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 single-dose safety study of LU AF82422 in July 2018. The study enrolled 59 healthy Japanese and non-Japanese volunteers and 15 people with Parkinson’s disease at four sites in the U.S. Healthy participants received infusions of one of six doses of antibody ranging from 75 to 9,000 mg, or placebo, followed by 12 weeks of observation. Parkinson’s patients received 2,250 or 9,000 mg, or placebo. The trial also measured exposure and pharmacokinetics of the antibody in blood. It was completed in July 2021, and results were published after peer review (Buur et al., 2024). The treatment was safe and well-tolerated, with no serious adverse events, or adverse events leading to study withdrawal. Pharmacokinetics were dose-proportional and did not differ between the healthy and PD volunteers. The antibody was detected in CSF at 0.1 to 0.5 percent of plasma levels. Two participants developed anti-drug antibodies, which did not affect pharmacokinetics. In a target engagement analysis, the antibody bound to and reduced levels of free α-synuclein in blood and CSF. The PD patients showed a 37 percent reduction in the ratio of free to total synuclein in CSF three weeks after dosing.

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

In November 2021, a Phase 2 study called AMULET began enrolling 64 patients with MSA. Participants were randomized 2:1 to monthly infusions of 4,200 mg Lu AF82422 or placebo for 48 to 72 weeks. 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 placebo-controlled part of this trial, running at 19 sites in the U.S. and Japan, finished in November 2023. According to results presented at the March 2024 AD/PD conference, the trial showed a trend on the primary endpoint but, at 19 percent slowing of decline, missed statistical significance. There were trends to slowing on secondary endpoints related to functional and motor deterioration. A 27 percent slowing of progression on the FDA-preferred endpoint of the modified USMARS just missed statistical significance. A post hoc subgroup analysis identified a statistically significant 42 percent slowing on the modified UMSARS in the less impaired subgroup. Other trends were slowing of brain volume loss in the pons and cerebellum, and a greater lowering of NfL in the CSF. Of 61 patients who began therapy, 49 completed the full 72 weeks. No safety concerns were identified, and no antidrug antibodies were elicited. A one-year, open-label extension is ongoing. Lundbeck intends to run a Phase 3 study (company release).

In February 2024, Lundbeck registered an additional Phase 1 trial to assess safety, tolerability, pharmacokinetics and immunogenicity of a single infusion of Lu AF82422 in healthy Caucasian and Chinese adults. It will run from March to September 2024. 

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