Background

LU AF82422 is a humanized monoclonal IgG1 antibody targeting the C-terminal of α-synuclein. Genetic and pathology evidence implicate aggregated forms of this protein in the molecular pathogenesis of Parkinson’s disease and other α-synucleinopathies such as dementia with Lewy bodies (DLB).

Preclinical evaluation established safety and CSF target engagement in rats and cynomolgus monkeys. Blood cells express α-synuclein, but the antibody did not bind to most types of human blood cell. It did bind to a small subset of monocytes, but reportedly neither inhibited nor activated them (Fjord-Larsen et al., 2021).

LU AF82422 is one of several α-synuclein antibodies being investigated for PD. Others include ABBV-0805, cinpanemab, TAK-341, prasinezumab, and UCB7853.

Findings

Lundbeck began a Phase 1 safety study of LU AF82422 in July 2018. The study enrolled 60 healthy Japanese and non-Japanese volunteers and 24 people with Parkinson’s disease at four sites in the U.S. Participants received one of three doses of antibody or placebo by infusion, followed by 12 weeks of observation. The trial was also to measure exposure and pharmacokinetics of the antibody in blood. It was completed in July 2021. No results were disclosed, but the company claims the antibody to be well-tolerated (press release).

In 2021, this antibody received orphan drug designation from the European Medicines Agency.

In November 2021, a Phase 2 study began enrolling 64 patients with multiple systems atrophy, for 48 to 72 weeks of monthly infusions of 4,200 mg Lu AF82422 or placebo. The primary outcome is change in the Unified Multiple Systems Atrophy Rating Scale at the end of treatment. Seventeen secondary outcomes span additional measures of symptoms, daily function, global impression, falls, and quality of life, plus volumetric MRI, neurofilament light chain concentrations, and pharmacokinetics. The trial, at 19 sites in the U.S. and Japan, is expected to run until November 2023.

For details on LU AF82422 trials, see clinicaltrials.gov.