WALTHAM, Mass.–Pretzel Therapeutics Inc., a Waltham-based biotechnology company developing treatments for mitochondrial disorders, has received regulatory authorization in the United Kingdom to advance its experimental drug PX578 into clinical testing in patients with POLG-mediated primary mitochondrial disease, a rare and potentially life-threatening genetic disorder.
The authorization from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) clears the way for the company to proceed with its planned Phase 2 POLARIS clinical trial, which will evaluate PX578 in adults with POLG disease.
The decision follows the U.S. Food and Drug Administration’s clearance of the drug’s Investigational New Drug application in August 2026 and the agency’s decision to grant PX578 Fast Track designation in September.
Pretzel Therapeutics expects to initiate the Phase 2 study before the end of 2026.
POLG disease is a progressive genetic disorder caused by mutations affecting the POLG gene, which plays a critical role in maintaining mitochondrial DNA.
Mitochondria are responsible for producing much of the energy required for normal cellular function. When mitochondrial DNA becomes depleted, cells can struggle to generate sufficient energy, leading to neurological problems, muscle weakness and other serious complications.
The disease can affect individuals at different stages of life, with symptoms and severity varying according to the age of onset.
Children who develop the condition before age 12 may experience severe liver disease, seizures and cognitive regression. Patients with juvenile or adult-onset disease can develop coordination problems, peripheral neuropathy and seizures, while those with later-onset disease may experience muscle weakness and impaired eye movement.
There are currently no approved disease-modifying treatments specifically targeting the underlying cause of POLG disease.
“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,” said Professor Sir Doug Turnbull, emeritus professor of neurology at Newcastle University.
“Advancing therapies that have the potential to address the underlying biology of POLG disease represents an important step for the field. The clinical development of PX578 is particularly encouraging, and I look forward to seeing its potential evaluated in patients.”
PX578 is an investigational small-molecule drug designed to activate the POLG enzyme and increase mitochondrial DNA levels.
The treatment is intended to improve mitochondrial function and potentially slow or alter disease progression by addressing the underlying biological mechanism responsible for POLG-related disorders.
The drug is also designed to penetrate the central nervous system, potentially allowing it to address neurological complications associated with mitochondrial dysfunction.
“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,” said Jay Parrish, Ph.D., chairman and chief executive officer of Pretzel Therapeutics.
The company’s upcoming Phase 2 POLARIS study will be randomized, double-blind and placebo-controlled.
Researchers will evaluate the safety and tolerability of PX578, how the drug is absorbed and processed by the body, its biological effects and whether it produces measurable clinical benefits in adults with POLG disease.
The study represents the next stage of clinical development following a recently completed Phase 1 trial involving healthy volunteers.
Pretzel Therapeutics said preclinical studies conducted in laboratory and animal models, along with findings from the Phase 1 study, supported the decision to advance PX578 into patient testing.
“With regulatory pathways now cleared in both the U.S. and UK, we are focused on advancing our Phase 2 POLARIS study and working toward initiating clinical development in patients by year end 2026,” said Ashish Dugar, Ph.D., chief development officer of Pretzel Therapeutics.
The FDA’s Fast Track designation is intended to facilitate the development and review of treatments addressing serious conditions with unmet medical needs. However, the designation does not constitute approval of the drug or establish its effectiveness.
Pretzel Therapeutics is developing PX578 as a potential treatment for mitochondrial disorders involving impaired cellular energy production.
The company is pursuing clinical development in both the United States and United Kingdom as it investigates whether increasing mitochondrial DNA levels can improve disease outcomes in patients with POLG-related conditions.
PX578 remains investigational, and its safety and effectiveness in treating POLG disease have not yet been established.
