The goal of this clinical trial is to evaluate the long-term safety and tolerability of zagociguat in patients with MELAS who completed study medication treatment in the lead-in study TIS6463-203. TIS6463-204 is evaluating zagociguat in an open-label extension study at the daily dose of 15mg. The study medication is a once daily oral table and will be provided at the clinic and/or shipped to the participant's home. Study assessments will be conducted during clinic visits which will occur at three months and then at six months. Thereafter, clinic visits will occur every six months.

On Screening Visit Day -1 (which corresponds to Period 2 Week 12 Visit from lead-in study TIS6463-203), participants will sign the informed consent form, be confirmed eligible for this open-label extension study and undergo Screening Visit assessments. Eligible participants will begin dosing the next day on Day 1 (there is no Day 0) at home. Participants will have a 3-month visit and 6-month study visit at the clinic and thereafter will have a clinic visit every 6 months. Participants should have a Follow-up Visit 4 (+1) weeks after zagociguat discontinuation.

Inclusion Criteria:

1. Signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent form (ICF).
2. Completed TIS6463-203 treatment through the Period 2 Week 12 Visit.
3. Agrees to follow lifestyle restrictions.
4. Other criteria per the protocol.

Exclusion Criteria:

1. Any medical condition or clinical finding that, per investigator judgement, would preclude safe study participation and/or completion of all trial requirements.