Phase 1, randomized trials of MEDI1341: cerebrospinal fluid free α-synuclein lowered by >50%
Bibliographic record
Abstract
Abstract 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; n = 6 each) or placebo (n = 13 total) in healthy participants and a multiple ascending dose study (NCT04449484) of 4-weekly MEDI1341 (1200 or 2000 mg; n = 9 each) or placebo (n = 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, n = 17; placebo, n = 6) and 10 participants with Parkinson’s disease (MEDI1341, n = 9; placebo, n = 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 AUC0–∞ 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".