Active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease
Inventors
Taylor, Steven John • Proudfoot, John Robert • Kim, Mi-Jeong • NUDEL, Kathleen • Briggs, Timothy F. • KAMALI SARVESTANI, Afrand • Buckbinder, Leonard • LANTER, Bernard • MASSARI, Ferdinand Edward • Yasuda, Koji • PECK, Spencer Cory • Snedeker, Cheri • LE, Diana • ALEXANDER, Jessica • LIANG, Anna • GUNASEKERA, Dinara • Berry, David Arthur • CASEY, JR., John Patrick
Assignees
Flagship Pioneering Innovations V Inc • Flagship Pioneering Inc
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10953027-B2
Publication Date
2021-03-23
Expiration Date
Abstract
Disclosed herein are active agents, compositions containing them, unit dosage forms containing them, and methods of their use, e.g., for treating a metabolic disorder or nonalcoholic fatty liver disease or for modulating a metabolic marker or nonalcoholic fatty liver disease marker.
Core Innovation
The invention provides a method of modulating a metabolic marker in a subject in need thereof or ameliorating a metabolic disorder in a subject in need thereof by administering an effective amount of an active agent having a specified structure. The disclosed active agents include acylated active agents, esterified prodrugs, acylated catechin polyphenols, acylated ellagic acid and ellagic acid analogues, acylated hydroxybenzoic acids, acylated shikimic acid, acylated stilbenoids, acylated sugars, acylated vitamins, acylated carotenoids, acylated bile acids, and related structural variants, including isotopes, stereoisomers, pharmaceutically acceptable salts, cleavable forms in the gastrointestinal tract, and combinations of an acylated active agent with a ketone or pre-ketone agent.
The disclosed material includes specific compounds and stereochemical variants, including deuterated analogs, α/β isomer mixtures, and stereochemically defined indole-containing and non-indole variants. The compounds are presented with chemical structures and, for many examples, characterization information such as LCMS, 1H NMR, yields, purities, and purification notes. The text explicitly lists compound embodiments and associated analytical outputs for selected members.
The disclosed active agents are directed to treating metabolic disorders by modulating metabolic marker endpoints, with dependent content also addressing obesity-related measures and NAFLD/NASH-related marker endpoints. The documented endpoints include total fat percentage, cellular adiposity, body mass index, rate of weight gain, abdominal fat quantity, the ratio of white to brown fat, levels of lipogenesis or fat storage, insulin, GLP-1, PYY, blood sugar, hemoglobin A1c, glucose tolerance, ALT, AST, liver weight, liver fibrosis, γ-glutamyltransferase, fibrotic markers, miRNA-92a, transient elastography, and MR elastography.
The disclosure further encompasses orally administered, hydrolyzable forms in which the active agent is cleavable in the gastrointestinal tract after oral administration. The stated subject populations include subjects who are overweight or have obesity, severe obesity, morbid obesity, or super obesity, and the disorder is characterized in the claims as an obesity disorder.
Claims Coverage
The provided claims center on a method of administering an effective amount of an active agent having a specified structure to modulate a metabolic marker in a subject in need thereof or ameliorate a metabolic disorder. The inventive features across the dependent claims include obesity-focused disorder targeting, specified overweight and obesity severity categories, defined fatness and metabolism response measures, metabolic hormone and glycemic endpoints, NAFLD/NASH-related marker endpoints, oral administration with gastrointestinal cleavability, and combination use with a ketone or pre-ketone agent.
Administering an active agent having a specified structure
Administering to the subject an effective amount of an active agent having the structure recited in the claim for modulating a metabolic marker or ameliorating a metabolic disorder.
Modulating metabolic markers or ameliorating a metabolic disorder
The method is directed to modulating a metabolic marker in a subject in need thereof or ameliorating a metabolic disorder in a subject in need thereof.
Treating an obesity disorder
The method is limited to treating a metabolic disorder that is an obesity disorder.
Treating specified overweight or obesity severity categories
The subject is overweight or has obesity, severe obesity, morbid obesity, or super obesity.
Reducing fatness and metabolism measures
The method reduces one or more measures of fatness and metabolism, including total fat percentage, cellular adiposity, body mass index, rate of weight gain, abdominal fat quantity, the ratio of white to brown fat, and levels of lipogenesis or fat storage.
Modulating metabolic hormones and glycemic endpoints
After administering an active agent to a subject, the method increases insulin, GLP-1, or PYY levels and/or reduces blood sugar or hemoglobin A1c, and/or increases glucose tolerance.
Modulating NAFLD/NASH-related marker endpoints
The method includes marker endpoints such as alanine transaminase (ALT), aspartate transaminase (AST), liver weight, liver fibrosis, γ-glutamyltransferase, fibrotic markers, transient elastography, and MR elastography.
Oral administration with gastrointestinal tract cleavability
Following oral administration to the subject, the active agent is cleavable in the gastrointestinal tract of the subject.
Combination with a ketone or pre-ketone agent
The disclosure includes combinations of an acylated active agent with a ketone or pre-ketone agent, including regimens described as a first active agent and a second active agent.
Across the provided claims, the core coverage is administering an active agent of a specified structure to modulate a metabolic marker or ameliorate a metabolic disorder, with dependent limitations addressing obesity-related subject categories, fatness and metabolism measures, insulin/GLP-1/PYY and glycemic endpoints, NAFLD/NASH-related markers, oral gastrointestinal cleavability, and combination use with a ketone or pre-ketone agent.
Stated Advantages
Modulates a metabolic marker in a subject in need thereof.
Ameliorates a metabolic disorder in a subject in need thereof.
Reduces measures of fatness and metabolism, including total fat percentage, cellular adiposity, body mass index, rate of weight gain, abdominal fat quantity, the ratio of white to brown fat, and levels of lipogenesis or fat storage.
Increases insulin, GLP-1, and/or PYY levels.
Reduces blood sugar or hemoglobin A1c.
Increases glucose tolerance.
Documented Applications
In vitro stability assessment of acylated active agents in simulated gastric fluid, simulated intestinal fluid, fecal incubation, and pH-buffer conditions.
In vivo metabolic disorder evaluation in HFD-fed mice, including weight loss, improved glucose tolerance, and liver histology scoring for steatosis, ballooning, and inflammation.
Evaluation of active combinations and NAFLD/NASH models.
Regulatory T-cell differentiation evaluation and PBMC cytokine modulation.
GI barrier integrity evaluation using Caco-2 barrier integrity (TEER).
Adipocyte and myocyte lipolysis evaluation.
Glucose disposal and lipidemia studies.
Use of the disclosed active agent structures in a method of modulating a metabolic marker in a subject and/or ameliorating a metabolic disorder.
Use directed to obesity disorder within the claimed method.
Treatment of subjects who are overweight or have obesity, severe obesity, morbid obesity, or super obesity.
Treatment of metabolic disorders, including obesity disorders, by modulating metabolic marker endpoints and NAFLD/NASH-related marker endpoints.
An oral administration use case in which, after oral administration to the subject, the active agent is cleavable in the gastrointestinal tract.
Interested in licensing this patent?