avexitide (exendin 9-39) / Amylyx - LARVOL DELTA

Medium-chain triglycerides tricaprin TC10 and tricaprylin TC8 attenuated HFD-induced cognitive decline in a manner dependent on or independent of GLP-1. (PubMed, Sci Rep) - "The administration of the GLP-1 receptor antagonist, exendin(9-39), blocked the cognitive-enhancing effects of TC10...In conclusion, we herein demonstrated that TC8 and TC10 attenuated cognitive decline through different mechanisms. This is the first study to suggest that TC10 attenuates cognitive decline via GLP-1."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Cardioprotective effects of semaglutide on isolated human ventricular myocardium. (PubMed, Eur J Heart Fail) - "Semaglutide directly modulates ion homeostasis in human cardiomyocytes, reducing proarrhythmic diastolic SR Ca leak and enhancing systolic function, which may explain its observed clinical benefits. These findings provide mechanistic insights into the cardioprotective effects of semaglutide and suggest its potential therapeutic use in HF."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity

Amylyx Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Completion of enrollment for the pivotal Phase 3 LUCIDITY clinical trial of avexitide in PBH expected in 2025, with a data readout anticipated in the first half of 2026 and, if approved, commercial launch anticipated in 2027; Early cohort data from the Phase 1 LUMINA clinical trial of AMX0114 in ALS expected in 2025."

Enrollment status • Launch • P1 data • Amyotrophic Lateral Sclerosis • Hypoglycemia

Amylyx Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "Completion of enrollment for the pivotal Phase 3 LUCIDITY clinical trial of avexitide in PBH expected in 2025, with a data readout anticipated in the first half of 2026 and, if approved, commercial launch anticipated in 2027....Amylyx plans to share Week 48 data from the ongoing Phase 2 HELIOS trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in Wolfram syndrome in the coming months. Data from participants at Week 48 and regulatory interactions will inform the design of a Phase 3 trial of AMX0035 in Wolfram syndrome."

Launch • P3 data: top line • Trial status • Genetic Disorders • Hypoglycemia

Fatty Acid Transport Protein-2 (FATP2) Inhibition Enhances Glucose Tolerance through α-Cell-mediated GLP-1 Secretion. (PubMed, bioRxiv) - "Direct evidence of FATP2KO-induced α-cell-mediated GLP-1 secretion included increased GLP-1-positive α-cell mass in FATP2KO db/db mice, small molecule FATP2 inhibitor enhancement of GLP-1 secretion in αTC1-6 cells and human islets, and exendin[9-39]-inhibitable insulin secretion in FATP2 inhibitor-treated human islets. FATP2-dependent enteroendocrine GLP-1 secretion was excluded by demonstration of similar glucose tolerance and plasma GLP-1 concentrations in db/db FATP2KO mice following oral versus intraperitoneal glucose loading, non-overlapping FATP2 and preproglucagon mRNA expression, and lack of FATP2/GLP-1 co-immunolocalization in intestine. We conclude that FATP2 deletion or inhibition exerts glucose-lowering effects through α-cell-mediated GLP-1 secretion and paracrine β-cell insulin release."

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • SLC27A2

Ashitaba Chalcone 4-Hydroxydericcin Promotes Glucagon-Like Peptide-1 Secretion and Prevents Postprandial Hyperglycemia in Mice. (PubMed, Mol Nutr Food Res) - "Verapamil and nifedipine, blockers of VGCC, and treatment in Ca2+-free buffer abolished 4-HD effects on [Ca2+]i and GLP-1 secretion...Furthermore, exendin 9-39, a GLP-1R antagonist, and compound C, an AMPK inhibitor, completely canceled the 4-HD-caused anti-hyperglycemic activities. 4-HD stimulated GLP-1 secretion through membrane depolarization coupled with [Ca2+]i increase via VGCC in L-cells and activated AMPK- and insulin-induced GLUT4 translocation in skeletal muscle. Thus, 4-HD possesses dual mechanisms for the prevention of hyperglycemia."

Journal • Preclinical • Diabetes • SLC2A4 • STC1

LUCIDITY: Avexitide for Treatment of Post-Bariatric Hypoglycemia (clinicaltrials.gov) - P3 | N=75 | Recruiting | Sponsor: Amylyx Pharmaceuticals Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Hypoglycemia

Glucagon Can Increase Force of Contraction via Glucagon Receptors in the Isolated Human Atrium. (PubMed, Int J Mol Sci) - "The effects of exenatide on the FOC were attenuated by exendin(9-39). Hence, glucagon and GLP-1R agonists act functionally via different receptors in the human right atrium. Clinically, these data suggest that endogenous or exogenous glucagon can stimulate glucagon receptors in the human atrium, but only in the presence of PDE inhibitors."

Journal

LUCIDITY: Avexitide for Treatment of Post-Bariatric Hypoglycemia (clinicaltrials.gov) - P3 | N=75 | Not yet recruiting | Sponsor: Amylyx Pharmaceuticals Inc.

New P3 trial • Hypoglycemia

Regulation of Insulin Secretion by the GLP-1 Receptor (clinicaltrials.gov) - P4 | N=6 | Terminated | Sponsor: VA Office of Research and Development | Completed ➔ Terminated; Funding expired

Trial termination • Obesity • Type 2 Diabetes Mellitus

GLP-1 enhances β-cell response to protein ingestion and bariatric surgery amplifies it. (PubMed, Obesity (Silver Spring)) - "These findings are consistent with both pancreatic and extra-pancreatic roles for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery."

Bariatric surgery • Journal • Surgery • Gastrointestinal Disorder

Role of GLP-1 in Hyperinsulinemic Hypoglycemia Post-bariatric Surgery (clinicaltrials.gov) - P1 | N=10 | Terminated | Sponsor: Tracey McLaughlin | N=30 ➔ 10 | Unknown status ➔ Terminated

Bariatric surgery • Enrollment change • Surgery • Trial termination • Hypoglycemia

Evaluation of Single Ascending Doses of Subcutaneous Exendin 9-39 in Patients With Post-Bariatric Hypoglycemia (clinicaltrials.gov) - P1 | N=9 | Completed | Sponsor: Tracey McLaughlin | Unknown status ➔ Completed

Bariatric surgery • Surgery • Trial completion • Hypoglycemia

A Study to Evaluate the Effect of Genetic Variation on Beta-cell Function During Fasting and Hyperglycemia in Nondiabetics (clinicaltrials.gov) - P3 | N=40 | Recruiting | Sponsor: Adrian Vella | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Oct 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date

GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation. (PubMed, Exp Mol Med) - "GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Among the exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20-29 as a promising therapeutic candidate."

Journal • Pain

Uncovering CNS Access of Lipidated Exendin-4 Analogues by Quantitative Whole-brain 3D Imaging (OBESITY WEEK 2024) - "Other mice were administered C16MA-acylated exendin 9-39 (Ex9-39_C16MA), a selective GLP-1R antagonist, serving as negative control for GLP-1R mediated agonist internalization. Peptide lipidation increases CNS accessibility of Ex4. Our fully automated LSFM pipeline is suitable for mapping whole-brain distribution of fluorescently labelled drugs."

CNS Disorders

Lactiplantibacillus plantarum SG5 inhibits neuroinflammation in MPTP-induced PD mice through GLP-1/PGC-1α pathway. (PubMed, Exp Neurol) - "Importantly, the GLP-1R antagonist Exendin 9-39 and PGC-1α inhibitor SR18292 attenuated the protective effects of SG5 in PD mice. In conclusion, we demonstrate a neuroprotective role of L. plantarum SG5 in the MPTP-induced PD mouse model, which likely involves modulation of the gut microbiota and, significantly, the GLP-1/PGC-1α signaling pathway."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner. (PubMed, Metabolism) - "Fam3a deficiency in α-cells enhances pancreatic GLP-1 production to improve β-cell function via paracrine signaling in an Nr4a2-Foxa2-PC1/3-dependent manner. Our study unveils a novel strategy for reprogramming α-cell proglucagon processing output from glucagon to GLP-1 and deepen the understanding of crosstalk between α-cells and β-cells."

Journal • Diabetes • FOXA2 • NR4A2 • PCSK1

Development of a 68Ga-labeled molecular probe targeting insulinoma based on glucagon-like peptide-1 receptor antagonists (EANM 2024) - "In 2014, our group conducted the first clinical trial of a positron emitting nuclide labelled exendin-4 in localizing insulinomas...Consequently, we pioneered the synthesis of 68Ga-NOTA-exendin (9-39), a GLP-1R antagonist, aimed at enhancing tracer safety and facilitating positron emission tomography (PET) imaging in mouse models of insulinoma... We have devised a pioneering PET probe utilizing the GLP-1R antagonist, demonstrating effective tumor tissue accumulation. Notably, its administration does not precipitate hypoglycemia in patients, suggesting a promising clinical potential for this probe."

Endocrine Cancer • Hypoglycemia • Neuroendocrine Tumor • Oncology • Solid Tumor

Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling. (PubMed, Biochem Pharmacol) - "In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9-39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions."

IO biomarker • Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders • BAX • BCL2 • CAT • MFN2 • SOD2

Cyclic adenosine monophosphate critically modulates cardiac GLP-1 receptor's anti-inflammatory effects. (PubMed, Inflamm Res) - "cAMP, via activation of both PKA and Epac, is essential for GLP1R`s anti-inflammatory signaling in cardiac cells and that cAMP levels crucially regulate the anti-inflammatory efficacy of GLP1R agonists in the heart. Strategies that elevate cardiac cAMP levels, such as PDE4 inhibition, may potentiate the cardiovascular, including anti-inflammatory, benefits of GLP1R agonist drugs."

Journal • Cardiovascular • Genetic Disorders • Inflammation • Obesity • Oncology • IL6 • MMP9 • TNFA

Pyruvate kinase controls cAMP production and amplifies insulin secretion downstream of the GLP-1 receptor in beta cells (EASD 2024) - "Genetically-encoded biosensors were used to monitor cytosolic cAMP (Ad-RIP-Epac-S H187 ) or plasma membrane protein kinase A (PKA pm ) signaling (Ad-RIP-Lyn-AKAR4) over time in response to glucagon, GLP-1, GIP, and tirzepatide in human and mouse islets using biosensors targeted to the β-cell. These data link glycolysis to GPCR signaling, and suggest that biased GPCR agonists working via pyruvate kinase can be used to increase insulin secretion more efficiently."

Diabetes • Metabolic Disorders • GCG • LYN • PKM

The glucagon-like peptide-1 receptor antagonist, exendin (9-39) amide, improves the impaired glucagon response to hypoglycaemia in the non-obese diabetic mouse model of type 1 diabetes (EASD 2024) - "Autoimmune diabetes in the NOD mouse is associated with an increase in islet-derived GLP-1 secretion. The impaired glucagon response to hypoglycaemia from alpha-cells in diabetic mice was significantly improved by GLP-1R blockade using the GLP-1R antagonist, exendin(9-39) amide. This suggests that intra-islet GLP-1 has a significant role in the defective glucagon secretion seen in type 1 diabetes and provides a rationale for GLP-1R antagonists as a promising adjunct therapy to insulin for reducing the risk of hypoglycaemia in individuals with type 1 diabetes."

Preclinical • Diabetes • Hypoglycemia • Metabolic Disorders • Obesity • Type 1 Diabetes Mellitus • KEAP1

Intestinal glucagon-like peptide-1: A new player associated with impaired counterregulatory responses to hypoglycaemia in type 1 diabetic mice. (PubMed, World J Diabetes) - "Excessive intestinal GLP-1 is strongly associated with impaired counterregulatory responses to hypoglycaemia, leading to reduced appetite and compromised secretion of adrenaline, noradrenaline, and GCG during hypo-glycaemia."

Journal • Preclinical • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus • GCG

Exendin-4 intervention attenuates atherosclerosis severity by modulating myeloid-derived suppressor cells and inflammatory cytokines in ApoE-/- mice. (PubMed, Int Immunopharmacol) - "Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE-/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids."

Journal • Myeloid-derived suppressor cells • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • APOE • IL10 • IL6 • TGFB1