Methods and compositions for treating conditions associated with an abnormal inflammatory responses

Inventors

Glick, Gary D. • Franchi, Luigi

Assignees

Entero Therapeutics Inc

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 an abnormal inflammatory response, including inflammatory bowel disease such as ulcerative colitis and Crohn’s disease, by orally administering niclosamide or niclosamide analogs. The disclosure includes local delivery to the digestive or GI tract, GI concentration exceeding plasma concentration, and plasma first-pass metabolism, with the stated rationale of reducing systemic toxicity through low systemic exposure.

The approach includes contacting pathogenic and/or activated T cells with niclosamide or niclosamide analogs and attributes the effect to mitochondrial uncoupling in T cells. The disclosed mechanism interferes with mitochondrial respiration, oxidative phosphorylation, and transmembrane potential, and is presented as inducing T-cell death, including death of lamina propria mononuclear cells.

The effect is described as reducing inflammatory cytokine expression including TNF-alpha, IFNγ, and IL-17A. The disclosure also includes niclosamide and niclosamide analogs, including pharmaceutically acceptable salts, hydrates, cocrystals, solvates, prodrugs, and substituted niclosamide-like compounds with representative structure variations.

Claims Coverage

The consolidated claim coverage centers on oral administration of niclosamide, or a pharmaceutically acceptable salt thereof, to treat autoimmune colitis in a subject in need thereof. Across the provided claim sets, the inventive features repeatedly include local GI delivery, a GI-versus-plasma concentration relationship, plasma first-pass metabolism, and additional refinements directed to iatrogenic autoimmune colitis and CTLA-4-targeted immune checkpoint concepts.

Overall, the claims are directed to oral administration of niclosamide, or a pharmaceutically acceptable salt thereof, for treating autoimmune colitis, with refinements directed to local GI delivery, higher GI than plasma concentration, plasma first-pass metabolism, iatrogenic autoimmune colitis, and CTLA-4-targeting immune checkpoint inhibition.

Stated Advantages

Documented Applications