Methods for the treatment of cysteamine sensitive disorders
Inventors
Stanton, Jr., Vincent P. • RIOUX, Patrice P. • Barski, Piotr • Witt, Dariusz
Assignees
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Publication Number
US-12569456-B2
Publication Date
2026-03-10
Expiration Date
Abstract
The invention features methods for the treatment of cystinosis and other cysteamine sensitive disorders in a subject including administration of a disulfide convertible to cysteamine in vivo. The methods can include the separate administration of a reducing agent to the subject to increase the bioavailability and extend the plasma pharmacokinetic profile of the cysteamine produced following administration of the disulfide. The methods permit sustained cysteamine plasma concentrations in a subject.
Core Innovation
The invention relates to oral administration of cysteamine precursors and cysteamine producing or generating compounds, including compound 1 or a pharmaceutically acceptable salt thereof, together with a reducing agent, for treating a subject having a cysteamine sensitive disorder. The disclosure includes thiol- and disulfide-type cysteamine precursors, including pantetheine/pantethine, 4-phosphopantetheine/dephospho-coenzyme A/coenzyme A precursors, and N-acetylcysteamine disulfide homodimer.
Conversion pathways are described in terms of pantetheinase activity, including VNN1 and VNN2, together with reduction and thiol-disulfide exchange processes. The disclosure frames delivery and conversion as a way to avoid saturating uptake and saturating enzymes, while enabling cysteamine exposure that is sustained and with lower peak levels compared with cysteamine salts.
The invention further relates to formulation strategies and targeting within the gastrointestinal tract, including gastroretentive, controlled-release, instant or early-late release, sustained release, and mixed formulations. Intestinal localization is described using ileum and colon targeting via enteric bacterial enzyme-digestible polymers and pH-sensitive coatings.
Claims Coverage
The partial set includes two independent methods. Across these independent claims, there are two inventive features centered on oral dosing of compound 1 with a reducing agent for treating a cysteamine sensitive disorder.
Oral dosing of compound 1 with a reducing agent for multi-times-daily treatment
Orally administering to a subject a reducing agent and a dose of from 50 to 150 mg/kg of compound 1 or a pharmaceutically acceptable salt thereof one or more times daily, for treating a cysteamine sensitive disorder.
Once-daily oral dosing of compound 1 with a reducing agent
Orally administering to a subject a reducing agent and a dose of from 2,000 to 10,000 mg of compound 1 or a pharmaceutically acceptable salt thereof once daily, for treating a cysteamine sensitive disorder.
The claim coverage focuses on treating cysteamine sensitive disorders by combining oral administration of compound 1 with a reducing agent, using either a 50-150 mg/kg dose given one or more times daily or a 2,000-10,000 mg once-daily dose.
Stated Advantages
Reduces peak-to-trough fluctuations and improves tolerability.
Sustained and lower peak cysteamine exposure versus cysteamine salts.
Reduced toxicity.
Avoidance of saturating uptake and saturating enzymes.
Disulfide stability is described for salt-form preparation including TTI-0102 (compound 1).
Targeting of disease tissues (e.g., kidney/lung) via circulating delivery of 4-phosphopantetheine.
Documented Applications
Treatment of cysteamine sensitive disorders, including cystinosis.
Treatment of neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease.
Treatment of fibrotic diseases, including kidney, liver, and lung fibrotic diseases.
Treatment of infectious diseases, including bacterial, viral, or parasitic diseases.
Treatment of mitochondrial diseases.
Treatment of sickle cell anemia.
Treatment of cancer.
Treatment of ischemic disease, including ischemic heart disease and stroke.
Treatment of COPD.
Treatment of cystic fibrosis.
Treatment of NASH, ASH, and NAFLD.
Treatment of chronic liver or lung diseases.
Oral cysteamine-precursor therapies, including gastroretentive and controlled-release formulation concepts.
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