Fig. 6: Disposition and pharmacokinetic profiles in healthy participants and participants with ALS in DNL343 clinical trials. | Nature Communications

Fig. 6: Disposition and pharmacokinetic profiles in healthy participants and participants with ALS in DNL343 clinical trials.

From: Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial

Fig. 6

a CONSORT diagram describing Phase 1 screening and randomization. b CONSORT diagram describing Phase 1b screening and randomization. c Healthy participants plasma concentration-time profiles upon single doses of DNL343 in the fasted state (n = 6 in each group). Presented as the geometric mean (95% CI) and colored by dose level. d, e Healthy participants (n = 6, 7, 7, 7, and 6 participants, for the 45 mg, 100 mg, 145 mg, 200 mg, and 260 mg group respectively) (d) and participants with ALS (n = 9, 7 participants in the 100 mg and 200 mg groups, respectively) (e) plasma pharmacokinetics upon QD dosing of DNL343 at steady state. Presented as the geometric mean (95% CI) and colored by dose level. f, g Healthy participants (n = 6, 7, 7, 7, and 6 participants, for the 45 mg, 100 mg, 145 mg, 200 mg, and 260 mg group respectively) (f) and participants with ALS (n = 8, 7 participants in the 100 mg and 200 mg groups respectively) (g) DNL343 CSF:unbound plasma concentration ratios after multiple doses. Presented as individual datapoints colored by dose level overlayed over a boxplot summarizing all the data in the panel. The middle line of the boxplot displays the median, the lower and upper limits of the box display the first and third quartiles, and the whiskers extend from the box to the largest and smallest values no further than 1.5-fold the interquartile range from the box. The lower and upper limits of quantification (LLOQ and ULOQ) for CSF concentrations was 0.005 and 5 µM, respectively. The LLOQ and ULOQ for plasma concentrations was 0.002 and 2 µM, respectively. Note: In the 100 mg group, data were not collected and/or analyzed for two participants due to dose reduction (1 participant), and no collection of CSF samples (1 participant). In the 200 mg group, data were not collected or analyzed for two participants due to dose reduction (1 participant) and early discontinuation of treatment (1 participant). Source data are provided in Source Data file.

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