Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor-Positive Allosteric Modulator, in Patients With Parkinson Disease

Darren Wilbraham, Kevin M Biglan, Kjell A Svensson, Max Tsai, Melissa Pugh, Paul Ardayfio, William Kielbasa, Darren Wilbraham, Kevin M Biglan, Kjell A Svensson, Max Tsai, Melissa Pugh, Paul Ardayfio, William Kielbasa

Abstract

Mevidalen (LY3154207) is a positive allosteric modulator of the dopamine D1 receptor that enhances the affinity of dopamine for the D1 receptor. The safety, tolerability, motor effects, and pharmacokinetics of mevidalen were studied in patients with Parkinson disease. Mevidalen or placebo was given once daily for 14 days to 2 cohorts of patients (cohort 1, 75 mg; cohort 2, titration from 15 to 75 mg). For both cohorts, the median time to maximum concentration for mevidalen plasma concentration was about 2 hours, the apparent steady-state clearance was 20-25 L/h, and mevidalen plasma concentrations were similar between the 1st and 14th administration in cohort 1, indicating minimal accumulation upon repeated dosing. Mevidalen was well tolerated, and most treatment-emergent adverse events were mild. Blood pressure and pulse rate increased when taking mevidalen, but there was considerable overlap with patients taking placebo, and vital signs normalized with repeated dosing. In the Movement Disorder Society-United Parkinson's Disease Rating Scale, all patients taking mevidalen showed a better motor examination sub-score on day 6 compared to only some patients in the placebo group. These data support examining mevidalen for symptomatic treatment of patients with Parkinson disease and Lewy body dementia.

Trial registration: ClinicalTrials.gov NCT02562768.

Keywords: D1PAM; LY3154207; Parkinson disease; dopamine; mevidalen; pharmacokinetics; safety; tolerability.

Conflict of interest statement

D.W., K.M.B., M.P., P.A., and W.K. are employees of Eli Lilly and Company Inc. and may own stock in this company. K.A.S. and M.T. are former employees of Eli Lilly and Company Inc. and may own stock in this company.

© 2021 Eli Lilly and Company. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
(A) Change from baseline in vital signs. Data shown as mean ± 1 standard error. Cohort 1: 75 mg mevidalen once daily for 14 consecutive days. Cohort 2: 15 mg mevidalen on days 1 to 3, 30 mg on days 4 to 6, and 75 mg on days 7 to 14. (B) Change from baseline in ABPM. Data shown as mean ± 1 standard error. Cohort 1: 75 mg mevidalen once daily for 14 consecutive days. Cohort 2: 15 mg mevidalen on days 1 to 3, 30 mg on days 4 to 6, and 75 mg on days 7 to 14. ABPM, ambulatory blood pressure monitoring; Avg, average; BP, blood pressure; VS, vital signs.
Figure 1
Figure 1
(A) Change from baseline in vital signs. Data shown as mean ± 1 standard error. Cohort 1: 75 mg mevidalen once daily for 14 consecutive days. Cohort 2: 15 mg mevidalen on days 1 to 3, 30 mg on days 4 to 6, and 75 mg on days 7 to 14. (B) Change from baseline in ABPM. Data shown as mean ± 1 standard error. Cohort 1: 75 mg mevidalen once daily for 14 consecutive days. Cohort 2: 15 mg mevidalen on days 1 to 3, 30 mg on days 4 to 6, and 75 mg on days 7 to 14. ABPM, ambulatory blood pressure monitoring; Avg, average; BP, blood pressure; VS, vital signs.
Figure 2
Figure 2
Movement Disorder Society–United Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III – Motor function as a measure of tolerability outcome. To evaluate drug tolerability, patients were tested at days –1, 6, and 15 of the study using the MDS‐UPDRS motor examination. Line graphs show the individual subscores for part III of the MDS‐UPDRS for patients at baseline (day –1), during treatment (day 6), and after cessation of treatment (day 15). Lines connect points for single patients. Two mevidalen‐treated patients in cohort 2 were tested on day 16 rather than day 15. One mevidalen‐treated patient in cohort 1 discontinued before the day 6 MDS‐UPDRS measurement and is not included in the figure. Cohort 1: 75 mg mevidalen once daily for 14 consecutive days. Cohort 2: 15 mg mevidalen on days 1 to 3, 30 mg on days 4 to 6, and 75 mg on days 7 to 14. MDS‐UPDRS, Movement Disorder Society–United Parkinson's Disease Rating Scale.
Figure 3
Figure 3
Mevidalen plasma concentration vs time profiles in patients with Parkinson disease. Mevidalen plasma concentrations are expressed as arithmetic mean. Patients in cohort 1 received 75 mg of mevidalen once daily for 14 consecutive days, and cohort 2 received titrated doses of 15 mg on days 1 to 3, 30 mg on days 4 to 6, and 75 mg on days 7 to 14. Left panel shows the PK profile following the initial administration of mevidalen on day 1, and the middle and right panels show the PK profile following the 7th and 14th daily administration of mevidalen, respectively. h, hour; PK, pharmacokinetics.

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