Long-acting Analogue Research Articles

Twice-daily injections and multiple daily injections of insulin in toddlers with type 1 diabetes: a retrospective cohort study.

Twice-daily injections and multiple daily injections of insulin in toddlers with type 1 diabetes: a retrospective cohort study.

Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure.

Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin-2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long-acting relaxin analogue to be tested in the treatment of chronic heart failure. LY3540378 is a long-acting protein therapeutic composed of a human relaxin analogue and a serum albumin-binding VHH domain. LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half-life of LY3540378 in preclinical species is extended through high affinity binding of the albumin-binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin-mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol-induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378. LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials.

Evolution and Revolution-Our Changing Relationship With Insulin.

Type 2 diabetes is a progressive condition with a complex pathophysiology. Over time, additional therapies are needed to maintain glycemic control. It is well known that, by the time of diagnosis, beta cell function has already declined by 50% to 80%. When the body is no longer able to make enough insulin to control blood glucose levels, insulin replacement therapy is needed. However, barriers to initiation of insulin therapy are multifactorial and contribute to delays in treatment and consequent uncontrolled glycemia; this leads to an increased risk of disease complications. In this roundtable discussion, the authors review how people living with type 2 diabetes and their healthcare providers view the initiation of insulin. Other topics include the benefits of longer-acting basal insulin analogs compared with long-acting analogs. The authors emphasize the importance of early and positive conversations about insulin therapy, as well as the benefits of shared decision-making and the use of the wider medical team for the timely initiation of basal insulin therapy.

Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently affects about 25% of the world's population, and the numbers continue to rise as the number of obese patients increases. However, there are currently no approved treatments for NAFLD. This study reports on the evaluation of the therapeutic effect of a recombinant human serum albumin-fibroblast growth factor 21 analogue fusion protein (HSA-FGF21) on the pathology of NAFLD that was induced by using two high-fat diets (HFD), HFD-60 and STHD-01. The HFD-60-induced NAFLD model mice with obesity, insulin resistance, dyslipidemia and hepatic lipid accumulation were treated with HSA-FGF21 three times per week for 4weeks starting at 12weeks after the HFD-60 feeding. The administration of HSA-FGF21 suppressed the increased body weight, improved hyperglycemia, hyperinsulinemia, and showed a decreased accumulation of plasma lipid and hepatic lipid levels. The elevation of C16:0, C18:0 and C18:1 fatty acids in the liver that were observed in the HFD-60 group was recovered by the HSA-FGF21 administration. The increased expression levels of the hepatic fatty acid uptake receptor (CD36) and fatty acid synthase (SREBP-1c, FAS, SCD-1, Elovl6) were also suppressed. In adipose tissue, HSA-FGF21 caused an improved adipocyte hypertrophy, a decrease in the levels of inflammatory cytokines and induced the expression of adiponectin and thermogenic factors. The administration of HSA-FGF21 to the STHD-01-induced NAFLD model mice resulted in suppressed plasma ALT and AST levels, oxidative stress, inflammatory cell infiltration and fibrosis. Together, HSA-FGF21 has some potential for use as a therapeutic agent for the treatment of NAFLD.

Antiandrogenic treatment of obsessive compulsive neurosis: A case review

IntroductionObsessive-compulsive disorder (OCD) is a mental disorder in which patients who suffer from it have repetitive and undesirable thoughts, feelings, ideas, sensations (obsessions) and behaviors that drive them to do something over and over again (compulsions).Often the person tries to get rid of the obsessive thoughts through compulsions, but this only provides short-term relief. Not carrying out the obsessive rituals can cause enormous anxiety and suffering.ObjectivesTo describe a 23-year-old male patient, who suffers from anxiety and mood symptoms, reacts to ego-dystonic obsessive ideas and sexual content, of months of evolution, and who manages to calm down through compulsive masturbation or watching sexual videos on the internet. All this clinic negatively interferes with their quality of life, asking the patient for medical help to calm these ideas.MethodsWe carried out a review in Pubmed with the terms Antiandrogens and TOC, in order to make a better description of the clinical case.ResultsAfter several treatment attempts (Sertraline, Paroxetine, Clomipramine, Clomipramine + SSRI), reaching maximum doses according to clinical guidelines, and with poor therapeutic response, it was decided to discuss the case with the endocrinology department of our hospital, deciding to start treatment with antiandrogens, in order to alleviate the persistent intrusive ideas of a sexual nature. The administration of antiandrogens in men can cause a decrease or increase in the development or involution of secondary sexual characteristics in men, reducing the activity or function of accessory sexual organs, and hyposexuality, with decreased sexual desire or libido.After several weeks, there was improvement in the obsessive symptoms with a decrease in compulsive rituals. However, after the 3rd mo, some symptoms reappeared, but not with the same severity and intensity as before treatment. In addition, we cannot ignore the adverse effects that have occurred, such as involution of secondary sexual characteristics. However, and taking into account the negative repercussion that this clinic had on the patient’s quality of life, the benefit obtained exceeded the risk, having noted clear improvement with this therapy, and maintaining evolutionary controls by both psychiatry and endocrinology.ConclusionsPatients suffering from obsessive-compulsive disorder can be effectively treated with anti-androgenic pharmacological agents with various modes of action. The most effective group of such agents is the long-acting analogues of the gonadotropin-releasing hormone. The objective of this review is to elucidate the possibility of using such powerful anti-androgenic agents in the treatment of obsessive-compulsive disorder.Disclosure of InterestNone Declared

Hepatoprotective effects of the long-acting fibroblast growth factor 21 analog PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of nonalcoholic steatohepatitis.

Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged as promising drug candidates for the treatment of nonalcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the long-acting FGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start of the study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion, PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogs for the treatment of NASH.NEW & NOTEWORTHY It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled the clinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model of NASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers and histological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued exploration of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases.

Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment.

Glepaglutide is a novel, ready-to-use, long-acting, glucagon-like peptide-2 (GLP-2) analog intended for the treatment of patients with short bowel syndrome (SBS). This study investigated the impact of renal function on the pharmacokinetics and safety of glepaglutide. In this 3-site, non-randomized, open-label study, 16 subjects were enrolled: 4 with severe renal impairment (eGFR 15 to < 30mL/min/1.73m2), 4with end stage renal disease (ESRD) not on dialysis (eGFR < 15mL/min/1.73m2), and 8 matching controls with normal renal function (eGFR ≥ 90mL/min/1.73m2). Blood samples were collected over a 14-day period following a single subcutaneous (SC) dose of glepaglutide 10mg. Safety and tolerability were assessed throughout the study. The primary pharmacokinetic parameters were area under the curve between dosing and 168h (AUC0-168h) and the maximum plasma concentration (Cmax). There was no clinically relevant difference between subjects with severe renal impairment/ESRD and normal renal function with respect to total exposure (AUC0-168h) and peak plasma concentrations (Cmax) of glepaglutide following a single SC dose. A single SC dose of glepaglutide 10mg appeared safe and well tolerated in subjects with normal renal function and subjects with severe renal impairment or ESRD. No serious adverse events were reported, and no safety issues were identified. No difference in glepaglutide pharmacokinetics was seen between renal impaired and normal subjects. Based on this trial, dose adjustment appears not to be warranted in SBS patients with renal impairment. The trial is registered at http://www. gov (NCT04178447) and has the EudraCT number: 2019-001466-15.

Human growth hormone and insulin, from tissue extracts to recombinant DNA technology, their biosimilars and analogues in treatment of Endocrine Disorders

Forty years ago, recombinant DNA technology caused a revolution in the way growth disorders and diabetes could be treated. Bacteria or human cells were modified so as to be able to produce human hormones instead of relying on cadaveric material in the case of growth disorders and porcine insulin in the case of diabetics. The new technology also removed the risk of contracted hepatitis or fatal Creutzfeldt Jacob disease. A signal peptide was used to transport the new protein into the periplasmic space giving rise to an exact, correctly folded version of monomeric human growth hormone. More eligible patients could be treated, resulting not only in a large number of clinical trials. Daily tiny subcutaneous injections were found to be much more effective than twice or thrice weekly in the treatment of children and adults, The progress for recombinant human insulin turned out to be somewhat different. Insulin is a more complicated protein, with an Alpha and Beta chain joined by two disulphide bridges, but is produced in the human pancreas as a single chain, proinsulin, the C peptide is removed to make the active molecule. Recombinant insulin development was in a way the opposite to growth hormone since human insulin acts faster than porcine. Short fast and long-acting analogues have been developed all to improve the treatment regimens for both type 1 and type 2 diabetics, A similar development is now taking place in the growth hormone field. Depot preparations for weekly administration are under development to achieve better compliance. One recently approved depot uses an analogue, modified in one amino acid of the peptide chain to permit acylation and albumin binding. In a way this is a retrograde step and it remains to be seen if the patient’s growth and metabolic responses are comparable to the daily administration of tiny amount of recombinant natural sequence hormone over several years of treatment.

The potential function and clinical application of FGF21 in metabolic diseases.

As an endocrine hormone, fibroblast growth factor 21 (FGF21) plays a crucial role in regulating lipid, glucose, and energy metabolism. Endogenous FGF21 is generated by multiple cell types but acts on restricted effector tissues, including the brain, adipose tissue, liver, heart, and skeletal muscle. Intervention with FGF21 in rodents or non-human primates has shown significant pharmacological effects on a range of metabolic dysfunctions, including weight loss and improvement of hyperglycemia, hyperlipidemia, insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the poor pharmacokinetic and biophysical characteristics of native FGF21, long-acting FGF21 analogs and FGF21 receptor agonists have been developed for the treatment of metabolic dysfunction. Clinical trials of several FGF21-based drugs have been performed and shown good safety, tolerance, and efficacy. Here we review the actions of FGF21 and summarize the associated clinical trials in obesity, type 2 diabetes mellitus (T2DM), and NAFLD, to help understand and promote the development of efficient treatment for metabolic diseases via targeting FGF21.

Quest for superior insulins

Chronic metabolic illnesses, like diabetes mellitus, have become diseases that harm human health and are now one of the most critical public health problems in almost half a century, as a result of societal development and lifestyle changes. For decades, conventional insulin therapy has been playing a significant role while treating millions of patients around the globe. Unfortunately, despite breakthroughs in DNA recombinant technology and pharmacotherapy, these therapeutic goals are rarely met, and results have not improved significantly. The low effectiveness rate of insulin treatment is becoming recognized as a result of intra-individual and inter-individual differences in insulin needs. Thus, our review focuses on finding superior insulin derivatives to treat diabetes more effectively and efficiently. Insulin analogs hold the potential to overcome the limitations of conventional insulin. We have taken a deep dive into rapid acting and long-acting analogs by discussing their pharmacokinetics, pharmacodynamics, dosage and therapeutic efficacy. But their safety profile has been questioned several times and therefore we have thrown some light on the current innovation trends that are being scrutinized.

HM15912, a Novel Long-Acting Glucagon-Like Peptide-2 Analog, Improves Intestinal Growth and Absorption Capacity in a Male Rat Model of Short Bowel Syndrome.

Extensive bowel resection caused by various diseases that affect the intestines, such as Crohn's disease, volvulus, and cancer, leads to short bowel syndrome (SBS). Teduglutide is the only approved glucagon-like peptide-2 (GLP-2) drug for SBS; however, it requires daily administration. A novel GLP-2 analog with a prolonged duration of action to reduce dosing frequency and promote a greater efficacy may provide patients with a better quality of life. In the present study, the sustained exposure of HM15912 was characterized in normal male rats. The efficacy of HM15912 on intestinal growth and absorption capacity was also evaluated in normal male mice, rats, and SBS rats. HM15912 exhibited a remarkably extended half-life (42.3 hours) compared with teduglutide (0.6 hours) in rats. Despite somewhat lower in vitro potency on GLP-2 receptor than human GLP-2 or teduglutide, this longer-lasting mode of action promotes HM15912 to be more effective in terms of small intestinal growth than existing GLP-2 analogs even with a less frequent dosing interval of as little as once a week in rodents, including SBS rats. Furthermore, the small intestinal weight was approximately doubled, and the D-xylose absorption was significantly increased after pre-treatment of existing GLP-2 analogs on the market or under clinical development followed by HM15912 in rodents. These results indicate that HM15912 possesses a significant small bowel trophic effect driven by continuously increased exposure, supporting that HM15912 may be a novel treatment option with greater efficacy and the longest dosing interval among existing GLP-2 analogs for SBS with intestinal failure. SIGNIFICANCE STATEMENT: HM15912, a novel long-acting glucagon-like peptide-2 (GLP-2) analog, has a significant small bowel hypertrophic effect in rodents with a reduced frequency of administration compared to the existing GLP-2 analogs on the market or currently under clinical development. This study supports the possibility that HM15912 could be administered much less frequently than other long-acting GLP-2 analogs for patients with short bowel syndrome.

Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice

ObjectiveTreatment with glucagon receptor antagonists (GRAs) reduces blood glucose but causes dyslipidemia and accumulation of fat in the liver. We investigated the acute and chronic effects of glucagon on lipid metabolism in mice. MethodsChronic effects of glucagon receptor signaling on lipid metabolism were studied using oral lipid tolerance tests (OLTTs) in overnight fasted glucagon receptor knockout (Gcgr−/−) mice, and in C57Bl/6JRj mice treated with a glucagon receptor antibody (GCGR Ab) or a long-acting glucagon analogue (GCGA) for eight weeks. Following treatment, liver tissue was harvested for RNA-sequencing and triglyceride measurements. Acute effects were studied in C57Bl/6JRj mice treated with a GRA or GCGA 1 h or immediately before OLTTs, respectively. Direct effects of glucagon on hepatic lipolysis were studied using isolated perfused mouse liver preparations. To investigate potential effects of GCGA and GRA on gastric emptying, paracetamol was, in separate experiments, administered immediately before OLTTs. ResultsPlasma triglyceride concentrations increased 2-fold in Gcgr−/− mice compared to their wild-type littermates during the OLTT (P = 0.001). Chronic treatment with GCGR Ab increased, whereas GCGA treatment decreased, plasma triglyceride concentrations during OLTTs (P < 0.05). Genes involved in lipid metabolism were upregulated upon GCGR Ab treatment while GCGA treatment had opposite effects. Acute GRA and GCGA treatment, respectively, increased (P = 0.02) and decreased (P = 0.003) plasma triglyceride concentrations during OLTTs. Glucagon stimulated hepatic lipolysis, evident by an increase in free fatty acid concentrations in the effluent from perfused mouse livers. In line with this, GCGR Ab treatment increased, while GCGA treatment decreased, liver triglyceride concentrations. The effects of glucagon appeared independent of changes in gastric emptying of paracetamol. ConclusionsGlucagon receptor signaling regulates triglyceride metabolism, both chronically and acutely, in mice. These data expand glucagon´s biological role and implicate that intact glucagon signaling is important for lipid metabolism. Glucagon agonism may have beneficial effects on hepatic and peripheral triglyceride metabolism.

Treating Mares with the Long-Acting Kisspeptin Analog C6 Increases Circulating Gonadotropins but Does Not Trigger Ovulation

The role of the neuropeptide kisspeptin (Kp) in mammalian reproduction is well established. Nevertheless, species-specific differences exist. In the horse, administration of the shortest endogenous Kp isoform, Kp10, is unable to trigger ovulation even though it increases plasma gonadotropins concentrations. To check if this issue would be dependent on Kp10 short half-life, we tested two degradation-resistant Kp analogs. The first analog was based on the equine Kp10 sequence (eC6), the second on the ovine Kp10 sequence (oC6). During the non-breeding season, a dose of 150 nmol/mare of either molecule had no significant effect on LH concentration, while oC6 provided a better stimulation of FSH than eC6 (p = 0.01). Furthermore, oC6 was more effective when injected intravenously than intramuscularly. Due to its best pharmacodynamics profile, oC6 (150 nmol/mare) was probed for ovulation induction during the breeding season. The molecule was injected during the preovulatory phase when the follicle diameter ranged from 34 to 37 mm and a uterine oedema was observed. oC6 consistently increased the total amount of gonadotropins released (FSH, p = 0.01 and LH, p = 0.02). However, as shown by transrectal ultrasonography and plasma progesterone levels, oC6 did not anticipate ovulation compared to the control group. Our results provide further evidence of the peculiar reproductive endocrinology of the mare but leave open questions regarding the exact role of Kp in the control of ovulation and breeding in the mare, which we attempt to identify and discuss.

Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.

Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.

Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.

ODP222 Liragluitde Increased IL-1RA Concentrations in Obese Type 2 Diabetes: A Small Randomized Controlled Trial

Abstract Background Therapy with exenatide, exendin-4-based glucagon liked peptide-1 receptor agonist (GLP-1 RA) increased plasma interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein which protected pancreatic ß cells independent of glycemic and weight controlled. We hypothesized that liraglutide, long-acting GLP-1 analogue might contribute to a potential protective effect on ß cells in diabetes. Methods Twenty-four obese patients with type 2 diabetes receiving oral hypoglycemic agents with insulin therapy, except pioglitazone or incretin-based therapy, were randomly assigned to receive either maximum tolerate dose of liraglutide (n=12) or standard therapy (n=12) for twelve weeks. Results Among 24 participants who completed over 12 weeks of this study, median change was +258.7% (78.7, 656.6) and +101. 0% (-3.3, 189.4) of IL-1RA; P&amp;lt;0. 04, and -1.2% (-1.7, -0.8) and -0.4% (-1. 0, 0.3) of A1c; P&amp;lt;0. 03 in liraglutide and standard group, respectively. Percent changes of fasting plasma glucose, body weight, neck circumference and body mass index were all not statistically significant, when comparing between group. Pearson correlation between percent change of IL-1RA and percent change of A1c response to therapy were also not statistically significant. Conclusion Liraglutide might have anti-inflammatory effect independent of the glycemic control during initial short-term duration. Keywords: Liraglutide, Interleukin-1 receptor antagonist, obese type 2 diabetes. Presentation: No date and time listed

Metabolomics Provides Insights into Renoprotective Effects of Semaglutide in Obese Mice.

Semaglutide, a new long-acting glucagon-like peptide-1 analogue, has shown benefits for renal diseases, but its direct role on kidney metabolism under obesity remains unclear. The study aims to elucidate the protective effect and metabolic modulation mechanism of semaglutide on obesity-related kidney injury. Male C57BL/6J mice were divided into control and obesity groups. Mice in the obesity group had a high-fat diet and were treated with or without semaglutide (30nmol/kg/day). The study assayed blood biochemistry and then evaluated renal pathological injury through Periodic Acid-Schiff staining and electron microscopy. Metabolomics was utilized to analyze obesity-related metabolites in kidney samples. Semaglutide significantly improved glucose homeostasis, insulin resistance, and kidney injury in obese mice. We successfully identified 377 altered metabolites (P<0.05). It was suggested that semaglutide directly improved oxidative stress and inflammation-related metabolites such as nicotinamide adenine dinucleotide (NAD+) and adenosine in the kidney of obese mice, which have not been documented in obesity-related kidney injury. Relevant enriched pathways were included phospholipids and lysophospholipids metabolism, purine metabolism, NAD+ metabolism, and insulin resistance-related metabolism. They could serve as potential targets for intervention of obesity-related kidney injury. Our study revealed the metabolomics-based renoprotective mechanism of semaglutide in obese mice for the first time. The innovation lied in the identified metabolites such as NAD+ and adenosine targeted by semaglutide, which have not been documented in obesity-related kidney injury. Semaglutide may be a promising therapy for obesity-related kidney diseases.

PSUN305 A Double-Blind, Placebo-Controlled Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HM15136 in Obese or Overweight Subjects with Co-morbidities

Abstract HM15136 is a novel long-acting glucagon analogue with an extended half-life. In vivo efficacy studies of HM15136 in animal models showed its therapeutic potential in obesity, and treatment requiring hypoglycemia. We enrolled an obese and overweight subjects without diabetes (study Part 1) and with diabetes (study Part 2) in a randomized, double-blind, placebo-controlled study to assess the safety, pharmacokinetics, and pharmacodynamics of multiple subcutaneous doses of HM15136 for 12 weeks (NCT04167553). In Part 1, a total of 36 non-diabetic subjects randomly received HM15136 or its matching placebo in a ratio of 9: 3 in 3 cohorts (0.02, 0.04, and 0.06 mg/kg). The baseline mean age was 37.5 years, BMI was 33.9 kg/m2, and Fasting Plasma Glucose (FPG) was 92.3 mg/dL. The FPG increased with escalating doses of HM15136. The mean (SD) changes from baseline in FPG at week 12 were -1.0 (13.0) mg/dL for 0.02 mg/kg, 12.0 (10.7) mg/dL for 0.04 mg/kg, 17.9 (16.9) mg/dL for 0.06 mg/kg vs. 0.6 (6.5) mg/dL for placebo group. The FPG had returned to baseline at 3 weeks after study drug discontinuation. The presence of Anti-Drug Antibodies (ADAs) was confirmed in 5 subjects (18.5%) but dose-dependency was not observed. One (1) out of 5 ADA positive subjects had neutralizing ADA activity with no cross reactivity to endogenous glucagon. The most frequent Treatment Related Adverse Event (TRAE) was injection site erythema (11.1%), the frequency of TRAEs was not dose dependent. Throughout Part 1 and Part 2, all TRAEs were mild except for moderate hyperglycemia in patients with diabetes. Part 2 was completed earlier than planned due to the impact of COVID-19 and discontinued subjects due to the hyperglycemia. Part 2 was not included in this presentation because the interpretability of the data was limited. In conclusion, HM15136 was safe and well tolerated in non-diabetic obese subjects during the 12-week treatment at various dose levels. Treatment with HM15136 showed a dose dependent blood glucose increase. These results suggest future development opportunities for the management of treatment requiring hypoglycemia. A phase 2, Proof-of-Concept study in patients with congenital hyperinsulinism is currently ongoing (NCT04732416). Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

A novel glucagon analog with an extended half-life, HM15136, normalizes glucose levels in rodent models of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a rare genetic condition characterized by uncontrolled insulin secretion, resulting in hypoglycemia. Although glucagon has lately been regarded as a therapeutic option for CHI, its use is severely hampered by its poor solubility and stability at physiological pH, as well as its short duration of action. To address these constraints, we developed HM15136, a novel long-acting glucagon analog composed of a glucagon analog conjugated to the Fc fragment of human immunoglobulin G4 via a polyethylene glycol linker. In this study, we established that HM15136 was more soluble than natural glucagon (≥ 150 mg/mL vs 0.03 mg/mL). Next, we confirmed that HM15136 activated glucagon receptor in vitro and induced glycogenolysis and gluconeogenesis in rat primary hepatocytes. Pharmacokinetics (PK)/Pharmacodynamics (PD) analysis of HM15136 shows that HM15136 has a markedly longer half-life (36 h vs. < 5 min) and increased bioavailability (90%) compared to native glucagon in mice. Further, HM15136 could effectively reverse acute hypoglycemia induced by insulin challenge, and multiple doses of HM15136 could sustain increased blood glucose levels in CHI rats. In conclusion, our findings indicate that HM15136 promotes sustained elevation of blood glucose, demonstrating the potential for development as a once-weekly therapy for CHI.

Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells

The pancreatic hormone, glucagon, is known to regulate hepatic glucose production, but recent studies suggest that its regulation of hepatic amino metabolism is equally important. Here, we show that chronic glucagon receptor activation with a long-acting glucagon analog increases amino acid catabolism and ureagenesis and causes alpha cell hypoplasia in female mice. Conversely, chronic glucagon receptor inhibition with a glucagon receptor antibody decreases amino acid catabolism and ureagenesis and causes alpha cell hyperplasia and beta cell loss. These effects were associated with the transcriptional regulation of hepatic genes related to amino acid uptake and catabolism and by the non-transcriptional modulation of the rate-limiting ureagenesis enzyme, carbamoyl phosphate synthetase-1. Our results support the importance of glucagon receptor signaling for amino acid homeostasis and pancreatic islet integrity in mice and provide knowledge regarding the long-term consequences of chronic glucagon receptor agonism and antagonism.