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INTRODUCTION: This study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia. METHODS: Patients with AD were enrolled into the single-ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients proceeded into the multiple-ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12-week follow-up period. The relative exposure assessment of an unblinded, single, subcutaneous 3-mg/kg dose of donanemab in patients with AD was also performed, followed by a 12-week follow-up period. One cohort of healthy subjects received an unblinded, single, IV 1-mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase. RESULTS: Donanemab was generally well tolerated up to 10 mg/kg. After single-dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half-life was ≈4 days, increasing to ≈10 days at 10 mg/kg. Only the 10-mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti-drug antibodies at 3 months after a single intravenous dose. DISCUSSION: Intravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half-life.
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BACKGROUND: Diabetes is reported to be linked to poorer cognitive function. The purpose of this study is to examine (a) clinical correlation between cognitive function and the biochemical perturbations in T2DM, and (b) the impact of statin treatment on cognitive function in diabetic subjects. METHODS: Forty Singaporean Chinese males with diabetes and twenty Singaporean Chinese males without diabetes were recruited for this study. Twenty-two of the diabetic subjects were on statin therapy and all subjects were non-demented. This was a 2-period non-interventional case-control study in which subjects were assessed for cognitive function in period 1 and blood samples taken over 2 periods, approximately 1 week apart. Blood was collected to determine the level of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, glucose and insulin. Cognitive performance was measured by a neuropsychological battery covering domains of attention, language, verbal and visual memory, visuomotor speed and executive function. Z-scores were derived for each cognitive domain using the mean and standard deviations (SDs), and they were used to compare between (a) diabetic and non-diabetic groups, and (b) diabetic subjects with and without statin treatment. ANCOVAs with age, education, BMI, and the duration of diabetes as covariates were employed to examine differences in mean score of cognitive domains and subtests between the two groups. RESULTS: Overall cognitive function was similar among diabetics and age matched non-diabetic controls. Among diabetic statin users, HDL, LDL and total cholesterol were negatively correlated with executive function, whereas peripheral insulin levels and insulin resistance were negatively associated with attention. CONCLUSION: Diabetic statin users were likely to have poorer performance in attention and executive function. Increasing levels of the peripheral biomarkers are likely to contribute to poorer cognitive performance.
