Objective: Evaluate the safety, tolerability, and plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of LY3154207 (LY) following oral dosing in healthy subjects (HS).

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.

Method: This randomized, double-blind, placebo-controlled study had 2 parts: Part A (n=18) had a 3-period, crossover design with 2 alternating, dose-escalating cohorts (25, 75, 100, 150, and 200mg LY), and Part B (n=24) had a single-period, parallel-arm design with 2 cohorts (25 and 75 mg LY). The washout between consecutive dosing periods for each HS in Part A was ≥7 days. Adverse events (AEs) were recorded, and vital signs were collected frequently up to 24-48 h postdose. Ambulatory blood pressure monitoring (ABPM) was used in Part A. Samples collected for PK analyses included blood, urine and CSF (Part B only).

Results: No serious or severe AEs occurred. Part A: Treatment-related AEs (TRAEs) (≥ 3 events, primarily at doses ≥100mg) were mostly mild: insomnia, decreased appetite, anxiety, dizziness, nausea, dysgeusia, increased energy, feeling hot, and headache. Dose-related increases in systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) from ABPM were seen, peaking between 4-12 h postdose and mostly resolving within 24 hours. Based on ABPM, the 4-to 8-h estimates at 200mg LY (estimate of the difference in least square means compared to placebo) were 32 bpm for HR and 14 mmHg and 10 mmHg for SBP and DBP, respectively. Vital sign data were consistent with the ABPM data. Median LY plasma tmax was 2-3 h, t1/2 was 11-13 h, and CL/F was 19-25 L/h across the dose range, with minimal renal CL. Part B: TRAEs, all at 75mg, were mild: energy increased, anxiety, decreased appetite, and dizziness. Vital sign data was consistent with data from Part A and showed increases in SBP, DBP, and pulse rate at the 75mg dose. In CSF, the median tmax was 3-4 h and the t1/2 was 8 h. The ratio of CSF/plasma exposure was 1% and 37% relative to total and unbound plasma exposure, respectively.

Conclusion: Doses of 25-200 mg LY had acceptable safety and tolerability. LY PK was linear, and central penetration of LY was confirmed. These data support further study of LY for the symptomatic treatment of LBDs.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/first-in-human-study-of-ly3154207-a-dopamine-d1-receptor-positive-allosteric-modulator-d1pam/