Therapy Type: Immunotherapy (passive) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Biogen, Neurimmune
BIIB054 is a human-derived monoclonal antibody directed against α-synuclein. Genetic and pathology evidence implicate this protein in the molecular pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies such as dementia with Lewy bodies (DLB). In 2010, Biogen licensed BIIB054 from Neurimmune (see company press release). The antibody was generated with reverse translational medicine technology from naturally occurring, presumably protective antibodies found in healthy aged donors, as were aducanumab and other antibodies in the Biogen-Neurimmune partnership.
BIIB054 binds to α-synuclein residues 1-10, with 800-fold higher affinity for aggregated over monomeric α-synuclein. The antibody inhibits α-synuclein spreading in cell-based assays, and slows pathology and motor symptoms in mice (Weihofen et al., 2019).
From July 2015 through 2017, Biogen evaluated single-ascending, intravenous doses of BIIB054 in 48 healthy volunteers and 18 people with early Parkinson's, at eight sites in the U.S. Outcomes included safety measures, the MOCA cognition screen, BIIB054 serum levels and pharmacokinetics, as well as presence of anti-BIIB054 antibodies.
In 2017 at AD/PD, Biogen reported some data on the healthy participants, aged 40 to 65. They had received infusions of 1, 5, 15, 45, 90, or 135 mg/kg, had MRI scans at baseline, day three, and week four, and had CSF samples drawn at baseline, eight hours, 24 hours, and week three. Participants were followed for 16 weeks after dosing with clinical assessments and electrocardiograms. Doses up to 90 mg/kg were reported to have been well tolerated; in the 135 mg/kg cohort, one participant developed asymptomatic ischemia in the right parietal lobe. Side effects included headache, dizziness, pain, or skin rash related to the infusion. BIIB054’s half-life was 28 days, the CSF/serum ratio was 0.2 percent at all doses, and maximum concentration in blood was dose-proportional (see May 2017 conference news).
At the 2018 AAN conference, Biogen presented first results of the same trial's PD cohort. Thirteen men and five women, aged 47 to 75, had received a single infusion of either zero, 15, or 45 mg/kg of BIIB054. Nine were not on PD medication, five were on levodopa, two on rasagiline, two on both. The pharmacokinetics of BIIB054 in patients were similar to those in healthy volunteers, with a 33-day serum half-life, a threefold higher plasma concentration in the high-dose versus low-dose group, and 0.4 and 0.3 percent reaching CSF in the high and low-dose groups, respectively. None of the patients developed anti-BIIB054 antibodies.
According to Biogen, BIIB054 formed plasma complexes with α-synuclein in both cohorts. Both doses formed similar amounts of complex, suggesting saturation of blood synuclein with antibody. BIIB054 is more selective for aggregated than soluble α-synuclein, but at high doses binds soluble protein, according to Biogen. No serious adverse events were reported, and trial results were subsequently published (May 2018 conference news; Brys et al., 2019).
In December 2017, Biogen started SPARK, a two-year Phase 2 trial in an estimated 311 people with PD. Year one will compare monthly infusions of three doses of BIIB054—250mg, 1,250mg, or 3,500mg—to placebo to evaluate safety, pharmacodynamic effects on nigrostriatal dopaminergic nerve terminals, pharmacokinetics and immunogenicity of BIIB054. In year two, placebo recipients will switch to receive BIIB054 as well. Primary outcome measures include adverse events, clinical labs, vital signs, neurological exam, as well as EKG and MRI. Secondary measures are I123 SPECT (DaTscan), BIIB054 serum concentration, and percent of participants generating anti-BIIB054 serum antibodies. The trial is running at 75 sites in the U.S., Canada, and Europe; enrollment is complete. The one-year placebo-controlled treatment period will end in May 2020, with trial completion planned for summer 2021.
In March 2019, a Phase 1 trial in 24 people with Parkinson's started at nine sites in Japan.
For all trials on this antibody, see clinicaltrials.gov.
Last Updated: 01 Nov 2019
- α-Synuclein Antibodies Enter Phase 2, Sans Biomarker
- New Alzheimer’s and Parkinson’s Immunotherapy Data at AAN
- Brys M, Fanning L, Hung S, Ellenbogen A, Penner N, Yang M, Welch M, Koenig E, David E, Fox T, Makh S, Aldred J, Goodman I, Pepinsky B, Liu Y, Graham D, Weihofen A, Cedarbaum JM. Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054. Mov Disord. 2019 Aug;34(8):1154-1163. Epub 2019 Jun 17 PubMed.
- Weihofen A, Liu Y, Arndt JW, Huy C, Quan C, Smith BA, Baeriswyl JL, Cavegn N, Senn L, Su L, Marsh G, Auluck PK, Montrasio F, Nitsch RM, Hirst WD, Cedarbaum JM, Pepinsky RB, Grimm J, Weinreb PH. Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models. Neurobiol Dis. 2019 Apr;124:276-288. Epub 2018 Oct 28 PubMed.
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