Methods and compositions for treating conditions associated with an abnormal inflammatory responses
Inventors
Glick, Gary D. • Franchi, Luigi
Assignees
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Publication Number
US-10744103-B2
Publication Date
2020-08-18
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 a method for treating an autoimmune colitis in a subject in need thereof by administering an effective amount of niclosamide, or a pharmaceutically acceptable salt thereof, to the GI tract of the subject. The treatment context includes autoimmune colitis as an inflammatory bowel disease and further defines autoimmune colitis as iatrogenic autoimmune colitis. In this refined context, the autoimmune colitis is addressed using niclosamide administered to the GI tract.
The disclosure also includes niclosamide and niclosamide analogues, including pharmaceutically acceptable salt forms, hydrates, and cocrystals. It describes broad structural definitions for niclosamide analogs and niclosamide identities, salt/solvate forms, and cocrystals with coformers held by non-covalent interactions. The disclosure further references physicochemical design criteria associated with low oral bioavailability and low solubility/permeability.
The disclosed treatment context includes local GI administration to achieve low systemic exposure, reduced toxicity, and improved convenience/cost versus biologics. It describes embodiments including rectal/local administration and an enema delivery device, and reports reduction of cytokines in intestinal tissue in the context of intestinal inflammation models. The mechanism described is mitochondrial uncoupling in pathogenic or activated T cells, including disruption of mitochondrial respiration from oxidative phosphorylation and induction of T-cell death.
Claims Coverage
The claim coverage centers on a method of treating autoimmune colitis by administering an effective amount of niclosamide, or a pharmaceutically acceptable salt thereof, to the GI tract. Dependent features refine the route and disease scope, including rectal administration, defining autoimmune colitis as inflammatory bowel disease, narrowing to iatrogenic autoimmune colitis, requiring a colon-versus-plasma concentration relationship, and specifying immune checkpoint inhibitor target selection.
Treating autoimmune colitis via GI tract administration of niclosamide
Administering an effective amount of niclosamide, or a pharmaceutically acceptable salt thereof, to the GI tract of a subject in need thereof to treat autoimmune colitis.
Rectal administration of niclosamide
Administering niclosamide, or a pharmaceutically acceptable salt thereof, via rectal administration as part of the treating method.
Autoimmune colitis as inflammatory bowel disease
Defining the autoimmune colitis as an inflammatory bowel disease.
Iatrogenic autoimmune colitis
Defining the autoimmune colitis as iatrogenic autoimmune colitis.
Immune-checkpoint inhibitor target selection
Requiring that the immune checkpoint inhibitor targets an immune checkpoint receptor selected from a specified group including CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, IL-2, IDO, IL-10, TGFβ, TIM3 (HAVCR2) and related TIM3 complexes, LAG3 and related complexes, TNF-family and costimulatory receptor/ligand pairs, HVEM/BTLA and CD160 complexes, CD80/CD86 and related complexes, CD27/CD70 and related complexes, and additional listed checkpoint ligands/receptors including VISTA, TMIGD2/HHLA2-TMIGD2, Butyrophilins (BTNL2), Siglec family members, TIGIT/PVR family members, KIRs, ILTs/LIRs, NKG2D/NKG2A, MICA/MICB, CD39/CD73, CXCR4-CXCL12, phosphatidylserine/TIM3, SIRPA-CD47, VEGF/neuropilin, CD30, and CD155.
Colon concentration about 5 times higher than plasma
After administration, requiring that the concentration of niclosamide in the colon is about 5 times higher than in the plasma compartment.
Across the claims, the core coverage is a method of treating autoimmune colitis by GI administration of niclosamide (or a pharmaceutically acceptable salt), with dependent refinements including rectal administration, definition of autoimmune colitis as inflammatory bowel disease, narrowing to iatrogenic autoimmune colitis, a colon-versus-plasma concentration relationship, and immune checkpoint inhibitor target selection.
Stated Advantages
Enhanced localized GI/colon/rectal exposure relative to plasma exposure.
Low systemic exposure.
Reduced toxicity.
Improved convenience/cost versus biologics.
Reduction of colitis in TNBS-induced colitis, accompanied by corresponding clinical and histologic improvements.
Cellular activity consistent with mitochondrial uncoupling leading to T-cell death, including effects associated with mitochondrial membrane potential (ΔΨm) and apoptosis/necrosis markers.
Modulation of human T-cell cytokines (IL-17A, TNF-α, IFN-γ).
Documented Applications
Treatment of autoimmune colitis in a subject in need thereof via GI administration of niclosamide (or a pharmaceutically acceptable salt), including rectal/enema delivery formats.
Use in inflammatory bowel disease, including TNBS-induced colitis.
Use in iatrogenic autoimmune colitis associated with immune checkpoint inhibitor therapy, including specified immune checkpoint inhibitor target receptors.
Treating autoimmune colitis, including inflammatory bowel disease subtypes such as ulcerative colitis and Crohn’s disease, by GI administration of niclosamide or a pharmaceutically acceptable salt.
Local GI treatment including rectal administration and enema delivery device embodiments.
Killing of lamina propria T cells or lamina propria mononuclear cells associated with inflammatory bowel disease, including mitochondrial uncoupling-related effects and cytokine reduction in intestinal tissue.
Efficacy in a murine TNBS colitis model of ulcerative colitis after rectal local dosing.
Material and compound embodiments for niclosamide and niclosamide analogues, including niclosamide salts, hydrates, and cocrystals with coformers held by non-covalent interactions.
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