Pretzel advances mitochondrial therapy with PX578 Phase 1 trial
Treatment designed to boost mitochondrial function
Pretzel Therapeutics has launched a Phase 1 clinical trial to study PX578, a therapy designed to boost the function of mitochondria, the cell’s energy-producing powerhouses, and address conditions caused by faulty energy production. These include rare genetic conditions and neurodegenerative disorders like Parkinson’s and Alzheimer’s.
The Phase 1 study (ACTRN12625000230459p) will evaluate PX578’s safety and tolerability, as well as how the compound is processed in the body, by administering single and multiple increasing oral doses to healthy volunteers. Patient enrollment is expected to begin by the end of the month, and the trial aims to recruit up to 112 participants in New Zealand.
“The initiation of our Phase 1 clinical trial of PX578 reflects the important progress we are making in turning our unique bioenergetics approach into a reality, with a deep, first-in-class pipeline of energetics restoring and energetics modulating compounds to positively impact high unmet need indications,” Jay Parrish, PhD, chairman and CEO of Pretzel, said in a company press release.
Mitochondrial dysfunction has long been associated with neurodegenerative diseases, including Parkinson’s, Alzheimer’s, Huntington’s disease, and amyotrophic lateral sclerosis, in which faulty mitochondria contribute to nerve cell damage and death, accelerating disease progression.
There are no cures for these conditions, but targeting mitochondrial function has emerged as a potential disease-modifying treatment that could slow or halt the progression of neurodegenerative diseases.
Activating enzyme to aid mtDNA repair
PX578 is a small molecule that activates the mitochondrial DNA polymerase (POLG), an enzyme that helps copy and repair the DNA found in mitochondria (mtDNA) and is crucial for maintaining its integrity and replication.
Since mtDNA is essential for producing proteins that power energy production, boosting POLG activity with PX578 could increase mtDNA levels, enhancing mitochondrial function and ultimately improving energy availability in cells.
Trial participants will receive either a single dose of PX578 or a placebo for the single ascending dose part of the study. The doses range from 100 mg to a maximum of 1000 mg across six patient groups. For the multiple ascending dose part, participants will receive PX578 or placebo twice daily for 10 days, with doses also ranging from 100 to 1000 mg across six groups.
“Our energetics restoration franchise, led by PX578, our small molecule POLG activator, has broad potential spanning from rare mitochondrial DNA depletion syndromes for which there are no disease-modifying treatments to larger neurodegenerative conditions, such as Parkinson’s and Alzheimer’s disease,” Parrish said. “We look forward to reporting further progress in the months to come.”
A clinical trial in patients with mitochondrial DNA depletion syndrome (MDDS), a rare genetic condition, is planned for 2026, following the completion of this Phase 1 study in healthy volunteers.
Further strengthening its research efforts, the company received a grant from Parkinson’s UK to investigate PX578’s mechanism of action in Parkinson’s disease models, in collaboration with the Karolinska Institute in Sweden.
“We’re excited to be funding Pretzel Therapeutics to take early but important steps in the development of a compound that has potential for the treatment of Parkinson’s,” said David Dexter, PhD, research director at Parkinson’s UK and professor of neuropharmacology at Imperial College London. “Targeting the mitochondria, specifically boosting levels of mitochondrial DNA, could lead to us finding a way to slow or stop Parkinson’s, something that no treatment can currently do.”
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