There is a high, unmet need for medicines which address the fundamental causes of Parkinson’s disease and GBA-AP.
Rather than merely providing symptomatic relief, therapies targeting the underlying biological causes could potentially slow disease progression for certain patients.
For GBA-AP patients with compromised GCase enzymatic activity, several lines of evidence suggest that pharmacological activation of the GCase enzyme could provide therapeutic benefits.
Compromised levels of GCase activity have been shown to increase Parkinson’s risk and accelerate the decline of Parkinson’s patients.
BIA 28-6156 is the first activator of the GCase enzyme to have been tested in clinical studies. It is designed to target the GCase enzyme to increase activity and improve glycosphingolipid metabolism in the lysosome. Preclinical studies have shown that BIA 28-6156 easily crosses the blood-brain-barrier and accesses the GCase enzyme within the brain and central nervous system. BIA 28-6156 is under development as a novel, first-in-class drug compound for the potential treatment of patients with GBA-AP.
Several studies in human cell-based systems and animal models with compromised GCase activity have shown that administration of BIA 28-6156 restores the glycosphingolipid metabolism and lysosomal function. The effect of BIA 28-6156 mediated GCase activation is more profound when the GCase enzyme activity is more impaired. BIA 28-6156 normalized glycosphingolipid levels in a number of model systems.
Our clinical development program has progressed through the first stages of human clinical trials, including in healthy volunteers and GBA-AP patients. Based on the findings observed, the company is preparing the program for more advanced clinical development.
In addition to understanding the impact of homozygous mutations, the medical community is also now understanding the impact of heterozygous mutations of one of the two gene copies. Carrying a single mutant copy of the GBA1 gene causes moderately compromised GCase activity, resulting in 50% to 80% of normal enzyme activity. These heterozygous mutations are associated with a higher risk for developing Parkinson’s disease. Approximately 10% of the overall patient population in the U.S. with clinically diagnosed Parkinson’s disease carries a GBA1 mutation2. The numbers are similar in Europe and in various other countries around the world. In certain populations, such as those of Ashkenazi Jewish descent, up to 30% of PD patients carry a mutant copy of the GBA1 gene. In addition, GBA mutations have been reported as the most common genetic risk factor for other neurological conditions such as Lewy body dementia (LBD)3, which is the second most common form of dementia after Alzheimer’s disease.
Reports in 2004 were the first to describe that a mutation in one copy of the GBA1 gene is firmly associated with an increased lifetime risk of developing Parkinson’s disease. Since then, more than 250 different GBA1 mutations have been identified and categorized4 from “mild to severe” with each having a different compromising effect on GCase enzyme activity ranging from slight to major. Recent clinical research has not only shown that GBA1-carrying PD patients progress faster in their disease course than idiopathic PD patients (PD that does not have a known genetic cause), but has revealed a strong correlation between the severity of the mutation and the rate of disease progression. BIA 28-6156, which increases GCase activity, could potentially reduce the rate of symptom progression for these patients.
PD patients who carry the GBA1 mutation, also referred to as GBA-associated parkinsonism (GBA-AP), typically show the classic symptoms of PD, including slow movements and stiffness. While they might be indistinguishable from patients with iPD, patients with GBA-AP often manifest at a younger age, may progress more rapidly and may experience earlier and more significant cognitive (memory or thinking) impairment.
den Heijer J, Schmitz A, Lansbury P, Cullen V, Hilt D, Bonifati V & Jan Groeneveld G
Published: Nature Research Vol.:(0123456789) Scientific Reports volume 11, Article number: 161 (2021)
Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors
Di Martino S, Tardia P, Cilibrasi V, Lansbury P, Liu M, Skerlj R, etc.
Published: J. Med. Chem. 2020, 63, 3634−3664, Publication Date: March 16, 2020
Design, Synthesis, and Biological Evaluation of a Series of Oxazolone Carboxamides as a Novel Class of Acid Ceramidase Inhibitors
Caputo S, Di Martino S, Cilibrasi V, Tardia P, Mazzonna M, Russo D, Lansbury P, Liu M, etc.
Published: J. Med. Chem. 2020, 63, 24, 15821–15851, Publication Date: December 8, 2020
den Heijer J, Cullen V, Quadri M, Schmitz A, Hilt D, Lansbury P, etc.
Published: Movement Disorders 02 July 2020 https://doi.org/10.1002/mds.28112
A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator
den Heijer J, Kruithof A, van Amerongen G, de Kam M, Thijssen E, Grievink H, Moerland M, Walker M, Been K, Skerlj R, Justman C, Dudgeon L, Lansbury P, Cullen V, Hilt D, Jan Groeneveld G
Published: 11 February 2021 https://doi.org/10.1111/bcp.14772
1- Schulze, H., & Sandhoff, K. (2011). Lysosomal Lipid Storage Diseases. Cold Spring Harbor Perspectives in Biology, 3(6), a004804. http://doi.org/10.1101/cshperspect.a004804
2- Liu, G., Boot, B., Locascio, J. J., Jansen, I. E., Winder-Rhodes, S., Eberly, S., Elbaz, A., Brice, A., Ravina, B., van Hilten, J. J., Cormier-Dequaire, F., Corvol, J.-C., Barker, R. A., Heutink, P., Marinus, J., Williams-Gray, C. H., Scherzer, C. R. and for the International Genetics of Parkinson Disease Progression (IGPP) Consortium (2016), Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. Ann Neurol., 80: 674–685. http://doi.org/10.1002/ana.24781
3- Tsuang, D., Leverenz, J. B., Lopez, O. L., Hamilton, R. L., Bennett, D. A., Schneider, J. A., … Zabetian, C. P. (2012). GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology, 79(19), 1944–1950. http://doi.org/10.1212/WNL.0b013e3182735e9a
4- Gan-Or, Z., Amshalom, I., Kilarski, L. L., Bar-Shira, A., Gana-Weisz, M., Mirelman, A., … Orr-Urtreger, A. (2015). Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology, 84(9), 880–887. http://doi.org/10.1212/WNL.0000000000001315
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