Lead Compound  TTI-0102

Thiogenesis has synthesized novel compounds, that are New Chemical Entities (“NCEs”) and act as precursors to thiols. Thiols are compounds that have a functional R-SH group, where S is sulfur and H is hydrogen. Highly reactive sulfur makes the R-SH component of thiols one of the most active functional groups in chemistry, these activities have been widely studied for several decades and provide thiols with vast therapeutic potential.

The lead compound, TTI-0102, is an asymmetric disulfide made up of two thiols that have been synthesized. It was created to address the obstacles that hinder thiol-active drugs, they typically have: short elimination half-lives, discomforting side effects and dosing limitations, any of which can lead to compliance issues.

TTI-0102 is a prodrug, which only becomes active after its administration through the normal metabolic process. The metabolism of a prodrug can act as a gating mechanism in slowing the release of the active compound, in this case cysteamine. Eliminating a spike in cysteamine has the potential to significantly reduce its side effects and provide increased dosing flexibility. As a prodrug, TTI-0102 is eligible for the expedited 505 (b)(2) regulatory pathway in the US and its equivalent in the EU.

In a comparative dose escalation study on healthy volunteers in Australia, TTI-0102 was dosed up to 4x the cysteamine equivalent of Cystagon® (immediate release cysteamine).  Study results with TTI-0102 (2400 mgs of cysteamine equivalent) demonstrated that:

  • It did not exceed the peak levels of cysteamine that were measured in plasma with Cystagon® (600 mgs)
  • Only mild body odor was observed at the highest level of dosing of TTI-0102 (2400 mgs)
  • Minimum therapeutic availability of cysteamine was maintained for a period of 24 hours, offering the potential of dosing once-a-day


The compound cysteamine, is a well-studied thiol with an active functional R-SH group and giving it multiple mechanisms of action with potential therapeutic benefits, including:

  • Provides cysteine, which is a precursor to the important anti-oxidant glutathione - the lack of cysteine is usually the limiting factor in the human production of glutathione
  • Precursor to the amino acid taurine, which has cytoprotective properties
  • Binds to the ACE2 receptor, giving it important anti-viral properties
  • Is an anti-inflammatory, potentially inhibiting cytokine storm in viral disease
  • Acts as a mucolytic (mucus thinner)
  • Promotes the production of brain-derived neurotropic factor (BDNF), a protein important in nerve growth and brain function

Historically cysteamine was studied as a shield against radiation poisoning in the 1950’s. In the 1970’s it was studied as a therapeutic for sickle cell anemia and later to protect against paracetamol toxicity. In the 2000’s cysteamine was studied in Huntington’s disease and NASH, among several other indications. None of these applications were commercialized.

However, cysteamine bitartrate formulations were approved in 1994 as Cystagon® (immediate release) and in 2013 as Procysbi® (delayed release) - both for the treatment of cystinosis. Cystinosis is a life-threatening lysosomal storage disease where the transporter for the disulfide cystine is not functioning. It results in the toxic buildup of cystine in the lysosome of cells; it damages tissues and kidneys, often leading to transplantation. Cysteamine aids in the orderly removal of cystine from the lysosome.

Cysteamine causes unpleasant side-effects at peak blood concentrations. These include halitosis, body odor, nausea/vomiting, fatigue and gastrointestinal pain. The side effects and dosing limitations of cysteamine have historically been a major obstacle to the development of additional applications for thiol-containing drugs. TTI-0102, Thiogenesis’ lead compound, was created to reduce or eliminate side-effects, provide dosing flexibility and improve compliance.

Cysteamine (HS-CH2-CH2-NH2) - Mechanisms of Action

Cystine depletion by reacting with disulfude bridge within cystine

  • Cystinosis

Thiol-disulfide balancing mechanism (redox activity)

  • Mitochondrial disease (MELAS, Leigh…)
  • Parkinson’s disease
  • Alzheimer’s disease

Antioxidative effect by increasing intracellular glutathione levels

  • Radiation protection
  • Cystinosis
  • Huntington's disease
  • Rett syndrome
  • Mitochondrial disease (MELAS, Leigh)

Changing gene expression

Promotes BDNF

  • Huntington's disease
  • Rett syndrome
  • Parkinson's disease
  • Schizophrenia
  • Major depression

Changing enzymatic activity

Caspase 3 (decreased apoptosis causes increased cell survival)

  • Cystinosis
  • Huntington's disease
  • Rett syndrome

Transglutaminases (decreased crosslinking of several proteins)

  • Huntington's disease
  • Rett syndrome
  • Protein kinase C Cystinosis
  • Parasitic enzymes
  • Malaria
Adapted from: Besouw M, et al. Cysteamine: an old drug with new potential. Drug Discovery Today 2013; 18: 785–92.

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