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

Linking GLP-1 activation with steroidogenesis, redox, endoplasmic reticulum stress, mitophagy, and the apoptotic regulatory network unlocks the emerging impacts of semaglutide on 5-fluorouracil-induced testicular toxicity. (PubMed, Life Sci) - "This study highlighted the use of Sema as adjunctive therapy in the 5-FU treatment protocol to guard against the associated testicular dysfunction, via modulating oxidative stress, ERS, and mitochondrial dysfunction in the rat experimental model."

Journal • Metabolic Disorders • Oncology • ATF6 • DAZL • HSPA5

Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study. (PubMed, Diabetes Obes Metab) - "Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets."

Journal • Diabetes • Metabolic Disorders

The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: Mayo Clinic | Initiation date: Sep 2025 ➔ Dec 2025

Trial initiation date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Fatty acid transport protein-2 inhibition enhances glucose tolerance through α-cell-mediated GLP-1 secretion. (PubMed, J Clin Invest) - "Direct evidence of FATP2KO-induced α-cell-mediated glucagon-like peptide-1 (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 ß-cell insulin release."

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

The effect of GLP-1 receptor antagonists and agonists on islet function in non-diabetic subjects with the GLP1R polymorphism at rs3765467 (EASD 2025) - P3 | "The T allele at rs3765467 increases responsiveness of GLP1R to its endogenous ligand. These effects are relevant to the fasting state and less apparent when the islet is stimulated by hyperglycemia or liraglutide."

Clinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Glucagon-like Peptide 1, Glucose Metabolism and Gastric Bypass (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date

The Effects of Bariatric Surgeries on Glucose Metabolism (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Gastrointestinal Disorder • Hypoglycemia

Role of Neural and Hormonal Regulation Factors on Insulin Secretion After Gastric Bypass Surgery (clinicaltrials.gov) - P1 | N=160 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Trial primary completion date: Aug 2025 ➔ Aug 2026 | Trial completion date: Aug 2026 ➔ Aug 2027

Trial completion date • Trial primary completion date • 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

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

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

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...Mechanistically, we found that HIF-2α enhances lipid sensing in L-cells through the GPR40 receptor, leading to increased 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

Glucagon-like peptide-1 is involved in fasting and postprandial blood flow regulation of subcutaneous adipose tissue. (PubMed, Diabetes Obes Metab) - "GLP-1 seems to be involved in ATBF regulation, which is reduced when GLP-1 action is blocked in situ, but has no role in the blunting of ATBF response in non-responders. Blunted postprandial ATBF may be implicated in higher postprandial circulating TAG levels."

Journal

Effect of Central UAG on Metabolic Associated Fatty Liver Disease: a Possible Mechanism involving in GLP-1 Neural Pathway. (PubMed, Peptides) - "These findings suggest that central UAG might alleviate MAFLD by modulating GLP-1 neuronal pathway from NTS to PVN and VTA. Further studies are needed to identify the specific receptor for UAG and its potential interaction with GLP-1 or GLP-1R, which could provide direct evidence for the role of central UAG in regulating food intake and lipid metabolism in MAFLD."

Journal • Hepatology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • FASN • SCD

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 primary completion date: Jun 2025 ➔ Sep 2025

Trial primary completion date

Effect of GLP-1 Receptor Antagonism or Incretin Enhancer on Ad-Libitum Energy Intake in Subjects with and without Bariatric Surgery (ADA 2025) - "We compared the acute effects of increased incretin concentrations or GLP-1R blockade on ad-libitum energy intake (AdLibEI) among 3 BMI- and age-matched non-diabetic obese cohorts of GB (n=7), SG (n=9), and non-operated controls (CN, n=7). Participants were studied with 3-h meal test on 4 separate days: (A) 50-gram glucose ingestion with (OGT+S) and without (OGT) 200 mg sitagliptin (S) taken orally 2-h prior to OGT; (B) 50-gram whey protein ingestion with (OPT+Ex9) and without intravenous infusion of GLP-1R antagonist (exendin-(9-39) [Ex9], 750 pm/kg/min). These data indicate that, in the current model, enhancing or blocking endogenous GLP-1R signal has an acute affect on food intake in humans with intact gastrointestinal system. Unaffected energy intake by GLP-1R manipulation in GB and SG subjects, however, undermines a significant role for GLP-1 in mediating surgical-induced weight loss."

Bariatric surgery • Clinical • Surgery • Metabolic Disorders • Obesity

GLP-1 Receptor Agonists Induce Lasting Cyclic-AMP Generation and Insulin Secretion in Beta Cells (ADA 2025) - "This study investigated the mechanisms underlying these differences, with a focus on cAMP, the crucial second messenger involved in incretin-induced potentiation of insulin secretion. Islets from mice expressing a genetically encoded cAMP sensor in beta cells were perfused with GIP and GLP-1 receptor (GLP-1R) agonists (GLP-1, exendin-4, and semaglutide), and kinetics of cAMP levels and glucose-stimulated insulin secretion were assessed. Acute GIP treatment induced a transient cAMP response that dissipated with peptide washout. These data show that beta cells respond with distinct kinetics of cAMP generation in response to different incretins, with GLP-1R agonists capable of triggering lasting cAMP generation and insulin secretion. These findings reveal the mechanism(s) that underlie the effectiveness of incretin-based drugs."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

MBX 1416, a Selective GLP-1 Antagonist, Elevates and Sustains Blood Glucose in Rats without Change in Body Weight (ADA 2025) - "Differential effects of MBX 1416 on glucose elevation following glucose challenge in DIO mice vs an unmodified GLP-1 antagonist exendin 9-39 (Ex9) were assessed with an intraperitoneal glucose tolerance test (IPGTT) 24 h post dosing to highlight MBX 1416's lengthy time action. Dose-proportional plasma MBX 1416 exposures were seen with a single dose (Cmax and AUCinf, ≤2-fold across doses). MBX 1416 demonstrated expected PK/PD effects in rats, increasing blood glucose excursions in DIO mice with no change in food intake or body weight vs vehicle in healthy rats."

Preclinical • Hypoglycemia • Metabolic Disorders

GLP-1 Receptor Agonists Induce Lasting Cyclic-AMP Generation and Insulin Secretion in Beta Cells (ADA 2025) - "This study investigated the mechanisms underlying these differences, with a focus on cAMP, the crucial second messenger involved in incretin-induced potentiation of insulin secretion. Islets from mice expressing a genetically encoded cAMP sensor in beta cells were perfused with GIP and GLP-1 receptor (GLP-1R) agonists (GLP-1, exendin-4, and semaglutide), and kinetics of cAMP levels and glucose-stimulated insulin secretion were assessed. Acute GIP treatment induced a transient cAMP response that dissipated with peptide washout. These data show that beta cells respond with distinct kinetics of cAMP generation in response to different incretins, with GLP-1R agonists capable of triggering lasting cAMP generation and insulin secretion. These findings reveal the mechanism(s) that underlie the effectiveness of incretin-based drugs."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

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

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