Therapy Type: Immunotherapy (passive) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: AstraZeneca, Takeda Pharmaceutical Company
This is a high-affinity monoclonal antibody to monomeric and aggregated α-synuclein, originally developed by AstraZeneca. Genetic and pathological evidence implicates α-synuclein in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies such as dementia with Lewy bodies (DLB).
In preclinical studies, MEDI1341 entered the brain after intravenous administration to rats or monkeys, where it was reported to lower concentrations of free α-synuclein in cerebrospinal fluid and brain interstitial fluid. The antibody intercepted cell-to-cell spreading of human α-synuclein fibrils in cell culture and in a mouse model of α-synuclein pathology propagation in brain. A version of the antibody with diminished Fc receptor binding was equally potent in the mouse model, suggesting that antibody-mediated immune mechanisms are not required for its activity (Schofield et al., 2019).
In October 2017, Astra Zeneca began a Phase 1 single-ascending-dose study in 48 healthy volunteers age 18 to 65. Each volunteer receives a one-hour intravenous infusion of MEDI1341 or placebo, followed by three months of observation. The study will test up to six doses, safety data permitting. Starting with the lowest dose, each cohort of eight volunteers will be completed before the trial moves to the next-higher dose in a new group of volunteers. Primary outcomes are adverse events; secondary outcomes include pharmacokinetics, quantification of α-synuclein in blood and CSF, and detection of anti-drug antibodies in serum. In August 2019, the sponsor updated the qualifying criteria to exclude anyone with a significant eye disorder, and added assessment of vision and eye health to the primary outcomes. The trial is being run by the CRO Covance in Dallas; Madison, Wisconsin; and Leeds, U.K., and slated to end in January 2021.
In June 2020, the sponsor registered a second Phase 1 trial, assessing multiple ascending doses in people with Parkinson’s disease. The study will begin in September 2020 to enroll 36 participants who will receive antibody or placebo, three times over eight weeks, with 13 weeks of follow-up. Increasing doses will be tested in three successive cohorts of 12 volunteers each. Primary outcomes include adverse events and clinical and lab safety measures, electrocardiogram, plus ophthalmic assessments and measures of cognitive impairment, suicidal ideation and behavior. The study will run through July 2022.
For details, see clinicaltrials.gov.
Last Updated: 16 Jul 2020
- Schofield DJ, Irving L, Calo L, Bogstedt A, Rees G, Nuccitelli A, Narwal R, Petrone M, Roberts J, Brown L, Cusdin F, Dosanjh B, Lloyd C, Dobson C, Gurrell I, Fraser G, McFarlane M, Rockenstein E, Spencer B, Masliah E, Spillantini MG, Tan K, Billinton A, Vaughan T, Chessell I, Perkinton MS. Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. Neurobiol Dis. 2019 Dec;132:104582. Epub 2019 Aug 21 PubMed.