Pretzel Therapeutics Initiates Phase 1 Clinical Study Evaluating PX578, Lead Therapeutic in its Bioenergetics Restoration Franchise

- First-in-class approach to targeting mitochondrial DNA polymerase (POLG) with disease modifying potential across mitochondrial DNA depletion syndromes (MDDS) and broader neurodegenerative diseases -

- Regulating cellular bioenergetics to impede disease progression and severity across high unmet need indications -

- Awarded grant from Parkinson’s UK to evaluate POLG activation mechanisms in Parkinson’s disease models -

Pretzel Therapeutics, a leader in harnessing cellular energetics to develop novel treatments for a range of conditions spanning neurological, muscular atrophies, metabolic and rare disease, today announced that it has initiated recruitment in a Phase 1 clinical study of PX578, the lead therapeutic in its bioenergetics restoration franchise. The randomized, double-blind, placebo-controlled study is designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of PX578 in healthy adult participants, with a potential clinical trial in MDDS patients planned for 2026.

“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,” said Jay Parrish, Ph.D., Chairman of the Board and Chief Executive Officer of Pretzel. “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. We look forward to reporting further progress in the months to come.”

The company also announced that it has been awarded grant funding from Parkinson’s UK to support evaluation of Pretzel’s POLG activation mechanism in Parkinson's disease models in collaboration with Dr. Roberta Filograna’s lab at the Karolinska Institute, Stockholm, 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. 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," said Professor David Dexter of Parkinson’s UK.

About Pretzel Therapeutics

Pretzel Therapeutics is dedicated to developing life-changing medicines with a broad pipeline of first-in-class treatments addressing novel targets within the mitochondria. By harnessing cellular energetics to modulate disease processes and improve survival, function and quality of life, we are ushering in a new treatment paradigm for a breadth of conditions spanning neurological, muscular atrophies, metabolic and rare disease. PX578, the lead therapeutic in Pretzel’s bioenergetics restoration franchise, represents a first-in-class approach to targeting mitochondrial DNA polymerase (POLG) across mitochondrial DNA depletion syndromes (MDDS). PX578 is in Phase 1 clinical development. POLRMT, the lead program in our energetics modulation franchise, targets mitochondrial RNA polymerase for the treatment of metabolic conditions including obesity. POLRMT is in late preclinical development. 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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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.