Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease

Abstract

Objective: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication.

Methods: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study.

Results: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated.

Interpretation: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

FIGURE 1

Foslevodopa and foscarbidopa are designed and prepared as highly water‐soluble prodrugs to enable continuous s.c. infusion therapy. (A) Mechanism of action for foslevodopa/foscarbidopa leading to increased brain DA levels. (B) Stages of PD, with representation of ideal DA level to achieve optimal therapeutic benefit. (C) Structures of DA, LD, CD, foslevodopa, and foscarbidopa. CD = carbidopa; DA = dopamine; LD = levodopa; PD = Parkinson's disease. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

pH–solubility profiles of levodopa, carbidopa, foslevodopa, and foscarbidopa drug substance at 25°C. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Estimated levodopa and carbidopa plasma concentration–time profiles following continuous s.c. infusions of foslevodopa/foscarbidopa. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 4

Clinical pharmacokinetic results. (A) Group 1, Period 1, foslevodopa‐to‐foscarbidopa dosing ratio of 4:1. (B) Group 2, foslevodopa‐to‐foscarbidopa dosing ratio of 4:1. (C) Group 2, foslevodopa‐to‐foscarbidopa dosing ratio of 10:1. (D) Group 2, foslevodopa‐to‐foscarbidopa dosing ratio of 20:1. (E) Group 1, Period 2, oral levodopa‐to‐carbidopa dosing ratio of 4:1. (F) Group 3, foslevodopa‐to‐foscarbidopa dosing ratio of 20:1, 72 hour infusion. ER = levodopa‐to‐carbidopa exposure ratio based on AUC_0–∞. [Color figure can be viewed at www.annalsofneurology.org]