of the condition. PX578 is being developed with the goal of targeting the biological mechanisms associated with POLG dysfunction rather than focusing solely on the symptoms experienced by patients.
Regulatory Progress Supports Global Development of PX578
The MHRA authorization follows two regulatory milestones achieved in the United States during 2026. In August, the FDA cleared Pretzel Therapeutics’ IND application for PX578, allowing the company to proceed with its clinical development plans under the US regulatory framework. The following month, the FDA granted Fast Track Designation to the investigational candidate for the treatment of POLG-mediated primary mitochondrial disorders.
Fast Track Designation is intended to facilitate the development and review of investigational medicines addressing serious conditions with unmet medical needs. The designation provides a regulatory pathway designed to support communication between drug developers and the FDA during clinical development. For Pretzel Therapeutics, the designation represents recognition of the need for additional treatment approaches in POLG-mediated disease and supports the advancement of PX578 through its development program.
The subsequent authorization from the MHRA expands the regulatory progress achieved by the company and supports its intention to pursue clinical development in both the United States and the United Kingdom. Securing authorization in these two markets is an important step toward establishing a broader development pathway for PX578.
Pretzel Therapeutics plans to evaluate the candidate through its Phase 2 POLARIS study, which is designed to investigate the potential of PX578 in adults living with POLG disease. The study will assess several aspects of the investigational therapy, including safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy.
The company expects to begin the Phase 2 trial by the end of 2026. The planned study will provide an opportunity to evaluate PX578 in patients with the condition and generate clinical data to inform its continued development.
POLG Disease and the Need for Disease-Modifying Treatments
POLG disease refers to a group of rare genetic disorders caused by mutations in the POLG gene. This gene provides instructions for producing DNA polymerase gamma, an enzyme that plays an essential role in mitochondrial DNA replication and maintenance.
Mitochondria are specialized structures within cells responsible for producing much of the energy required for normal cellular activity. They contain their own genetic material, known as mitochondrial DNA, which supports the production of proteins involved in energy generation. Maintaining the integrity and appropriate quantity of this genetic material is essential for normal mitochondrial function.
The POLG gene is central to this process because the enzyme it encodes helps replicate and maintain mitochondrial DNA. Genetic variants that affect POLG function can interfere with mitochondrial DNA maintenance, resulting in mitochondrial DNA depletion and impaired cellular energy production.
Because cells and tissues rely on mitochondria to meet their energy requirements, disruptions in mitochondrial function can have significant consequences. The nervous system is particularly dependent on a continuous energy supply, making neurological manifestations an important feature of many mitochondrial disorders. Depending on the specific genetic changes and disease presentation, POLG-related conditions can vary in severity and progression.
POLG-mediated mitochondrial disorders are associated with progressive disease, and affected individuals may experience substantial challenges as the underlying mitochondrial dysfunction develops. The clinical course can be serious and potentially life-threatening, creating a significant need for therapies capable of addressing the biological mechanisms responsible for disease.
Despite the importance of POLG in mitochondrial DNA maintenance, there are currently no approved disease-modifying treatments specifically targeting the underlying cause of POLG-mediated disease. This lack of targeted treatment options highlights the need for continued research into approaches that could improve mitochondrial function and potentially influence disease progression.
Pretzel Therapeutics is developing PX578 to address this unmet need by targeting POLG activity and mitochondrial DNA levels.
PX578 Designed to Activate POLG and Increase Mitochondrial DNA
PX578 is the company’s lead therapeutic candidate for POLG-mediated mitochondrial disorders. Its development is based on the strategy of activating POLG and increasing mitochondrial DNA, with the objective of restoring mitochondrial function and potentially modifying the underlying disease process.
By targeting POLG activity, PX578 is intended to address a central biological mechanism associated with POLG disease. The candidate is designed to support mitochondrial DNA maintenance by increasing the activity of the enzyme involved in mitochondrial DNA replication. The company’s approach aims to improve the cellular energy systems affected by mitochondrial dysfunction.
Mitochondrial DNA depletion is a defining feature of POLG-mediated disease. When mitochondrial DNA levels are insufficient, mitochondria may be unable to maintain the normal cellular processes required for energy production. This can contribute to the functional impairment associated with mitochondrial disorders.
Pretzel Therapeutics is therefore pursuing a therapeutic strategy focused on mitochondrial biology, with PX578 intended to increase mitochondrial DNA and support the restoration of mitochondrial function. The candidate is being developed with the longer-term goal of potentially modifying disease progression by addressing an underlying biological contributor to POLG-mediated disorders.
The clinical evaluation of PX578 will be important in determining whether its proposed mechanism translates into meaningful effects in patients. The planned Phase 2 POLARIS study will assess the candidate across multiple measures, including pharmacodynamic parameters that can help characterize its biological activity, alongside safety, tolerability and clinical efficacy assessments.
The company has not announced clinical efficacy findings from the planned Phase 2 study. Its immediate development priority is to initiate the trial and evaluate PX578 in adults with POLG disease.
POLARIS Phase 2 Study to Evaluate Safety and Clinical Efficacy
Pretzel Therapeutics plans to advance PX578 through POLARIS, a randomized, double-blind, placebo-controlled Phase 2 clinical trial. The study is designed to evaluate the investigational candidate in adult patients with POLG disease.
The name POLARIS stands for POLG Activation and Recovery in Subjects, reflecting the central objective of the program: evaluating an approach intended to activate POLG and support recovery of mitochondrial function.
The trial will assess several important aspects of PX578’s clinical profile. These include safety and tolerability, which will help investigators understand how patients respond to treatment and characterize any potential adverse effects. The study will also evaluate pharmacokinetics, providing information about how the investigational medicine behaves in the body, and pharmacodynamics, which will help assess its biological effects.
Clinical efficacy will also be evaluated to explore whether treatment with PX578 may produce meaningful clinical effects in adults with POLG disease. Together, these assessments are expected to provide information about the candidate’s potential and help guide subsequent development decisions.
The randomized, double-blind, placebo-controlled design is intended to support a structured assessment of PX578. Randomization helps distribute participants among the study groups, while blinding is intended to reduce the potential influence of expectations on the evaluation of treatment outcomes. The placebo-controlled approach provides a comparison for assessing the investigational candidate.
The company expects to initiate POLARIS by the end of 2026. The MHRA authorization, together with the earlier FDA IND clearance, provides regulatory support for moving toward the planned clinical evaluation in the United States and United Kingdom.
The study represents the next major development stage for PX578 following the regulatory progress achieved during 2026. Its findings will be important in assessing the candidate’s safety profile, biological activity and potential clinical benefit in the target patient population.
Experts Highlight the Need for New Approaches to POLG Disease
The development of PX578 has drawn attention to the need for treatments that address the underlying biology of POLG-mediated mitochondrial disorders.
Professor Sir Doug Turnbull, Emeritus Professor of Neurology at Newcastle University, emphasized the substantial unmet medical need among people living with POLG disease and the importance of developing therapies that could target the mechanisms responsible for the condition.
“For people living with POLG disease, the need for effective treatments is profound, and the lack of disease-modifying options leaves patients and families facing progressive disease with very few options,” Professor Turnbull said.
He added that advancing therapies with the potential to address the underlying biology of POLG disease represents an important step for the field. He also described the clinical development of PX578 as particularly encouraging and expressed interest in seeing its potential evaluated in patients.
His comments underscore the challenges faced by individuals and families affected by POLG-mediated disorders. Because the condition is associated with genetic changes that disrupt an essential mitochondrial process, treatment strategies capable of addressing the underlying biology are an important area of research.
The planned clinical evaluation of PX578 will help determine whether the candidate can demonstrate the safety, biological activity and clinical effects needed to support further development.
Company Leadership Views Authorization as an Important Milestone
Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics, said the MHRA authorization represents an important milestone for both PX578 and the company’s broader effort to develop a potential disease-modifying treatment for patients with POLG-mediated mitochondrial disorders.
“Receiving UK authorization following FDA clearance of our IND represents an important milestone for PX578 and for our efforts to bring a potential disease-modifying treatment to people living with POLG-mediated mitochondrial disorders,” Parrish said.
The company views the regulatory progress in the United States and United Kingdom as a foundation for advancing its clinical program. The FDA IND clearance and MHRA authorization provide regulatory support for the planned international development strategy, while the FDA Fast Track Designation adds another significant milestone for the candidate.
Ashish Dugar, Ph.D., Chief Development Officer of Pretzel Therapeutics, said the company is now focused on advancing the Phase 2 POLARIS study and preparing to begin clinical development in patients.
“With regulatory pathways now cleared in both the US and UK, we are focused on advancing our Phase 2 POLARIS study and working toward initiating clinical development in patients by year end 2026,” Dugar said.
The company’s stated goal is to begin the Phase 2 study before the end of 2026. Initiation of the trial would move PX578 from its regulatory preparation stage into clinical evaluation in adults with POLG disease.
Focus on Mitochondrial Function and Rare Neurological Disorders
Pretzel Therapeutics is developing medicines intended to restore mitochondrial function, improve cellular energetics and impede disease progression across neurological and rare diseases. The company’s approach is centered on mitochondrial biology, an area of research relevant to conditions in which impaired mitochondrial activity contributes to disease.
PX578 represents the company’s lead clinical-stage candidate and is being advanced for POLG-mediated mitochondrial disorders. Its proposed mechanism focuses on activating POLG and increasing mitochondrial DNA, with the aim of supporting mitochondrial function and potentially influencing the underlying disease process.
The latest regulatory authorizations position the program for its next stage of development. Following FDA IND clearance in August 2026, FDA Fast Track Designation in September 2026 and MHRA authorization in the United Kingdom, the company is preparing to initiate the Phase 2 POLARIS trial.
The planned study will evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy in adults with POLG disease. Its results will be important for determining whether PX578 can demonstrate a clinical profile that supports continued development.
For patients and families affected by POLG-mediated disorders, the lack of approved disease-modifying therapies remains a major challenge. Although the candidate’s potential benefit has yet to be established in clinical trials, its development represents an investigational effort to address a biological mechanism central to the disease.
Pretzel Therapeutics expects to initiate the Phase 2 POLARIS study by the end of 2026. The upcoming clinical evaluation will mark a significant step in determining whether PX578 can advance as a potential treatment approach for people living with this rare and progressive mitochondrial disorder.
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 present 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 .