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:
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:
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.