Treatment of Parkinson's disease in patients using glucocerebrosidase activators

Abstract

Provided is a method for preventing, limiting, or delaying the progression of clinical motor symptoms in a Parkinson's disease subject with low GCase activity, e.g., a PD patient with a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), comprising administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide for use in the treatment or prevention of Parkinson's disease. [Background technology]

[0002] Parkinson's disease (PD) is a multicentric neurodegenerative disorder characterized pathologically by the loss of dopaminergic neurons in the substantia nigra pars compacta and other brainstem nuclei, and by the presence of Lewy bodies and alpha-synuclein (SNCA) aggregates in neurites.

[0003] GCase, encoded by the GBA1 gene, is an enzyme involved in the hydrolysis of glucosylceramide (GluCer) to glucose and ceramide in lysosomes. Dysfunction of GCase activity is associated with Parkinson's disease. GCase mutations are known to be a major risk factor for the development of PD. Loss of GCase function contributes to the pathogenesis of PD, even independent of gene mutations.

[0004] Carrying even a single mutant allele of GBA1 significantly increases the lifetime risk of developing PD. Approximately 10%-15% of patients clinically diagnosed with PD (GBA-PD) have a GBA1 pathogenic variant. The magnitude of the increased risk of being diagnosed with PD conferred by a heterozygous pathogenic variant depends on the magnitude of the reduction in GCase activity and can range from 2.2- to 19.2-fold. This increased risk for PD has been documented for over 100 GBA1 pathogenic variants in large cohorts from the United States (Grabowski, 2008), Israel (Guimaraes, 2012), Sweden (Jesus, 2016), Spain (Liu, 2016), the United Kingdom (Mata, 2016), Greece (Moraitou, 2011), China (Neudorfer, 1996), and South America (Neumann, 2009), as well as in various meta-analyses (Gan-Or, 2015). In Israel, approximately 20%-30% of patients with PD and Ashkenazi Jewish background are carriers of a GBA1 pathogenic variant. Therefore, pathogenic variants in GBA1 are the most common genetic risk factor for PD in various clinical conditions.

[0005] As a group, GBA-PD patients generally have a distinct clinical course compared with idiopathic PD patients (i.e., those without GBA1 pathogenic variants). On average, GBA-PD patients present at an earlier age of onset (Grabowski, 2008; Gan-Or, 2015). They exhibit relatively more prominent postural instability / gait disturbance than tremor, and their disease is characterized by frequent falls. GBA-PD patients typically progress more rapidly than idiopathic PD (iPD) patients (Gan-Or, 2008; Ran, 2016), and, on average, their survival from the time of diagnosis is shorter (Rosenbloom, 2011). GBA-PD patients also exhibit more frequent cognitive impairment than iPD patients, with more rapid progression to dementia (Rosenbloom, 2013; Pal, 2016; Ran, 2016). GBA-PD is further characterized by higher prevalence of depression, anxiety, hallucinations, and REM sleep behavior disorder (Liu, 2016; Mata, 2016). Among the many known genetic risk factors for PD, only GBA1 has recently been reported to increase the rate of disease progression (Tan, 2021).

[0006] Despite this, low / reduced GCase activity has also been observed in certain PD patients who do not have GBA1 pathogenic variants (e.g., wild-type GBA1-PD patients) (Moloney, 2021).

[0007] 5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (also referred to herein as "Compound A") is an allosteric activator of the enzyme beta-glucocerebrosidase (GCase). Compound A is therefore a potential treatment for Parkinson's disease (PD) for patients with mutations in the GBA1 gene (GBA-PD), and more generally for patients with low / reduced GCase activity who may benefit from treatment options that increase GCase activity.

[0008] Compound A has been shown to be safe for administration to healthy humans (JM den Heijer, 2021). The compound was generally well tolerated, with no treatment-related serious adverse events or deaths, and no subjects have withdrawn from the study due to adverse events to date in the clinical development program.

[0009] Currently available drug therapies for PD primarily target the dopaminergic system and alleviate motor symptoms without addressing non-motor symptoms or otherwise affecting / modifying disease progression. Despite promising results in various preclinical studies of PD disease-modifying agents, no successful clinical disease-modifying agents exist. Similarly, attempts have been made to modify disease progression in GBA-PD patients, but no successful clinical candidates exist. For example, MOVES-PD was a global Phase 2 study to evaluate the efficacy and safety of the drug candidate benglustat in Parkinson's patients with GBA-1 gene mutations. Despite promising preclinical studies, when final data were collected, the results of the study indicated that the drug had no effect on slowing the progression of the condition (Peterschmitt et al., 2021a,b).

[0010] This leaves a large unmet need for disease-modifying Parkinson's treatments.

[0011] Additionally, there is a need for methods for administering Compound A to patients in need thereof, where the patients are also receiving other concomitant medications. The present disclosure meets these and other needs, as will become apparent with reference to the disclosure below. Summary of the Invention

[0012] In a first aspect, the present invention describes Compound A or a pharmaceutically acceptable salt thereof for use in preventing or limiting the progression of clinical motor symptoms in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale. In certain embodiments, the progression of clinical motor symptoms is also assessed using the modified Hoehn-Jahr scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39) score, and / or the EuroQol 5 Dimension 5 Level (EQ-5D-5L) score.

[0013] In a further aspect of the present invention, a method is described for preventing or limiting the progression of clinical motor symptoms in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. The progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale. In certain embodiments, the progression of clinical motor symptoms is also assessed using the Modified Hoehn-Jahr scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39) score, and / or the EuroQol 5 Dimension 5 Level (EQ-5D-5L) score.

[0014] Many studies have been conducted to prevent or limit the progression of clinical motor symptoms in Parkinson's disease subjects by activating GCase, but despite successful ex vivo studies demonstrating effective activation of GCase, no evidence has been found to prevent or limit the progression of clinical motor symptoms in Parkinson's disease subjects.

[0015] It should also be noted that despite the success of disease-modifying interventions in preclinical models, this has not translated into significant clinical success. No commercially available medication has the ability to halt, prevent, or reduce the progression of clinical motor symptoms in PD. While not wishing to be bound by theory, it is postulated that one reason for the failure to translate preclinical success into clinical success is the existence of multiple different PD pathophysiologies and heterogeneity among individual patients. This makes clinical success extremely difficult to predict. Recent failed trials include the various NET-PD trials (Tilley and Galpern, 2007), the ADAGIO trial (Rascol et al., 2016), and more recent α-synuclein immunotherapy trials (ClinicalTrials.gov, 2021), and the benglustat trial (Peterschmitt et al., 2021a, b).

[0016] The present invention stems from the finding that Compound A may be effective in preventing, limiting, or slowing the progression of motor symptoms in certain PD subjects, particularly PD patients with reduced, decreased, or low GCase activity, e.g., GBA-PD patients. That is, Compound A may treat the underlying pathology of PD in these patients, rather than simply treating the symptoms of PD.

[0017] The treatment involves Parkinson's disease (GBA-PD) subjects with pathogenic variants in the glucocerebrosidase 1 (GBA1) gene. Numerous pathological / pathogenic mutations in the GBA1 gene that affect the activity of the GCase enzyme are known. Pathological / pathogenic mutations in the GBA1 gene include, but are not limited to, N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, and R120W. Frequent / severe mutations include, but are not limited to, heterozygotes for D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, and R120W. Infrequent / mild mutations include, but are not limited to, heterozygotes for T369M or E326K. Further information regarding subjects heterozygous for a pathogenic variant in the GBA1 gene is provided below.

[0018] Additional pathological / pathogenic variants in the GBA1 gene include, but are not limited to, those contained in the table in Appendix 1, including, but not limited to, the GBA1 gene containing one of the following nucleotide variants: NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G >A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_00100 5741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1297G>T, NM_001005741.3:c.721G> A, NM_001005741.3: c.259C>T, NM_001005741.3: c.928A>G, NM_001005741.3: c.764T>A, NM_001005741.3: c.1246G>A, NM_001005741.3: c.946C>T, NM_001005741.3: c.26_27del, NM_001005741.3: c.604C>T, NM_001005741.3: c.1090G>A, NM_001005741.3: c.1296G>A, NM_001005741.3: c.1192C>T, NM_001005741.3: c.914del, NM_001005741.3: c.256C>T, NM_001005741.3: c.586A>C, NM_001005741.3: c.1312G>A, NM_001005741.3: c.203dup, NM_001005741.3: c.475C>T, NM_001005741.3: c.476G>A, NM_001005741.3: c.887G>A, NM_001005741.3: c.762-1G>C, NM_001005741.3: c.115+1G>A, NM_001005741.3: c.1505+1G>T, NM_001005741.3: c.123_217del, NM_001005741.2: c.1265_1319del, NM_001005741.3: c.715C>T, NM_001005741.3: c.1085C>T, NM_001005741.3: c.413del, NM_001005741.3: c.882T>G, NM_001005741.3: c.1193G>A and NM_001005741.3: c.1_2344del.

[0019] In some embodiments, this includes, but is not limited to, a GBA1 gene containing one of the following nucleotide mutations: NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C ...448T>C, NM_001005741.3:c.1448T>C, NM_001005741.3:c.1448T>C, NM_001005741.3:c.1448T>C, NM_00100 05741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_001005741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.129 7G>T, NM_001005741.3:c.721G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, NM_001005 741.3:c.1246G>A, NM_001005741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_001005741.3:c.604C>T, NM_001005741.3:c.10 90G>A, NM_001005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741.3:c.914del, NM_001005741.3:c.256C>T, NM_001 005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_001005741.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.47 6G>A, NM_001005741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, and NM_001005741.3:c.1505+1G>T.High frequency / severe sudden change, limited number, NM_001005741.3:c.1448T>C, NM_001005741.3:c.1342G>C, NM_00100 5741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_001005741.3:c.84dup, NM_001005741.3:c. 754T>A, NM_001005741.3:c.1297G>T, NM_001005741.3:c.721G>A, NM_001005741.3:c.1246G>A, NM_001005741.3:c.26_27del, NM_001005741.3:c.604C>T, NM_001005741.3:c.1090G>A, NM_00. 1005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741.3:c.9 14del、NM_001005741.3:c.256C>T、NM_001005741.3:c.586A>C、NM_001005 741.3:c.1312G>A, NM_001005741.3:c.203dup, NM_001005741.3:c.475C>T , NM_001005741.3:c.476G>A, NM_001005741.3:c.887G>A, NM_001005741.3: c.762-1G>C, NM_001005741.3:c.115+1G>A, NM_001005741.3:c.1505+1G>T, NM_001005741.3:c.123_217del, NM_001005741.2:c.1265_1319del, NM_0 01005741.3:c.715C>T、NM_001005741.3:c.1085C>T、NM_001005741.3:c.4 13del, NM_001005741.3:c.882T>G and NM_001005741.3:c.1_2344del.

[0020] In some embodiments, frequent / severe mutations include, but are not limited to, NM_001005741.3:c.1448T>C, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_001005741.3:c.84dup, NM_001005741.3:c.1606C>T ... 05741.3:c.754T>A, NM_001005741.3:c.1297G>T, NM_001005741.3:c.721G>A, NM_001005741.3:c .1246G>A, NM_001005741.3:c.26_27del, NM_001005741.3:c.604C>T, NM_001005741.3:c.1090G>A , NM_001005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741.3:c.914del, NM_0010 05741.3:c.256C>T, NM_001005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_001005741.3:c. 203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.476G>A, NM_001005741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, and NM_001005741.3:c.1505+1G>T. Low frequency / mild mutations include, but are not limited to, NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1604G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, NM_001005741.3:c.946C>T, and NM_001005741.3:c.1193G>A.In some embodiments, infrequent / mild mutations include, but are not limited to, NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1604G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, and NM_001005741.3:c.946C>T.

[0021] With respect to the GCase amino acid sequence, pathological / pathogenic mutations in the GCase amino acid sequence include, but are not limited to, those contained in the table in Appendix 1. This includes, but is not limited to, the GBA1 gene encoding the GCase enzyme containing one of the following amino acid mutations: p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Leu483Pro, p.Arg535His, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Ala. fs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg, p.Arg87Trp, p.Ser310Gly, p.Phe255Tyr, p.Gly416Ser, p.Arg316Cys, p.Glu9G lyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, p.Asp438Asn, p.Thr69Asp fs*12, p.Arg159Trp, p.Arg159Gln, p.Arg296Gln, p.Pro42Trpfs*7, p.Pro42TrpfsTer7, p.Leu422ProfsTer4, p.Leu422Profs*4, p .Gln239*, p.Gln239Ter, p.Thr362Ile, p.Pro138Leufs*62, p.Pro138LeufsTer62, p.His294Gln, p.Arg398Gln and p.Met1_*537del. In some embodiments, this includes, but is not limited to, a GBA1 gene encoding a GCase enzyme containing one of the following amino acid mutations: p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Leu483Pro, p.Arg535His, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg , p.Arg87Trp, p.Ser310Gly, p.Phe255Tyr, p.Gly416Ser, p.Arg316Cys, p.Glu9Glyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Ar g398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, p.Asp438Asn, p.Thr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, and p.Arg296Gln.Frequent / severe mutations include, but are not limited to, p.Leu483Pro, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg, p.Gly416Ser, p.Glu9Glyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, and p.A sp438Asn, p.Thr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, p.Arg296Gln, p.Pro42Trpfs*7, p.Pro42TrpfsTer7, p.Leu422ProfsTer4, p.Leu422Profs*4, p.Gln239*, p.Gln239Ter, p.Thr362Ile, p.Pro138Leufs*62, p.Pro138LeufsTer62, p.His294Gln and p.Met1_*537del.

[0022] In some embodiments, frequent / severe mutations include, but are not limited to, p.Leu483Pro, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg, p.Gly416Ser, p.Glu9Glyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, p.Asp438Asn, p.Thr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, and p.Arg296Gln. Infrequent / mild mutations include, but are not limited to, p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Arg535His, p.Arg87Trp, p.Ser310Gly, p.Phe255Tyr, p.Arg316Cys, and p.Arg398Gln. In some embodiments, infrequent / mild mutations include, but are not limited to, p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Arg535His, p.Arg87Trp, p.Ser310Gly, p.Phe255Tyr, and p.Arg316Cys.

[0023] In the above and additional embodiments below, Compound A is used or administered to a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene. The subject will have two alleles of the GBA1 gene, neither of which affects the total GCase activity in the subject's cells. Thus, in some embodiments, the subject is heterozygous for the GBA1 gene, with one allele containing a pathogenic variant and one allele that is non-pathogenic (e.g., a wild-type allele for the GBA1 gene). In other embodiments, the subject is heterozygous for the GBA1 gene, with one deletion allele (i.e., a complete gene deletion) and one allele that is non-pathogenic (e.g., a wild-type allele for the GBA1 gene). In the present disclosure, the term "heterozygous," when the second allele is not defined, should be interpreted to mean that the second allele is non-pathogenic (e.g., a wild-type allele). This is in contrast to the term "compound heterozygous," which is used to mean that both alleles of the GBA1 gene contain at least one pathogenic variant, and the pathogenic variants are not the same between the two alleles. The term "homozygous" means that both alleles of the GBA1 gene contain the same pathogenic variant(s).

[0024] In some embodiments, the subject is heterozygous for the GBA1 gene having one allele containing one of the following nucleotide variations: NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_00100 5741.3:c.1504C>T, NM_001005741.3:c.84dup, NM_001005741.3:c.754T> A, NM_001005741.3:c.1297G>T, NM_001005741.3:c.721G>A, NM_001005741 .3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, NM _001005741.3:c.1246G>A, NM_001005741.3:c.946C>T, NM_001005741.3:c .26_27del, NM_001005741.3:c.604C>T, NM_001005741.3:c.1090G>A, NM_ 001005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741.3:c .914del, NM_001005741.3:c.256C>T, NM_001005741.3:c.586A>C, NM_001 005741.3:c.1312G>A, NM_001005741.3:c.203dup, NM_001005741.3:c.475 C>T, NM_001005741.3:c.476G>A, NM_001005741.3:c.887G>A, NM_0010057 41.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, NM_001005741.3:c.1505 +1G>T, NM_001005741.3:c.123_217del, NM_001005741.2:c.1265_1319del , NM_001005741.3:c.715C>T, NM_001005741.3:c.1085C>T, NM_001005741.3:c.413del, NM_001005741.3:c.882T>G, NM_001005741.3:c.1193G>A, and NM_001005741.3:c.1_2344del (the other allele is non-pathogenic).

[0025] In some embodiments, the subject is heterozygous for the GBA1 gene having one allele containing one of the following nucleotide variations: NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c .1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005 741.3:c.1504C>T, NM_001005741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1297G>T, NM_00 1005741.3:c.721G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, N M_001005741.3:c.1246G>A, NM_001005741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_001005741.3:c.60 4C>T, NM_001005741.3:c.1090G>A, NM_001005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741 .3:c.914del, NM_001005741.3:c.256C>T, NM_001005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_00100 5741.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.476G>A, NM_001005741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, and NM_001005741.3:c.1505+1G>T (the other allele is non-pathogenic). The subject may also be homozygous for the GBA1 gene with either the pathogenic variant NM_001005741.3:c.1093G>A or the pathogenic variant NM_001005741.3:c.1223C>T.

[0026] With respect to the GCase amino acid sequence, a subject may be heterozygous for the GBA1 gene having one allele encoding a GCase enzyme containing one of the following amino acid mutations: p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Leu483Pro, p.Arg535His, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg, p.Arg87Trp, p.Ser310Gly, p.Phe255Tyr, p.Gly416Ser, p.Arg316Cys, p.Glu9Glyfs*8, p.Arg202*, p.Gly 364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, p.Asp438Asn, p.T hr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, p.Arg296Gln, p.Pro42Trpfs*7, p.Pro42TrpfsTer7 , p.Leu422ProfsTer4, p.Leu422Profs*4, p.Gln239*, p.Gln239Ter, p.Thr362Ile, p.Pro138Leufs*62, p.Pro138LeufsTer62, p.His294Gln, p.Arg398Gln, and p.Met1_*537del (the other allele is non-pathogenic).In some embodiments, a subject may be heterozygous for the GBA1 gene having one allele encoding a GCase enzyme containing one of the following amino acid mutations: p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Leu483Pro, p.Arg535His, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg, p. The amino acid mutations are: Arg87Trp, p.Ser310Gly, p.Phe255Tyr, p.Gly416Ser, p.Arg316Cys, p.Glu9Glyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, p.Asp438Asn, p.Thr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, and p.Arg296Gln (the other allele is non-pathogenic). The individual may be homozygous for the GBA1 gene, having both alleles encoding the GCase enzyme containing p.Glu365Lys or p.Thr408Met.

[0027] In a further aspect of the present invention, Compound A or a pharmaceutically acceptable salt thereof is described for use in preventing and / or delaying the progression of clinical motor symptoms in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0028] In a further aspect of the present invention, a method is described for preventing and / or delaying the progression of clinical motor symptoms in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0029] In another aspect of the present invention, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in treating Parkinson's disease in subjects with a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD).

[0030] In a related aspect of the present invention, a method of treating Parkinson's disease in a subject having a pathogenic variant in the glucocerebrosidase (GBA1) gene is described, comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0031] In a further aspect of the present invention, Compound A or a pharmaceutically acceptable salt thereof is described for use in preventing or delaying cognitive impairment in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0032] In a related aspect of the present invention, a method is described for preventing or delaying cognitive impairment in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0033] In another aspect of the invention, there is provided Compound A, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2.

[0034] In a related aspect of the invention, a method is described for treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0035] Pathogenic / pathogenic variants in the LRRK2 gene include, but are not limited to, G2019S, G2385R, R1628P, and A419V. Pathogenic variants in LRRK2 are associated with hereditary sporadic PD. In a preferred embodiment, the subject does not have a PD-associated pathogenic variant in the LRRK2 gene selected from N1437H, R1441C, R1441H, and G2019S.

[0036] A further aspect of the present invention provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have Gaucher disease.

[0037] A related aspect of the invention provides a method for treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have Gaucher disease, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0038] Gaucher disease is a genetic disorder characterized by the accumulation of glucosylceramide (GluCer) in cells and certain organs. It is thought to be caused by a genetic defect in the GBA1 gene. Homozygous pathogenic variants in the GBA1 gene, leading to a significant reduction in enzymatic activity, can cause Gaucher disease, a chromosomal recessive peripheral lysosomal storage disorder resulting from impaired catabolism of glycosphingolipids in lysosomes (Clark, 2007; Cilia, 2016). This, in turn, leads to abnormal substrate accumulation and, thereby, dysfunction in cell signaling pathways, calcium homeostasis, and intracellular trafficking. Manifestations of Gaucher disease include dysfunction in various tissues, most notably the viscera, bone, and bone marrow, and, rarely (types 2 and 3), the brain (Cilia, 2016). For the disease to manifest, patients must have pathogenic mutations in both alleles of the GBA gene, either homozygous or compound heterozygous. An exception to this is when a patient is homozygous for the GBA1 mutation NM_001005741.3:c.1093G>A (E326K) or NM_001005741.3:c.1223C>T (T369M), which are observed in GBA-PD patients but not in GD patients. GCase pathogenic variants that cause GD are those that lead to a substantial reduction in enzyme activity (severe pathogenic variants), which can lead to a reduction of GCase activity of about 60%, about 70%, about 80%, about 90%, or more. Identification of patients with Gaucher disease is well known to those of skill in the art. For example, it can be diagnosed based on clinical signs and symptoms (e.g., hepatosplenomegaly, cytopenias, bone disease) and / or a history of significant deficiency in GCase activity corresponding to Gaucher disease (e.g., GCase activity of less than about 40%, less than about 30%, less than about 20%, or less than about 10% of that of a healthy subject or a representative sample of healthy subjects).

[0039] In another aspect, the present invention provides Compound A, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or who is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

[0040] Pathogenic variants associated with Gaucher disease include, but are not limited to, heterozygous p.L483P and p.S310G mutations, and homozygous mutations N370S, L444P, 84GG, and IVS2+1.

[0041] In some embodiments, the pathogenic variant associated with a subject with Gaucher disease is These include, but are not limited to, subjects who are homozygous for a GBA1 pathogenic variant or who are compound heterozygous for two GBA1 pathogenic variants, where the variant(s) is one of the following nucleotide variations: NM_001005741.3:c.1226A>G (N370S), NM_001005741.3:c.1342G>C (D409H), H255Q, D140H, G202R, L324P, I260T, NM_001005741.3:c.1448T>C (L444P), A190T, and R120W.

[0042] Additionally, pathogenic variants associated with subjects having Gaucher disease include, but are not limited to, subjects homozygous for the GBA1 gene containing one of the following nucleotide variations: NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_001005741.3:c. c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1297G>T, NM_00 1005741.3:c.721G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.92 8A>G, NM_001005741.3:c.764T>A, NM_001005741.3:c.1246G>A, NM_00100 5741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_001005741.3:c.604C >T, NM_001005741.3:c.1090G>A, NM_001005741.3:c.1296G>A, NM_001005 741.3:c.1192C>T, NM_001005741.3:c.914del, NM_001005741.3:c.256C> T, NM_001005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_00100574 1.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.476G>A, NM _001005741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3 :c.115+1G>A, NM_001005741.3:c.1505+1G>T, NM_001005741.3:c.123_21 7del, NM_001005741.2:c.1265_1319del, NM_001005741.3:c.715C>T, NM_001005741.3:c.1085C>T, NM_001005741.3:c.413del, NM_001005741.3:c.In some embodiments, pathogenic variants associated with subjects with Gaucher disease include, but are not limited to, subjects homozygous for the GBA1 gene containing one of the following nucleotide variations: NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604 G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_00 1005741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1297G>T, NM_001005741.3:c .721G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, NM_ 001005741.3:c.1246G>A, NM_001005741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_00100574 1.3:c.604C>T, NM_001005741.3:c.1090G>A, NM_001005741.3:c.1296G>A, NM_001005741.3:c.119 2C>T, NM_001005741.3:c.914del, NM_001005741.3:c.256C>T, NM_001005741.3:c.586A>C, NM_001. 005741.3:c.1312G>A, NM_001005741.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.476G>A, NM_0010 05741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, and NM_001005741.3:c.1505+1G>T.

[0043] Pathogenic variants associated with subjects with Gaucher disease also include, but are not limited to, subjects who are compound heterozygous for two GBA1 genes containing one of the following nucleotide variations: NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_00100 5741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1297G> T, NM_001005741.3:c.721G>A, NM_001005741.3:c.259C>T, NM_001005741. 3:c.928A>G, NM_001005741.3:c.764T>A, NM_001005741.3:c.1246G>A, NM _001005741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_001005741.3: c.604C>T, NM_001005741.3:c.1090G>A, NM_001005741.3:c.1296G>A, NM_ 001005741.3:c.1192C>T, NM_001005741.3:c.914del, NM_001005741.3:c. 256C>T, NM_001005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_001 005741.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.476G >A, NM_001005741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005 741.3:c.115+1G>A, NM_001005741.3:c.1505+1G>T, NM_001005741.3:c.12 3_217del, NM_001005741.2:c.1265_1319del, NM_001005741.3:c.715C>T, NM_001005741.3:c.1085C>T, NM_001005741.3:c.413del, NM_001005741.NM_001005741.3:c.882T>G, NM_001005741.3:c.1193G>A, and NM_001005741.3:c.1_2344del. In some embodiments, pathogenic variants associated with subjects with Gaucher disease include, but are not limited to, subjects who are compound heterozygous for two GBA1 genes containing one of the following nucleotide variations: NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.160 4G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_00100 5741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1297G>T, NM_001005741.3:c.721G>A , NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, NM_001005741.3 :c.1246G>A, NM_001005741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_001005741.3:c.604C>T, NM _001005741.3:c.1090G>A, NM_001005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741.3 :c.914del, NM_001005741.3:c.256C>T, NM_001005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_. 001005741.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.476G>A, NM_001005741.3:c.8 87G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, and NM_001005741.3:c.1505+1G>T.

[0044] In a related aspect, the present invention provides a method for treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or who is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0045] Examples of compound heterozygous mutations for Gaucher disease include p.L483P and p.S310G. Further examples of GBA1 pathogenic variants associated with Gaucher disease are described above.

[0046] Another aspect of the invention describes Compound A for use in preventing or limiting the progression of clinical motor symptoms in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who do not have a PD-associated pathogenic variant in LRRK2. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0047] A related aspect of the invention describes a method of preventing or limiting the progression of clinical motor symptoms in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0048] A further aspect of the present invention describes Compound A for use in preventing or limiting the progression of clinical motor symptoms in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who do not have Gaucher disease. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0049] A related aspect of the present invention describes a method for preventing or limiting the progression of clinical motor symptoms in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and does not have Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0050] Yet another aspect of the invention relates to a patient with a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and no PD-associated pathogenic variant in LRRK2; Also described is Compound A for use in preventing or limiting the progression of clinical motor symptoms in Parkinson's disease subjects who do not also have Gaucher disease. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

[0051] A related aspect of the invention describes a method for preventing or limiting the progression of clinical motor symptoms in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression-Change (CGI-C) scale, and / or Patient Global Impression-Change (PGI-C) scale.

[0052] A further aspect of the present invention describes Compound A for use in preventing or limiting the progression of clinical motor symptoms in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), do not have a PD-associated pathogenic variant in LRRK2, and are not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or are not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression-Change (CGI-C) scale, and / or Patient Global Impression-Change (PGI-C) scale.

[0053] A further aspect of the present invention describes a method for preventing or limiting the progression of clinical motor symptoms in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society-Uniform Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression-Change (CGI-C) scale, and / or Patient Global Impression-Change (PGI-C) scale.

[0054] Another aspect of the present invention describes Compound A for use in preventing or treating Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease.

[0055] Another aspect of the present invention describes a method for preventing or treating Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), who does not have a PD-associated pathogenic variant in LRRK2, and who does not have Gaucher disease, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0056] Yet another aspect of the invention is a method for treating a patient with a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), without a PD-associated pathogenic variant in LRRK2, without Gaucher disease, and without a GBA1 pathogenic variant known to be associated with Gaucher disease. Compound A is described for use in preventing or treating Parkinson's disease in subjects who are not homozygous for a variant or compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

[0057] Yet another aspect of the present invention describes a method for preventing or treating Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, does not have Gaucher disease, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0058] A further aspect of the present invention describes Compound A for use in preventing or treating Parkinson's disease in subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), who do not have Gaucher disease, and who are not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or who are not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

[0059] A further aspect of the present invention describes a method for preventing or treating Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have Gaucher disease, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0060] Another aspect of the present invention describes Compound A for use in preventing or limiting the progression of clinical motor symptoms in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), do not have Gaucher disease, and are not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or are not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression-Change (CGI-C) scale, and / or Patient Global Impression-Change (PGI-C) scale.

[0061] Another aspect of the present invention describes a method for preventing or limiting the progression of clinical motor symptoms in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have Gaucher disease, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, the progression of clinical motor symptoms is assessed using the Movement Disorder Society-Uniform Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression-Change (CGI-C) scale, and / or Patient Global Impression-Change (PGI-C) scale.

[0062] Another aspect of the present invention provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson's disease in a subject with decreased, reduced or low GCase activity.

[0063] Another aspect of the present invention is a method of treating Parkinson's disease in a subject in need of such treatment and having decreased, reduced or low GCase activity, comprising administering to said subject a therapeutically effective amount of GCase. administering to the subject an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0064] A further aspect of the invention provides Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the progression of clinical motor symptoms in a subject having Parkinson's disease and having reduced, decreased or low GCase activity.

[0065] Another aspect of the present invention provides a method for preventing or limiting the progression of clinical motor symptoms in a subject having Parkinson's disease and having decreased, reduced or low GCase activity, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0066] An aspect of the present invention provides Compound A or a pharmaceutically acceptable salt thereof for use in preventing or delaying cognitive impairment in a subject having Parkinson's disease and having reduced, decreased or low GCase activity. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0067] A related aspect of the invention provides a method of preventing or delaying cognitive impairment in a subject with Parkinson's disease and having decreased, reduced, or low GCase activity, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0068] According to another aspect of the present invention, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in preventing motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject having Parkinson's disease and having reduced, decreased, or low GCase activity.

[0069] In a related aspect of the present invention, a method is described for preventing motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject having Parkinson's disease and having reduced, decreased, or low GCase activity, said method comprising administering to said subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0070] Motor complications may be assessed using any method known to those skilled in the art, for example, using MDS-UPDRS Part II, III, or IV. Preferably, MDS-UPDRS Part IV is used to assess motor complications. Non-motor complications may be assessed using any method known to those skilled in the art. For example, non-motor complications may be assessed using MDS-UPDRS Part I. "Non-motor complications" may also be referred to as "non-motor symptoms," which may be assessed using MDS-UPDRS Part I.

[0071] In some embodiments, decreased, reduced, or low GCase activity means that the patient's GCase activity is lower than that measured in a healthy subject or a representative sample of healthy subjects. For example, decreased, reduced, or low GCase activity may be about 10% to about 50%, or about 20% to about 50% lower than the GCase activity in a healthy subject or a representative sample of healthy subjects. In other embodiments, decreased, reduced, or low GCase activity may be less than about 20%, less than about 30%, less than about 40%, or less than about 50% lower than the GCase activity in a healthy subject or a representative sample of healthy subjects. In further embodiments, decreased, reduced, or low GCase activity may be less than the GCase activity in a healthy subject or a representative sample of healthy subjects. Alternatively, it may be about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, or about 40% to about 50% lower than the GCase activity in a representative sample of healthy subjects.

[0072] In some embodiments, decreased, reduced, or low GCase activity means that the GCase activity is equal to or comparable to the activity measured in GBA-PD patients or a representative sample of GBA-PD patients. For example, decreased, reduced, or low GCase activity may be about 80% to about 120%, about 90% to about 110%, or about 95% to about 105% of the GCase activity found in GBA-PD patients or a representative sample of GBA-PD patients.

[0073] Alternatively, in some embodiments, decreased, reduced, or low GCase activity means that the subject's GCase activity is lower than that measured in the same patient after initiation of treatment, e.g., once steady state treatment with Compound A is achieved. In some embodiments, this may be 4, 26, 52, or 78 weeks after initiation of administration of Compound A. In some embodiments, the subject's GCase activity measured after initiation of treatment is, at a minimum at steady state, more than about 20% higher, more than about 30% higher, more than about 40% higher, or more than about 50% higher than the subject's GCase activity measured before initiation of treatment.

[0074] In some embodiments, the subject's GCase activity measured after initiation of treatment is, at a minimum at steady state, about 20% to about 380% higher, about 50% to about 125% higher, or about 69.7% to about 123% higher than the subject's GCase activity measured before initiation of treatment, about 150% to about 310% higher, or about 163% to about 306% higher than that measured before initiation of treatment, or about 250% to about 380% higher, or about 255% to about 376% higher than that measured before initiation of treatment.

[0075] In some embodiments, the subject's GCase activity measured after initiation of treatment is about 50% to about 125% higher, or about 69.7% to about 123% higher, at a minimum at steady state, than that measured before initiation of treatment when the subject is administered 10 mg of Compound A per day.

[0076] In some embodiments, the subject's GCase activity measured after initiation of treatment is about 150% to about 310% higher, or about 163% to about 306% higher, at a minimum at steady state, than that measured before initiation of treatment when the subject is administered 30 mg of Compound A per day.

[0077] In some embodiments, the subject's GCase activity measured after initiation of treatment is about 250% to about 380% higher, or about 255% to about 376% higher, at a minimum at steady state, than that measured before initiation of treatment when the subject is administered 60 mg of Compound A per day.

[0078] Methods for determining GCase activity are known to those skilled in the art. Any suitable method may be used to measure a subject's GCase activity. An overview of possible methods is provided in Ysselstein, 2021. Possible methods for measuring GCase activity are summarized in Table 1 below. Each method may produce slightly different results. Therefore, it is preferable to use the same measurement method when comparing the GCase activity of subjects potentially eligible for treatment, GBA-PD, and healthy subjects.

[0079] [Table 1]

[0080] Another aspect of the present invention provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson's disease in a subject with altered lysosomal activity.

[0081] Another aspect of the present invention is a method of treating Parkinson's disease in a subject in need thereof and having altered lysosomal activity, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. The method further comprises administering to the subject an acceptable salt thereof.

[0082] A further aspect of the invention provides Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the progression of clinical motor symptoms in a subject having Parkinson's disease and having altered lysosomal activity.

[0083] Another aspect of the present invention provides a method of preventing or limiting the progression of clinical motor symptoms in a subject having Parkinson's disease and having altered lysosomal activity, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0084] An aspect of the present invention provides Compound A or a pharmaceutically acceptable salt thereof for use in preventing or delaying cognitive impairment in a subject having Parkinson's disease and having altered lysosomal activity. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0085] A related aspect of the invention provides a method of preventing or delaying cognitive impairment in a subject having Parkinson's disease and altered lysosomal activity, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0086] According to another aspect of the present invention, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in preventing motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject having Parkinson's disease and having altered lysosomal activity.

[0087] In a related aspect of the present invention, a method is described for preventing motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject having Parkinson's disease and having altered lysosomal activity, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0088] Methods for determining lysosomal activity are known to those skilled in the art. Any suitable method may be used to measure the lysosomal activity of a subject. In some embodiments, the regulated levels of GCase substrate glucosylceramide (GluCer) and / or glucosylsphingosine (GluSph) can be used to determine lysosomal activity, particularly altered lysosomal activity. For example, GluSph has been described as a clinically relevant marker for GBA-PD (Leyns et al. 2023; Surface et al. 2022); GluSph levels have been shown to be increased in GBA-PD patients compared to healthy controls (Pires et al. 2023).

[0089] According to an embodiment of the above aspect of the present invention, the Parkinson's disease patient has increased or high GluSph levels prior to the initiation of treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0090] Increased or elevated GluSph levels mean that the patient's GluSph levels are higher than those measured in a healthy subject or a representative sample of healthy subjects. Alternatively, increased or elevated GluSph levels may refer to a level higher than that measured in a healthy subject or a representative sample of healthy subjects prior to the start of treatment (e.g., baseline). "Compound A" means that the patient's GluSph levels (at the time of administration) are higher than those measured after chronic administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., after once-daily administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof for 12, 26, 39, 52, 65, 78 or more weeks).

[0091] According to an embodiment of the above aspect of the invention, administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof reduces GluSph levels in patients suffering from Parkinson's disease, e.g., GBA-PD.

[0092] A reduction in GluSph levels means that a patient's GluSph levels are lower after chronic administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., after 12, 26, 39, 52, 65, 78 weeks or more of once-daily administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof) than those measured in the same patient prior to administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., at baseline).

[0093] Baseline levels of GluSph and / or GluCer may also be used as baseline predictors of treatment response to long-term administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., after 12, 26, 39, 52, 65, 78 weeks or more of once-daily administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof), e.g., patient response may depend on baseline levels of GluSph and / or GluCer.

[0094] Methods for measuring both GluCer and GluSph are described in Heijer et al. (2021), which is incorporated herein in its entirety. Briefly: GluCer and GluSph can be measured in K2EDTA plasma using an LC-MS / MS method. The carbon chain of the ceramide group, like GluCer, can vary in length and saturation. Concentrations of GluCer C16:0, C18:0, C22:0, C24:0, and C24:1 were measured. For GluCer, the assay range was 1.00-2500 pmol. For GluSph, the assay range was 0.0500-10.0 pmol.

[0095] Available methods for measuring lysosomal activity may yield slightly different results, so it is preferred that the same measurement method be used when comparing lysosomal activity in subjects potentially eligible for treatment, GBA-PD and / or healthy subjects.

[0096] Another aspect of the invention provides the use of Compound A for use in preventing or reducing the risk of Parkinson's disease in a subject determined to be at risk for Parkinson's disease, for example a subject who has not been diagnosed with Parkinson's disease and has been determined to have a GBA1 pathogenic variant for PD.

[0097] A related aspect of the invention provides a method for preventing or reducing the risk of Parkinson's disease in a subject determined to be at risk for Parkinson's disease, e.g., a subject who has not been diagnosed with Parkinson's disease and has been determined to have a GBA1 pathogenic variant for PD, comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0098] Another aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or delaying cognitive impairment in a subject with Parkinson's disease who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0099] A related aspect of the invention describes a method for preventing or delaying cognitive impairment in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and does not have a PD-associated pathogenic variant in LRRK2, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to embodiments, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0100] A further aspect of the present invention describes Compound A or a pharmaceutically acceptable salt thereof for use in preventing or delaying cognitive impairment in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who are not affected by Gaucher disease. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0101] A related aspect of the present invention describes a method for preventing or delaying cognitive impairment in a subject with Parkinson's disease who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have Gaucher disease, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0102] Yet another aspect of the present invention describes Compound A or a pharmaceutically acceptable salt thereof for use in preventing or delaying cognitive impairment in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0103] A related aspect of the present invention describes a method for preventing or delaying cognitive impairment in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0104] A further aspect of the present invention describes Compound A or a pharmaceutically acceptable salt thereof for use in preventing or delaying cognitive impairment in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease. According to an embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0105] A further aspect of the present invention describes a method for preventing or delaying cognitive impairment in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof. According to an embodiment, the cognitive impairment is associated with Parkinson's disease. It is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0106] According to another aspect of the present invention, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in preventing motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or ameliorating clinical movement disorders in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene.

[0107] A related aspect of the present invention provides a method for treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0108] Another aspect of the present invention provides Compound A for use in treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene.

[0109] Another aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject with Parkinson's disease who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2.

[0110] A related aspect of the invention describes a method of treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0111] A further aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who do not have Gaucher disease.

[0112] A related aspect of the present invention describes a method for treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have Gaucher disease, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0113] Yet another aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject with Parkinson's disease who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease.

[0114] A related aspect of the invention is the use of a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene.

[0003] The present invention describes a method for treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a subject with Parkinson's disease who has a PD-associated pathogenic variant (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0115] A further aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

[0116] A further aspect of the present invention describes a method for treating motor or non-motor complications, limiting the progression of clinical motor symptoms, and / or reducing clinical movement disorders in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0117] Motor complications may be assessed using any method known to those skilled in the art, for example, using MDS-UPDRS Part II, III, or IV. Preferably, MDS-UPDRS Part IV is used to assess motor complications. Non-motor complications may be assessed using any method known to those skilled in the art. For example, non-motor complications may be assessed using MDS-UPDRS Part I. "Non-motor complications" may also be referred to as "non-motor symptoms," which may be assessed using MDS-UPDRS Part I.

[0118] In another aspect of the present invention, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in preventing or limiting decline in quality of life and / or improving quality of life in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene.

[0119] A related aspect of the present invention provides a method for preventing or limiting decline in quality of life and / or improving quality of life in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0120] Another aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting decline in quality of life and / or improving quality of life in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2.

[0121] A related aspect of the invention is a method for treating a patient with a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and a PD-associated pathogenic variant in LRRK2.

[0003] The present invention describes a method for preventing or limiting the decline in quality of life and / or improving the quality of life in a subject with Parkinson's disease who does not have Parkinson's disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0122] A further aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the decline in quality of life and / or improving quality of life in Parkinson's disease subjects who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who do not have Gaucher disease.

[0123] A related aspect of the present invention describes a method for preventing or limiting decline in quality of life and / or improving quality of life in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0124] Yet another aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting decline in quality of life and / or improving quality of life in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease.

[0125] A related aspect of the invention describes a method for preventing or limiting decline in quality of life and / or improving quality of life in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and does not have Gaucher disease, comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0126] A further aspect of the present invention describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting decline in quality of life and / or improving quality of life in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

[0127] A further aspect of the present invention describes a method for preventing or limiting decline in quality of life and / or improving quality of life in a Parkinson's disease subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), does not have a PD-associated pathogenic variant in LRRK2, and is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0128] Quality of life may be assessed using any method known to those skilled in the art, for example, using the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) score and / or the Parkinson's Disease Questionnaire (PDQ-39).

[0129] The PDQ-39 is the most thoroughly validated and widely used self-report measure for the assessment of health-related quality of life in PD patients. , a patient-reported outcome measuring five dimensions of health.

[0130] In an embodiment, the effect of said use or treatment according to any of the above aspects on quality of life is assessed using the Parkinson's Disease Questionnaire 39-item (PDQ-39) score, and / or the EuroQol 5 Dimension 5 Level (EQ-5D-5L) score.

[0131] In an embodiment, the use or treatment described in any of the above aspects results in a ≧2 point increase in the MDS-UPDRS Part II score and an increase in the time to no improvement in the Part III score (i.e., a score greater than or equal to zero) compared to subjects treated with a placebo. In another embodiment, the use or treatment described in any of the above aspects results in an increase in the time to clinically meaningful progress from baseline in experiencing the motor aspects of daily living, as assessed by a ≧2 point increase in the MDS-UPDRS Part II score and no improvement in the Part III score (i.e., a difference from baseline greater than or equal to zero), compared to subjects treated with a placebo.

[0132] In an embodiment, the use or treatment according to any of the above aspects results in an increase in time to a ≧5 point increase in MDS-UPDRS Part III total score compared to subjects treated with a placebo.

[0133] MDS-UPDRS scores range from 0 to 132, with 32 or less being mild and 59 or more being severe. An increase of 5 or more points on the MDS-UPDRS Part III is considered a measurable deterioration in motor function.

[0134] In an embodiment, the use or treatment described in any of the above aspects results in an increase in time to a ≧3 point increase in the MDS-UPDRS Part III total score compared to subjects treated with a placebo, which is considered the smallest possible measure of deterioration in motor function.

[0135] In an embodiment, the use or treatment described in any of the above aspects results in an increase in time to a ≧2 point increase in MDS-UPDRS part II score and a ≧5 point increase in MDS-UPDRS part III score compared to subjects treated with a placebo.

[0136] In an embodiment, the use or treatment described in any of the above aspects results in an increase in the time to any deterioration in at least one scale selected from CGI-C, PGI-C, CGI-S, or PGI-S compared to subjects treated with a placebo.

[0137] In embodiments, the above-described uses or treatments, compared to subjects treated with placebo, result in: i) first levodopa equivalent daily dose escalation (LEDD); ii) any worsening on the Clinical Global Impression-Change (CGI-C) scale; iii) any worsening on the Patient Global Impression-Change (PGI-C) scale; iv) Any worsening on the Clinical Global Impression-Severity (CGI-S) scale; or v) Any worsening of the Patient Global Impression-Severity scale (PGI-S) This results in an increase in the time to

[0138] In an embodiment, the above-mentioned use or treatment is a placebo-treated subject. results in a reduced change from baseline in one or more of the following measures compared to: i) MDS-UPDRS total (parts I-IV) score; ii) MDS-UPDRS Part I score; iii) MDS-UPDRS Part II score; iv) MDS-UPDRS Part III score; v) MDS-UPDRS Part IV score; vi) MDS-UPDRS Part II + Part III score; vii) bradykinesia measured by MDS-UPDRS Part III, total spontaneity of movement; viii) Modified Hoehn-Yar scale; and / or ix) PD-CRS score

[0139] In embodiments, the above-described use or treatment results in improved walking speed compared to placebo-treated subjects, hi some embodiments, the use or treatment results in prevention, limitation or delay of walking speed decline.

[0140] Motor symptoms, such as bradykinesia, postural instability, resting tremor, stiffness, and slowness of movement, are commonly present in PD. These symptoms promote changes in gait parameters. Self-selected walking speed (SSWS) is reduced in people with PD. Specifically, individuals with PD walk with a higher cadence, shorter stride length, and longer double support periods.

[0141] Improved walking speed is therefore indicative of improved clinical motor function.

[0142] Walking speed may be measured using any method known to those skilled in the art, for example, a pedometer or a "smart" watch.

[0143] In an embodiment, said use or treatment results in improved cerebral blood flow as measured using arterial spin labelling and / or MRI free water imaging.

[0144] Abnormal cardiovascular regulation due to autonomic nervous system (ANS) dysfunction can lead to a rapid drop in blood pressure (BP) upon standing, sitting, or activity / exercise in patients with Parkinson's disease. Cerebral blood flow, or perfusion, is a measure of the rate of delivery of arterial blood to capillary beds in tissues and is an indicator of cardiovascular health.

[0145] In embodiments, the use or treatment according to any of the above aspects results in reduced neurofilament light chain concentrations.

[0146] Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large-diameter myelinated axons. Its levels in cerebrospinal fluid (CSF) and blood increase in proportion to the degree of axonal damage in neurodegenerative diseases and Parkinson's disease. A new immunoassay capable of detecting biomarkers at ultralow levels enables measurement of NfL in blood, thereby enabling easy and repeated measurement of NfL to monitor the course of Parkinson's disease.

[0147] In embodiments, the use or treatment described in any of the above aspects comprises administering to the subject Compound A at a dose of about 10 mg per day.

[0148] In embodiments, the use or treatment described in any of the above aspects comprises administering to the subject Compound A at a dose of about 30 mg per day.

[0149] In embodiments, the use or treatment described in any of the above aspects comprises administering to the subject Compound A at a dose of about 60 mg per day.

[0150] In embodiments, the use or treatment described in any of the above aspects results in a minimal activation of the subject's GCase activity at steady state of between about 50% and about 125%, or between about 69.7% and about 123%, when the subject is administered 10 mg of Compound A per day.

[0151] In embodiments, the use or treatment described in any of the above aspects results in a minimal activation of the subject's GCase activity at steady state of between about 150% and about 310%, or between about 163% and about 306%, when the subject is administered 30 mg of Compound A per day.

[0152] In embodiments, the use or treatment described in any of the above aspects results in a minimal activation of the subject's GCase activity at steady state of between about 250% and about 380%, or between about 255% and about 376%, when the subject is administered 60 mg of Compound A per day.

[0153] In embodiments, the use or treatment described in any of the above aspects results in a minimal activation of the subject's GCase activity at steady state of more than about 20%, more than about 30%, more than about 40%, or more than about 50%.

[0154] In embodiments, the use or treatment described in any of the above aspects results in a minimal activation of the subject's GCase activity at steady state of between about 20% to about 380%, about 50% to about 125%, about 69.7% to about 123%, about 150% to about 310%, about 163% to about 306%, about 250% to about 380%, or about 255% to about 376%.

[0155] GCase activity may be measured by any of the methods discussed above. Suitable methods include measuring GCase plasma activity or GCase whole blood activity.

[0156] In any of the above aspects, Compound A or a pharmaceutically acceptable salt thereof may be used or administered to a subject for an extended period of time, which may be 12 weeks or more, 26 weeks or more, 39 weeks or more, 52 weeks or more, 65 weeks or more, or 78 weeks or more.

[0157] Preferably, in any of the aspects or embodiments described herein, Compound A is administered once daily. Preferably, Compound A is administered orally.

[0158] In an embodiment, the use or treatment described in any of the above aspects comprises administration to a subject who is a carrier of at least one frequent / severe GBA1 mutation, for example a GBA1 mutation heterozygous for N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T or R120W, or homozygous for T369M or E326K.

[0159] In an embodiment, the use or treatment described in any of the above aspects comprises administration to a subject who is a carrier of at least one low frequency / mild GBA1 mutation, for example, a GBA1 mutation heterozygous for T369M or E326K.

[0160] Furthermore, the use or treatment according to any of the above aspects may be performed in a setting where at least one pathological / pathogenic GBA1 mutation is present, for example selected from one of the following nucleotide mutations: Default numbers and names are:NM_001005741.3:c.1093G>A and NM_0010057 41.3:c.1223C>T、NM_001005741.3:c.1226A>G、NM_001005741.3:c.1448T >C、NM_001005741.3:c.1604G>A、NM_001005741.3:c.1342G>C、NM_00100 5741.3:c.680A>G、NM_001005741.3:c.1504C>T、NM_001005741.3:c.84du p、NM_001005741.3:c.754T>A、NM_001005741.3:c.1297G>T、NM_0010057 41.3:c.721G>A、NM_001005741.3:c.259C>T、NM_001005741.3:c.928A>G、 NM_001005741.3:c.764T>A、NM_001005741.3:c.1246G>A、NM_001005741. 3:c.946C>T、NM_001005741.3:c.26_27del、NM_001005741.3:c.604C>T、N M_001005741.3:c.1090G>A、NM_001005741.3:c.1296G>A、NM_001005741 .3:c.1192C>T、NM_001005741.3:c.914del、NM_001005741.3:c.256C>T、N M_001005741.3:c.586A>C、NM_001005741.3:c.1312G>A、NM_001005741.3 :c.203dup、NM_001005741.3:c.475C>T、NM_001005741.3:c.476G>A、NM_0 01005741.3:c.887G>A、NM_001005741.3:c.762-1G>C、NM_001005741.3: c.115+1G>A、NM_001005741.3:c.1505+1G>T、NM_001005741.3:c.123_217 del、NM_001005741.2:c.1265_1319del、NM_001005741.3:c.715C>T、NM_0 01005741.3:c.1085C>T、NM_001005741.3:c.413del、NM_001005741.3:c.882T>G, NM_001005741.3:c.1193G>A and NM_001005741.3:c.1_2344del. .

[0161] In some embodiments, the at least one pathological / pathogenic GBA1 mutation may be selected from one of the following nucleotide variations: NM_001005741.3:c.1093G>A, NM_001005741.3:c.1223C>T, NM_001005741.3:c.1226A>G, ​​NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.1448T>C, NM_001005741.3:c.1604G>A, NM_001005741.3:c.1342G>C, NM_001005741.3:c.1448T>C, NM_001005741.3:c.1448G>C, NM_001005741.3:c.1448G>A, NM_001005741.3:c.1448G>C ... 01005741.3:c.680A>G, NM_001005741.3:c.1504C>T, NM_001005741.3:c.84dup, NM_001005741.3:c.754T>A, NM_001005741.3:c.1 297G>T, NM_001005741.3:c.721G>A, NM_001005741.3:c.259C>T, NM_001005741.3:c.928A>G, NM_001005741.3:c.764T>A, NM_0010 05741.3:c.1246G>A, NM_001005741.3:c.946C>T, NM_001005741.3:c.26_27del, NM_001005741.3:c.604C>T, NM_001005741.3:c.1 090G>A, NM_001005741.3:c.1296G>A, NM_001005741.3:c.1192C>T, NM_001005741.3:c.914del, NM_001005741.3:c.256C>T, NM_00 1005741.3:c.586A>C, NM_001005741.3:c.1312G>A, NM_001005741.3:c.203dup, NM_001005741.3:c.475C>T, NM_001005741.3:c.4 76G>A, NM_001005741.3:c.887G>A, NM_001005741.3:c.762-1G>C, NM_001005741.3:c.115+1G>A, and NM_001005741.3:c.1505+1G>T .

[0162] Alternatively, the use or treatment according to any of the above aspects may further comprise any of the following mutations: p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Leu483Pro, p.Arg535His, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Va l433Leu, p.Gly241Arg, p.Arg87Trp, p.Ser310Gly, p.Phe255Tyr, p.Gly416Ser, p.Arg316Cys, p .Glu9Glyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, The method may comprise administering to a subject who is a carrier of at least one pathological / pathogenic GBA1 mutation in the amino acid sequence of the GCase enzyme selected from p.Lys196Gln, p.Asp438Asn, p.Thr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, p.Arg296Gln, p.Pro42Trpfs*7, p.Pro42TrpfsTer7, p.Leu422ProfsTer4, p.Leu422Profs*4, p.Gln239*, p.Gln239Ter, p.Thr362Ile, p.Pro138Leufs*62, p.Pro138LeufsTer62, p.His294Gln, p.Arg398Gln and p.Met1_*537del.In some embodiments, the at least one pathological / pathogenic GBA1 mutation in the amino acid sequence of the GCase enzyme is selected from the group consisting of p.Glu365Lys, p.Thr408Met, p.Asn409Ser, p.Leu483Pro, p.Arg535His, p.Asp448His, p.Asn227Ser, p.Arg502Cys, p.Leu29Alafs*18, p.Phe252Ile, p.Val433Leu, p.Gly241Arg, p.Arg87Trp, p .Ser310Gly, p.Phe255Tyr, p.Gly416Ser, p.Arg316Cys, p.Glu9Glyfs*8, p.Arg202*, p.Gly364Arg, p.Trp432*, p.Arg398*, p.Pro305Leufs*31, p.Arg86*, p.Lys196Gln, p.Asp438Asn, p.Thr69Aspfs*12, p.Arg159Trp, p.Arg159Gln, and p.Arg296Gln.

[0163] Further information on subject groups to which Compound A may be administered, for example with regard to the hetero / homozygous nature of the pathological / pathogenic GBA1 variant, can be found above.

[0164] In some embodiments, the use or treatment described in any of the above aspects comprises administering to a subject with a clinical diagnosis of PD for at least 1 year and not more than 7 years, as confirmed by using the MDS criteria for Parkinson's disease.

[0165] In some embodiments, the use or treatment described in any of the above aspects comprises administering to a subject with a modified Hoehn-Yahr index of ≦2.5.

[0166] In some embodiments, the use or treatment described in any of the above aspects comprises administering to a subject with a score of ≧22 on the MoCA scale.

[0167] In some embodiments, the use or treatment described in any of the above aspects comprises administering to a subject who does not have moderate (or severe) motor complications as assessed by a score of ≧3 on any of the sub-items of the MDS-UPDRS Part IV. In some embodiments, the subject has no motor complications or very mild or mild motor complications as assessed by a score of <3, e.g., a score of 0, 1, or 2, on any of the sub-items of the MDS-UPDRS Part IV.

[0168] In some embodiments, the use or treatment described in any of the above aspects comprises administering to a subject who does not have clinically significant psychosis.

[0169] Compound A may be administered in combination with a therapeutically effective amount of one or more of the following concomitant medications: dopamine agonists (e.g., levodopa, levodopa / DOPA decarboxylase inhibitor (DDCI) preparations such as levodopa / carbidopa, levodopa / benserazide, and levodopa / carbidopa / entacapone; the levodopa or levodopa preparations may be provided as immediate-release, controlled-release, or sustained-release formulations), dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine, antihistamines (e.g., benzodiazepines), monoamine oxidase B inhibitors (e.g., rasagiline mesyl, safinamide, selegiline), catechol-O-methyltransferase inhibitors (e.g., entacapone, tolcapone, opicapone), N-methyl-D-aspartate receptor antagonists (e.g., amantadine), adenosine receptor antagonists (e.g., istradefylline), anticholinergics (e.g., benztropine, biperiden, trihexyphenidyl), and neuroprotective agents (e.g., ambroxol).

[0170] When such a combination is used, the administration time of Compound A and the concomitant drug is not limited, and Compound A or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof may be administered to a subject at the same time or at different times. The dosage of the concomitant drug may be determined according to the dose used in clinical practice and may be appropriately selected depending on the subject, administration route, disease, combination, etc.

[0171] In some embodiments of the use or treatment described in any of the above aspects, Compound A is administered in combination therapy with levodopa or a levodopa / DDCI preparation.

[0172] It has been found that Compound A can be administered simultaneously with levodopa or levodopa / DDCI preparations; however, potentially clinically significant DDIs in PD patients can be precluded.

[0173] Therefore, when used in combination, the administration regimen of Compound A and levodopa (or levodopa / DDCI preparations) may vary: each may be administered simultaneously (at the same time) or at different times, e.g., one before or after the other. Those skilled in the art can easily determine when Compound A and levodopa (or levodopa / DDCI preparations) may need to be administered simultaneously or at different times. For example, if co-administration of Compound A and levodopa (or levodopa / DDCI preparations) results in undesirable effects (e.g., dyskinesia and / or dopaminergic side effects, e.g., nausea, vomiting, hallucinations, dizziness, or hypotension) due to an undesirable increase in systemic exposure to levodopa, Compound A and levodopa (or levodopa / DDCI preparations) should preferably be administered at different times.

[0174] In some embodiments, the use or treatment described in any of the above aspects comprises administering Compound A or a pharmaceutically acceptable salt thereof simultaneously with a daily dose of levodopa or a levodopa / DDCI preparation. For example, Compound A is administered at the same time as the daily administration of levodopa or a levodopa / DDCI preparation, or sequentially, with less than 30 minutes, preferably less than 20 minutes, and more preferably less than 10 minutes between the administration of Compound A and the daily administration of levodopa or a levodopa / DDCI preparation.

[0175] In some embodiments, the use or treatment described in any of the above aspects comprises administering Compound A or a pharmaceutically acceptable salt thereof before or after a daily dose of levodopa or a levodopa / DDCI preparation. In some embodiments, Compound A is administered at least 30-50 minutes after the daily administration of levodopa or a levodopa / DDCI preparation. Preferably, it is administered at least 1 hour before or after. In another embodiment, Compound A is administered 30 to 150 minutes before or after the daily administration of levodopa (or levodopa / DDCI preparations).

[0176] When Compound A is administered following daily administration of levodopa (or a levodopa / DDCI preparation), preferably the subsequent administration of levodopa (or a levodopa / DDCI preparation) is administered at least 30 minutes, preferably at least 50 minutes, more preferably at least 1 hour after administration of Compound A.

[0177] When Compound A is administered prior to daily administration of levodopa (or a levodopa / DDCI preparation), preferably, the prior administration of levodopa (or a levodopa / DDCI preparation) is administered at least 30 minutes, preferably at least 50 minutes, more preferably at least 1 hour before administration of Compound A.

[0178] In some embodiments, the use or treatment described in any of the above aspects comprises administering Compound A or a pharmaceutically acceptable salt thereof in the morning, afternoon, evening, before sleep, before bedtime, or at bedtime.

[0179] In still other embodiments, the use or treatment described in any of the above aspects comprises administering Compound A or a pharmaceutically acceptable salt thereof in the morning, afternoon, or evening, before or after a daily dose of levodopa or a levodopa / DDCI preparation.

[0180] In other embodiments, the use or treatment described in any of the above aspects comprises administering Compound A or a pharmaceutically acceptable salt thereof before sleep, before bedtime or at bedtime.

[0181] In still other embodiments, the use or treatment described in any of the above aspects comprises administering Compound A or a pharmaceutically acceptable salt thereof before sleep, before or at bedtime, before or after the final daily dose of levodopa or a levodopa / DDCI preparation is administered to the patient, and before the next day's dosage of levodopa or a levodopa / DDCI preparation is administered.

[0182] The term "before sleep" means that Compound A is administered shortly before the patient falls asleep, for example less than 90 minutes before sleep, particularly less than 1 hour before sleep, less than 30 minutes before sleep or immediately before sleep.

[0183] The term "before bedtime" (i.e., before going to bed) particularly means less than 90 minutes before going to bed, particularly less than 60 minutes before going to bed or less than 30 minutes before going to bed. The term "bedtime" means less than 5 minutes before going to bed, for example, when going to bed.

[0184] In other words, Compound A is taken by the patient before they go to bed (i.e., before or at bedtime), for example, less than 90 minutes before bedtime, particularly less than 60 minutes before bedtime, less than 30 minutes before bedtime, or less than 5 minutes before bedtime.

[0185] As will be clear in the context of the present invention, the term "before sleep" or "before bedtime" does not refer to any time during the day before sleep or going to bed, and particularly does not include, for example, 12 hours before sleep or going to bed. Rather, the term means that the drug is taken in a period close to when the patient goes to bed and perhaps as part of the patient's bedtime ritual.

[0186] The administration form of the concomitant drug is not particularly limited, and compound A and the concomitant drug are combined as a result of administration. It is sufficient to know that. Examples of such dosage forms include: (1) Administration of a single preparation obtained by simultaneous treatment of the compound of the present invention and the concomitant drug; (2) Simultaneous administration of two or more preparations of the compound of the present invention and the concomitant drug, which have been separately prepared, by the same administration route; (3) Alternating administration of two or more preparations of the compound of the present invention and the concomitant drug, which have been separately prepared, by the same administration route; (4) Simultaneous administration of two or more preparations of the compound of the present invention and the concomitant drug, which have been separately prepared, by different administration routes; (5) Alternating administration (e.g., administration of the compound of the present invention and the concomitant drug in the order of, or in the reverse order of, administration) of two or more preparations of the compound of the present invention and the concomitant drug, which have been separately prepared, by different administration routes; etc.

[0187] The dosage of the concomitant drug can be appropriately determined based on the dosage used in clinical situations. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc.

[0188] Compound A can be used as it is, or in the form of a pharmaceutical composition (also called a drug) by mixing with a pharmacologically acceptable carrier or the like. As the pharmacologically acceptable carrier, various organic or inorganic carriers conventionally used as formulation materials can be used. These can be incorporated as excipients, lubricants, buffers, and disintegrants for solid preparations; or solvents, solubilizers, suspending agents, isotonicity agents, buffers, and emollients for liquid preparations; and formulation additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. can be added as needed.

[0189] Examples of dosage forms of the pharmaceutical compositions include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, and buccal tablets), capsules (including soft capsules and microcapsules), pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, films (e.g., orally disintegrating films and oral mucosal adhesive films), and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, and adhesive preparations), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal drops, pulmonary preparations (inhalants), and eye drops. The compounds and drugs of the present invention can be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraviscerally, intranasally, intradermally, infusion, intracerebrally, intravaginally, and intraperitoneally).

[0190] These preparations may be controlled release preparations (eg, sustained release microcapsules), eg, immediate release preparations, sustained release preparations, and the like.

[0191] The pharmaceutical composition can be manufactured according to a method conventionally used in the field of pharmaceutical preparations.

[0192] The various aspects and embodiments of the present invention described above relate to uses and methods involving Compound A or a pharmaceutically acceptable salt thereof. Those skilled in the art will appreciate that these aspects and embodiments may also be formulated as the use of Compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the described uses, methods and treatments. [Brief explanation of the drawings]

[0193] [Figure 1] Time course of percent GluCer and LacCer isomers from pre-dose (all doses combined). [Figure 2-1] Time course of percent GluCer and LacCer from pre-dose in GBA-PD subjects with Gaucher mutations compared to non-Gaucher mutations. [Figure 2-2] Time course of percent GluCer and LacCer from pre-dose in GBA-PD subjects with Gaucher mutations compared to non-Gaucher mutations. [Figure 3] In vitro CGase activity in human brain homogenate by Compound A. Superposition of the amount of Compound A in the human brain (Δ curves) at three dose ranges: 10 mg, 30 mg, and 60 mg. DETAILED DESCRIPTION OF THE INVENTION

[0194] Detailed Description The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical chemistry, organic chemistry, pharmacology, cell biology, and biochemistry.

[0195] Various embodiments of the invention are described in sections; however, an embodiment of the invention described in one particular section is not limited to any particular section.

[0196] definition To facilitate the understanding of this invention, a number of terms and phrases are defined below.

[0197] The terms "a" and "an" as used herein mean "one or more" and include pluralities, unless the context is inappropriate.

[0198] As used herein, the term "solid dosage form" refers to a combination of an active agent with at least one carrier or excipient, inert or active, that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic applications.

[0199] As used herein, "treating" or "treatment" of a disease includes: (1) inhibiting the disease, i.e., arresting or reducing the onset of the disease or its clinical symptoms; and / or (2) palliating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0200] As used herein, "treating" or "treatment" of Parkinson's disease includes the reduction in: (1) Preventing, limiting, or slowing the progression of clinical motor symptoms; (2) preventing, limiting, or delaying motor impairment; (3) preventing or delaying the onset and / or development of Parkinson's disease; (4) preventing, limiting, or delaying the decline of cognitive impairment; (5) Preventing, limiting, or delaying the decline in quality of life; (6) improving walking speed; (7) Preventing, limiting, or delaying the decline in walking speed; (8) preventing, limiting, or slowing the progression of non-motor symptoms; (9) postponement of delayed motor complications; (10) Limiting or delaying the disability caused by Parkinson's disease; (11) Slowing or slowing disease progression; prevention; (12) affecting or altering the course of a disease; and / or (13) preventing, limiting, and / or slowing the rate of disease progression; Includes:

[0201] As used herein, the term "progression of clinical motor symptoms" refers to the worsening of cardinal motor characteristics such as, but not limited to, stiffness, bradykinesia, and tremor.

[0202] The term "suffering" or "suffering" when associated with the term "treatment" refers to a patient or individual who has been diagnosed with or is susceptible to the disease. A patient may not be at risk for Parkinson's disease because of a history of the disease in their bloodline or because of the presence of a genetic mutation associated with the disease. It is sometimes referred to as "having a problem."

[0203] 5,7-dimethyl-N-((1S*,4S)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A, also known as LTI-291 or BIA28-6156) has the following structure: [ka]

[0204] Compound A exists in four polymorphic forms: Form A, Form B (the most thermodynamically stable at room temperature), Form C (a metastable form), and Form D (a hydrated form), which can be prepared using the methods described in WO 2019 / 126776.

[0205] PD can be assessed using the following scores and rating scales: MDS-UPDRS (Goetz, 2008), Parkinson's Disease Cognitive Rating Scale (PD-CRS) (Pagonabarraga, 2008), the Modified Horn-Yahr Scale (Goetz, 2004), and the 39-item Parkinson's Disease Questionnaire (PQD-39) (Peto, 1998). These scales are specifically developed to follow the time course of PD and response to treatment. These scales are reliably measurable; meaningful to clinicians, patients, and caregivers; and address the "core" symptoms of PD. The EQ-5D-5L (EuroQol 5 Dimensions 5 Levels) scale (Herdman, 2011) is a widely used patient-based survey instrument for measuring economic priorities for health status. It is applicable to a wide range of health conditions and treatments and provides a brief descriptive profile and a single index value for health status.

[0206] The modified Hoehnyahr scale is used to assess the staging of functional disability associated with Parkinson's disease. It helps describe the progression of the disease through various stages, thereby allowing the severity of the case to be measured. Clinical signs are described below:

[0207] [Table 2]

[0208] The MDS-UPDRS (Goetz, 2008) is a multidimensional scale that assesses the motor and non-motor symptoms of PD through four parts. The scale is completed using a combination of physician and patient ratings and collection of information from the patient or caregiver: Part I, Non-Motor Aspects of Daily Living Experience, includes 13 items, six of which are rated by the clinician (Part IA) and seven of which are rated by the patient (Part IB). Part II, Motor Aspects of Daily Living Experience, includes 13 items rated by the patient and / or caregiver. The 13 items in Part II and 7 items in Part IB make up the patient questionnaire portion of the MDS-UPDRS. Part III, the motor test, includes 18 items assessed by the investigator (resulting in a 33 score depending on location and lateralization). Part IV, Motor Complications, includes six items (two for dyskinesia, three for fluctuations, and one for "OFF" dystonia) and requires the physician to assess dyskinesias and motor fluctuations using history and objective information.

[0209] Each item is rated on a scale of 0 to 4, with 0 = normal, 1 = very mild, 2 = mild, 3 = moderate, and 4 = severe.

[0210] The PD-CRS (Pagonabarraga, 2008) is a brief, PD-specific questionnaire designed to cover the full range of cognitive impairments associated with PD. It includes items assessing frontal-subcortical dysfunction and cortical dysfunction. It includes tasks assessing immediate free-recall verbal memory (score, 0–12), face-to-face naming (score, 0–20), sustained attention (score, 0–10), working memory (score, 0–10), spontaneous clock drawing (score, 0–10), clock drawing replication (score, 0–10), delayed free-recall verbal memory (score, 0–12), alternating verbal fluency (score, 0–20), and behavioral verbal fluency (score, 0–30). Scores for each task are based on the number of correct responses. Subcortical (range, 0-114) and cortical (range, 0-20) PD-CRS scores are obtained by adding the raw scores of the items within each group. The total PD-CRS score is calculated by adding the cortical PD-CRS scores.

[0211] The CGI-C is a 7-point scale that requires clinicians to assess how much a patient's illness has improved or worsened compared to their baseline condition at the start of the intervention (Guy, 1976). Raters select one response based on the following question: "Compared to your patient's condition at the start of treatment, how much has your patient changed?" and scores are as follows: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worsened; 6 = much worsened; and 7 = very much worsened.

[0212] The CGI-S is a 7-point scale that requires clinicians to rate the severity of a patient's illness at the time of assessment compared with the clinician's past experience with patients with the same diagnosis (Guy, 1976). The clinician asks: "Considering your total clinical experience with this particular population, how sick is the patient at this point?" Possible ratings are: 1) normal, not at all ill, 2) borderline ill, 3) mildly ill, 4) moderately ill, 5) markedly ill, 6) severely ill, and 7) among the most extremely ill patients.

[0213] The PGI-S is the patient-reported counterpart to the CGI-S (Guy, 1976). The PGI-S is a single-item questionnaire designed to assess the patient's impression of illness severity. The PGI-S item asks the respondent to best describe how their symptoms currently feel on a 4-point scale: 1 = normal, 2 = mild, 3 = moderate. degree, or 4 = severe.

[0214] The PGI-C is a patient-reported outcome counterpoint to the CGI-C. A quantitative assessment of meaningful change is determined by the patient's perception of their condition in response to the question, "Compared to your condition at the start of treatment, how much has your condition changed?", with scores as follows: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worsened; 6 = much worsened; and 7 = very much worsened.

[0215] The PDQ-39 is the most thoroughly validated and widely used self-report measure for the assessment of health-related quality of life in PD patients. The questionnaire includes 39 items assessing eight domains of health: mobility (10 items), activities of daily living (6 items), emotional well-being (6 items), symptoms (4 items), social support (3 items), cognition (4 items), communication (3 items), and bodily discomfort (3 items) (Peto, 1998). Each item is scored on the following scale: 0 = never, 1 = occasionally, 2 = sometimes, 3 = often, and 4 = always. Items in the subscales and the overall scale can be combined into indices and linearly transformed into a scale ranging from 0 (perfect health as assessed by the scale) to 100 (worst health as assessed by the scale).

[0216] The EQ-5D-5L (Herdman, 2011) is a patient-reported outcome that measures five dimensions of health. It is a widely used survey instrument for measuring economic priorities for health status, is applicable to a wide range of health conditions and procedures, and provides a brief descriptive profile and a single index value for health status. The EQ-5D-5L consists of a descriptive system and a visual analog scale (VAS).

[0217] The descriptive system includes five dimensions: mobility, self-care, ability to perform daily activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no problem, very mild problem, moderate problem, severe problem, and extremely problem. Patients are asked to indicate their health status by checking the box next to the most appropriate statement in each of the five dimensions. This determination results in a single-digit number representing the level selected for that dimension. The numbers for the five dimensions are combined into a five-digit number that describes the patient's health status.

[0218] The EQ-5D-5L VAS records patients' self-rated health on a vertical VAS with endpoints labeled "best health you can imagine" and "worst health you can imagine." The VAS is used as a quantitative measure of health outcomes that reflects patients' own judgments.

[0219] The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It was validated in the setting of mild cognitive impairment (MCI) and has since been adopted in many other clinical settings. The test consists of 30 points and includes assessments of short-term memory, executive function, attention, and focal cognitive impairment. MoCA scores range from 0 to 30.

[0220] It should be understood that elements and / or features of the various aspects, methods, uses, etc. described herein, whether express or implied herein, can be combined in various ways without departing from the spirit and scope of the present invention. For example, when reference is made to a particular subject population (optionally defined by genetic characteristics), test criteria, or treatment options, such features may be applicable to and used in various embodiments of the present invention unless otherwise understood from the context. In other words, within this application, embodiments are described and illustrated in such a way that a clear and concise application may be written and depicted, but the actual implementation may be varied. It is contemplated and recognized that embodiments may be variously combined or separated without departing from the present teachings and invention(s). For example, it will be recognized that all features described and illustrated herein may, where appropriate, be applicable to all aspect(s) of the invention described and illustrated herein. [Example]

[0221] The following examples are provided to illustrate various embodiments of the present invention and should not be considered limiting. "LTI-291" and "BIA-28" are used in the study numbers to refer to studies using Compound A.

[0222] Example 1 - Human Clinical Studies Compound A was evaluated in two Phase 1 studies evaluating the safety, tolerability, PK, and pharmacodynamic effects of single and multiple doses of Compound A in healthy volunteers, and in two Phase 1b studies evaluating the safety, tolerability, PK, and pharmacodynamic effects of Compound A in subjects with Parkinson's disease with mutations in the GBA1 gene (GBA-PD). Compound A was also evaluated in a Phase 1 mass balance recovery study, a Phase 1 thorough QTc study, and a Phase 1 drug-drug interaction study. Design features of these studies are summarized in Table 2 below.

[0223] [Table 3-1]

[0224] [Table 3-2]

[0225] [Table 3-3]

[0226] [Table 3-4]

[0227] In a Phase 1b study, 40 subjects (20 males) aged 40-80 years with GBA-PD were enrolled. 14 subjects (13 men and 1 woman) received multiple doses of 10, 30, or 60 mg Compound A or placebo once daily for up to 28 days (Study LTI-291-003), and 14 subjects (13 men and 1 woman) received multiple doses of 10 or 60 mg Compound A or placebo once daily for up to 28 days (Study LTI-291-004).

[0228] The PK of Compound A was similar between healthy subjects and subjects with GBA-PD. The geometric mean CSF concentration increased with increasing dose, and the CSF-to-plasma concentration ratio was similar between dose levels after the 28th daily dose. The mean ratio was consistent with an approximately 1:1 distribution of unbound Compound A in plasma to CSF, indicating that Compound A was found in the CSF and could cross the blood-brain barrier to reach GCase in brain tissue.

[0229] LTI-291-001 - Single Ascending Dose Study This study was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose study evaluating the safety and tolerability, PK, and PD of ascending single oral doses of Compound A (3, 10, 30, and 90 mg) in four cohorts of healthy subjects. A total of 32 subjects received a single oral dose of Compound A (8 per dose group), and 8 subjects received placebo. The effect of food on the PK of Compound A was assessed by administering a second single oral dose of 10 mg of Compound A to subjects in Cohort 2 at a separate time after they had completed a high-fat breakfast. Blood samples for Compound A PK were collected up to 48 hours after each dose.

[0230] Pharmacodynamic evaluation consisted of a battery of CNS (NeuroCart®) assessments, including eye saccades, smooth pursuit eye movements, adaptive tracking, body sway, visual verbal learning tests, and EEG. GluCer was measured in plasma and PBMCs as a biomarker of pharmacological effect.

[0231] Pharmacokinetic results Median T max occurred within 1 to 3 hours (median) and ranged between 1.0 and 8.2 after a single dose under fasting conditions. max No relationship was observed between the geometric mean t of Compound A and dose level. 1 / 2 was similar between fasted and fed subjects and ranged from 21.2 to 23.4 hours between groups. Across the entire dose range, total exposure (C max and AUC 0-inf ) appeared to increase proportionally with dose, and the dose-normalized AUC and C max The 10 mg dose in the fed state resulted in a slower T max (Under fasting conditions, median 8.0 h vs. 1.0 h), lower C max led to similar t compared to dosing in the fasting state. 1 / 2 and AUC.

[0232] A summary of the PK parameters of LTI-291 following a single oral dose to healthy participants in the fed and fasted state is presented in Table 3 below:

[0233] [Table 4]

[0234] The ratio of geometric means (90% CI) for the fed vs. fasted treatment comparison was C max The AUC 0-last and AUC 0-inf The ratios for were 103% and 111%, and the 90% CIs were generally within the range of 80.0 to 125.0%.

[0235] Pharmacodynamic results There was no dose-dependent effect of Compound A in any of the CNS (Neurocart) studies. No overall treatment effect was observed in GluCer variables tested in plasma. Differences between Compound A and placebo treatment were observed in several GluCer variables measured in PBMCs, indicating an increase in glycolipid flux with Compound A treatment.

[0236] Safety Results No deaths, other SAEs, severe AEs, or discontinuations due to AEs were observed. The most common AEs after Compound A were fatigue (3 subjects, 7.5%), headache (5 subjects, 12.5%), and somnolence (4 subjects, 10%), while the most common AE after placebo was somnolence (2 subjects, 25%). Three subjects (7.5%) across Compound A treatment groups experienced G All patients reported at least one AE in System Organ Class I, while subjects in the placebo group did not report any GI AEs. Most AEs were mild in intensity, with only one moderate AE (unrelated to Compound A) reported.

[0237] There were no clinically significant safety observations from vital sign measurements, laboratory safety assessments, or ECG parameters.

[0238] Multiple, ascending dose study This study was a phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study of Compound A in four cohorts of healthy middle-aged and older participants (52-75 years of age). The objectives of the study were to investigate the safety, tolerability, and PK, as well as to examine the pharmacodynamics of multiple ascending doses of Compound A, which had been shown to be well-tolerated in a single ascending-dose study (LTI-291-001). A total of 39 healthy subjects were enrolled in four sequential cohorts. Subjects in each cohort received a once-daily oral dose of 3 mg (n=7), 10 mg (n=8), 30 mg (n=8), or 60 mg (n=8) of Compound A or placebo (n=8) for 14 days. Pharmacokinetic parameters were determined for each dose on days 1, 7, and 14. Cerebrospinal fluid samples for Compound A concentrations were measured before the first dose and 4 hours after the final dose at each dose level. GluCer, glucosylsphingosine (GluSph), and lactosyl-ceramide (LacCer) were measured in plasma, PBMC, and CSF as biomarkers of pharmacological effect. Pharmacodynamic measurements consisted of a series of CNS (NeuroCart®) assessments, including eye saccades, smooth pursuit eye movements, adaptive tracking, body sway, visual verbal learning tests, and pharmacological EEG.

[0239] Pharmacokinetic results Following 1, 7, and 14 consecutive daily oral doses of 3, 10, 30, and 60 mg of Compound A, peak plasma concentrations occurred within 1 to 4 hours (median) and ranged between 1.0 and 8.12 hours after dosing. max No relationship was observed between the value of t and dose level or dose frequency. 1 / 2 The values ​​of t ranged from 20.7 to 27.9 hours after the first dose, 25.7 to 35.8 hours after the seventh dose, and 32.1 to 75.0 hours after the 14th dose. 1 / 2No trends were observed for the cumulative index. Accumulation results suggested that a steady-state condition was achieved by the seventh daily dose, with cumulative index values ​​ranging from 2.11 to 2.72 after the seventh daily dose and 2.49 to 2.78 after the 14th daily dose, except at the 30 mg dose level (cumulative index = 5.22). No trends were observed for the cumulative index to change as a function of increasing dose or dose frequency. Over the dose range of 3 to 60 mg, the total exposure (C max and AUC 0-24 ) appeared to increase dose-proportionally after each of the first, seventh, and fourteenth daily oral doses, with dose-normalized AUC and C changes across dose levels. max were similar values.

[0240] Geometric mean CSF concentrations increased with increasing dose. CSF-to-plasma concentration ratios were similar across dose levels after the 14th daily dose, with mean values ​​ranging from 0.0122 to 0.0128. These values ​​are consistent with an approximately 1:1 distribution of unbound Compound A in plasma to CSF, demonstrating brain penetration of Compound A at all doses.

[0241] A summary of the PK parameters of LTI-291 following a single oral dose to healthy participants in the fed and fasted state is presented in Table 4 below.

[0242] [Table 5-1]

[0243] [Table 5-2]

[0244] Pharmacodynamic results There were no dose-dependent effects of Compound A in any of the CNS (Neurocart) tests. A significant increase in saccadic inaccuracy was observed in the 10 and 30 mg Compound A groups compared to placebo. No changes in saccadic peak velocity or reaction time were observed. A significant decrease (uV) in EEG alpha-power Pz-Oz under eyes-closed conditions was observed in the 3 mg dose compared to placebo.

[0245] Sporadic, statistically significant increases were observed in some GluCer and LacCer variables in plasma and PBMC, and sporadic, statistically significant decreases were observed in some GluCer and LacCer variables in CSF. Overall, no consistent pharmacodynamic effects of Compound A on glycolipids over 14 days of dosing were observed in healthy subjects.

[0246] Safety Results No deaths, other SAEs, severe AEs, or discontinuations due to AEs were observed. All AEs were mild or moderate and self-limited, and no unusual AE patterns related to administration of Compound A were evident. The most common AEs after multiple oral doses of Compound A once daily for 14 days were headache (12 subjects, 39%), somnolence (5 subjects, 16%), myalgia (5 subjects, 16%), and back pain (4 subjects, 13%), whereas the most common AEs after placebo were back pain (2 subjects, 25%) and dizziness (2 subjects, 25%).

[0247] Drowsiness was reported more frequently in the 60 mg dose group (50% of subjects) than in the 3 mg (14%), 10 mg (0%), or 30 mg (0%) dose groups or in the placebo group (13%). In 4 of 5 subjects (including the placebo subject) who reported drowsiness during the study, the AE resolved within 2-3 episodes of onset. In 1 subject, the AE occurred intermittently over a 24-day period. Drowsiness was possibly related to Compound A administration, but no effect was seen on NeuroCart measurements.

[0248] Myalgia was reported more frequently in the 60 mg dose group (38% of subjects) than in the 3 mg (14%), 10 mg (0%), or 30 mg (13%) dose groups or in the placebo group (13%). AEs began between days 1 and 4 in all subjects, lasted 3 to 10 days in 5 of 6 subjects, and resolved within 8 hours in 1 subject (3 mg group). Rhabdomyolysis was excluded because no clinically significant creatine kinase abnormalities were found in the 60 mg group. There were no clinically significant safety observations from vital sign measurements, laboratory safety assessments (including creatine kinase), or ECG parameters.

[0249] Compound A - Multiple Dose Study in Subjects with PD and Mutations in the GBA1 Gene (LTI-291-003) This study was a phase 1b, randomized, double-blind, placebo-controlled, multiple-dose oral study of Compound A in 40 subjects (ages 40-80) with GBA-PD. Approximately 50% of enrolled subjects had high-frequency (30%-50% loss of total activity) mutations in GCase, and 50% had polymorphic (10%-20% loss of total activity) mutations in GCase. The objective of this study was to investigate the safety, tolerability, and PK of multiple once-daily oral doses of Compound A and to examine the associated pharmacodynamic changes in subjects with GBA-PD who had high-frequency and polymorphic mutations. Subjects received once-daily oral doses of 10 mg (n=10), 30 mg (n=10), or 60 mg (2 x 30 mg capsules) (n=10) of Compound A or placebo (n=10) for 28 consecutive days.

[0250] Blood samples for Compound A concentrations were collected up to 6 hours after the first and final dose. CSF samples for Compound A concentrations were taken before the first dose and 4 hours after the final dose at each dose level.

[0251] GluCer, GluSph, and LacCer were measured in plasma, PBMC, and CSF as biomarkers of pharmacological effect. Pharmacodynamic evaluation also consisted of a battery of NeuroCart assessments (saccadic eye movements, smooth pursuit eye movements, adaptive tracking, body sway, and visual verbal learning tests); functional outcome measures (MDS-UPDRS Part III and MMSE); and pharmacological EEG.

[0252] Pharmacokinetic results Peak plasma concentrations occurred at a median of 2.0 hours after the first and 28th daily dose of Compound A, and ranged from 2.0 to 6.0 hours across dosing periods and dose levels. Due to the limited sampling scheme, t 1 / 2 Accumulation of Compound A over the study period was assessed by comparing C after the 28th dose to corresponding parameters after the first dose. max , AUC 0-last , and AUC 0-6 When the data were grouped by dose level, the median ratios for the three parameters were between 1.93 and 2.47, consistent with the results observed in healthy subjects. Over the dose range of 10 to 60 mg, the total exposure (C max and AUC 0-last ) appeared to increase dose-proportionally after the first and 28th dose, with the observed dose-normalized AUC and C across dose levels. max were similar values.

[0253] [Table 6]

[0254] Geometric mean CSF concentrations increased with increasing dose, and CSF-to-plasma concentration ratios were similar across dose levels after the 28th daily dose. The mean (SD) values ​​for the ratios were 0.0113 (0.00233) at the 10 mg dose, 0.0122 (0.0036) at the 30 mg dose, and 0.0115 (0.00305) at the 60 mg dose. These results are similar to those observed in a 14-day multiple-dose study in healthy subjects (Study LTI-291-002) and are consistent with the approximately 1:1 distribution of unbound Compound A in plasma to CSF ​​determined in preclinical studies.

[0255] Pharmacodynamic results There were no dose-dependent effects of Compound A on either the NeuroCart test, MMSE, MDS-UPDRS, or EEG.

[0256] Significant time-dependent changes in intracellular PBMC glycolipid levels (GluCer and LacCer) Increased activity was observed in all dose groups (10, 30, and 60 mg / day) in treated subjects with GBA-PD, demonstrating changes in glycolipid flux due to Compound A (Figure 1). This was demonstrated by statistically significant increases in GluCer and LacCer in PBMCs at 7 and 14 days of treatment, with smaller increases observed at 28 days of treatment.

[0257] There was no clear dose- or exposure-response relationship for these effects, but responder analysis showed that the greatest changes occurred in the 60 mg GluCer PBMC group (a steep dose-response was not expected because exposures at all three doses exceeded those required to double in vitro GCase activity). GBA1 mutation severity (i.e., degree of loss of function and relative risk of PD) was a statistically significant covariate in ANCOVA analyses, showing that effects were generally greater in Parkinson's disease subjects with "Gaucher" or high-frequency (30%-50% loss of total activity) mutations versus polymorphic (10%-20% loss of total activity) GBA1 mutations (Figure 2).

[0258] This relationship is consistent with the prediction that the GSL pathway in patients with low GCase activity would be more altered than in patients with moderate GCase activity. No GSL pathway changes were observed in healthy elderly subjects. Overall, these changes indicate that Compound A increases GCase activity, increasing GSL "flux" through GCase and altering the levels of key components of the pathway (GluCer and LacCer).

[0259] Intracellular GluSph in PBMCs showed no clear response to Compound A compared to placebo, and there were no apparent changes in plasma or CSF levels of glycolipids.

[0260] Safety Results No deaths, other SAEs, severe AEs, or discontinuations due to AEs were observed. The most common AEs after multiple oral doses of Compound A in subjects with GBA-PD were fatigue (5 patients, 16.7%), back pain (4 patients, 13.3%), headache (4 subjects, 13.3%), and worsening of Parkinson's disease symptoms (4 subjects, 13.3%). In the placebo group, the most frequently reported AEs were headache (3 subjects, 30.0%) and fatigue (2 subjects, 20.0%). Worsening of Parkinson's disease symptoms was reported by 1 subject (10%) in the placebo group. Given the natural variation in the severity of Parkinson's disease symptoms and the progressive disease process, the worsening of Parkinson's disease symptoms was considered unlikely to be related to Compound A.

[0261] Most AEs were mild in intensity, with only three moderate AEs (all unrelated to Compound A) reported; no severe AEs were reported. There were no clinically significant safety observations from vital sign measurements, laboratory safety assessments, or ECG parameters.

[0262] A Multiple-Dose Imaging Study in Subjects with Parkinson's Disease and Mutations in the GBA1 Gene (GBA-PD) (LTI-291-004) This study was a Phase 1B, randomized, double-blind, placebo-controlled, multiple-dose oral study of Compound A in 14 subjects (51-81 years old) with GBA-PD. The objective of this study was to investigate the safety, tolerability, and PK of multiple once-daily oral doses of Compound A and to examine any associated pharmacodynamic changes. Subjects received once-daily oral doses of 10 mg (n=6) or 60 mg (2 x 30 mg capsules) (n=6) Compound A or placebo (n=2) for 28 consecutive days. PK samples were measured once on days 7 and 14, and four times after the final dose on day 28. Plasma concentrations were summarized at each time point. PK parameters were not estimated. PD assessments included fMRI measures; FDG-PET to determine glucose metabolic rates in specific brain regions; and functional outcome measures (MDS-UPDRS part III and MMSE). GluCer, GluSph, and LacCer, as well as other sphingolipids, were measured in PBMCs and plasma as biomarkers of pharmacological effect.

[0263] Pharmacokinetic results Mean plasma concentrations were higher after the 60 mg dose than after the 10 mg dose at all time points (7, 14, and 28 days before dosing, and 1.5, 3, and 6 hours after the dose on day 27).

[0264] Pharmacodynamic results The fMRI and FDG-PET results generally supported the pharmacodynamic effects of Compound A in subjects with GBA-PD. Compound A improved the large-scale network of different brain regions, the default mode network (DMN), as assessed by fMRI. Due to the small sample size, the differences between groups were not statistically significant.

[0265] Significant changes in PBMC glycolipid levels were observed, similar to those observed in Study LTI-291-003. The 60 mg dose group tended to show a greater effect than the 10 mg dose group. Some changes in imaging measures (fMRI analysis) suggested physiological effects of Compound A in GBA-PD subjects. Plasma LacCer tended to decrease upon Compound A treatment, but no effect was observed on plasma GluCer or GluSph. Overall, the results showed that administration of Compound A for 28 days transiently increased the abundance of glycosphingolipid pathway intermediates measured in PBMCs compared to placebo. This may indicate increased GCase activity.

[0266] MDS-UPDRS III and MMSE scores at day 28 were unchanged from (day -1) in all subjects.

[0267] Safety Results No deaths, other SAEs, or severe AEs were reported. Most AEs were transient and resolved without sequelae. One subject in the 10 mg group withdrew from the study on Day 25 due to moderate back pain that was deemed unrelated to study drug by the investigator. No other moderate AEs were reported. Only muscle cramps (2 events, 1 subject in each dose group) and frequent urination (2 events, 2 subjects in the 60 mg dose group) were reported in more than one subject. All other AEs were reported in only one subject. No AEs were considered related to study treatment.

[0268] There were no clinically significant safety observations from vital sign measurements, laboratory safety assessments, physical examinations, or ECG parameters.

[0269] Overview of Pharmacokinetics and Pharmacodynamics of a Phase 1 Study in GBA-PD Patients In two Phase 1b, placebo-controlled, multiple-dose studies in subjects with GBA-PD (LTI-291-003 and LTI-291-004), the PK of Compound A was similar between healthy subjects and subjects with GBA-PD. Geometric mean CSF concentrations increased with increasing dose, and CSF-to-plasma unbound drug concentration ratios were similar between dose levels after the 28th daily dose. There were equivalent amounts of unbound Compound A in plasma compared with CSF, indicating that Compound A is capable of penetrating into the CSF and crossing the blood-brain barrier to reach GCase in brain tissue. Significant changes in PBMC glycolipid levels were observed in treated GBA-PD subjects in all dose groups (10, 30, and 60 mg / day), indicating that Compound A significantly increased the PK of Compound A in healthy subjects. These data demonstrated changes in glycolipid flux resulting from Compound A treatment. The effects were generally greater in subjects with a higher polymorphic GBA1 mutation. Changes were maximal by week 4 of treatment, with the magnitude of the effect decreasing, possibly indicating the establishment of a new equilibrium in sphingolipid flux. Some changes in imaging measures—e.g., functional magnetic resonance imaging (fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET)—suggested a normalization of physiological effects in some subjects with GBA-PD. Overall, these data supported the hypothesis that Compound A engaged GCase targets and induced significant glycosphingolipid changes secondary to increased flux through the system.

[0270] Compound A - In-depth QTc study (BIA28-6156-105) This was a phase 1, randomized, double-blind, placebo-controlled, single-dose, four-period crossover study to evaluate the effects of Compound A on cardiac repolarization in healthy male and female subjects (20-55 years of age). A total of 37 subjects (20 males and 17 females) were randomized to one of 12 treatment sequences and received single oral doses of 60 mg Compound A (n=34), 150 mg Compound A (n=36), placebo (as placebo control; n=35), and 400 mg moxifloxacin (as positive control; n=34) under fed conditions in four periods in a four-way crossover fashion. Objectives included assessing the effects of single-treatment (60 mg) and single-supertherapeutic (150 mg) oral doses of Compound A on heart rate-corrected QT interval (HR[QTc]) (QTcF) based on the Fridericia correction, evaluating the PK, safety, and tolerability of Compound A, correlating any observed effects on QTcF to plasma concentrations of Compound A, and determining the effect of moxifloxacin on QTcF in healthy subjects compared to Compound A. Blood samples for PK measurements were collected throughout 72 hours after each dose in each period, and continuous Holter monitoring was performed for 24 hours after each dose.

[0271] Pharmacokinetic results Median plasma compound AT max and geometric mean plasma compound At 1 / 2 was similar between the 60 mg and 150 mg doses of Compound A, with exposures being higher after 150 mg Compound A compared to 60 mg Compound A (Table 6). Median plasma moxifloxacin T max The geometric mean moxifloxacin t 1 / 2 was 13.1 hours.

[0272] [Table 7]

[0273] Continuous cardiac monitoring and safety results At the study doses of 60 and 150 mg, BIA-28 had no clinically relevant effects on cardiac ECG parameters. Results of concentration-QTc analysis suggested no effect on ΔΔQTcF greater than 10 ms within the entire observed range of plasma concentrations of Compound A up to approximately 7150 ng / mL. The positive control, moxifloxacin, demonstrated a statistically significant effect on ΔΔQTcF greater than 5 msec as demonstrated by concentration-QTc analysis, demonstrating the sensitivity of the study to detect positive results on cardiac conduction parameters.

[0274] A total of 90 TEAEs were reported in 24 of 37 (64.9%) subjects during the study; 88 of these TEAEs were transient and resolved without sequelae by follow-up. Two persistent TEAEs were both mild in severity and considered unrelated to Compound A or moxifloxacin. No deaths or other SAEs were reported.

[0275] A total of four of the 90 TEAEs were reported in two subjects and were considered related to 150 mg of Compound A (headache and nausea reported by one subject, and increased ALT and increased GGT reported by another subject). Most TEAEs were infrequent / mild in severity, with one TEAE being Grade 2 (moderate) in severity (pulpitis considered unrelated to study drug) and one TEAE being Grade 3 (severe) in severity (hypersensitivity considered related to moxifloxacin). Two subjects withdrew from the study due to TEAEs: one due to increased ALT and increased GGT after receiving the 150 mg dose of Compound A, which were Grade 1 in severity and considered related to Compound A; and one due to hypersensitivity (Grade 3 in severity), frequent urination (Grade 1 in severity), and nervousness (Grade 1 in severity) after receiving 400 mg of moxifloxacin.

[0276] Vital signs, physical examination, safety ECG parameters, or 150 mg of the compound There were no clinically significant safety observations from laboratory values ​​reported during the study and considered related to Compound A, other than an increase in ALT and an increase in GGT in one subject after A.

[0277] Compound A - Mass Balance Recovery and Metabolite Profiling Study (BIA28-6156-106) This was a cohort of healthy male subjects (aged 30-65 years) 14 C - A Phase 1, single-dose, mass balance restoration study of Compound A. A total of 6 subjects received ≤3.7 MBq of DMSO under fasting conditions. 14 Each patient received a single oral dose of 60 mg of Compound A containing C. 14 C - These included determining the route and rate of excretion of Compound A, identifying the structure of metabolites that accounted for more than 10% of the total circulating radioactivity in plasma and the total radioactivity in urine and feces, examining the PK of Compound A, assessing the extent of distribution of TR into blood cells, and gathering further safety and tolerability information about Compound A.

[0278] Mass balance and metabolite profiling results The mean (range) recovery of radioactivity in excreta over the 288-hour sampling period was approximately 93% (84.00% to 96.25%). The majority of the total recovery was in urine (mean: approximately 71%; range: 66.64% to 80.77%). Approximately 21% of the total recovery (range: 15.24% to 27.20%) was in feces. Exposure to Compound A was measured by AUC 0-inf Based on the data, Compound A accounted for approximately 92% of the total circulating plasma recovery, indicating that Compound A was the predominant circulating species in plasma after oral administration.

[0279] Metabolite profiling and identification suggested that no systemic metabolites of Compound A existed above an AUC of >10% of the drug-related exposure.

[0280] Pharmacokinetic results The geometric mean plasma half-life of Compound A was 14 C After BIA-28, it was 21.5 hours (range: 10.7-34.1 hours). Median T max The geometric mean (CV%) plasma C was 1.5 hours (range: 1.00-8.00 hours). max , AUC 0-last , and AUC 0-inf were 1750 ng / mL (38.3%), 41,700 ng.h / mL (10.4%), and 42,100 ng.h / mL (10.5%).

[0281] The geometric mean (geometric mean CV%) whole blood to plasma total radioactivity concentration ratios ranged from 0.542 (5.6%) to 0.562 (3.1%), indicating a nonselective distribution of total recovery to the cellular components of whole blood.

[0282] Safety Results No deaths, other SAEs, severe AEs, or discontinuations due to AEs were observed. In total, 3 (50.0%) subjects reported a total of 4 AEs. 2 (33.3%) subjects reported infrequent / mild headaches, and 1 (16.7%) subject reported moderate irritability. All AEs were assessed by the investigator as unrelated to IMP, were self-limited, and resolved by study termination. There were no clinically significant safety observations from vital sign measurements, laboratory safety assessments, or ECG parameters.

[0283] Drug-drug interaction study (Study BIA-6156-107) (Compound A) In a Phase 1, non-randomized, open-label, crossover, drug-drug interaction study of the effect of multiple doses of oral carbamazepine (a CYP3A4 inducer) on the single-dose PK of oral Compound A, 12 male and female subjects aged 24 to 69 years received 1) a single oral dose of 60 mg of Compound A alone and 17 oral doses of carbamazepine ER, up to 300 mg twice daily. The number of patients gradually increased.

[0284] Additionally, in a Phase 1, non-randomized, open-label, crossover, drug-drug interaction study of single-dose oral Compound A versus single-dose PK of oral carbidopa-levodopa, 12 male and female subjects aged 24 to 69 years received a single oral dose of carbidopa-levodopa 25 / 100 mg (25 mg carbidopa and 100 mg levodopa) IR alone and a single oral dose of 60 mg Compound A.

[0285] The results for Study Compound A BIA28-6156-107 are summarized below.

[0286] Effect of multiple doses of oral carbamazepine on the single dose PK of Compound A Median T of compound A concentration maxwas extended from 1 hour post-dose for Compound A administered alone to 2 hours post-dose for Compound A co-administered with carbamazepine. Systemic exposure to Compound A was reduced when Compound A was co-administered with the CYPP3A4 inducer, carbamazepine, compared to Compound A administered alone. Based on the ratios of geometric least squares means and associated 90% confidence intervals for the test versus reference treatment comparisons, Compound AC max was reduced by approximately 12% (point estimate: 0.877; 90% CI: 0.672-1.146), and AUC 0-last was reduced by 63% (point estimate: 0.367; 90% CI 0.333-0.405), and AUC 0-inf was reduced by 64% (point estimate: 0.363; 90% CI: 0.328-0.402). 1 / 2 was 28 hours for Compound A administered alone and 12 hours for Compound A co-administered with carbamazepine.

[0287] Effect of a single dose of Compound A on the single dose PK of carbidopa-levodopa Levodopa Median T for levodopa concentration max was observed at 0.5 hours post-dose when carbidopa-levodopa was administered alone and at 1 hour post-dose when carbidopa-levodopa was co-administered with Compound A. Similar systemic exposure to levodopa was observed when carbidopa-levodopa was co-administered with Compound A and when carbidopa-levodopa was administered alone. Based on the ratios of geometric least squares means and associated 90% CIs for the test versus reference treatment comparisons, the point estimates and 90% CIs for levodopa exposure parameters were C max 1.061 (0.918-1.227), AUC 0-last 1.048 (0.954-1.152), and AUC 0-inf The geometric mean t for levodopa was 1.035 (0.945-1.132). 1 / 2 was similar under both treatment conditions (1.7 hours after carbidopa-levodopa alone and 1.4 hours after carbidopa-levodopa and Compound A co-administration).

[0288] Carbidopa Median T for carbidopa concentrations max was observed at 2.5 hours post-dose when carbidopa-levodopa was administered alone and at 2 hours post-dose when carbidopa-levodopa was co-administered with Compound A. Relative to carbidopa-levodopa administered alone, a modest increase in maximum exposure to carbidopa (by approximately 3%) and a modest increase in systemic exposure (by approximately 9%) was observed when carbidopa-levodopa was co-administered with Compound A. Based on the ratios of geometric least squares means and associated 90% CIs for the test versus reference treatment comparisons, the point estimates and 90% CIs for carbidopa exposure parameters were C max 1.031 (0.777-1.368), and AUC 0-last The geometric mean t was 0.909 (0.630-1.313). 1 / 2 The geometric mean t 1 / 2 was similar under both treatment conditions (2–2.3 h).

[0289] Metabolite 3-O-methyldopa (3-OMD) Median T for 3-OMD concentration max The results showed that 6 days after dosing, both when carbidopa-levodopa was administered alone and when carbidopa-levodopa was co-administered with Compound A, Similar systemic exposure to 3-OMD was observed when carbidopa-levodopa was co-administered with Compound A and when carbidopa-levodopa was administered alone. Based on the ratios of geometric least squares means and associated 90% CIs for the test versus reference treatment comparisons, the point estimates and 90% CIs for 3-OMD exposure parameters were C max and AUC 1.056 (0.993-1.123). 0-last The geometric mean t for 3-OMD was 1.060 (1.010-1.112). 1 / 2 could not be calculated because most subjects did not have a terminal phase for their 12-hour PK profile.

[0290] Safety Results Several TEAEs were observed. All TEAEs were transient and resolved without sequelae by follow-up.

[0291] A total of two AEs (mild back pain, n=1; mild headache, n=1) were reported in two of 12 subjects (16.7%) after monotherapy with 60 mg of Compound A, and a total of three AEs (mild myalgia, n=1; mild headache, n=2) were reported in three of 12 subjects (25.0%) after coadministration of 60 mg of Compound A with 300 mg of extended-release carbamazepine. No AEs were reported after coadministration of 60 mg of Compound A with 25 mg / 100 mg of immediate-release carbidopa-levodopa. No SAEs were reported, and no TEAEs of grade 3 or greater in severity were reported. The majority of TEAEs were grade 1 (mild) in severity. Only four TEAEs were of grade 2 (moderate) severity: abdominal pain (considered related to Compound A or carbamazepine), hepatobiliary disorders (considered related to Compound A, carbamazepine, or carbidopa-levodopa), falls (considered unrelated to any of the study medications), and constipation (considered related to carbamazepine and Compound A, or unrelated to carbidopa-levodopa).

[0292] Two subjects discontinued study treatment due to TEAEs. A decrease in platelet count, which led to early discontinuation of the study in one subject, was reported as a Grade 1 (mild) TEAE and was considered related to carbamazepine. Viral infection (primary reason) and abdominal pain led to early discontinuation of the study in one subject. The viral infection was of Grade 1 (mild) severity and was considered unrelated to either study medication. The abdominal pain was of Grade 2 (moderate) severity and was considered related to Compound A or carbamazepine, but the subject was receiving carbamazepine alone at the time of the event.

[0293] Vital signs measurement, physical examination, ECG parameters, or C-SSRS (Posner There were no clinically significant safety observations from the 2011 study. Other than one subject who had a decrease in platelet count and one subject who had a transient increase in liver enzymes, there were no other clinically significant laboratory values ​​reported during the study.

[0294] Drug-drug interaction study (BIA-28-6156-109) This was a phase 1, non-randomized, open-label, two-cohort, crossover, DDI study in healthy male and female subjects. The study evaluated the effects of multiple doses of Compound A on the single-dose PK and safety of levodopa-carbidopa and levodopa-benserazide.

[0295] In Cohort 1, a single oral dose of 100 mg / 25 mg levodopa-carbidopa (Sinemet®) was administered IR alone on day 1. A single 60 mg dose of Compound A was administered on days 2 through 6. On day 7, a single 60 mg dose of Compound A and a single 100 mg / 25 mg dose of levodopa-carbidopa (Sinemet®) were administered IR.

[0296] In Cohort 2, a single oral dose of 100 mg / 25 mg levodopa-benserazide (Madopar®) IR was administered alone on day 1. A single 60 mg dose of Compound A was administered on days 2 through 6. On day 7, a single 60 mg dose of Compound A and a single 100 mg / 25 mg dose of levodopa-benserazide (Madopar®) IR were administered.

[0297] For the Sinemet® portion, carbidopa plasma PK samples were analyzed outside the demonstrated stabilization period and underwent a sample reproducibility assessment that did not meet the acceptance criteria; therefore, carbidopa results were not presented in this CSR.

[0298] In the Madopar® portion, benserazide plasma PK results were not reported in this CSR because all benserazide concentrations measured in this study (except for 2) were below the LLOQ. Statistical analysis of DDIs was performed for validation purposes only. Therefore, the application of the default bioequivalence range should be interpreted in this context. In both portions, an effect of multiple doses of Compound A on the single-dose PK of levodopa could not be excluded because the upper limit of the 90% CI for the AUC ratio did not fall within the default "no effect" boundary of 80% to 125%. Further exploration may be necessary to confirm possible clinical DDIs. Nevertheless, the possible effect of Compound A on levodopa PK appears to be limited (AUC increases of approximately 13% and 24% for cohorts 1 and 2, respectively). The Food and Drug Administration's guidance on drug-drug interactions ("Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions") provides guidance on the use of benserazide in clinical trials. Interactions, Guidance for Industry”. USD Department of Health and Human Services,Food and Drug Administration,Center for Per Drug Evaluation and Research (CDER). January 2020, Clinical Pharmacology, this may have a minimal effect, as an AUC increase between >1.25-fold and <2-fold is considered a weak DDI effect.

[0299] Levodopa-Sinemet® moiety: Effect of multiple doses of Compound A on single doses Plasma PK of levodopa and 3-OMD For levodopa, the 90% CI of the ratio of geometric least squares means showed a significant difference in C after Sinemet® / Compound A co-administration compared with Sinemet® alone. max 1.231 (1.006-1.508), AUC 0-t1.130 (1.004-1.272), and AUC 0-inf These results indicate that, compared with Sinemet® alone, maximum exposure to levodopa was increased by approximately 23% in Cmax (based on an estimated value of 1.231), and systemic exposure to levodopa was increased by approximately 23% in AUC 0-t (based on the estimated value of 1.130) and AUC 0-inf This suggests an increase of approximately 13% (based on an estimated value of 1.132).

[0300] However, the 90% CI of the ratio of geometric least squares means, Cmax (estimated value of 1.077; 90% CI ranged from 0.980 to 1.184) and AUC 0-t There was no effect of Compound A on Sinemet® regarding 3-OMD PK based on an estimated value of 1.065; 90% C ranging from 0.979 to 1.159. The geometric mean t values ​​of levodopa were similar after combined administration of Compound A and Sinemet® (1.59 hours) compared to Sinemet® alone (1.69 hours), suggesting that levodopa clearance is not affected by coadministration of Compound A. The steady-state concentrations of Compound A showed a t of 25 hours after multiple doses in Study LTI-291-002. Because the geometric mean trough plasma concentration-time curves were ~35 hours, it was predicted that steady-state concentrations of Compound A would have been reached 6 days after dosing. However, based on visual inspection of the geometric mean trough plasma concentration-time curves, steady-state concentrations of Compound A did not appear to have been reached 6 days after dosing with 60 mg Compound A (Days 2-7) because trough concentrations on these days were still increasing. However, the curves had flattened by Day 7, indicating that steady-state Compound A concentrations could be reached quickly.

[0301] [Table 8]

[0302] [Table 9]

[0303] [Table 10]

[0304] Levodopa-Madopar® moiety: Effect of multiple doses of Compound A on single doses Plasma PK of levodopa and 3-OMD For levodopa, the 90% CI of the ratio of geometric least squares means showed a significant difference in C after Madopar® / Compound A co-administration compared to Madopar® administration alone. max 1.330 (1.124-1.575), AUC 0-t 1.238 (1.146-1.337), and AUC 0-inf These results indicate that, compared with administration of Madopar® alone, the maximum exposure to levodopa was increased by approximately 33% in Cmax (based on an estimated value of 1.330), and the systemic exposure to levodopa was increased by approximately 33% in AUC 0-t (based on the estimated value of 1.238) and AUC 0-inf This suggests an increase of approximately 24% (based on an estimated value of 1.237).

[0305] However, the 90% CI of the ratio of geometric least squares means, Cmax (estimated value of 1.131; 90% CI ranged from 1.086 to 1.178) and AUC 0-t There was no effect of Compound A on Madopar® on 3-OMD PK based on an estimate of 1.115; 90% CI ranged from 1.075 to 1.158. The geometric mean t values ​​for levodopa were similar after combined administration of Compound A and Madopar® (2.45 hours) compared to Madopar® alone (2.26 hours), suggesting that levodopa clearance was not affected by co-administration of Compound A.

[0306] It was predicted that steady-state concentrations of Compound A would have been reached 6 days after dosing because the t was 25 to 35 hours after multiple doses in Study LTI-291-002. However, based on visual inspection of the geometric mean trough plasma concentration-time curves, steady-state concentrations of Compound A did not appear to have been reached 6 days after dosing with 60 mg of Compound A (Days 2 to 7) because trough concentrations on these days were still increasing. However, the curves had flattened by Day 7, indicating that steady-state Compound A concentrations could be reached sooner.

[0307] Based on statistical analysis, maximum systemic exposure to levodopa increased by approximately 23% for Cmax, and systemic exposure to levodopa increased by approximately 13% for both AUC0-t and AUC0-inf following combined administration of Compound A and Sinemet® compared to Sinemet® alone. However, there was no effect of Compound A on Sinemet® based on plasma exposure PK parameters of 3-OMD.

[0308] Based on statistical analysis, maximum systemic exposure to levodopa increased by approximately 33% for Cmax, and systemic exposure to levodopa increased by approximately 24% for both AUC0-t and AUC0-inf following combined administration of Compound A and Madopar® compared to Madopar® alone. However, there was no effect of Compound A on Madopar® based on the plasma exposure PK parameters of 3-OMD.

[0309] The geometric mean t values ​​for levodopa were similar after administration of the combination of Compound A and Sinemet® compared to Sinemet® alone, suggesting that levodopa clearance is not affected by Compound A. The geometric mean t values ​​for levodopa were similar after administration of the combination of Compound A and Madopar® compared to Madopar® alone, suggesting that levodopa clearance is not affected by co-administration of Compound A.

[0310] Steady state concentrations of Compound A did not appear to be reached with Sinemet® / Compound A co-administration on Day 7 or Madopar® / Compound A co-administration on Day 7.

[0311] [Table 11]

[0312] [Table 12]

[0313] [Table 13]

[0314] Overall, the results of this study suggest that coadministration of levodopa-carbidopa or levodopa-benserazide is feasible; however, potentially clinically significant DDIs in PD patients cannot be excluded.

[0315] Drug-drug interaction study (BIA28-6156-110) This was a phase 1, non-randomized, open-label, two-cohort, crossover, DDI study in healthy male and female subjects. The study evaluated the effects of multiple doses of Compound A on the single-dose PK and safety of rosuvastatin and metformin.

[0316] In Cohort 1, a single oral dose of 10 mg rosuvastatin was administered alone on Day 1. No drug was administered on Day 2. A single daily dose of 60 mg Compound A was administered on Days 3 through 8. On Day 9, a single dose of 60 mg Compound A and a single dose of 10 mg rosuvastatin were administered.

[0317] In Cohort 2, a single oral dose of 500 mg metformin was administered alone on day 1. A single daily dose of 60 mg Compound A was administered on days 2 through 7. On day 8, a single dose of 60 mg Compound A and a single dose of 500 mg metformin were administered.

[0318] Statistical analysis of the DDI was performed for validation purposes only, and therefore the application of the default bioequivalence ranges should be interpreted in this context.

[0319] In the rosuvastatin portion, an effect of multiple doses of Compound A on single-dose PK of rosuvastatin could not be excluded because both the upper and lower 90% CIs for the AUC ratio were outside the default "no effect" boundary of 80% to 125%. The effect of Compound A on rosuvastatin PK was an approximately three-fold increase in AUC, increasing from 304% to 344%. In the metformin portion, the 90% CI for the metformin AUC ratio was within the default "no effect" boundary of 80% to 125%, suggesting no effect of multiple oral doses of Compound A on metformin PK after a single oral dose of metformin.

[0320] The truncated PK profiles of rosuvastatin over 48 hours and metformin over 24 hours are deemed sufficient to allow characterization and comparison of the rate and extent of absorption when administered alone or in combination with Compound A. However, parameters related to excretion have a higher degree of uncertainty and should be interpreted with caution.

[0321] Rosuvastatin moiety: Effect of multiple doses of Compound A on the single-dose plasma pharmacokinetics of rosuvastatin The 90% CI of the geometric least squares mean ratios for rosuvastatin, Cmax (estimated value 3.467; 90% CI range 3.141-3.826), AUC0-t (estimated value 3.437; 90% CI range 3.151-3.750), and AUC0-inf (estimated value 3.041; 90% CI range 2.759-3.352) were not included within the default 80%-125% boundary for "no effect." Thus, Compound A coadministration, compared with rosuvastatin administration alone, resulted in a 347% increase in maximum rosuvastatin exposure (based on an estimated value of 3.467) in Cmax, a 344% increase in systemic rosuvastatin exposure (based on an estimated value of 3.437) in AUC0-t, and a 304% increase in systemic rosuvastatin exposure (based on an estimated value of 3.041) in AUC0-inf. It was predicted that steady-state concentrations of Compound A would have been reached after 6 days of dosing. However, based on visual inspection of the geometric mean trough plasma concentration-time curves, steady-state concentrations of Compound A did not appear to have been reached after 6 days of dosing with 60 mg Compound A (Days 3–9), as trough concentrations on these days were still increasing.

[0322] Metformin moiety: Effect of multiple doses of Compound A on single-dose plasma pharmacokinetics of metformin The 90% CI of the geometric least squares mean ratios for metformin, Cmax (estimate of 0.950; 90% CI range of 0.877 to 1.028), AUC0-t (estimate of 0.938; 90% CI range of 0.881 to 1.000), and AUC0-inf (estimate of 0.940; 90% CI range of 0.882 to 1.002), were within the 80% to 125% of the default "no effect" boundary for metformin PK after a single oral dose of metformin. These results suggest that there is no effect of multiple oral doses of Compound A on the efficacy of Compound A. It was predicted that steady-state concentrations of Compound A would have been reached 6 days after dosing. However, based on visual inspection of the geometric mean trough plasma concentration-time curves, steady-state concentrations of Compound A did not appear to have been reached 6 days after dosing with 60 mg of Compound A (Days 2-8) because trough concentrations on these days were still increasing.

[0323] Example 2 In vitro measurements of GCase activity in human brain homogenates were used to correlate exposure and GCase activity, and to assess C activity at steady state across different dose levels. min (C b,min,ss We estimated the increase in GCase activity in the brain of GBA-PD patients at 100 mg / kg / day. We used the relationship between the concentrations observed in the brain and CSF in rats to obtain the brain concentrations of Compound A in humans and assumed that the same relationship holds across mammalian species. b,min,ss The range of concentrations was superimposed on the corresponding concentrations from in vitro studies with human brain homogenates to obtain GCase activation by Compound A.

[0324] The minimum GCase activity in GBA-PD patients across the dose ranges of 10, 30, and 60 mg was found to be 69.7-123%, 163-306%, and 255-376%, respectively (Figure 3). Based on GCase activity, we concluded that all three dose levels were associated with efficacy because the minimum GCase activity in GBA-PD patients during the 24-h dosing interval at 10 mg (69.7%) was approximately two-fold higher than the effective GCase activity.

[0325] In vitro GCase brain homogenate activity assay The activity of Compound A in the GCase assay was determined using 4-MUG (1 mM) as the substrate and brain homogenate (5 μg / well) as the oxygen source.

[0326] A 500 μl aliquot of a 1.0 mg / ml chloroform solution of phosphatidylserine (PS, Sigma P7769) was evaporated under a nitrogen stream for 1 h. The lipid film was dissolved by vigorous vortexing for 4 min in 41 ml of 176 mM KHPO / 50 mM citric acid (pH 4.7) containing 7.7 μl of Triton X-100, resulting in a mixed micelle preparation with a composition of 0.32 mM Triton and 4.6 mol% PS.

[0327] 4-Methylumbelliferyl-beta-D-glucopyranoside (4-MUG, ACROS-337025000) was dissolved in the micellar solution to a final concentration of 2 mM for use as a reaction substrate.

[0328] A micelle / homogenate solution was prepared by adding 3.2 ml of Triton X-100 / phosphatidylserine mixed micelles containing 400 μg / ml brain homogenate. A 1.6 ml portion of this mixture contained 32 μl of conduritol B epoxide (CBE, 100 mM stock solution in DMSO) for a final concentration of 2 mM CBE. The remaining 1.6 ml portion contained 32 μl of DMSO as a solvent control. Compound A was diluted with DMSO from a 10 mM stock solution to the desired assay concentration, and 0.45 μl of compound in DMSO was added to 75 μl of the micelle / homogenate solution (+ / - CBE).

[0329] After 30 minutes of pre-incubation at room temperature, the reaction was initiated by combining 25 μl of substrate solution with 25 μl of compound / GCase / homogenate mixture. The reaction proceeded at room temperature for 30 minutes for rat, Cyno, and Dog brain homogenates, and for 60 minutes for mouse and human brain homogenates. The reaction was stopped by adding 150 μl of 1 M glycine, pH 12.5. The end-point fluorescence intensity of the reaction was measured. Measurements were taken on a SpectraMax i3 instrument (Molecular Devices) at excitation 365 nm and emission 440 nm. Compound activity was expressed relative to the DMSO control. GCase activity in CBE-containing samples was subtracted from GCase activity in DMSO-containing samples to obtain GBA1 activity, which was plotted in a dose-response curve.

[0330] Method for quantification of Compound A in human CSF To measure the amount of Compound A in CSF, CSF was diluted 1:1 (v / v) with 0.2% bovine serum albumin and sample processing was performed by protein precipitation / dilution using a sample volume of 50.0 μL and Compound A as the internal standard. Separation between metabolites and interfering endogenous compounds was achieved by HPLC using a Shim-pack XR-ODS column (3.0 × 50 mm, 2.2 μm particles) at a temperature of 60 °C using 0.1% formic acid in water as mobile phase A and acetonitrile as mobile phase B, operated isocratically at 55% B, followed by a step gradient to 85% B, at a flow rate of 0.900 mL / min.

[0331] An API 4000 mass spectrometer equipped with a turbo ion spray source was used for detection in positive ion mode. Quantification was based on multiple reaction monitoring (MRM) of the transitions m / z 359.2 to 174.2 for LTI-291 and m / z 365.3 to 180.2 for its internal standard. A linear calibration curve with a weighting factor of 1 / x2 was used for LTI-291 in the range of 0.0500 to 100 ng / mL in CSF (0.0250 to 50.0 ng / mL in CSF:0.2% BSA 1:1 (v / v)).

[0332] Results were plotted and analyzed using Analyst version 1.6.2 (AB Sciex, Concord, Canada).

[0333] Example 3 This study is a phase 2, randomized, double-blind, placebo-controlled, multiple-dose oral study of Compound A in subjects (35-80 years of age, inclusion) with GBA-PD. Subjects must have a clinical diagnosis of PD for at least 1 year and no more than 7 years prior to the start of screening (Part A), confirmed by a neurologist using MDS criteria for Parkinson's disease, a modified Hoehn-Jahr scale of ≤2.5, a score of ≥22 on the Montreal Cognitive Assessment (MoCA), and be receiving symptomatic treatment for PD. In some embodiments, subjects do not have moderate (or severe) motor complications as assessed by a score of ≥3 on any of the subscales of the MDS-UPDRS Part IV, and subjects do not have clinically significant psychosis in the investigator's clinical judgment. The objective of this study is to investigate the efficacy, safety, tolerability, pharmacodynamics, and PK of once-daily oral administration of Compound A.

[0334] Genetic screening of subjects is performed using collected blood (preferably whole blood samples). Subjects are screened by sequencing the entire GBA1 gene, using the specifications of any identified PD risk-related variants. Subjects are also screened for the presence or absence of PD risk-related variants in the LRRK2 (leucine-rich repeat kinase 2) gene. Subjects with LRRK2 pathogenic variants are not eligible for Part B (double-blind treatment) of the study.

[0335] Subjects with a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) (see, e.g., Appendix 1) and who have been taking PD medication continuously for at least 30 days (at least 60 days for rasagiline mesylate) prior to treatment initiation will be included in the next stage of testing. In addition, subjects with the following will be excluded from further treatment: Subject has clinical signs and symptoms (i.e., hepatosplenomegaly, cytopenias, bone disease), and / or have Gaucher disease (GD), as defined by a history of marked deficiency in GCase plasma activity (preferably GCase whole blood activity) corresponding to GD. The subject is homozygous for a GBA1 pathogenic variant known to be associated with GD or compound heterozygous for two alleles of GBA1 known to be associated with GD. The subject has a known PD-associated LRRK2 pathogenic variant (see, e.g., Appendix 2). The subject has atypical or secondary parkinsonism, either by medical history or in the opinion of the investigator. Atypical parkinsonism includes, but is not limited to, diagnoses of progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. Secondary parkinsonism includes drug-induced, toxic, post-infectious, post-traumatic, or vascular parkinsonism. Subject is using a strong CYP3A4 modulator at the time of screening for Part B. Subject is using a breast cancer resistance protein (BCRP) substrate (e.g., pravastatin, rosuvastatin, glyburide) at the time of screening for Part B. (Optional) Subject is using any of the following medications within 60 days prior to baseline: typical or atypical antipsychotics (including but not limited to clozapine, pimavanserin, olanzapine, quetiapine, risperidone, and aripiprazole); metoclopramide; prochlorperazine; methyldopa; tetrabenazine; deutetrabenazine; valbenazine; reserpine; or a history of or continued or initiated during the study ambroxol at a dose of >120 mg / day.

[0336] Subjects will be randomly assigned to one of three groups: i) Compound A 10 mg orally once daily; ii) Compound A 60 mg orally once daily; or iii) placebo orally once daily. Subjects will also receive their usual PD medications throughout the study. Randomization will be stratified by frequent / severe PD risk-related variants (e.g., heterozygous for N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, R120W; homozygous for T369M or E326K) or infrequent / mild (e.g., heterozygous for T369M or E326K) PD risk-related variants. Alternatively, randomization will be stratified by severity as mild or severe GBA1 variants, as described in Parlar, 2023 (see also Appendix 1). Subjects with other PD risk-associated variants will be classified as either frequent / severe or infrequent / mild based on new data and randomized accordingly.

[0337] Subjects will receive treatment for up to 78 weeks, followed by 30 days (or 4 weeks) of safety follow-up. Efficacy, safety, tolerability, pharmacodynamics, and PK will be assessed at baseline and at visits at 4, 12, 26, 39, 52, 65, and 78 weeks. Study personnel will contact subjects before each scheduled visit to remind them to collect their last dose of non-investigational PD medication ≥ 10 hours before each visit. Subjects will resume non-investigational PD medication after visit assessments are completed. For subjects who took non-investigational PD medication < 10 hours before a scheduled visit, the visit will be rescheduled.

[0338] Visits will be scheduled at approximately the same time to ensure consistent completion of assessment measures throughout the study. Every effort will be made to have the same assessors administer the same assessments to each subject throughout the study. When possible, efficacy assessments will be conducted first, followed by safety assessments, and then blood draws.

[0339] Subjects may require unscheduled visits for any adjustments of non-investigational PD medication. In such circumstances, the final dose of non-investigational PD medication is taken ≥ 10 hours before each unscheduled visit, where MDS-UPDRS Parts I-IV, CGI-C, and PGI-C are administered. The assessment will occur before any adjustment of non-investigational PD medication. Subjects may resume non-investigational PD medication after the visit assessment is completed.

[0340] The following criteria were assessed at regular intervals throughout the study: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I, II, III, and IV Clinical Global Impression - Change (CGI-C) and Severity (CGI-S) Patient Global Impression - Change (PGI-C) and Severity (PGI-S) Levodopa equivalent daily dose (LEDD) Modified Horn-Yar degree. Parkinson's Disease Cognitive Rating Scale (PD-CRS) · 39-item Parkinson's Disease Questionnaire (PDQ-39) EuroQol 5 Dimensions 5 Levels Scale (EQ-5D-5L) Walking speed

[0341] In addition, PD biomarkers and GCase activity in whole blood samples are measured at baseline and 78 weeks (preferably at baseline and 4, 26, 52, and 78 weeks). This may include biomarkers of lysosomal activity (e.g., glucosylsphingosine (GluSph) and / or glucosylceramide (GluCer)). Methods for measuring lysosomal activity (e.g., GluSph and / or GluCer) are described above. Methods for measuring GCase activity are described below. Magnetic resonance imaging (MRI) scans are performed in a cohort of GBA-PD subjects at baseline and 78 weeks.

[0342] Efficacy, safety, tolerability, and pharmacodynamic assessments will be performed at baseline and at visits conducted at weeks 4, 12, 26, 39, 52, 65, and 78. A telephone contact will be conducted at week 8 to inquire about the occurrence of any adverse events (AEs) and any changes in concomitant medications.

[0343] Blood for determination of Compound A plasma concentrations for population PK analysis will be obtained from all subjects prior to administration of the first dose of IMP at the study site at the baseline visit and at visits at weeks 4, 12, 26, 39, 52, 65, and 78. Subjects will be instructed to take their dose of IMP in the morning prior to the week 4, 12, 26, 39, 52, 65, and 78 visits. The times of PK blood sample collection will be recorded.

[0344] A baseline magnetic resonance imaging (MRI) scan will be obtained during the screening period from subjects who are deemed ineligible and who provide consent to participate in the optional MRI substudy. The baseline MRI will be obtained within the 35-day screening window and after all other screening assessments have confirmed that the subject is eligible for the study. A post-treatment MRI will be obtained at week 78 for subjects participating in the MRI substudy; a window of week -2 to day +1 will be allowed for the 78-week MRI.

[0345] Plasma concentrations were compiled at each time point, and PK parameters were not estimated. PD assessments included fMRI assessments; FDG-PET to determine glucose metabolic rates in specific brain regions; and functional outcome measures (MDS-UPDRS Part III and MMSE). GluCer, GluSph, and LacCer, as well as other sphingolipids, were measured in PBMCs and plasma as biomarkers of pharmacological effect.

[0346] A preferred method for measuring GCase activity in whole blood is described below and also in Totorelli, 2016, which is incorporated herein by reference: A 5-plex cocktail assay for GCase, acid α-glucosidase (GAA), galactocerebrosidase (GALC), α-galactosidase A (GLA), and α-L-iduronidase (IDUA) activity was prepared. Vials containing substrates (S) and internal standards (IS) for GCase and GAA were reconstituted with methanol and transferred to the GALC S+IS vial, followed by evaporation. The GLA S+IS vial was reconstituted with 1.8 mL of 96 g / L sodium taurocholate in water, then transferred to the dry GALC S+IS vial and heated to 60°C to dissolve all solids. The following reagents are added to a GALC S+IS vial: 0.3 mL of 0.8 mmol / L acarbose (GAA inhibitor) in water and 2.88 mL of 1 mol / L N-acetylgalactosamine (GLA inhibitor) in buffer (0.2 mol / L sodium phosphate + 0.1 mol / L sodium citrate, pH = 4.4). The IDUA S+IS vial is then reconstituted with 12.52 mL of buffer (0.2 mol / L sodium phosphate + 0.1 mol / L sodium citrate, pH = 4.4) and 0.5 mL of 3 mmol / L D-saccharinic acid 1,4-lactone in water. The reconstituted IDUA S+IS vial is transferred to a GALC S+IS vial. Prepare the acid sphingomyelinase (ASM) cocktail separately by reconstituting an ASM S+IS vial with 0.15 mL of 96 g / L sodium taurocholate in water, then adding 17.85 mL of buffer (0.85 mol / L sodium acetate + 0.604 mmol / L zinc chloride, pH = 5.7). After mixing, store 1-mL aliquots of these reagents at -20 °C for up to 2 months.

[0347] Three 3-mm disks were extracted from dried blood spots (DBS) obtained by spotting blood onto Whatman 903 filter paper and allowing it to dry at ambient conditions for at least 3 hours and placed in individual microtiter plates. The first disk was treated with 30 μL of ASM cocktail, and the second with 30 μL of a 5-plex cocktail containing S and IS for GCase, GAA, GLA, GALC, and IDUA. The two enzyme plates were sealed, centrifuged at 493 g for 2 minutes, and incubated at 37°C for 19 hours. The third disk was treated with 300 μL of 12 ng / mL d4-C as described by Turgeon et al. (Turgeon, 2015). 26 Extraction is performed with methanol containing lysophosphatidylcholine (LPC). The extract is then evaporated under heated nitrogen, reconstituted in 130 μL of mobile phase (800 mL methanol / 200 mL water with 5 mmol / L ammonium formate), and stored refrigerated. Following a 19-hour incubation, the 5-plex and ASM reactions are stopped by adding 200 μL of 1:1 ethyl acetate:methanol to each plate. The 5-plex and ASM plates are combined into a single deep-well plate, and liquid-liquid extraction is performed by adding 400 μL of ethyl acetate, followed by 400 μL of water, to each plate. The plates are sealed and centrifuged at 493 g for 2 minutes. 150 μL of the organic layer is transferred to a new plate, evaporated under nitrogen, and reconstituted in 150 μL of 19:1 ethyl acetate:methanol. The reconstituted extract is added to a silica-containing filter plate that has been pre-washed with 200 μL of 19:1 ethyl acetate. The samples are transferred through the filter plate via positive pressure, and the plate is eluted with an additional 200 μL of 19:1 ethyl acetate. The collected 350 μL of eluate is evaporated under a nitrogen stream and then reconstituted with the stored (X-adrenoleukodystrophy) ALD plate. The samples are subjected to flow injection-tandem mass spectrometry (FIA-MS / MS). The total time to process the 96-sample plate is 60 and 70 minutes, respectively, before and after the 19-hour incubation.

[0348] MS / MS Procedure: A triple quadrupole MS / MS system (power supply voltage, 5500 V) operated in positive ion mode is used. The mass calibration and splitting of both split quadrupoles are optimized by poly(propylene) glycol solution introduced by an infusion pump. The optimization of the method is The analysis is performed by infusing a solution containing the measured enzyme product, LPC species, and IS at 0.6 mL / h. The instrument is optimized to monitor the progress. A single reaction monitoring experiment (100 ms dwell, each experiment) is added to the MS / MS method. Sample introduction into the atmospheric pressure chemical ionization source is achieved by an autosampler and HPLC system. Autosampler injections of 20 μL per sample into a 0.250 mL / min flow of liquid chromatography (LC) mobile phase (800 mL methanol / 200 mL water and 5 mmol / L ammonium formate) are performed without using a chromatography column. Between injections, the analysis time is 1 minute per sample. C 26 Each sample, prepared with apparently increasing concentrations of LPC, was validated by reflectance analysis using LC-MS / MS as described by Turgeon (Turgeon, 2015) and Hubbard et al. (Hubbard, 2009) to minimize false positive results. This was done to ensure that unknown substances inconsistently present in DBS could be identified by C analysis using flow injection-tandem mass spectrometry (FIA-MS / MS). 26 -which may interfere with accurate quantification of LPC).

[0349] Preparation of Calibrators and Controls. One skilled in the art will know which controls are appropriate for the comparison of interest and will select these for use in the GCase activity protocol.

[0350] For example, controls for enzyme activity levels can be prepared and supplied by the Centers for Disease Control and Prevention (CDC) in the USA. These controls include a base pool control lacking enzyme activity (CDC Base Pool), a low dose control with reduced enzyme activity (CDC Low), a medium dose control with moderate enzyme activity (CDC Medium), and a high dose control with normal enzyme activity (CDC High). Liquid calibrators with product (P) to IS ratios (P / IS) of 0.00, 0.05, 0.5, 1.0, 2.0, and 5.0 for each enzyme were used to obtain C values ​​of 0.00, 0.58, 0.97, 1.16, 1.74, and 2.32 mg / L in 3-mm DBS used in linearity studies. 20 -, C 22 -, C 24 - and C 26 -LPC, as well as the corresponding liquid calibrators, may be supplied by the CDC.

[0351] In some instances, controls for the level of enzyme activity may be prepared from samples taken from the patient before the start of treatment or at various time points during the early stages of treatment.

[0352] It may also be useful to provide a basal pool lacking enzymatic activity, a basal pool with low activity and / or a basal pool prepared from a basal pool of healthy subjects.

[0353] Efficacy results Some subjects treated with Compound A exhibit an increased time to deterioration compared to placebo-treated subjects on at least one of the measures described herein. Clinical deterioration can be defined by a ≥ 2-point increase in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II total score and no improvement in motor testing as assessed by a ≥ 0-point increase in the MDS-UPDRS Part III total score.

[0354] Alternatively or additionally, time to deterioration can be defined as the time to a ≥ 5-point increase in the MDS-UPDRS Part III total score, or the time to a ≥ 3-point increase in the MDS-UPDRS Part III total score, and / or the time to a ≥ 2-point increase in the MDS-UPDRS Part II total score and a ≥ 5-point increase in motor testing assessed by the MDS-UPDRS Part III total score.

[0355] Alternatively or additionally, subjects treated with Compound A may also show an increase in the time from baseline to any worsening in the CGI-C, CGI-S, PGI-S, and / or PGI-C scales and / or an increase in the time to the first increase in LEDD compared to subjects treated with placebo.

[0356] Alternatively or additionally, subjects treated with Compound A may show less change from baseline to week 78 in MDS-UPDRS score (I-IV), modified H&Y score, PD-CRS score, PDQ-39, EQ-5D-5L score, CGI-C score, and / or PGI-C score compared to subjects treated with placebo.

[0357] Pharmacokinetic results The mean plasma concentrations of Compound A were higher after the 60 mg dose than after the 10 mg dose at all measured time points.

[0358] Pharmacodynamic results The mean change in plasma concentration of neurofilament light chains is lower in subjects treated with Compound A compared to subjects treated with placebo.

[0359] The mean change in GCase activity in whole blood samples was higher in subjects treated with Compound A compared to subjects treated with placebo.

[0360] The mean change in lysosomal activity was higher in subjects treated with Compound A compared to subjects treated with placebo. Additionally, the mean change in GluSph levels was higher in subjects treated with Compound A compared to subjects treated with placebo.

[0361] The mean change in cerebral blood flow, as measured by arterial spin labeling by MRI, is higher in subjects treated with Compound A compared to subjects treated with placebo.

[0362] [Table 14-1]

[0363] [Table 14-2]

[0364] [Table 14-3]

[0365] GBA-PD patients will be enrolled if they meet the following criteria: a) "Risk variant (mild)": heterozygous for any listed mutation, including heterozygous for a listed mutation; or b) "Risk variant (mild)" homozygous for the listed mutation.

[0366] Patients with GD (to exclude): 1. "Mild" or "Severe" homozygous for a listed mutation, or 2. "Mild" or "Severe": Compound heterozygous for the listed mutations.

[0367] [Table 15]

[0368] References The contents of the following documents and any documents cited anywhere in this disclosure are incorporated herein by reference in their entirety: ClinicalTrials.gov(2021).A Study to Evaluate the Efficacy of Prasinezumab(RO7046015 / PRX002)in Participants With Early Parkinson's Disease(PASADENA).United States: ClinicalTrials.gov.Available: https: / / clinicaltrials.gov / ct2 / show / NCT03318523 Den Heijer, JM, Kruithof, AC, Amerongen, G, de Kam, ML, Thijssen E., Grievink, HW, et al. A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator. British Journal of clinical Pharmacology, 2021;87(2);3561-3571. Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70(24):2277-83. Gan-Or Z,Amshalom I,Kilarski LL,Bar-Shira A,Gana-Weisz M,Mirelman A,et al.Differential effects of severe vs mild GBA mutations on Parkinson disease.Neurology.2015;84(9):880-7. Goetz CG,Poewe W,Rascol O,et al.Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations.Mov Disord.2004;19(9):1020-8. Goetz CG,Tilley BC,Shaftman SR,et al.Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale(MDS-UPDRS): scale presentation and clinimetric testing results.Mov Disord.2008;15;23(15):2129-70. Grabowski GA.Phenotype,diagnosis,and treatment of Gaucher’s disease.Lancet.2008;372(9645):1263-71. Guimaraes Bde C,Pereira AC,Rodrigues Fda C,Vaz dos Santos A,Campos Jr M,Mendonca dos Santos J,et al.Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson’s disease in Brazilian patients.Parkinsonism Relat Disord.2012;18(5):688-9.

[0369] Guy W,editor.ECDEU Assessment Manual for Psychopharmacology.Rockville,MD: US Department of Health,Education,and Welfare Public Health Service Alcohol,Drug Abuse,and Mental Health Administration;1976. Herdman M,Gudex C,Lloyd A,et al.Development and preliminary testing of the new five-level version of EQ-5D(EQ-5D-5L).Qual Life Res.2011;20(10):1727-36. Hubbard WC,Moser AB,Liu AC,Jones RO,Steinberg SJ,Lorey F,et al.Newborn screening for X-linked adrenoleukodystrophy(X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric(LC-MS / MS)method.Mol Genet Metab 2009;97: 212-20. Jesus S,Huertas I,Bernal-Bernal I,Bonilla-Toribio M,Caceres-Redondo MT,Vargas-Gonzalez L,et al.GBA variants influence motor and non-motor features of Parkinson’s disease.PLoS One.2016;11(12):e0167749. Leyns C,et al.Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease.NPJ Parkinsons Dis.2023 May 11;9(1):74. Liu G,Boot B,Locascio JJ,Jansen IE,Winder-Rhodes S,Eberly S,et al.Specifically neuropathic Gaucher’ mutations accelerate cognitive decline in Parkinson’s.Ann Neurol.2016;80(5):674-85. Mata IF,Leverenz JB,Weintraub D,Trojanowski JQ,Chen-Plotkin A,Van Deerlin VM,et al.GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease.Mov Disord.2016;31(1):95-102. Moraitou M,Hadjigeorgiou G,Monopolis I,Dardiotis E,Bozi M,Vassilatis D,et al.β-Glucocerebrosidase gene mutations in two cohorts of Greek patients with sporadic Parkinson’s disease.Mol Genet Metab.2011;104(1 2):149-52.

[0370] Neudorfer O,Giladi N,Elstein D,Abrahamov A,Turezkite T,Aghai E,et al.Occurrence of Parkinson’s syndrome in type 1 Gaucher disease.QJM.1996;89(9):691-4. Neumann J,Bras J,Deas E,O’Sullivan SS,Parkkinen L,Lachmann RH,et al.Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease.Brain.2009;132(Pt 7):1783-94. Pagonabarraga J,Kulisevsky J,Llebaria G,et al.Parkinson’s disease-cognitive rating scale: A new cognitive scale specific for Parkinson’s disease.Mov Disord.2008;23(7):998-1005. Parlar SC,Grenn FP,Kim JJ,et al.Classification of GBA1 variants in Parkinson’s disease: the GBA1-PD Browser.Mov Disord.2023 Jan 4.doi: 10.1002 / mds.29314. Peterschmitt M.J.,Giladi N.,Alcalay R.N.,Simuni T.,Marek K.,Investigators M.-P.(2021a).“Ven-glustat In Parkinson’s Disease Patients with a GBA Mutation: resultsFrom Part 2 of the Phase 2 MOVES-PD Trial” in 15th International Conference on Alzheimer’s & Parkinson’s Diseases(Virtual; Peto V,Jenkinson C,Fitzpatrick R.PDQ-39: a review of the development,validation and application of a Parkinson’s disease quality of life questionnaire and its associated measures.J Neurol.1998;245(Suppl 1):S10-4. Pires N et al.(2023)Profile Of Glucocerebrosidase 1(GCase)Activity And Glucosylsphingosine Levels In GBA-PD,PD Patients And Healthy Volunteers. International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders. AD / PD 2024 Posters. P1124 / #1065. Posner K,Brown GK,Stanley B,et al.The Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults.Am J Psych.2011;168(12):1266-77.

[0371] Tilley B.C.,Galpern W.R.(2007).Screening potential therapies: lessons learned from new paradigms used in Parkinson disease.Stroke 38 800-803. Rascol O.,Hauser R.A.,Stocchi F.,Fitzer-Attas C.J.,Sidi Y.,Abler V.,et al.(2016).Long-term effects of rasagiline and the natural history of treated Parkinson’s disease.Mov.Disord.31 1489-1496. Rosenbloom B,Balwani M,Bronstein JM,Kolodny E,Sathe S,Gwosdow AR,et al.The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry.Blood Cells Mol Dis.2011;46(1):95-102. Rosenbloom BE,Weinreb NJ.Gaucher disease: a comprehensive review.Crit Rev Oncog.2013;18(3):163-75. Surface M et al.(2022)Plasma Glucosylsphingosine in GBA1 Mutation Carriers with and without Parkinson’s Disease.Mov Disord,37: 416-421. Tortorelli S,Turgeon CT,Gavrilov DK,Oglesbee D,Raymond KM,Rinaldo P,Matern D.Simultaneous Testing for 6 Lysosomal Storage Disorders and X-Adrenoleukodystrophy in Dried Blood Spots by Tandem Mass Spectrometry.Clin Chem.2016 Sep;62(9):1248-54.doi: 10.1373 / clinchem.2016.256255.Epub July 20, 2016. PMID: 27440509. Turgeon CT, Moser AB, Morkrid L, Magera MJ, Gavrilov DK, Oglesbee D, et al. Streamlined determination of lysophosphatidylcholines in dried blood spots for new- born screening of X-linked adrenoleukodystrophy. Mol Genet Metab 2015;114:46-50. US Food and Drug Administration (FDA). Guidance for Industry: E10 choice of control group and related issues in clinical trials; May 2001. US Food and Drug Administration (FDA). Gu idance for Industry: Multiple endpoints in clinical trials; January 2017. Ysselstein D, Young TJ, Nguyen M, Padmanabhan S, Hirst WD, Dzamko N, Krainc D, Evaluation of Strategies for Measuring Lysosomal Glucocerebrosidase Activity, Movement Disorders, 2021;36(12):2719-2730

[0372]

Table 16-1

[0373]

Table 16-2

[0374] Table 16-3

Claims

1. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in preventing or limiting the progression of clinical motor symptoms in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene.

2. 1. A method for preventing or limiting the progression of clinical motor symptoms in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, comprising administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof.

3. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2.

4. 1. A method for treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have a PD-associated pathogenic variant in LRRK2, comprising administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof.

5. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who is not affected by Gaucher disease.

6. 1. A method for treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who does not have Gaucher disease, comprising administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof.

7. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in treating or preventing Parkinson's disease in a subject who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and who is not homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease or who is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

8. A patient has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD) and is homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease.

1. A method for treating or preventing Parkinson's disease in a subject who is not heterozygous or who is not compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof.

9. 1. A method of preventing or delaying cognitive impairment in a subject with Parkinson's disease (GBA-PD) who has a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, comprising administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof.

10. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in preventing or delaying cognitive impairment in subjects with Parkinson's disease (GBA-PD) who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene.

11. A method for treating Parkinson's disease in a subject having decreased, reduced, or low GCase activity, comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

12. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease in a subject with decreased, reduced or low GCase activity.

13. 13. A method of treatment or use according to any one of claims 1 to 12, wherein the treatment or progression of clinical motor symptoms is assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Clinical Global Impression-Change (CGI-C) scale, and / or the Patient Global Impression-Change (PGI-C) scale.

14. 14. A method of treatment or use according to any one of claims 1 to 13, wherein said use or treatment results in a ≧2 point increase in the MDS-UPDRS Part II score and an increase in the time to no improvement (i.e. a score above zero) in the Part III score compared to subjects treated with a placebo.

15. 15. A method of treatment or use according to any one of claims 1 to 14, wherein said use or treatment results in a ≥ 2 point increase in the MDS-UPDRS Part II score and an increase in the time to no improvement (i.e. a difference from baseline of ≥ zero) in the Part III score compared to subjects treated with a placebo.

16. 16. A method of treatment or use according to any one of claims 1 to 15, wherein said use or treatment results in an increase in time to a ≥ 5 point increase in MDS-UPDRS Part III total score compared to subjects treated with placebo.

17. 17. A method of treatment or use according to any one of claims 1 to 16, wherein said use or treatment results in an increase in time to a ≥ 3 point increase in MDS-UPDRS part III total score compared to subjects treated with placebo.

18. 18. A method of treatment or use according to any one of claims 1 to 17, wherein said use or treatment results in an increase in the time to a ≥ 2 point increase in MDS-UPDRS part II score, confirmed by a ≥ 5 point increase in MDS-UPDRS part III score, compared to subjects treated with placebo.

19. The use or treatment, compared to a placebo-treated subject: i) First levodopa equivalent daily dose escalation (LEDD); ii) any worsening on the Clinical Global Impression-Corrected (CGI-C) scale; iii) any worsening on the Patient Global Impression-Corrected (PGI-C) scale; iv) Any worsening on the Clinical Global Impression-Severity (CGI-S) scale; or v) Any deterioration in the Patient Global Impression-Scaling (PGI-S) scale 19. A method of treatment or use according to any one of claims 1 to 18, which results in an increase in the time to

20. 20. A method of treatment or use according to any one of claims 1 to 19, wherein said use or treatment results in improved walking speed or wherein said use or treatment prevents, limits or delays a decline in walking speed.

21. 21. A method of treatment or use according to any one of claims 1 to 20, wherein said use or treatment results in improved cerebral blood flow measured using arterial spin labelling and / or MRI free water imaging.

22. 22. A method of treatment or use according to any one of claims 1 to 21, wherein said use or treatment results in reduced neurofilament light chain concentrations.

23. 23. A method of treatment or use according to any one of claims 1 to 22, wherein said use or treatment results in preventing or limiting a decrease in quality of life.

24. 24. A method of treatment or use according to any one of claims 1 to 23, wherein said use or treatment results in an improved quality of life.

25. 25. A method of treatment or use according to any preceding claim, wherein GCase activity in the cerebrospinal fluid (CSF) of said subject is at least doubled.

26. 26. A method of treatment or use according to any one of claims 1 to 25, wherein the subject has been clinically diagnosed as having Parkinson's disease, e.g. GBA-PD.

27. 27. A method of treatment or use according to any one of claims 1 to 26, wherein the subject has a clinical diagnosis of PD for at least 1 year and not more than 7 years prior to the start of treatment, the subject has a modified Hohenyahr scale of ≦2.5, and the subject is receiving symptomatic treatment for PD.

28. 28. A method of treatment or use according to any one of claims 1 to 27, wherein the subject has been diagnosed as having Parkinson's disease and having reduced, decreased or low GCase activity.

29. 29. A method of treatment or use according to any one of claims 1 to 28, wherein compound A is administered in combination with a therapeutically effective amount of one or more of the following concomitant medications: dopaminergic agents, dopamine receptor agonists, monoamine oxidase B inhibitors, catechol-O-methyltransferase inhibitors, N-methyl-D-aspartate receptor antagonists, adenosine receptor antagonists, and anticholinergic agents.

30. 30. A method of treatment or use according to any one of claims 1 to 29, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of a dopamine agonist.

31. 31. The method of treatment or use of claim 30, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of levodopa or a levodopa / DDCI preparation.

32. 32. The method of treatment or use of claim 31, wherein Compound A or a pharmaceutically acceptable salt thereof and levodopa or the levodopa / DDCI preparation are administered simultaneously or sequentially within less than 30 minutes.

33. 33. A method of treatment or use according to claim 32, wherein Compound A or a pharmaceutically acceptable salt thereof and the levodopa or levodopa / DDCI preparation are administered separately, at least 30 minutes apart.

34. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolol[1,5-a]pyrimidine-3-carboxamide (Compound A) or a pharmaceutically acceptable salt thereof for use in preventing or reducing the risk of Parkinson's disease in a subject determined to be at risk for Parkinson's disease, for example a subject who has not been diagnosed with Parkinson's disease and has been determined to have a GBA1 pathogenic variant for PD.

35. A method for preventing or reducing the risk of Parkinson's disease in a subject determined to be at risk for Parkinson's disease, e.g., a subject who has not been diagnosed with Parkinson's disease and has been determined to have a GBA1 pathogenic variant for PD, comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

36. 36. A method of treatment or use according to claim 34 or 35, wherein said subject has been determined to have decreased, reduced or low GCase activity.

37. 37. A method of treatment or use according to any one of claims 34 to 36, wherein GCase activity in the cerebrospinal fluid (CSF) of said subject is at least doubled.

38. 38. A method of treatment or use according to any one of claims 34 to 37, wherein the subject has been determined to harbor a GBA1 pathogenic variant for PD.

39. 39. A method of treatment or use according to any one of claims 34 to 38, wherein said use or treatment results in the prevention or delay of the onset of Parkinson's disease.

40. 40. A method of treatment or use according to any one of claims 34 to 39, wherein said use or treatment results in the prevention, limitation or delay of a decline in quality of life.

41. 41. A method of treatment or use according to any one of claims 1 to 40, wherein said use or treatment comprises administering to said subject Compound A at a dose of from about 10 mg to about 60 mg per day.

42. 42. A method of treatment or use according to any one of claims 1 to 41, wherein said use or treatment comprises administering to said subject a dose of Compound A of about 10 mg per day.

43. 43. A method of treatment or use according to any one of claims 1 to 42, wherein said use or treatment comprises administering to said subject a dose of Compound A of about 60 mg per day.

44. Compound A or a pharmaceutically acceptable salt thereof is administered to a subject over an extended period of time, e.g., 52 44. A method of treatment or use according to any one of claims 1 to 43, which is used or administered for a week or more.

45. 45. A method of treatment or use according to any one of claims 1 to 44, wherein Compound A or a pharmaceutically acceptable salt thereof is used or administered to the subject once daily.

46. Preface: のGBA1 における pathogenic variant が, the following variant: NM_001005741.3: c. 1093G>A, NM_001005741.3: c. 1223C>T, NM_001005741.3: c. 1226A>G, ​​NM_001005741.3: c. 1448T>C、NM_001005741.3:c. 1604G>A, NM_001005741.3: c. 1342G>C, NM_001005741.3: c. 680A>G, NM_001005741.3: c. 1504C>T, NM_001005741.3: c. 84dup, NM_001005741.3: c. 754T>A, NM_001005741.3: c. 1297G>T、NM_001005741.3:c. 721G>A, NM_001005741.3: c. 259C>T, NM_001005741.3: c. 928A>G, NM_001005741.3: c. 764T>A, NM_001005741.3: c. 1246G>A, NM_001005741.3: c. 946C>T, NM_001005741.3: c. 26_27del, NM_001005741.3: c. 604C>T, NM_001005741.3: c. 1090G>A, NM_001005741.3: c. 1296G>A, NM_001005741.3: c. 1192C>T, NM_001005741.3: c. 914del, NM_001005741.3: c. 256C>T, NM_001005741.3: c. 586A>C, NM_001005741.3: c. 1312G>A, NM_001005741.3: c. 203dup, NM_001005741.3: c. 475C>T, NM_001005741.3: c. 476G>A, NM_001005741.3: c. 887G>A, NM_001005741.3: c. 762-1G>C, NM_001005741.3: c. 115+1G>A, NM_001005741.3: c. 1505+1G>T, NM_001005741.3: c. 123_217del、NM_001005741.2:c. 1265_1319del, NM_001005741.3: c. 715C>T, NM_001005741.3: c. 1085C>T, NM_001005741.3: c. 413del、NM_001005741.3:c.882T>G, NM_001005741.3:c.1193G>A and NM_001005741.3:c.1_2344del.

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