A randomized, double-blind, placebo-controlled crossover study evaluating the efficacy and safety of zagociguat in participants with MELAS

A drug called zagociguat is being tested in a clinical trial to see if it can reduce fatigue and improve thinking in people with a rare genetic disorder called MELAS. MELAS damages mitochondria, the energy-producing parts of cells, leading to severe fatigue, cognitive problems, and muscle weakness. Current treatments are limited. The drug works by boosting levels of a molecule called cGMP, which may help restore energy flow in cells. This trial randomly assigns participants to receive either zagociguat or a placebo tablet, then swaps them, so each person serves as their own control. Neither the patient nor the doctor knows which tablet is being taken at any time. If zagociguat proves effective, it would be one of the first treatments specifically targeting fatigue and cognition in MELAS—symptoms that profoundly affect daily life, from holding a conversation to getting out of bed. Because the nitric oxide pathway it targets is also disrupted in other mitochondrial diseases, success here could open the door to treating broader patient populations. The trial will also clarify whether the drug is safe enough for long-term use.