DS-8500 / Daiichi Sankyo - LARVOL DELTA

GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates. (PubMed, Expert Opin Investig Drugs) - "However, in more recent studies, acute and chronic dosing with the GPR119 agonist DS-8500a had increased efficacy, although this compound was discontinued for further development. New trials on GPR119 agonists are needed, however it may be that the future of GPR119 agonists lie in the development of combination therapy with other T2D therapeutics."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Species differences between rats and primates (humans and monkeys) in complex cleavage pathways of DS-8500a characterized by C-ADME studies in humans and monkeys after administration of two radiolabeled compounds and in vitro studies. (PubMed, Drug Metab Pharmacokinet) - "The other cleavage metabolite (M20), produced via hydrolysis of the amide side chain, was detected as the major plasma metabolite in humans and monkeys, and its subsequent metabolite (M21) was excreted in feces, whereas M21 was not a major component in rats, indicating a notable species difference in the amide hydrolysis. In conclusion, this study comprehensively revealed the pronounced species difference of the cleavage pathways: reductive ring-opening by intestinal microflora and liver, and amide hydrolysis."

Journal • Preclinical • Gastrointestinal Disorder

A Phase2 Study of DS-8500a in Japanese Subjects With Type 2 Diabetes Mellitus (T2DM) (clinicaltrials.gov) - P2; N=335; Recruiting; Sponsor: Daiichi Sankyo Co., Ltd.

New P2 trial • Biosimilar • Diabetes

In vivo multiple metabolic pathways for a novel G protein-coupled receptor 119 agonist DS-8500a in rats: involvement of the 1,2,4-oxadiazole ring-opening reductive reaction in livers under anaerobic conditions. (PubMed, Xenobiotica) - "5. These results suggest an in vivo unique reductive metabolism of DS-8500a mediated by human non- cytochrome P450 enzymes."

Journal • Preclinical

Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects. (PubMed, Clin Drug Investig) - P1; "Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS."

Clinical • Journal • PK/PD data

Non-invasive evaluation of GPR119 agonist effects on β-cell mass in diabetic male mice using 111In-exendin-4 SPECT/CT. (PubMed, Endocrinology) - "These results indicate that DS-8500a attenuates the progression of BCM loss beyond that of dietary restriction alone in prediabetic db/db mice. 111In-exendin-4 SPECT/CT will be useful for non-invasive longitudinal investigation of BCM in vivo."

Journal • Preclinical

Non-invasive evaluation of GPR119 agonist effects on β-cell mass in diabetic male mice using 111In-exendin-4 SPECT/CT. (PubMed, Endocrinology) - "These results indicate that DS-8500a attenuates the progression of BCM loss beyond that of dietary restriction alone in prediabetic db/db mice. 111In-exendin-4 SPECT/CT will be useful for non-invasive longitudinal investigation of BCM in vivo."

Journal • Preclinical

DS-8500a, an orally available G protein-coupled receptor 119 agonist, upregulates glucagon-like peptide-1 and enhances glucose-dependent insulin secretion and improves glucose homeostasis in type 2 diabetic rats. (PubMed, J Pharmacol Exp Ther) - "In a repeat-dosing study, DS-8500a had statistically significant glucose-lowering effects at OGTT performed at the 1st day and after 2 weeks of treatment in neonatal streptozotocin-treated (nSTZ) rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982, which had been clinically tested previously as GPR119 agonists. Single dose of DS-8500a showed dose dependent glucose lowering effects at OGTT in ZF rats. In the repeat dosing study, DS-8500a had statistically significant glucose lowering effects at OGTT performed at the first day and after 2-weeks treatment in nSTZ rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982 which had been clinically tested GPR119 agonists."

Journal

Pharmacokinetics and Safety of DS-8500a, an Antidiabetic Drug, in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center, Open-Label, Single-Dose Study. (PubMed, Adv Ther) - "DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD."

Clinical • Journal • PK/PD data

The role of pharmacology to produce firuglipel (DS-8500a), an orally available GPR119 agonist for type 2 diabetes mellitus (PubMed, Nihon Yakurigaku Zasshi) - "In parallel with the study for the differentiation from other GPR119 agonists, we compared firuglipel with dipeptidyl peptide-4 (DPP-4) inhibitor in NONcNZO10/LtJ mice and evaluated their combination in streptozotocin (STZ) treated C57BL/6J mice to clarify future positioning among anti-diabetics therapy. These pharmacological studies illustrated here can draw out a clinical value of compound and expected to lead the production of first-in-class agent in pharmaceutical companies."

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