Phase 1, randomized trials of MEDI1341: cerebrospinal fluid free α-synuclein lowered by >50.

Accumulation of pathological forms of α-synuclein is a hallmark of Parkinson's disease. MEDI1341 (also known as TAK-341) is a high-affinity, α-synuclein-specific, fully human monoclonal antibody that binds the C-terminal region of human α-synuclein. Pre-clinical studies of MEDI1341 demonstrated significant reductions in α-synuclein accumulation and propagation along axons. Two randomized, double-blind, placebo-controlled, Phase 1 studies administering MEDI1341 intravenously were conducted; a single ascending dose study (NCT03272165) of MEDI1341 (70, 210, 400, 1200, 2400 or 4500 mg; = 6 each) or placebo ( = 13 total) in healthy participants and a multiple ascending dose study (NCT04449484) of 4-weekly MEDI1341 (1200 or 2000 mg; = 9 each) or placebo ( = 7 total) in participants with Parkinson's disease. Both studies assessed the safety and tolerability of MEDI1341 versus placebo, with MEDI1341 pharmacokinetics, pharmacodynamics and immunogenicity as secondary objectives. Pharmacokinetic (MEDI1341 in serum and CSF) and pharmacodynamic (total α-synuclein in plasma, and free α-synuclein in CSF) concentrations were determined using validated electrochemiluminescence assays. Overall, 49 healthy participants (67.3% male; mean [standard deviation] age 43.4 [9.5] years) were included in the single ascending dose study and 25 participants with Parkinson's disease (72.0% male; mean [standard deviation] age 63.0 [9.0] years; 88% Hoehn and Yahr stage 2) were included in the multiple ascending dose study. Treatment-emergent adverse events were reported in 23 healthy participants (MEDI1341, = 17; placebo, = 6) and 10 participants with Parkinson's disease (MEDI1341, = 9; placebo, = 1). The most common treatment-related treatment-emergent adverse events were headache, fall and nausea. Dose proportional increases were observed for maximum concentration in serum and area under the curve (AUC) in both studies, with the exception of a supra-proportional increase in AUC from 2400 to 4500 mg (single ascending dose study). Median time to maximum concentration was 1 h after intravenous administration and geometric mean terminal elimination half-life ranged from 16.6 to 24.3 days across both studies. Suppression of α-synuclein in CSF was greatest at the highest doses investigated: -53.6% median change from baseline on Day 15 [4500 mg (healthy participants)] and -59.0% median change from baseline on Day 85 [2000 mg (participants with Parkinson's disease)]. Across all doses and time points, individual participant CSF MEDI1341 concentrations were <1% of their respective serum concentrations. MEDI1341 had favourable safety, tolerability, pharmacokinetic and pharmacodynamic profiles in healthy participants and those with Parkinson's disease, supporting further clinical development. MEDI1341 is the first monoclonal antibody targeted against α-synuclein to demonstrate a > 50% reduction in CSF-free α-synuclein.