Long‐term safety and efficacy of fasiglifam (TAK‐875), a G‐protein‐coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52‐week open‐label phase III study

Kaku, Kohei; Enya, Kazuaki; Nakaya, Ryou; Ohira, Tetsuya; Matsuno, Ryosuke

doi:10.1111/dom.12693

Cited by 57 publications

(49 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMG 009 also affects other hepatic transporters involved in the regulation of hepatic bile acids (e.g., MRP2 (stimulation, followed by inhibition, no IC 50 generated), MRP3 (1.1 μmol/L), and MRP4 (13.5 μmol/L)). Recent work with TAK‐875, an agent that caused clinical hepatotoxicity in a small number of patients at 50 mg once daily during a Phase 3 clinical study, also showed similar potencies across numerous hepatic transporters involved in bile acid transport . Unfortunately, none of these studies had clinical samples which could be used to interrogate the possible causal effect relationship between BSEP inhibition as a purported mechanism driving liver injury with evidence in affected subjects or patients.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Aleo

Aubrecht

Bonin

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

During a randomized Phase 1 clinical trial the drug candidate, PF‐04895162 (ICA‐105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2‐weeks (NCT01691274). This was unexpected since studies in rats (<6 months) and cynomolgus monkeys (<9 months) treated up to 100 mg/kg/day did not identify the liver as a target organ. Mechanistic studies showed PF‐04895162 had low cytotoxic potential in human hepatocytes, but inhibited liver mitochondrial function and bile salt export protein (BSEP) transport. Clinical relevance of these postulated mechanisms of liver injury was explored in three treated subjects that consented to analysis of residual pharmacokinetic plasma samples. Compared to a nonresponder, two subjects with transaminase elevations displayed higher levels of miRNA122 and total/conjugated bile acid species, whereas one demonstrated impaired postprandial clearance of systemic bile acids. Elevated taurine and glycine conjugated to unconjugated bile acid ratios were observed in two subjects, one before the onset of elevated transaminases. Based on the affinity of conjugated bile acid species for transport by BSEP, the profile of plasma conjugated/unconjugated bile acid species was consistent with inhibition of BSEP. These data collectively suggest that the human liver injury by PF‐04895162 was due to alterations in bile acid handling driven by dual BSEP/mitochondrial inhibition, two important risk factors associated with drug‐induced liver injury in humans. Alterations in systemic bile acid composition were more important than total bile acids in the manifestation of clinical liver injury and may be a very early biomarker of BSEP inhibition.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Aleo

Aubrecht

Bonin

et al. 2019

Pharmacology Res & Perspec

View full text Add to dashboard Cite

show abstract

“…For example, dogs had a TAK-875 plasma AUC 0 – 24 of 3800 μg*h/ml after 14 days of dosing at this concentration (Supplementary Table 4). Humans were administered TAK-875 (fasiglifam) at 25 and 50 mg in phase 3 clinical trials that were ultimately discontinued due to concerns about liver safety (Kaku et al , 2015, 2016). By comparison of exposures, the 600 mg/kg dogs had an exposure approximately 40- to 100-fold greater than humans who received repeat doses of 25 or 50 mg TAK-875 (AUC 0 – 24 of 40.3 and 100.3 μg*h/ml, respectively) (Leifke et al , 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Clinical data indicated that there was a benefit for patients who received TAK-875 based on improved glycemic parameters (Kaku et al , 2013). However, the development activities of TAK-875 were voluntarily terminated in 2013 due to liver safety concerns (Kaku et al , 2015, 2016). This outcome presented an opportunity to investigate potential mechanisms of the toxicity with animal models.…”

mentioning

confidence: 99%

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

et al. 2017

View full text Add to dashboard Cite

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

show abstract

“…20 However, later studies did not persistently show the benefit of FFAR1 deficiency under chronic fatty acid loading in mouse models in vivo and in vitro. 23 A new generation of agonists with better safety profiles has been actively in development and may soon become a new class of therapeutic agents for T2D. 11 In humans, FFAR1 is not among the T2D risk loci in genome-wide association study (GWAS), and nonsynonymous variants of FFAR1 have not shown correlation with the development of T2D.…”

Section: How Do Fa and Lipid Metabolites Support Gsis?mentioning

confidence: 99%

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Imai

Cousins

Liu

et al. 2019

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans. To better understand the two‐sided relationship between lipids and beta cells, we present a current view of acute and chronic handling of lipids by beta cells and implications for beta cell function and health. We also discuss an emerging role for lipid droplets (LD) in the dynamic regulation of lipid metabolism in beta cells and insulin secretion, along with a potential role for LD under nutritional stress in beta cells, and incorporate recent advancement in the field of lipid droplet biology.

show abstract

Long‐term safety and efficacy of fasiglifam (TAK‐875), a G‐protein‐coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52‐week open‐label phase III study

Cited by 57 publications

References 10 publications

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Contact Info

Product

Resources

About