Tisento Therapeutics Doses First Participant in Phase 2b Trial of Zagociguat for MELAS

Tisento Therapeutics has announced the dosing of the first participant in its Phase 2b PRIZM study, a global trial investigating zagociguat for the treatment of MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes). This study marks a significant step forward in addressing the unmet needs of individuals living with this rare and debilitating mitochondrial disease.

The PRIZM study is a Phase 2b randomized, placebo-controlled, crossover trial designed to evaluate the efficacy and safety of oral zagociguat at doses of 15 mg or 30 mg, administered once daily for 12 weeks, compared to placebo. The trial includes a 4-week washout period between the two 12-week treatment periods, ensuring that all participants receive both zagociguat and placebo during the study. Approximately 44 participants will be enrolled at mitochondrial disease centers of excellence across North America, Europe, and Australia.

Patient-Centric Design

Recognizing the challenges faced by individuals with MELAS, the PRIZM study incorporates several patient-centric features to maximize convenience and participation. These include at-home assessments, the potential for at-home study visits, and door-to-door travel support. Furthermore, participants who complete the study may be eligible for continued access to zagociguat through an open-label extension study.

The clinical outcome assessments and endpoint strategy for the PRIZM study were informed by interviews with MELAS patients, ensuring that the trial addresses the symptoms and impacts of the disease that are most important to them.

Mechanism of Action

Zagociguat is a once-daily, oral, clinical-stage investigational medicine designed to positively impact both peripheral and central nervous system manifestations of mitochondrial diseases. As a first-in-class, brain-penetrant soluble guanylate cyclase (sGC) stimulator, zagociguat is hypothesized to rebalance dysregulated cellular pathways in MELAS. By stimulating sGC, an enzyme crucial for neuronal function and blood flow, zagociguat aims to restore mitochondrial energy production and physiological function.

In a previous Phase 2a study in MELAS patients, zagociguat demonstrated a favorable safety profile, exposure throughout the body (including the central nervous system), and improvements in neuronal function, mitochondrial function, and blood flow in the brain.

Expert Commentary

"MELAS is the most common condition we see in our mitochondrial clinic, with profound effects on patients' daily lives and wellbeing. Right now, we have no approved treatments, making the search for effective therapies absolutely critical," said Dr. Austin Larson, associate professor of pediatric clinical genetics and metabolism at the University of Colorado School of Medicine and PRIZM study investigator. "I am excited about zagociguat's potential to address both the severe fatigue and cognitive challenges that so significantly impact our MELAS patients."

Peter Hecht, PhD, chief executive officer of Tisento, added, "Since Tisento’s founding, we have been focused on initiating a thoughtful, well-designed clinical study to evaluate zagociguat for the treatment of MELAS, and we are humbled by the enthusiastic response we have received from physicians and the mitochondrial disease community."