An updated patent review of GLP-1 receptor agonists (2020-present)

ABSTRACTIntroduction Type 2 diabetes (T2DM) and obesity present significant global health issues, requiring the development of long-lasting and highly effective pharmacotherapies. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) are commonly used for diabetes treatment, their potential for addressing obesity is still being explored.Areas covered This review offers a comprehensive overview of recently published patents from January 2020 to July 2023, focusing on modified GLP-1RAs, small molecule GLP-1RAs, GLP-1 R-based multi-agonists, GLP-1RA-based fusion proteins, and combination therapies. The patents discussed pertain to the treatment and prevention of diabetes and obesity. Patent searches were conducted using the PATENTSCOPE database of the World Intellectual Property Organization, using the keywords GLP-1, GLP-1/GIP, GLP-1/GCG, and GLP-1/GCG/GIP.Expert opinion In recent years, patents have emphasized two main goals for developing GLP-1RAs drugs: oral delivery and improved weight reduction effects. To address the growing demand for improved treatments, researchers have focused their efforts on developing GLP-1 R-based multi-agonists, orally administered GLP-1RAs, and combination therapies utilizing GLP-1RAs. These new approaches offer promising benefits, such as improved effectiveness by targeting multiple pathways and reduced side effects. Additionally, the development of new uses, oral forms, and long-lasting preparations will be crucial in shaping the future market potential of GLP-1 drugs.KEYWORDS: Diabetesobesityglucagon-like peptide-1glucagon-like peptide-1 receptor agonistmulti-agonistDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Declaration of interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresOne reviewer is an ex-employee shareholder in Novo Nordisk. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.Author contribution statementWeiwen Lu: writing and coordinating the manuscript. Zhongbo Zhou: editing of the manuscript and literature and patents research. Neng Jiang: editing of the manuscript and literature and patents research. Jing Han: writing and coordinating the authors' activities.Data availability statementThe data supporting the findings of this study are available within the article and patents from Pubmed at https://pubmed.ncbi.nlm.nih.gov and from WIPO at https://patentscope.wipo.int/search/en/search.jsf.Article highlightsThe clinical achievements of GLP-1 receptor agonists (GLP-1RAs) have demonstrated their substantial potential in managing type 2 diabetes (T2DM) and obesity. GLP-1RAs are currently the only class of pharmaceuticals approved for both indications.GLP-1RAs have demonstrated considerable success; however, a discernible disparity in weight loss efficacy compared to bariatric surgery persists. Researchers are exploring GLP-1R-based multi-agonists and combination therapies to bridge this divide. This article reviews patents related to these strategies as well as traditional approaches in the development of GLP-1RAs.Oral preparations of GLP-1 drugs offer significant convenience advantages, particularly for chronic conditions such as T2DM and obesity.Small molecule GLP-1RAs show promise as weight loss drugs, demonstrating comparable efficacy and safety to current injectable GLP-1RAs while offering the convenience of oral administration. Recent years have seen an increasing application of patents relating to small molecule GLP-1RAs and oral peptide preparations.Figure 1. Structures of approved short-acting and long-acting GLP-1RAs.Display full sizeFigure 2. Structures of representative GLP-1RAs in recent patents and tirzepatide.Display full sizeFigure 3. Effects, working principles, and target tissues of GLP-1 and GIP. Blue arrows indicate data in rodents. Red arrows indicate data in humans. Red asterisks indicate likely indirect effects in humans. Red daggers indicate absence of evidence in humans.Display full sizeFigure 4. The mechanistic rationale for the action of GLP-1R/GCGR dual agonist. Blue arrows indicate data in rodents. Red arrows indicate data in humans. Red asterisks indicate likely indirect effects in humans. Red daggers indicate absence of evidence in humans.Display full sizeFigure 5. Structures of retarutide, representative GLP-1R/Y2R dual agonists, and FGF21/GLP-1RA fusion protein in recent patents.Display full sizeAdditional informationFundingThis paper was funded by the Guangxi Science Fund for Distinguished Young Scholars (Grant No. 2022GXNSFFA035030), the Special Funds for Science and Technology Development under the Guidance of the Central Government (Grant No. ZY20198020), the National Natural Science Foundation of China (Grant No. 82173663, 31970371).