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-11612576-B2
Publication Date
2023-03-28
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 bioavailablity 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 cysteamine precursor compounds and methods and regimens for treating a cysteamine sensitive disorder in a subject. The compounds generate cysteamine in the gastrointestinal tract through biochemical conversion, including pantetheinase activity and associated VNN1/VNN2-related processes, and are described as enabling controlled in vivo cysteamine generation.
The precursor chemistries include thiol-degradable compounds, cysteamine-containing mixed disulfides, pantetheine-containing disulfides, and 4-phosphopantetheine/dephospho-coenzyme A-containing disulfides. Circulating 4-phosphopantetheine is described as supporting targeting to diseased tissues, and pantetheinase expression is described as being modulated to influence generation profiles.
The document further describes oral gastroretentive and controlled-release delivery, including swelling, expandable, unfolding, and shape-changing retention technologies, an Accordion Pill, controlled release coatings and polymers, bilayer, trilayer, and multiparticulate forms, enteric coatings, and ileum/colon targeting cores using microcrystalline cellulose (MCC).
Claims Coverage
The independent claims cover two treatment regimens for cysteamine sensitive disorders using cysteamine precursor compounds. Across the independent claims, there are two main inventive feature sets: co-administration with a pantetheinase inducing agent, and a timed co-administration scheme in which compound 3 is administered within 30 minutes after compound 1 or compound 2.
Treating cysteamine-sensitive disorders with cysteamine precursor compound and pantetheinase induction
A method for treating a cysteamine sensitive disorder in a subject comprising administering a dose of from 50 to 150 mg/kg, one or more times daily, of compound 1 and/or compound 2 and/or compound 3, or a pharmaceutically acceptable salt thereof, wherein the method further comprises administering a pantetheinase inducing agent selected from PPAR alpha agonists, PPAR gamma agonists, or Nrf2 inducing agents.
Timed co-administration of cysteamine precursor compounds with early compound 3 dosing
A method for treating a cysteamine sensitive disorder in a subject comprising administering a dose of from 50 to 150 mg/kg, one or more times daily, of compound 1 and/or compound 2, or a pharmaceutically acceptable salt thereof, wherein within 30 minutes of administering compound 1 or compound 2, from 10 to 50 mg/kg of compound 3, or a pharmaceutically acceptable salt thereof, is further administered to the subject.
The independent claims focus on administering cysteamine precursor compounds at defined mg/kg dosing ranges for cysteamine sensitive disorders, either together with a pantetheinase inducing agent selected from PPAR alpha agonists, PPAR gamma agonists, or Nrf2 inducing agents, or via a timed regimen where compound 3 is administered within 30 minutes after compound 1 or compound 2.
Stated Advantages
Improved pharmacokinetics.
Reduced toxicity.
Prolonged cysteamine exposure without high Cmax.
Targeting to diseased tissues via circulating 4-phosphopantetheine.
Documented Applications
Treating cysteamine sensitive disorders, including cystinosis; neurodegenerative, neurodevelopmental, or neuropsychiatric disease; mitochondrial disease; kidney, liver, or lung fibrotic diseases; parasitic infection; sickle cell anemia; cancer; ischemic disease, including ischemic heart disease or stroke; COPD; cystic fibrosis; bacterial or viral infection; NASH; alcoholic steatohepatitis; or NAFLD.
Rat pharmacokinetic studies comparing cysteamine exposure parameters and tissue persistence following administration of specific disulfides, including compound 2 versus cysteamine HCl, and other PK comparisons.
Examples of individualized cystinosis therapy and NASH therapy described in the document background material.
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