Long-acting GLP-1 Agonists for Metabolic Disease

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Solution Overview

Problem

Existing GLP-1 receptor agonists for treating type 2 diabetes have poor patient adherence due to injectable and orally administered therapies, leading to suboptimal treatment and control of the condition.

Innovation Solution

Development of long-acting GLP-1 receptor agonist polypeptides with improved physicochemical properties, designed to have extended elimination half-lives, facilitating more reliable and convenient administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If injectable and orally administered GLP-1 receptor agonists are used, then therapeutic effect is achieved, but patient adherence deteriorates

Engineering Contradiction:

Improvetherapeutic effectVSAvoidpatient adherence

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent modifies the elimination half-life parameter of GLP-1 receptor agonists by introducing specific amino acid substitutions (e.g., F24, W28, L31, K35) and C-terminal modifications. These parameter changes extend the duration of action from minutes to hours or days, enabling less frequent administration and thereby improving patient adherence while maintaining therapeutic efficacy.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates dynamic formulations with controlled release characteristics through specific peptide modifications. The modified polypeptides exhibit extended circulation half-lives and sustained biological activity, transforming the static short-acting GLP-1 analogs into dynamic long-acting therapies that maintain therapeutic levels over extended periods without requiring frequent dosing.

Inventive Principle:

Principle #15Dynamics

2Reliability

If endogenous GLP-1 is used, then glucose dependent insulin secretion is enhanced, but duration of action deteriorates

Engineering Contradiction:

Improveglucose dependent insulin secretionVSAvoidelimination half-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent systematically modifies the elimination half-life parameter of GLP-1 by introducing specific amino acid substitutions at key positions (F24, W28, L31, K35) and C-terminal modifications. These changes extend the half-life from less than five minutes to hours or days, while the glucose-dependent insulin secretion mechanism remains intact through preservation of the core receptor-binding structure.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250034225A1Long acting glucagon like polypeptide-1 (GLP-1) receptor agonists and methods of use

Publication Date: 2025.01.30 I2O THERAPEUTICS INC

AI summary

This invention relates to isolated polypeptides that are long acting analogs of human GLP-1. The disclosed GLP-1 receptor agonist polypeptides have beneficial physicochemical properties relative to endogenous GLP-1 and known synthetic GLP-1 receptor agonist polypeptides, such as longer (i.e., “long-acting”) elimination half-lives (t1/2), and improved solubility and thermal stability. This invention also relates to methods of using presently disclosed GLP-1 receptor agonist polypeptides in a variety of therapeutic indications, as well as methods of producing the same. The disclosed GLP-1 receptor agonist polypeptides are particularly useful in methods of treating metabolic diseases or disorders, such as type 2 diabetes, treating obesity, and providing weight loss, and in methods of treating nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH).