Thiogenesis Therapeutics has initiated dosing in its Phase 2 clinical trial evaluating TTI-0102 for the treatment of Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS), a rare inherited mitochondrial disorder. The first two patients received doses on May 12, 2025, at Radboud University Medical Center in Nijmegen, Netherlands.
The Phase 2 trial represents a significant milestone for the San Diego-based biotechnology company in its efforts to develop a treatment for MELAS, which currently has no approved therapies in either the European Union or the United States.
"The dosing of the first two patients in our Phase 2 clinical trial is the culmination of a lot of planning and dedicated work from the Thiogenesis team and a major milestone for an emerging biotech company," said Patrice Rioux, MD, Ph.D., Chief Executive Officer of Thiogenesis.
Trial Design and Endpoints
The multi-center study is being conducted at leading institutions across the Netherlands and France. Designed as a randomized, double-blind, placebo-controlled trial, the study will assess the safety, tolerability, efficacy, and pharmacokinetics/pharmacodynamics of oral TTI-0102 in MELAS patients over a 6-month period.
The trial will enroll a total of 12 patients, with 8 receiving TTI-0102 and 4 receiving placebo. An interim analysis of safety and clinical efficacy is planned after 3 months.
Key clinical endpoints being evaluated include:
- 12-Minute Walking Test (12-MWT)
- Fatigue Severity Scale (FSS)
- Quality of Life Assessment (WHOQOL-BREF)
These endpoints were selected to measure both objective physical function and subjective quality of life improvements, providing a comprehensive assessment of TTI-0102's potential benefits.
Understanding MELAS
MELAS is an inherited mitochondrial disorder most commonly caused by a mutation (m.3243A>G) in the MT-TL1 gene in mitochondrial DNA. The condition typically manifests before age 20 with initial symptoms including seizures, vomiting, headaches, muscle weakness, loss of appetite, and fatigue. As the disease progresses, patients may experience loss of motor skills and intellectual disability.
Despite being one of the most prevalent inherited mitochondrial diseases, MELAS remains classified as an orphan disease, affecting approximately 4.1 per 100,000 people according to recent estimates (Ryytty et al. 2023).
Oxidative stress plays a significant role in the pathophysiology of MELAS. Patients typically exhibit deficiencies in glutathione and taurine, which contribute to mitochondrial dysfunction—a key mechanism underlying the disease.
TTI-0102: A Novel Approach
TTI-0102, Thiogenesis' lead product candidate, represents a novel approach to treating MELAS. The compound is an asymmetric disulfide and prodrug that acts as a precursor to the thiol compound cysteamine.
"TTI-0102 is a precursor to the thiol cysteamine and has been engineered to be well-tolerated and to intracellularly increase the antioxidant glutathione and the amino acid taurine, both of which are known to be deficient in MELAS patients and contribute to the disease," explained Dr. Rioux.
Thiols, which contain a functional SH group (sulfur and hydrogen), are versatile bioactive molecules involved in key biochemical reactions and metabolic processes. They serve as precursors to important antioxidants like glutathione and amino acids such as taurine, potentially restoring mitochondrial function.
The prodrug approach was specifically developed to address limitations of first-generation thiol-based drugs, including their short half-life, adverse side effects, and dosing constraints. As a prodrug, TTI-0102 only becomes active when metabolized in the body, potentially improving its therapeutic profile.
Regulatory Advantages of Prodrug Development
Prodrugs offer certain regulatory advantages that may accelerate development timelines. Since they contain previously approved active ingredients in modified form, companies can leverage existing third-party safety data in regulatory submissions.
This allows for a streamlined regulatory pathway—the 505(b)(2) pathway in the U.S. and its equivalent hybrid system in the EU—potentially enabling faster progression to human efficacy trials with regulatory clearance.
Future Directions
Beyond MELAS, Thiogenesis is planning additional clinical trials of TTI-0102 in other conditions with similar underlying mechanisms, including Leigh syndrome, Rett syndrome, and pediatric metabolic dysfunction-associated steatotic hepatitis (MASH).
The company's broader mission focuses on developing sulfur-containing prodrugs that act as precursors to previously approved thiol-active compounds, with potential applications in various serious pediatric diseases with unmet medical needs.
As the Phase 2 MELAS trial progresses, the results could provide valuable insights not only for MELAS treatment but also for the broader understanding of mitochondrial disorders and the therapeutic potential of thiol-based approaches.
