TTI-0102

TTI-0102 is a patented, next-generation cysteamine prodrug and new chemical entity (NCE), engineered to provide sustained-release delivery for cysteamine. TTI-0102 delivers cysteamine continuously over time, producing a flatter pharmacokinetic profile than existing cysteamine therapies, avoiding the sharp concentration spike that drives GI side effects and body odor with current treatments, while supporting higher doses and the potential for once-daily administration.

Cysteamine-based drugs have been approved twice for cystinosis, eliminating toxic cystine that accumulates inside cells and progressively damages the kidneys. Previous drugs carry the underlying side effect and adherence problems that TTI-0102 is designed to address. An investigator-initiated study is planned at Emory University to generate proof-of-concept data in cystinosis patients ahead of a planned pivotal Phase 3 trial.

TTI-0102 also holds an FDA-cleared IND for a Phase 2a trial in Leigh Syndrome Spectrum, planned in collaboration with a leading children's hospital in the US; LSS is a rare, severe mitochondrial disorder with no approved therapies. The planned LSS clinical trial is also relevant to the broader family of primary mitochondrial diseases which affects an estimated 75,000 patients in the US.

TTI-0102 - Phase 1 Study
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TTI-0102 was evaluated in a Phase 1 dose-escalation trial with healthy volunteers, assessing its pharmacokinetics and tolerability against generic cysteamine. Doses reached up to 2400 mg cysteamine equivalent (four times the standard 600 mg), with results showing:

  • TTI‑0102’s cysteamine Cmax did not surpass that of 600 mg generic cysteamine, 
  • Therapeutic levels lasted over 24 hours, potential for once-daily administration.
  • Only mild body odor occurred at the highest dose; no GI side effects were reported.

These findings suggest that TTI‑0102 reduced the spike in cysteamine associated with its side effects; offering improved tolerability, a significantly increased dosing range, and the potential for once-daily administration compared to generic cysteamine.

Cysteamine

Cysteamine is a thiol compound that has been studied for decades for its antioxidant, anti-inflammatory, and mitochondrial-protective properties. It works in part by boosting intracellular cysteine level, the rate-limiting precursor to glutathione, and is also metabolized into taurine and Coenzyme A (“CoA”). These compounds are central to maintaining redox balance and defending cells from oxidative damage, particularly in mitochondria.

Glutathione is the body’s most abundant intracellular antioxidant. It protects against oxidative stress by neutralizing reactive oxygen species (“ROS”), supporting enzymatic activity, and recycling other antioxidants. Taurine modulates antioxidant enzymes, stabilizes mitochondria, and supports calcium signaling. CoA is a vital cofactor in cellular energy metabolism and has been shown to protect cells from oxidative or metabolic stress.

Cysteamine was first approved in the 1990s to treat nephropathic cystinosis, a rare lysosomal storage disease, where it helped reduce cystine accumulation in tissues. Despite its proven efficacy, cysteamine’s broader therapeutic potential has been limited by tolerability issues, namely its short half-life, dose-limiting gastrointestinal side effects, and strong body odor associated with sulfur metabolism.

Thiogenesis’ lead candidate, TTI-0102, is a next-generation cysteamine prodrug designed to overcome these limitations, preserving cysteamine’s well-established biology while extending its reach across cystinosis, mitochondrial, and oxidative stress-related diseases.

Cysteamine - Mechanisms of Action

Relevant Publications - Available Online

  • Akerfeldt, S. (1963). Radioprotective Effects of S-Phosphorylated Thiols. Acta Radiologica: Therapy, Physics, Biology, 1(6), 465–470. https://doi: 10.3109/02841866309134122
  • Besouw, M., Blom, H., Tangerman, A., Graaf-Hess, A. de, & Levtchenko, E. (2007). The origin of halitosis in cystinotic patients due to cysteamine treatment. Molecular Genetics and Metabolism, 91(3), 228–233. doi: 10.1016/j.ymgme.2007.04.002
  • Guha, S., Konkwo, C., Lavorato, M., Mathew, N. D., Peng, M., Ostrovsky, J., … Falk, M. J. (2019). Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease. Human Molecular Genetics. doi: 10.1093/hmg/ddz023
  • Paul, B. D., & Snyder, S. H. (2019). Therapeutic Applications of Cysteamine and Cystamine in Neurodegenerative and Neuropsychiatric Diseases. Frontiers in Neurology, 10, 1315. doi: 10.3389/fneur.2019.01315
  • Pozzo-Miller, L., Pati, S., & Percy, A. K. (2015). Rett Syndrome: Reaching for Clinical Trials. Neurotherapeutics, 12(3), 631–640. doi: 10.1007/s13311-015-0353-y
  • Schwimmer, J. B., Lavine, J. E., Wilson, L. A., Neuschwander-Tetri, B. A., Xanthakos, S. A., Kohli, R., … Yates, K. (2016). In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. Gastroenterology, 151(6), 1141. doi: 10.1053/j.gastro.2016.08.027
  • Skrede, S., & Christophersen, B. (1966). Effects of cystamine and cysteamine on the peroxidation of lipids and the release of proteins from mitochondria. Biochemical Journal, 101(1), 37–41. doi: 10.1042/bj1010037
  • Thoene, J. G., Oshima, R. G., Crawhall, J. C., Olson, D. L., & Schneider, J. A. (1976). Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest, 58(1), 180–189. doi: 10.1172/jci108448
  • Wang, Y., Davis, I., Chen, Y., Naik, S. G., Griffith, W. P., & Liu, A. (2020). Characterization of the non-heme iron center of cysteamine dioxygenase and its interaction with substrates. Journal of Biological Chemistry, jbc.RA120.013915. doi: 10.1074/jbc.RA120.013915