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

The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: Mayo Clinic

New P2 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

The Role of Islet GLP-1 in the Pathogenesis of Prediabetes (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Mayo Clinic

New P2 trial • Metabolic Disorders

On the Pleiotropic Actions of Glucagon-like Peptide-1 in Its Regulation of Homeostatic and Hedonic Feeding. (PubMed, Int J Mol Sci) - "GLP1 administered into the ventromedial nucleus (VMN) reduced homeostatic feeding that again was associated with a diminished rate of consumption and abrogated by the GLP1 receptor antagonist exendin 9-39 and in AgRP-cre/PAC1Rfl/fl mice...Finally, apoptotic ablation of VMN PACAP neurons obliterated the anorexigenic effect of intra-VMN GLP1 on homeostatic feeding in PACAP-cre mice but not their wildtype counterparts. Collectively, these data demonstrate that GLP1 acts within the homeostatic and hedonic circuits to curb appetitive behavior by exciting PACAP neurons, and inhibiting NPY/AgRP and A10 dopamine neurons."

Journal • ADCYAP1

Amylyx Pharmaceuticals Announces First Participant Dosed in Pivotal Phase 3 LUCIDITY Trial of Avexitide in Post-Bariatric Hypoglycemia (Businesswire) - "Amylyx Pharmaceuticals, Inc...announced that the first participant has been dosed in the pivotal Phase 3 LUCIDITY clinical trial of avexitide, an investigational, first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist, for the treatment of post-bariatric hypoglycemia (PBH)....Amylyx expects completion of recruitment for the LUCIDITY trial in 2025, with topline data in first half of 2026."

P3 data: top line • Trial status • Hypoglycemia

Glucagon-like peptide-1 receptor modulates cerebrospinal fluid secretion and intracranial pressure in rats. (PubMed, Fluids Barriers CNS) - "Modulation of GLP-1R affects CSF production, which suggests that GLP-1R-mediated signalling may have the potential to control ICP in pathological conditions with disturbed CSF homeostasis."

Journal • Preclinical • CNS Disorders • Ventriculomegaly

HIF-2a signaling in L-cells is crucial for GLP-1 secretion in response to luminal lipids (ENDO 2025) - "This improvement in glucose tolerance is reversed when the GLP-1 receptor antagonist Exendin 9-39 is administered, confirming that L-cell HIF-2α enhances glucose homeostasis through GLP-1...We also investigated whether pharmacological activation of HIF-2α with FG-4592 affects intestinal lipid sensing and GLP-1 secretion...Thus, our study identifies a target to improve the endogenous production of GLP-1 in response to luminal nutrients, specifically lipids.*. .*"

Genetic Disorders • Obesity • EPAS1 • GCG

Reduction in Rate of Hypoglycemic Events with Avexitide in Post-Bariatric Hypoglycemia: Results from the Phase 2 and 2b Studies (ENDO 2025) - "Avexitide 30 mg BID and 60 mg QD led to a 40% and 55% reduction in the composite rate of Level 2&3 events, respectively. The impact of avexitide on composite rates of Level 2&3 hypoglycemia in the phase 2b trial, including at the higher 90 mg QD dose being tested in LUCIDITY, will be presented. Results of the complete analysis will provide valuable context given the planned LUCIDITY trial, which has topline data anticipated in 1H 2026.*."

P2 data • CNS Disorders • Epilepsy • Gastrointestinal Disorder • Hypoglycemia

Population PK (PopPK) and Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis of Avexitide in Individuals with Post-Bariatric Hypoglycemia (ENDO 2025) - "Mechanistically, Cmin is expected to be a primary driver of avexitide efficacy. Avexitide 90 mg once daily resulted in Cmin above EC50 for 24 hours, providing evidence that this dose can have continued biological effect between daily doses and further supporting the rationale for and appropriateness of the 90 mg once daily dosing regimen in the Phase 3 LUCIDITY trial.*. .*"

Clinical • PK/PD data • Hypoglycemia

Inhibition of microRNA-139-5p by glucagon-like peptide-1 ameliorates oxidative stress-induced damage via targeting SOD1/GCLc. (PubMed, Endocr Connect) - "The upregulation of miR-139-5p abrogated the protective effects of GLP-1 on cells exposed to palmitate, and GLP-1-induced downregulation of miR-139-5p was counteracted by the GLP-1 receptor antagonist Exendin(9-39). These findings demonstrated that GLP-1 ameliorates oxidative stress-induced endothelial dysfunction, at least in part, by suppressing miR-139-5p, which targets SOD1 and GCLc. This provides further evidence for the vascular protective effects of GLP-1 intervention in diabetes."

Journal • Diabetes • Metabolic Disorders • MIR139 • SOD1

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