Objective: Evaluation of safety, tolerability, pharmacokinetics (PK) and target engagement (TE) in healthy subjects (HS) and patients with Parkinson’s disease (PD) following single ascending doses (SAD) of Lu AF82422.

Background: Alpha-synuclein (aSyn) is key to the pathogenesis of neurodegenerative disorders, known as synucleinopathies, including PD, multiple system atrophy and dementia with Lewy bodies. Lu AF82422 is an anti-aSyn human IgG1 mAb, which binds all known forms of aSyn, including aggregated and/or C-terminal truncated aSyn. The MoA of Lu AF82422 is to reduce cell-to-cell spreading and seeding of aSyn, and thus delay synucleinopathy disease progression.

Method: 58 HS (17 PBO) and 15 PD patients (3 PBO) enrolled in the randomised, double-blinded, PBO-controlled study in 6 HS cohorts and 2 PD patient cohorts. Single doses of Lu AF82422 were administered via IV infusion and subjects were monitored for 12 weeks post-dose for safety and tolerability (vital signs, MRI, anti-drug antibodies, ECG, adverse events [AEs], blood closure time). PK and TE (free/total aSyn) samples were obtained throughout to measure plasma and cerebrospinal fluid (CSF) Lu AF82422 and aSyn concentrations.

Results: Lu AF82422 was safe and well tolerated at all tested doses. No serious treatment-emergent AEs (AEs that started or increased post-first dose) were reported, and non-serious AEs were primarily study related, particularly to lumbar punctures or common infections. The PK of free Lu AF82422 were linear with no differences between HS and PD. Clearance and half-life were as expected for a human IgG1, approx. 0.24 L/d and 29 days, respectively. CSF concentrations of Lu AF82422 increased dose-proportionally. The CSF/plasma ratios were 0.10–0.14% on Day 3, increasing to 0.16–0.51% on Day 21, and were comparable between HS and PD. Plasma free/total aSyn was described by an I_max model, with an IC₅₀ value similar to that observed in vitro and in a preclinical study in cynomolgus monkeys.

Conclusion: In this first-in-human (FIH) SAD study, Lu AF82422 was safe and well tolerated in HS and PD patients. PK and plasma TE were as expected. Data from the FIH SAD study combined with in vitro binding of Lu AF82422 to monomer and aggregated aSyn indicate that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of aSyn.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-anti-alpha-synuclein-antibody-lu-af82422-was-safe-and-well-tolerated-in-a-fih-sad-study-in-healthy-subjects-and-patients-with-pd/