Methods and compositions for treating conditions associated with an abnormal inflammatory response
Inventors
Glick, Gary D. • Franchi, Luigi
Assignees
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Publication Number
US-10905666-B2
Publication Date
2021-02-02
Expiration Date
Abstract
This disclosure features chemical entities (e.g., a compound exhibiting activity as a mitochondrial uncoupling agent or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, such as niclosamide or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound, such as a niclosamide analog, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) that are useful, e.g., for treating one or more symptoms of a pathology characterized by an abnormal inflammatory response (e.g., inflammatory bowel diseases) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.
Core Innovation
The invention relates to treating iatrogenic autoimmune colitis in a subject in need thereof by administering an effective amount of niclosamide or a pharmaceutically acceptable salt thereof. The method is directed to gastrointestinal contexts associated with iatrogenic autoimmune colitis and uses niclosamide as the active agent for colitis caused by iatrogenic autoimmune mechanisms.
The invention also relates to niclosamide analogue chemical structures and niclosamide-related forms, including pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and cocrystals. The disclosed subject matter provides generic formulas and substituent definitions, together with illustrative benzamide scaffold variants and specific example compounds listed in tables.
The described approach further focuses on local administration to the GI tract and rectal delivery forms such as an enema, rectal gel, rectal foam, rectal aerosol, or suppository. It also describes GI tract concentration that is about 5 times higher than in the plasma compartment, and links GI exposure of niclosamide to effects on pathogenic T cells and pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-17A.
Claims Coverage
The consolidated claims coverage includes 2 independent treatment concepts and 6 inventive features across the provided claim text. The claims center on niclosamide-based treatment of iatrogenic autoimmune colitis, with refinements describing GI-localized delivery, rectal delivery forms, a GI-to-plasma concentration relationship, and colitis induction context involving chemotherapeutic agents and immune checkpoint inhibitors.
Treating iatrogenic autoimmune colitis with niclosamide
A method for treating iatrogenic autoimmune colitis in a subject in need thereof by administering an effective amount of niclosamide, or a pharmaceutically acceptable salt thereof.
Local administration to the GI tract
Locally administering an effective amount of niclosamide, or a pharmaceutically acceptable salt thereof, to the GI tract of a subject.
Rectal delivery form options
Administering niclosamide, or a pharmaceutically acceptable salt, using an enema, rectal gel, rectal foam, rectal aerosol, or suppository.
GI-versus-plasma concentration constraint
After administration, the niclosamide concentration in the GI tract is about 5 times higher than in the plasma compartment.
Colitis induction using chemotherapeutic agents
Inducing iatrogenic autoimmune colitis using one or more chemotherapeutic agents.
Immune checkpoint inhibitor targeting an immune checkpoint receptor
Providing an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from a defined group of immune checkpoint receptor molecules.
Overall, the claims center on niclosamide-based treatment of iatrogenic autoimmune colitis, with dependent refinements emphasizing localized GI tract delivery, rectal delivery forms, a GI-versus-plasma concentration relationship, and a colitis induction scenario that can involve chemotherapeutic agents including immune checkpoint inhibitors targeting an immune checkpoint receptor set.
Stated Advantages
Localized delivery reduces systemic exposure and systemic toxicity.
Local GI exposure is characterized by a niclosamide concentration in the GI tract that is about 5 times higher than in the plasma compartment.
Modulation of pro-inflammatory cytokines including TNF-α, IFN-γ, and IL-17A in GI-associated contexts.
Rectal or local administration is described as effective in murine TNBS colitis while intraperitoneal or systemic administration lacks efficacy.
Documented Applications
Treating iatrogenic autoimmune colitis in a subject in need thereof, including contexts where iatrogenic autoimmune colitis is induced by chemotherapeutic agents.
Treating inflammatory bowel disease having an abnormal inflammatory response.
Rectal administration use cases for delivering niclosamide in rectal delivery forms such as an enema, rectal gel, rectal foam, rectal aerosol, or suppository.
Use in TNBS-induced colitis contexts for therapeutic efficacy and colon versus plasma exposure comparisons, as described in the partial document summary.
Use in murine TNBS colitis, with rectal or local administration showing efficacy and intraperitoneal or systemic administration lacking efficacy.
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