Pretzel Therapeutics Presents Preclinical Data on PX578 at MDA 2026, Further Supporting Clinical Advancement in Individuals Living with POLG Disease

Preclinical data across multiple disease models demonstrate that PX578 increases mtDNA levels, improves cellular respiration and energy production

Company on track to complete Phase 1 Healthy Volunteer study in first half of 2026 and initiate a Phase 2 study in second half of 2026

WALTHAM, Mass.--(BUSINESS WIRE)--Pretzel Therapeutics, a leader in harnessing cellular energetics to develop novel treatments for a range of conditions spanning neurological, muscle, metabolic and rare diseases, today announced the presentation of new preclinical data on the lead therapeutic in its bioenergetics restoration franchise, PX578, at the 2026 MDA Clinical & Scientific Conference in Orlando, Florida. PX578, a first-in-class small molecule activator of the mitochondrial DNA polymerase POLG, is currently in Phase 1 clinical development for the treatment of mitochondrial DNA depletion syndromes (MDDS), including POLG disease, a rare and often devastating condition for which no approved disease-modifying therapies currently exist.

Reduced mitochondrial DNA (mtDNA) levels are a central driver of MDDS, a group of rare disorders caused by mutations in genes responsible for mtDNA production and maintenance, including POLG. PX578 is designed to directly activate mutant POLG enzyme to increase mtDNA levels and address the underlying cause of disease. The therapy has demonstrated activity across all POLG mutations tested to date, including the four most common mutations found in approximately 70% of patients.

Preclinical studies across multiple in vitro and in vivo models have generated supportive evidence for the advancement of PX578, demonstrating improved cellular respiration and energy production, increased survival and mtDNA levels, and improved markers of liver health. Collectively, these findings support the disease-modifying potential of PX578 and its continued clinical advancement.

"These preclinical findings across multiple POLG mutation models and disease contexts give us strong confidence in PX578's mechanism and its potential to address the underlying driver of disease for patients who currently have no treatment options," added Gabriel Martinez, Ph.D., Chief Scientific Officer and Co-Founder of Pretzel Therapeutics.

Pretzel initiated a Phase 1 healthy volunteer study of PX578 in 2025 and is on track to complete Phase 1 in the first half of 2026. The company plans to initiate a Phase 2 clinical trial in the second half of 2026, designed to generate robust pharmacokinetic and safety data, as well as proof-of-concept data in relevant clinical and patient-reported outcomes.

"The data presented at MDA 2026 highlight the potential of PX578 as a meaningful treatment strategy in POLG disease," said Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics. "With Phase 1 on track for completion in the first half of this year and a study planned for individuals living with POLG disease planned for the second half, we are advancing with momentum to bring this first-in-class medicine to the patients who need it."

Presentation Details
The following presentations will be delivered at the 2026 MDA Clinical & Scientific Conference, Hilton Orlando, Orlando, Florida:

Oral Presentation
Title: PX578: A First-in-Class POLG Activator to Increase mtDNA for Treatment of Mitochondrial DNA Depletion Syndromes
Date/Time: Wednesday, March 11, 2026, 10:45 AM

Poster Presentation
Title: PX578: A First-in-Class POLG Activator to Increase mtDNA for Treatment of Mitochondrial DNA Depletion Syndromes
Poster Number: 430 O
Date: Tuesday, March 10, 2026

A copy of the poster will be available on the Pretzel Therapeutics website following presentation.

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, muscle, metabolic and rare diseases. PX578, the lead therapeutic in Pretzel’s bioenergetics restoration franchise, represents a first-in-class approach to targeting mitochondrial DNA polymerase (POLG) across primary mitochondrial disorders (PMD), including mitochondrial DNA depletion syndromes (MDDS) and broader neurodegenerative disease. 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.