Objective: Evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple oral LY3154207 (LY) doses in healthy subjects (HS) and persons with Parkinson’s disease (PWPD).

Background: LY, a novel D1PAM, may improve the motor and cognitive symptoms of Parkinson’s disease (PD) and Lewy Body Dementias (LBDs) by increasing the affinity of dopamine for the D1 receptor and amplifying the endogenous dopamine response. A single-ascending dose study of LY (25-200mg) in HS showed dose-related increases in systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR).

Method: In this randomized, double‑blind, placebo (PBO)-controlled study, HS (n=47, Part A) and PWPD (n=24, Part B) received 14 once-daily doses of PBO or LY. The LY doses were 15, 30, 75, or 150mg (Part A), and 75mg (Part B). Adverse events (AEs) were recorded and 24-hour ambulatory blood pressure monitoring (ABPM) profiles were collected. Blood and urine were collected for PK analyses. In Part B, Movement Disorders Society United Parkinson’s Disease Rating Scale (MDS-UPDRS) assessments were done.

Results: No serious or severe AEs occurred. Part A: Treatment-related AEs (TRAEs) (≥ 3 events, primarily at 150mg) were mild: insomnia, dizziness, nausea, nervousness, and palpitations. Dose-related increases in SBP, DBP, and HR from ABPM were seen on Day 1, peaking 4-8 hours postdose. By Day 7 (lower LY doses)-Day 14 (all doses), BP and HR increases were lower than at Day 1 and similar to PBO, suggesting accommodation to these effects. Across all doses, LY plasma concentrations peaked 2-3 hours postdose, steady state was achieved within 7 days, and oral clearance (CL/F) was 24-35 L/h with minimal renal clearance. Modest accumulation (AUCratio=1.34) was seen with 15mg LY but not higher doses. Part B: TRAEs were mostly mild: abdominal pain, hallucination, headache, and hypoaesthesia. LY evoked increases in SBP, DBP, and HR, but accommodation was less clear due to high variability. Increases in LY Cmax and AUC of 25% and 42%, respectively, in PWPD versus HS may possibly be due to differences in age (PWPD: 69 yr; HS: 39 yr). The MDS-UPDRS showed potential improvement in motor function.

Conclusion: Multiple once-daily doses of LY up to 150mg were well-tolerated in HS and PWPD, and LY-evoked increases in SBP, DBP, and HR appeared to accommodate with repeat dosing. These data support further study of LY for symptomatic treatment of LBDs.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-multiple-ascending-dose-study-of-ly3154207-a-dopamine-d1-receptor-positive-allosteric-modulator-d1pam/