Synonyms: ION859, IONIS-BIIB7Rx
Therapy Type: DNA/RNA-based
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Biogen, IONIS Pharmaceuticals
This drug is an antisense oligonucleotide (ASO). It binds the mRNA for leucine-rich repeat kinase 2 and mediates its degradation. This results in lower LRRK2 protein levels. BIIB094 is being developed to treat Parkinson’s disease.
Also known as Dardarin, LRRK2 is a large, multidomain protein containing serine and threonine kinase activity. Kinase-activating mutations in the LRRK2 gene are the most frequent genetic cause of inherited PD (reviewed in Schneider and Alcalay, 2020). Other LRRK2 variants are associated with higher risk of sporadic PD, and there is some evidence for LRRK2 kinase activation in idiopathic PD (Di Maio et al., 2018). Increased LRRK2 kinase activity impairs vesicle trafficking and lysosome function, and promotes neuroinflammation, processes that contribute to PD pathogenesis (reviewed by Taylor and Alessi, 2020; Shutinoski et al., 2019; Sept 2018 news). Multiple companies are pursing small-molecule LRRK2 inhibitors to treat PD. BIIB094 is the first antisense approach in clinical trials.
In preclinical models, intracerebral injection of LRRK2 ASOs reduced LRRK2 protein levels in brain. In a mouse model of α-synuclein fibril infection into the brain, treatment with LRRK2 ASOs lessened fibril formation by endogenous α-synuclein and dopaminergic neuron loss while improving grip strength (Zhao et al., 2017). Intracerebral injection did not reduce LRRK2 mRNA in kidney or lungs, a concern with systemic inhibitors (Fuji et al., 2015; April 2020 news).
In August 2019, a Phase 1 safety trial began evaluating BIIB094 in people with Parkinson’s disease. It will enroll 62 participants, with or without a PD-related LRRK2 mutation, for an intrathecal injection of a single dose, or multiple doses, of drug or placebo. The study will tally the number of participants with adverse events or serious adverse events for up to one year after injection. Secondary outcomes include pharmacokinetics of the ASO in blood. The trial will run through January 2022 at 15 centers in North America, Spain, Norway, the U.K., and Israel.
For details on BIIB094 trials, see clinicaltrials.gov.
Last Updated: 19 May 2020
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- LRRK2 Mutation Fires Up Immune Response, Harms Brain
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