Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease

Figures

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  Figure 1. Chemical structure of emestedastat [(5‐(1H‐Pyrazol‐4‐yl)thiophen‐3‐yl)(3‐hydroxy‐3‐(pyrimidin‐2‐yl)‐8 azabicyclo[3.2.1]octan‐8‐yl) methanone].

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  Figure 2. Composite VPC plots from the population PK analysis, showing postdose emestedastat plasma concentrations. (A) VPC plot for healthy participants in the MAD/ACW0001 trial. (B) VPC plots for healthy older participants in the XanaHES/ACW0003 trial, taken 3‐5 hours after dosing and at the trough. (C) VPC plots for participants with AD in the XanaMIA‐DR/ACW0005 trial, taken 3‐5 hours after dosing and at the trough. For each plot, shaded areas represent 95% PI of the median (pink) and 95% PIs of the 2.5th and 97.5th percentile of simulated data (blue). Red lines indicate the median (solid) and 2.5th and 97.5th percentile (dotted) of the observed data. AD, Alzheimer disease; BID, twice daily; MAD, multiple‐ascending‐dose; QD, once daily; PI, prediction interval; PK, pharmacokinetic; VPC, visual predictive check.

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  Figure 3. Line plot of mean plasma cortisol level (ng/mL) and standard deviation over time, before dosing, and 3‐5 hours after dosing, for 10 mg emestedastat (black line) and placebo (gray line) in the XanADu trial.

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  Figure 4. Mean fold increase from baseline in ACTH levels at the end of treatment across multiple‐dose trials. ACTH levels were measured at end of treatment in the MAD (20 mg [n = 6] emestedastat, 40 mg emestedastat [n = 6], and 70 mg emestedastat [n = 6] at 10 days), XanADu (10 mg emestedastat [n = 71] at 12 weeks), and XanaMIA‐DR (placebo [n = 37], 5 mg emestedastat [n = 36], and 10 mg emestedastat [n = 34] at 6 weeks) trials. Error bars represent ± standard error. ACTH, adrenocorticotropic hormone; MAD, multiple‐ascending‐dose.

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  Figure 5. LS mean change and standard error from baseline in scores in the Attention Composite of a CTB in healthy older participants in XanaHES (left) and XanaMIA‐DR (right). Solid lines represent the treatment period, and dotted lines represent the off‐treatment follow‐up period for the trials. For XanaHES, participants received 20 mg emestedastat (black line) or placebo (gray line). For XanaMIA‐DR, participants received 5 mg emestedastat (blue line), 10 mg emestedastat (purple line), or placebo (gray line). CTB, cognitive test battery; LS, least squares.