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Clinical Trial
. 2023 Jul;38(7):1197-1208.
doi: 10.1002/mds.29346. Epub 2023 May 17.

A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator

Jonas M den Heijer  1   2 , Annelieke C Kruithof  1   2 , Matthijs Moerland  1   2 , Mike Walker  3 , Lindsay Dudgeon  4 , Craig Justman  4 , Imelda Solomini  4 , Leslie Splitalny  4 , Nancy Leymarie  4 , Kshitij Khatri  4 , Valerie C Cullen  4 , Dana C Hilt  4 , Geert Jan Groeneveld  1   2 , Peter Lansbury  4   5
Affiliations
Clinical Trial

A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator

Jonas M den Heijer et al. Mov Disord. 2023 Jul.

Abstract

Background: Loss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease-modifying therapy. LTI-291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase.

Objectives: This first-in-patient study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of 28 daily doses of LTI-291 in GBA-PD.

Methods: This was a randomized, double-blind, placebo-controlled trial in 40 GBA-PD participants. Twenty-eight consecutive daily doses of 10, 30, or 60 mg of LTI-291 or placebo were administered (n = 10 per treatment allocation). Glycosphingolipid (glucosylceramide and lactosylceramide) levels were measured in peripheral blood mononuclear cells (PBMCs), plasma, and cerebrospinal fluid (CSF), and a test battery of neurocognitive tasks, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale and the Mini-Mental State Exam, were performed.

Results: LTI-291 was generally well tolerated, no deaths or treatment-related serious adverse events occurred, and no participants withdrew due to adverse events. Cmax , and AUC0-6 of LTI-291 increased in a dose-proportional manner, with free CSF concentrations equal to the free fraction in plasma. A treatment-related transient increase in intracellular glucosylceramide (GluCer) in PBMCs was measured.

Conclusion: These first-in-patient studies demonstrated that LTI-291 was well tolerated when administered orally for 28 consecutive days to patients with GBA-PD. Plasma and CSF concentrations that are considered pharmacologically active were reached (ie, sufficient to at least double GCase activity). Intracellular GluCer elevations were detected. Clinical benefit will be assessed in a larger long-term trial in GBA-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: clinical trial; disease modification; genetic; glucosylceramidase beta; parkinsonism.

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References

    1. Kalia LV, Lang AE. Parkinson's disease. Lancet 2015;386(9996):896-912. https://doi.org/10.1016/s0140-6736(14)61393-3
    1. Gan-Or Z, Amshalom I, Kilarski LL, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 2015;84(9):880-887. https://doi.org/10.1212/wnl.0000000000001315
    1. Gasser T. Usefulness of genetic testing in PD and PD trials: a balanced review. J Parkinsons Dis 2015;5(2):209-215. https://doi.org/10.3233/JPD-140507
    1. den Heijer JM, Cullen VC, Quadri M, et al. A large-scale full GBA1 gene screening in Parkinson's disease in The Netherlands. Mov Disord 2020a;35(9):1667-1674. https://doi.org/10.1002/mds.28112
    1. Ruskey JA, Greenbaum L, Ronciere L, et al. Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease. Eur J Med Genet 2019;62(1):65-69. https://doi.org/10.1016/j.ejmg.2018.05.005

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