A drug designed to switch the mitochondrial DNA copier back on clears the UK for a Phase 2 trial in POLG disease

Edited by Samael A. Tejada, Founder & Editor-in-Chief

Most mitochondrial medicine manages symptoms because the underlying defect — too little working mitochondrial DNA — has no drug that addresses it. PX578 aims at the defect itself: activate the one enzyme that copies mtDNA and let depleted cells rebuild their genomes. Regulators on both sides of the Atlantic have now cleared that idea to be tested in patients. The idea is all that has been cleared.

What is POLG disease, and why does mtDNA run out?

Every mitochondrion carries its own small genome, and one enzyme — DNA polymerase gamma, encoded by the POLG gene — is responsible for copying it. When POLG is mutated, mitochondrial DNA is replicated poorly and becomes depleted, so cells progressively lose the instructions for core parts of their energy machinery. The result is a progressive, potentially life-threatening disorder that can involve the brain, nerves, muscles and liver, with severity depending on the mutation. Because the defect is a shortage of mtDNA itself, a drug that raises the copier's activity is, mechanistically, an attempt to treat the cause rather than the consequences.

What exactly has been authorized, and what happens next?

The MHRA authorization is the third regulatory milestone the company reports in three months: FDA cleared the IND in August 2026, granted Fast Track designation in September, and the UK has now authorized the trial application. The planned study, POLARIS — POLG Activation and Recovery In Subjects — is a randomized, double-blind, placebo-controlled Phase 2 trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of PX578 in adults with POLG disease. Pretzel says it expects to initiate the study before the end of 2026, building on a recently completed Phase 1 trial in healthy volunteers. Chief Development Officer Ashish Dugar said the company is focused on advancing POLARIS and initiating clinical development in patients by year end.

What should readers not conclude from this news?

That PX578 helps anyone, yet. Regulatory authorization means a trial may proceed — that the plan, the manufacturing and the early safety data met the bar for testing in patients — and Fast Track means the agency will work with the company more intensively because the condition is serious and untreated. Neither says anything about efficacy, and the history of mitochondrial medicine is full of mechanistically beautiful drugs that failed in patients. The genuinely notable fact is structural: a first-in-class POLG activator, designed to raise mtDNA, has reached a placebo-controlled patient trial at all — a milestone this field has rarely achieved — and POLARIS will produce the first real answer.

Where the evidence stands

• Established: POLG encodes the mitochondrial DNA polymerase; its mutations deplete mitochondrial DNA and cause progressive primary mitochondrial disease, and no disease-modifying treatment is approved for POLG disease.
• Preliminary: PX578, a first-in-class CNS-penetrant POLG activator designed to increase mtDNA, completed Phase 1 testing in healthy volunteers and received FDA IND clearance (Aug 2026), FDA Fast Track designation (Sep 2026) and UK MHRA trial authorization (announced Oct 30, 2026), with the placebo-controlled Phase 2 POLARIS trial in adults due to start by the end of 2026.
• Absent: Any evidence that PX578 raises mtDNA, improves function or alters outcomes in patients — the patient trial has not yet dosed anyone.