Therapeutics

BIIB094

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Overview

Name: BIIB094
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

Background

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).

Findings

In August 2019, a Phase 1 safety trial began evaluating BIIB094 in people with Parkinson’s disease. It was to 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. After the trial started, two more single dose cohorts were added, increasing total enrollment to 82. The trial will run through December 2023 at 18 centers in North America, Spain, Norway, the U.K., and Israel.

For details on BIIB094 trials, see clinicaltrials.gov.

Last Updated: 12 May 2023

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References

News Citations

  1. Does LRRK2 Sweep α-Synuclein from the Cell?
  2. Sigh of Relief? Lung Effects of LRRK2 Inhibitors are Mild.

Paper Citations

  1. Schneider SA, Alcalay RN. Precision medicine in Parkinson's disease: emerging treatments for genetic Parkinson's disease. J Neurol. 2020 Mar;267(3):860-869. Epub 2020 Jan 23 PubMed.
  2. Di Maio R, Hoffman EK, Rocha EM, Keeney MT, Sanders LH, De Miranda BR, Zharikov A, Van Laar A, Stepan AF, Lanz TA, Kofler JK, Burton EA, Alessi DR, Hastings TG, Greenamyre JT. LRRK2 activation in idiopathic Parkinson's disease. Sci Transl Med. 2018 Jul 25;10(451) PubMed.
  3. Taylor M, Alessi DR. Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease. Curr Opin Cell Biol. 2020 Apr;63:102-113. Epub 2020 Feb 7 PubMed.
  4. Shutinoski B, Hakimi M, Harmsen IE, Lunn M, Rocha J, Lengacher N, Zhou YY, Khan J, Nguyen A, Hake-Volling Q, El-Kodsi D, Li J, Alikashani A, Beauchamp C, Majithia J, Coombs K, Shimshek D, Marcogliese PC, Park DS, Rioux JD, Philpott DJ, Woulfe JM, Hayley S, Sad S, Tomlinson JJ, Brown EG, Schlossmacher MG. Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci Transl Med. 2019 Sep 25;11(511) PubMed.
  5. Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB, West AB, Volpicelli-Daley LA. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017 Sep 15;8:508-519. Epub 2017 Aug 10 PubMed. Correction.
  6. Fuji RN, Flagella M, Baca M, Baptista MA, Brodbeck J, Chan BK, Fiske BK, Honigberg L, Jubb AM, Katavolos P, Lee DW, Lewin-Koh SC, Lin T, Liu X, Liu S, Lyssikatos JP, O'Mahony J, Reichelt M, Roose-Girma M, Sheng Z, Sherer T, Smith A, Solon M, Sweeney ZK, Tarrant J, Urkowitz A, Warming S, Yaylaoglu M, Zhang S, Zhu H, Estrada AA, Watts RJ. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015 Feb 4;7(273):273ra15. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Ding X, Ren F. Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present). Expert Opin Ther Pat. 2020 Apr;30(4):275-286. Epub 2020 Feb 18 PubMed.
  2. Kelly K, West AB. Pharmacodynamic Biomarkers for Emerging LRRK2 Therapeutics. Front Neurosci. 2020;14:807. Epub 2020 Aug 6 PubMed.
  3. Wojewska DN, Kortholt A. LRRK2 Targeting Strategies as Potential Treatment of Parkinson's Disease. Biomolecules. 2021 Jul 26;11(8) PubMed.