PRIZM is a Phase 2b randomized, double-blind, placebo-controlled, 3-treatment, 2-period, crossover study evaluating the efficacy and safety of oral zagociguat 15 and 30 mg vs. placebo when administered daily for 12 weeks in participants with genetically and phenotypically defined MELAS.

The goal of this clinical trial is to learn about the effectiveness of zagociguat in patients with MELAS. The main questions it aims to answer are:

• Does zagociguat improve fatigue in patients with MELAS?
• Does zagociguat improve cognitive performance in patients with MELAS?
• What is the safety and tolerability profile of zagociguat?

The PRIZM study is evaluating 2 dose levels of zagociguat in a crossover design consisting of two 12-week treatment periods separated by a 4-week washout. Patients will be screened and if eligible, randomly assigned either to receive placebo in period 1 followed by active drug in period 2 OR to receive active drug in period 1 followed by placebo in period 2. Study medication is a once daily oral tablet and will be provided at the clinic and/or shipped to the participant's home. Clinic visits will occur at screening and Week 1 and Week 12 of each treatment period. Visits at Week 4 and Week 8 of both crossover periods will either be in clinic or optionally at the participant's home. Study assessments will be conducted weekly on a phone app and a separate tablet and additional assessments will be conducted during visits. Patients who complete the study will be eligible for an open label extension study.

Inclusion Criteria:

1. Signed consent form.

2. 18 to 75 years of age.

3. Diagnosed with MELAS based on the presence of each of the following criteria:

   1. A documented pathogenic variant in a mitochondrial DNA (mtDNA) gene.
   2. History of one or more stroke-like episodes (SLEs) with magnetic resonance imaging (MRI) findings consistent with stroke-like lesions.

4. Scores below normal average on the iDSST and GMLT.

5. Reports fatigue due to MELAS.

6. Can complete at least 1 sit-to-stand in the 30-second test interval.

7. Completes all at-home weekly activities independently during the Screening Period (caregiver may help set up device/app, log-in, etc.).

8. Other criteria per the protocol.

Exclusion Criteria:

1. Systolic blood pressure (BP) 90 mmHg or diastolic BP 60 mmHg.
2. Orthostatic hypotension when measured after standing from a semi-recumbent/supine position.
3. Active cancer significant enough to confound the results of this study.
4. Severe gastrointestinal dysmotility that may impact participation.
5. Recent history (within last 6 months) of platelet dysfunction, hemophilia, von Willebrand disease, coagulation disorder, other bleeding diathesis condition(s), or significant, nontraumatic bleeding episodes.
6. History of spontaneous fracture(s) that in the investigator's opinion represents a safety risk for trial participation.
7. Current use of prohibited medication (reviewed by investigator).
8. Any medical or other condition that the investigator thinks would preclude study participation.
9. Other exclusion criteria per protocol.

This a double-blind study in which investigators, participants/caregivers, Sponsor, and all study personnel will be blinded.