Amel Karaa, MD, Genetics and General Metabolism, Director of the Mitochondrial Disease Program at Massachusetts General Hospital, discusses the PRIZM clinical trial of zagociguat in patients with MELAS.
MELAS, or Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes, is a rare maternally inherited mitochondrial disorder characterized by progressive deterioration of the nervous system that leads to neurological impairment and dementia in adolescence or early adulthood. MELAS typically appears in childhood after a period of normal early development. It is characterized by recurrent episodes of encephalopathy, myopathy, headache, and focal neurological deficits. A distinctive feature of the syndrome is the occurrence of stroke-like episodes leading to hemiparesis, hemianopia, or cortical blindness. Unfortunately, there is currently no known treatment for the disease. In most cases, MELAS is caused by a nucleotide substitution in transfer RNA (tRNA).
PRIZM (NCT06402123) is a phase 2b randomized, placebo-controlled trial evaluating the efficacy and safety of oral zagociguat 15 mg or 30 mg compared to placebo when administered once-daily for 12 weeks in participants with genetically and phenotypically defined MELAS. The study is fully enrolled with 43 adult patients and top-line data is expected in the fourth quarter of 2026.
Zagociguat is a once-daily, oral investigational soluble guanylate cyclase (sGC) stimulator hypothesized to rebalance dysregulated cellular pathways in MELAS, thus restoring mitochondrial energy production and physiological function. The therapy has received Fast Track Designation from the US Food and Drug Administration (FDA) for the treatment of MELAS.
As Dr. Karaa explains, the study design includes two 12-week treatment periods separated by a 4-week washout period. All patients will receive zagociguat during one 12-week period and placebo during the other. Patients who complete treatment in the trial are eligible to enroll in an open-label extension study.
The study is measuring subjective and objective measures of fatigue, cognitive function limitations, exercise intolerance, and muscle weakness. Dr. Karaa highlights that the endpoint strategy was informed by an interview study that gathered the experiences of adults with MELAS to ensure that PRIZM measures the most relevant and meaningful aspects of the disease. In the interview study, the heterogeneity of MELAS presentation was apparent, with fatigue- and cognitive-related symptoms reported most frequently.
For more information, visit Tisento Therapeutics Completes Enrollment in PRIZM, a Global Phase 2b Study of Zagociguat for the Treatment of MELAS.
To learn more about other rare metabolic conditions, visit https://checkrare.com/diseases/metabolic-disorders/
Reference:
Pia, S., & Lui, F. (2024, January 25). Melas Syndrome. StatPearls – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK532959/