AimTo assess the efficacy and safety of fasiglifam 25 and 50 mg in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.MethodsThis phase III, double-blind, placebo-controlled, multicentre study included 192 patients randomized to once-daily treatment with fasiglifam 25 mg (n = 63) or 50 mg (n = 62) or placebo (n = 67) for 24 weeks. The primary efficacy endpoint was the change from baseline in glycated haemoglobin (HbA1c) at week 24.ResultsAt week 24, both fasiglifam groups had significantly reduced HbA1c levels compared with the placebo group (p < 0.0001). The least squares mean change from baseline in HbA1c was 0.16% with placebo, −0.57% with fasiglifam 25 mg and −0.83% with fasiglifam 50 mg. The percentage of patients who achieved an HbA1c target of <6.9% at week 24 was also significantly higher (p < 0.05) for fasiglifam 25 mg (30.2%) and 50 mg (54.8%) compared with placebo (13.8%). Fasiglifam significantly reduced fasting plasma glucose levels at all assessment points, starting from week 2. The incidence and types of treatment-emergent adverse events in each fasiglifam group were similar to those in the placebo group, and hypoglycaemia was reported in 1 patient receiving fasiglifam 50 mg. There were no clinically meaningful changes in body weight in any treatment group.ConclusionsFasiglifam significantly improved glycaemic control and was well tolerated, with a low risk of hypoglycaemia in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise; however, in a recent review of data from overall fasiglifam global clinical trials, concerns about liver safety arose and the clinical development of fasiglifam was terminated after this trial was completed.

This multicentre, open-label, phase III study investigated the safety and efficacy of the G-protein-coupled receptor 40 agonist fasiglifam. Japanese patients with type 2 diabetes and inadequate glycaemic control despite diet and/or exercise (n = 282), or despite diet and/or exercise plus one oral antidiabetic agent [sulphonylurea (n = 262), rapid-acting insulin secretagogue (n = 124), α-glucosidase inhibitor (n = 141), biguanide (n = 136), thiazolidinedione (n = 139) or dipeptidyl peptidase-4 inhibitor (n = 138)] were randomized to treatment with fasiglifam 25 or 50 mg once daily for 52 weeks. The primary endpoints were safety variables. The overall incidence of treatment-emergent adverse events (TEAEs) was 75.4-85.1% in the 25 mg group and 78.9-89.9% in the 50 mg group; most TEAEs were mild. Hypoglycaemia was negligible with fasiglifam monotherapy and most common with sulphonylurea combination therapy (12.4 and 9.1% for 25 and 50 mg groups, respectively). Abnormal liver-related laboratory values were uncommon. Glycated haemoglobin levels decreased from week 2 in all groups and were maintained to week 52. Although fasiglifam as monotherapy or in combination regimens was well tolerated during long-term treatment, global concerns about liver safety led to termination of its development after study completion.

Funding information Takeda Pharmaceutical Company[Correction added on 2 July 2021, after first online publication: the ClinicalTrials.gov number in the Methods-Study subject section has been corrected from "NCT02802735" to "NCT02892409" in this current version.] Aims: Helicobacter pylori (Hp) eradication plays a key role in the treatment and prevention of peptic ulcer diseases. Increasing clarithromycin resistance in Hp necessitates more effective treatments for eradication, such as bismuth-containing quadruple therapy. We aimed to compare the safety and pharmacokinetics (PK) of bismuth between vonoprazan-and lansoprazole-containing quadruple therapy in Hppositive subjects.Methods: In this randomised, double-blind, parallel-group study, Hp-positive subjects were randomised to receive vonoprazan-or lansoprazole-containing quadruple therapy. Each subject received vonoprazan 20 mg or lansoprazole 30 mg combined with bismuth 220 mg, clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 14 days. Blood sampling and urine collection for bismuth PK were conducted predose and up to 12 hours postdose at steady-state. The PK parameters of bismuth were derived using a noncompartmental method and compared between treatments.An exploratory breath test for Hp was conducted at screening and at the follow-up visit on day 42. Safety was assessed by adverse event monitoring, physical examinations, vital signs, 12-lead electrocardiograms and clinical laboratory tests.Results: A total of 30 subjects were randomised and 26 subjects completed the study (12 in the vonoprazan group and 14 in the lansoprazole group). The systemic exposure of bismuth in the 2 treatments was comparable (5% difference). All subjects turned negative for Hp at the follow-up visit. No significant difference in safety profiles was noted between the 2 treatments. Conclusion:The systemic exposure of bismuth was similar between vonoprazan-and lansoprazole-containing quadruple therapy. Vonoprazan-containing quadruple therapy was safe and well tolerated.

Rasagiline is a monoamine oxidase type-B inhibitor in development in Japan for Parkinson’s disease (PD). This open-label study evaluated the long-term safety and efficacy of rasagiline in Japanese patients with PD receiving levodopa. Patients were aged 30–79 years and had wearing-off or weakened effect. Patients received rasagiline 1 mg/day for 52 weeks. The primary objective was to evaluate safety. Secondary endpoints included MDS-UPDRS Part II and Part III total scores (ON-state) and change from baseline in mean daily OFF-time. An additional endpoint was the Parkinson’s Disease Questionnaire-39 (PDQ-39) Summary Index (SI) score. In total, 222 patients were enrolled; 52.3% had wearing-off phenomena. Treatment-emergent adverse events (TEAEs) were mostly mild or moderate and occurred in 83.3% of patients; 63.1% had drug-related TEAEs; and 21.2% had TEAEs resulting in discontinuation. Fall (16.7%), nasopharyngitis (14.0%), and dyskinesia (10.8%) were the most frequent TEAEs. Serious TEAEs were reported in 17.6% of patients, and led to discontinuation in 9.5%. At week 52 (last-observation-carried forward), the mean change from baseline in MDS-UPDRS Part III total score (ON-state) was − 7.6; the mean change from baseline in daily OFF-time was − 0.89 h in patients with wearing-off phenomena at the start of the run-in period. The mean change from baseline in PDQ-39 SI was − 0.64. No major safety issues were observed during this 52-week trial of rasagiline as an adjunct to levodopa in Japanese patients. Mean changes in MDS-UPDRS scores and daily OFF-time suggested that adjunctive rasagiline treatment with levodopa was efficacious, with efficacy maintained for at least 52 weeks.

Namilumab was well tolerated in Japanese and Caucasian subjects; namilumab 150 mg had similar pharmacokinetics in both populations, supporting further clinical development of this dose.
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