Treatment of parkinson's disease in patients using glucocerebrosidase activators

Abstract

Provided are methods for preventing, limiting, or delaying clinical motor progression in a subject suffering from Parkinson's disease carrying low GCase activity, such as a PD (GBA-PD) patient carrying a pathogenic variation of the glucocerebrosidase 1 (GBA1) gene, comprising administering to the subject a therapeutically effective amount of 5, 7-dimethyl-N-((1R, 4R)-4-(pentyloxy) cyclohexyl) pyrazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, the present invention relates to a pharmaceutically acceptable salt of 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)pyrazolo[1,5-a]pyrimidine-3-carboxamide for use in the treatment or prevention of Parkinson’s disease.

[0002] BACKGROUND

[0003] Parkinson’s disease (PD) is a multi-centric neurodegenerative disease whose pathological features are the loss of dopaminergic neurons in the substantia nigra compacta and other brainstem nuclei, and the presence of alpha-synuclein (SNCA) aggregates in Lewy bodies and neurites.

[0004] GCase (glucocerebrosidase) encoded by the GBA1 (glucocerebrosidase 1) gene is the enzyme responsible for hydrolyzing glucosylceramide (GluCer) to glucose and ceramide in the lysosome. GCase activity dysfunction is associated with Parkinson’s disease. GCase mutations are known to be a major risk factor for the onset of PD. Loss of GCase function contributes to the pathogenesis of PD, even in the absence of genetic mutations.

[0005] Carrying one mutant allele of GBA1 significantly increases the risk of developing PD over a lifetime. Approximately 10% to 15% of patients clinically diagnosed with PD carry GBA1 pathogenic variants (PD with GBA1 pathogenic variant, GBA-PD). The degree of increased risk of being diagnosed with PD conferred by heterozygous pathogenic variants depends on the magnitude of the reduction in GCase activity and can range from 2.2-fold to 19.2-fold. This increased risk of PD has been validated in large samples of over 100 GBA1 pathogenic variants, covering the United States (Grabowski, 2008), Israel (Najafi, 2013), and the United Kingdom (Durr, 2019). The risk of developing PD is also increased in patients with GBA1 mutations who are heterozygous for other PD risk factors, such as LRRK2 mutations (Dardiotis, 2018). Sweden (Jesus, 2016), Spain (Liu, 2016), the United Kingdom (Mata, 2016), Greece (Moraitou, 2011), China (Neudorfer, 1996), South America (Neumann, 2009), and various meta-analyses (Gan-Or, 2015). In Israel, approximately 20-30% of PD patients of Ashkenazi Jewish descent carry pathogenic variants in GBA1. Thus, pathogenic variants in GBA1 are the most common genetic risk factor for PD in multiple clinical settings.

[0006] Overall, GBA-PD patients typically have a clinically distinct course of disease compared to idiopathic PD patients (i.e., those not carrying pathogenic variants in GBA1). On average, GBA-PD patients have an earlier age of onset (Grabowski, 2008; Gan-Or, 2015). They exhibit more prominent postural instability and gait impairment relative to tremor, and their disease is characterized by frequent falls. Generally, patients with GBA-PD progress more rapidly than patients with idiopathic PD (iPD) (Gan-Or, 2008; Ran, 2016), and on average, they have a shorter survival from diagnosis (Rosenbloom, 2011). GBA-PD patients also exhibit more frequent cognitive dysfunction, progressing more rapidly to dementia, than iPD patients (Rosenbloom, 2013; Pal, 2016; Ran, 2016). GBA-PD is further characterized by a higher prevalence of depression, anxiety, hallucinations, and rapid eye movement sleep behavior disorder (Liu, 2016; Mata, 2016). It was recently reported that among many known genetic risk factors for PD, only GBA1 increases the rate of disease progression (Tan, 2021).

[0007] Nonetheless, low / decreased GCase activity has also been observed in certain PD patients that do not carry pathogenic variants in GBA1 (e.g., wild-type GBA1 PD patients) (Moloney, 2021).

[0008] 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (also referred to herein as “Compound A”) is an allosteric activator of the enzyme beta-glucocerebrosidase (GCase). As such, Compound A is a potential treatment option for two classes of patients with Parkinson’s Disease (PD): one class is patients carrying GBA1 gene mutations (GBA-PD); the other class is patients with ubiquitous, low / reduced GCase activity, who can benefit from a treatment option that increases GCase activity.

[0009] Compound A has been shown to be safely administered to healthy humans (J.M den Heijer, 2021). In the clinical development program, the compound was overall well tolerated, no treatment-related serious adverse events or deaths occurred, and no subjects have withdrawn from the study due to adverse events to date.

[0010] Currently available PD medications primarily target the dopaminergic system and primarily alleviate motor symptoms, but do not address non-motor symptoms or otherwise affect / alter disease progression. Despite various preclinical studies of PD disease modulators that have shown promise, to date there have been no successful clinical disease modulators. Similarly, despite attempts to alter disease progression in patients with GBA-PD, to date there have been no successful clinical candidates. For example, MOVES-PD (monitoring of venglustat efficacy and safety in Parkinson’s disease) is a global Phase 2 study designed to assess the efficacy and safety of the candidate drug venglustat in Parkinson’s disease patients carrying GBA-1 gene mutations. Despite promising preclinical studies, when the final data were collected, the study results indicated that the drug had no impact on slowing disease progression (Peterschmitt et al., 2021a,b).

[0011] This indicates that there is still a huge unmet need for disease-modifying therapies for Parkinson’s disease.

[0012] In addition, there is a need for methods for administering Compound A to patients in need thereof who are also being administered other concomitant medications. As will be apparent from reference to the following disclosure, the present disclosure satisfies these and other needs. SUMMARY

[0013] In a first aspect of the application, described is Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD). According to one embodiment, the clinical motor progression 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 clinical motor progression is also assessed using the modified Hoehn and Yahr score, the 39-item Parkinson’s disease questionnaire (PDQ-39) score and / or the EuroQol 5 Dimension 5 Level (EQ-5D-5L) score.

[0014] In another aspect of the application, described is a method for preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD), the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, the clinical motor progression 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 clinical motor progression is also assessed using the modified Hoehn and Yahr score, the 39-item Parkinson’s disease questionnaire (PDQ-39) score and / or the EuroQol 5 Dimension 5 Level (EQ-5D-5L) score.

[0015] Many studies have been conducted to prevent or limit clinical motor progression in subjects with Parkinson’s disease by activating GCase. However, while ex vivo studies have successfully demonstrated the effective activation of GCase, it has not been demonstrated that it can prevent or limit clinical motor progression in subjects with Parkinson’s disease.

[0016] It is also noted that, while disease-modifying interventions have been successful in preclinical models, these successes have not translated into effective clinical success. There are currently no agents on the market that halt, prevent, or slow the clinical motor progression of PD. Without wishing to be bound by theory, one hypothesis is that one reason for the failure of preclinical research success to translate into clinical success is that PD has multiple different pathophysiology and there is heterogeneity between individual patients. Thus, predicting clinical success is very difficult. Recently failed trials include various NET-PD (Neurologic Explorations of Treatment in Parkinson's Disease) trials (Tilley and Galpern, 2007), the ADAGIO (Attenuation of Disease progression with Glucosidase Beta Attenuation of Disease Progression with given once daily) trial (Rascol et al., 2016), the recently failed alpha-synuclein immunotherapy trial (ClinicalTrials.gov, 2021), and the Venglustat trial (Peterschmitt et al., 2021a,b).

[0017] The present invention stems from the discovery that Compound A can effectively prevent, limit, or slow the motor progression in certain PD subjects, in particular PD patients carrying reduced, decreased, or low GCase activity, such as GBA-PD patients. That is, Compound A is able to treat the underlying pathology of PD in these patients, rather than simply treating the symptoms of PD.

[0018] The therapy involves subjects with Parkinson's disease carrying pathogenic variants in the glucocerebrosidase 1 (GBA1) gene (GBA-PD). There are many pathogenic / disease-causing variants known in the GBA1 gene that affect the activity of the GCase enzyme. Pathogenic / disease-causing variants in the GBA1 gene include, but are not limited to, N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, and R120W. Major / severe mutations include, but are not limited to, heterozygotes for D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, R120W. Minor / mild mutations include, but are not limited to, heterozygotes for T369M or E326K. Further information on subjects that are heterozygous for disease-causing variants in the GBA1 gene is provided below.

[0019] Further pathological / disease-causing variants in the GBA1 gene include, but are not limited to, those included in the tables of Appendix 1. This includes, but is not limited to, a 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_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.l_2344del. In some embodiments, this includes, but is not limited to, a GBA1 gene 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_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, and NM_001005741.3: c.1505+1G>T. Major / 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.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_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, and NM_001005741.3: c.1_2344del. In some embodiments, the major / 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.754T>A, NM_001005741.3: c.1297G>T, NM_001005741.3: c.721G>A, NM_001005741.3: c.1246 G>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_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, and NM_001005741.3: c.1505+1G>T. Secondary / 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, secondary / 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.

[0020] Pathological / disease-causing variations in the GCase amino acid sequence, in terms of GCase amino acid sequence, include, but are not limited to, those included in the table in Appendix 1. This includes, but is not limited to, GBA1 genes encoding GCase enzymes containing one of the following amino acid variations: 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, 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, GBA1 genes encoding GCase enzymes containing one of the following amino acid variations: 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. Major / 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, 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.In some embodiments, major / 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. Minor / 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, minor / 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.

[0021] In the above aspects and the following additional aspects, Compound A is used or administered to a subject having Parkinson’s disease carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene (GBA-PD). The subject will carry two alleles of the GBA1 gene, both of which will have an impact on total GCase activity within the subject’s cells. Thus, in some embodiments, the subject is a GBA1 gene heterozygote having one allele containing a pathogenic variant and one non-pathogenic allele (such as a wild-type allele of the GBA1 gene). In other embodiments, the subject is a GBA1 gene heterozygote having one deleted allele (i.e., complete gene deletion) and one non-pathogenic allele (such as a wild-type allele of the GBA1 gene). The term “heterozygote” in the present disclosure, where the second allele is not defined, is understood to mean that the second allele is non-pathogenic (such as a wild-type allele). This is in contrast to the term “compound heterozygote,” which is used to mean that both alleles of the GBA1 gene contain at least one pathogenic variant, which is not the same between the two alleles. The term “homozygote” means that both alleles of the GBA1 gene contain the same pathogenic variant.

[0022] In some embodiments, the subject is a GBA1 gene heterozygote 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_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.l_2344del (the other allele is non-pathogenic). In some embodiments, the subject is a GBA1 gene heterozygote 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_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, and NM_001005741.3: c.1505 +1 G>T (the other allele is non-pathogenic). In addition, the subject can be a GBA1 gene homozygote carrying the pathogenic variant NM_001005741.3: c.1093G>A or the pathogenic variant NM_001005741.3: c.1223C>T.

[0023] In terms of GCase amino acid sequence, the subject can be a GBA1 gene heterozygote having one allele encoding a GCase enzyme containing one of the following amino acid variations: 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, 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, the subject can be a GBA1 gene heterozygote having one allele encoding a GCase enzyme containing one of the following amino acid variations: 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 (the other allele is non-pathogenic). In addition, the subject can be a GBA1 gene homozygote in which both alleles encode a GCase enzyme containing the amino acid variation p.Glu365Lys or p.Thr408Met.

[0024] In another aspect of the application, there is described Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing and / or delaying clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD). According to one embodiment, the clinical motor progression 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.

[0025] In another aspect of the application, there is described a method for preventing and / or delaying clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD), the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, the clinical motor progression 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.

[0026] In another aspect of the application, there is described Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD).

[0027] In a related aspect of the application, there is described a method of treating Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, said method comprising administering to said subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0028] In another aspect of the application, there is described Compound A, or a pharmaceutically acceptable salt thereof, for use in the prevention or delay of cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD). According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0029] In a related aspect of the application, there is described a method for the prevention or delay of cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD), said method comprising administering to said subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0030] In another aspect of the application, there is provided Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Parkinson’s disease (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not carrying a pathogenic variant in LRRK2 (leucine-rich repeat kinase 2) associated with PD.

[0031] In a related aspect of the application, there is provided a method for the treatment or prevention of Parkinson’s disease (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not carrying a pathogenic variant in LRRK2 associated with PD, said method comprising administering to said subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0032] Pathological / disease-causing variations in the LRRK2 gene include, but are not limited to, G2019S, G2385R, R1628P, and A419V. Pathological variations in LRRK2 are associated with inherited sporadic PD. In a preferred embodiment, the subject does not carry a PD-associated disease-causing variation in the LRRK2 gene selected from N1437H, R1441C, R1441H, and G2019S.

[0033] Another aspect of the application provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Parkinson’s disease in a subject carrying a pathogenic variation in the glucocerebrosidase 1 (GBA1) gene and not suffering from Gaucher disease (GBA-PD).

[0034] A related aspect of the application provides a method for the treatment or prevention of Parkinson’s disease in a subject carrying a pathogenic variation in the glucocerebrosidase 1 (GBA1) gene and not suffering from Gaucher disease (GBA-PD), the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0035] Gaucher disease is a genetic disorder in which glucosylceramide (GluCer) accumulates in cells and certain organs. Gaucher disease is believed to be caused by genetic defects in the GBA1 gene. Homozygous pathogenic variants of the GBA1 gene cause a substantial reduction in enzyme activity, which triggers GD (Gaucher disease) (Clark, 2007; Cilia, 2016), a autosomal recessive lysosomal storage disorder caused by impaired catabolism of glycosphingolipids in the lysosome. This in turn causes abnormal substrate accumulation and, as a result, dysfunction of cellular signaling pathways, calcium homeostasis, and intracellular trafficking. Manifestations of GD include dysfunction of various tissues, particularly the internal organs, bones, and bone marrow, and, in rare cases (types 2 and 3), brain dysfunction (Cilia, 2016). For the disease to manifest, patients need to carry pathogenic mutations in both alleles of the GBA (glucocerebrosidase) gene, either homozygously or compound heterozygously. However, patients who are homozygous for the GBA1 mutations NM_001005741.3:c.1093G>A (E326K) or NM_001005741.3:c.1223C>T (T369M) are an exception, which can be observed in GBA-PD patients but not in GD patients. Pathogenic variants of GCase that cause GD are those that cause a substantial reduction in enzyme activity (severe pathogenic variants), which can cause a reduction in GCase activity of about 60%, about 70%, about 80%, about 90% or more. The identification of patients with Gaucher disease is well known to those skilled in the art. For example, diagnosis can be made based on clinical signs and symptoms (e.g., hepatosplenomegaly, cytopenias, skeletal disease) and / or a history of a marked lack of GCase activity consistent with Gaucher disease (e.g., GCase activity of less than about 40%, less than about 30%, less than about 20%, or less than about 10% in a healthy subject or a representative sample of a healthy subject).

[0036] In another aspect, the present application provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Parkinson’s disease GBA-PD in a subject carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene, which is neither homozygous for a GBA1 pathogenic variant known to be associated with Gaucher disease nor compound heterozygous for two alleles of GBA1 known to be associated with Gaucher disease.

[0037] Pathogenic variants associated with Gaucher disease include, but are not limited to, the heterozygous p.L483P and p.S310G mutations, as well as the homozygous mutations N370S, L444P, 84GG, and IVS2+1.

[0038] In some embodiments, pathogenic variations associated with a subject having Gaucher disease include, but are not limited to, a subject who is homozygous for a GBA1 pathogenic variation or who is a compound heterozygote carrying two GBA1 pathogenic variations that are 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.

[0039] In addition, pathogenic variants associated with subjects having Gaucher disease include, but are not limited to, subjects who are GBA1 gene homozygotes containing one of the following nucleotide variants: 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.l_2344del. In some embodiments, a pathogenic variant associated with a subject having Gaucher disease includes, but is not limited to, a subject who is a GBA1 gene homozygote containing one of the following nucleotide variants: 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, and NM_001005741.3: c.1505+1G>T. Further, a pathogenic variant associated with a subject having Gaucher disease includes, but is not limited to, a subject who is a compound heterozygote carrying two GBA1 genes containing one of the following nucleotide variants: NM_001005741.3: c.1226A>G, NM_001005741.3: c.1448 T>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. In some embodiments, a pathogenic variant associated with a subject having Gaucher disease includes, but is not limited to, a subject who is a compound heterozygote carrying two GBA1 genes containing one of the following nucleotide variants: 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, and NM_001005741.3: c.1505+1G>T.

[0040] In a related aspect, the present application provides a method for treating or preventing Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0041] Examples of compound heterozygote mutations for Gaucher disease include p.L483P and p.S310G. Further examples of pathogenic variants in GBA1 associated with Gaucher disease are described above.

[0042] Another aspect of the present application describes Compound A for use in preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD. According to one embodiment, clinical motor progression 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.

[0043] A related aspect of the present application describes a method of preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD, comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, clinical motor progression 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.

[0044] Another aspect of the present application describes Compound A for use in preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD) and not having Gaucher disease. According to one embodiment, clinical motor progression 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.

[0045] A related aspect of the application describes a method for preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not having Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, the clinical motor progression 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.

[0046] A further aspect of the application describes Compound A for use in preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), not carrying a pathogenic variant in LRRK2 associated with PD, and not having Gaucher disease. According to one embodiment, the clinical motor progression 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 application describes a method for preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), not carrying a pathogenic variant in LRRK2 associated with PD, and not having Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, the clinical motor progression 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 application describes Compound A for use in preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a pathogenic variant in LRRK2 associated with PD, the subject being neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease. According to one embodiment, the clinical motor progression 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] Another aspect of the application describes a method for preventing or limiting the clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson's disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD, which is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, the clinical motor progression 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] Another aspect of the application describes Compound A for use in the prevention or treatment of Parkinson's disease (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, not carrying a pathogenic variant in LRRK2 associated with PD and not suffering from Gaucher disease.

[0051] Another aspect of the application describes a method for preventing or treating Parkinson's disease (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, not carrying a pathogenic variant in LRRK2 associated with PD and not suffering from Gaucher disease, the method comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0052] Yet another aspect of the application describes Compound A for use in the prevention or treatment of Parkinson's disease (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, not carrying a pathogenic variant in LRRK2 associated with PD and not suffering from Gaucher disease, which is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease.

[0053] Yet another aspect of the application describes a method for preventing or treating Parkinson's disease (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, not carrying a pathogenic variant in LRRK2 associated with PD and not suffering from Gaucher disease, which is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0054] Another aspect of the application describes Compound A for use in the prevention or treatment of Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not suffering from Gaucher disease, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease (GBA-PD). According to one embodiment, the subject is a heterozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease.

[0055] Another aspect of the application describes a method for the prevention or treatment of Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not suffering from Gaucher disease, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0056] Another aspect of the application describes Compound A for use in the prevention or limitation of clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson’s disease and not suffering from Gaucher disease, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease. According to one embodiment, the clinical motor progression 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.

[0057] Another aspect of the application describes a method for the prevention or limitation of clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson’s disease and not suffering from Gaucher disease, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, the method comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, the clinical motor progression 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.

[0058] Another aspect of the application provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease in a subject carrying reduced, decreased or low GCase activity.

[0059] Another aspect of the application provides a method of treating Parkinson’s disease in a subject in need of such treatment and carrying reduced, decreased, or low GCase activity, comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0060] Another aspect of the application provides Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting clinical motor progression in a subject having Parkinson’s disease and carrying reduced, decreased, or low GCase activity.

[0061] Another aspect of the application provides a method of preventing or limiting clinical motor progression in a subject having Parkinson’s disease and carrying reduced, decreased, or low GCase activity, comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0062] One aspect of the application 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 carrying reduced, decreased, or low GCase activity. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0063] One related aspect of the application provides a method of preventing or delaying cognitive impairment in a subject having Parkinson’s disease and carrying reduced, decreased, or low GCase activity, comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0064] According to another aspect of the application, there is described Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject having Parkinson’s disease and carrying reduced, decreased, or low GCase activity.

[0065] In one related aspect of the application, there is described a method for preventing motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject having Parkinson’s disease and carrying reduced, decreased, or low GCase activity, comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0066] Motor complications can be assessed using any method known to the skilled person. For example, using MDS-UPDRS Part II, Part III or Part IV. Preferably, MDS-UPDRS Part IV is used to assess motor complications. Non-motor complications can be assessed using any method known to the skilled person. For example, non-motor complications can be assessed using MDS-UPDRS Part I. “Non-motor complications” can also be referred to as “non-motor symptoms” and can be assessed using MDS-UPDRS Part I.

[0067] In some embodiments, reduced, decreased or low GCase activity means that the GCase activity of the patient is lower than the GCase activity measured in a healthy subject or a representative sample of healthy subjects. For example, reduced, decreased or low GCase activity can be from about 10% to about 50%, or from about 20% to about 50% lower than the GCase activity of a healthy subject or a representative sample of healthy subjects. In another embodiment, reduced, decreased or low GCase activity can be less than about 20%, less than about 30%, less than about 40%, less than about 50% lower than the GCase activity in a healthy subject or a representative sample of healthy subjects. In further embodiments, reduced, decreased or low GCase activity can be from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, or from about 40% to about 50% lower than the GCase activity in a healthy subject or a representative sample of healthy subjects.

[0068] In some embodiments, reduced, decreased or low GCase activity means that the GCase activity is equal or comparable to the activity measured in a GBA-PD patient or a representative sample of GBA-PD patients. For example, reduced, decreased or low GCase activity can be from about 80% to about 120% of the GCase activity observed in a GBA-PD patient or a representative sample of GBA-PD patients, can be from about 90% to about 110%, or from about 95% to about 105%.

[0069] Alternatively, in some embodiments, reduced, decreased or low GCase activity means that the GCase activity of the subject is lower than the GCase activity measured in the same patient after the start of treatment, for example a measurement after Compound A has reached steady state. In some embodiments, this phenomenon can occur after 4 weeks, 26 weeks, 52 weeks or 78 weeks of starting administration of Compound A. In some embodiments, the GCase activity of the subject measured after the start of treatment is more than about 20% higher, more than about 30% higher, more than about 40% higher or more than about 50% higher at the minimum value of steady state than the GCase activity of the subject measured before the start of treatment.

[0070] In some embodiments, the minimum value of the subject’s GCase activity measured at steady state after treatment has begun is from about 20% to about 380% higher, from about 50% to about 125% higher, or from about 69.7% to about 123% higher than the subject’s GCase activity measured before treatment has begun, from about 150% to about 310% higher, or from about 163% to about 306% higher than the GCase activity measured before treatment has begun, or from about 250% to about 380% higher, or from about 255% to about 376% higher than the GCase activity measured before treatment has begun.

[0071] In some embodiments, when the subject is administered 10 mg of Compound A per day, the minimum value of the subject’s GCase activity measured at steady state after treatment has begun is from about 50% to about 125% higher, or from about 69.7% to about 123% higher than the GCase activity measured before treatment has begun.

[0072] In some embodiments, when the subject is administered 30 mg of Compound A per day, the minimum value of the subject’s GCase activity measured at steady state after treatment has begun is from about 150% to about 310% higher, or from about 163% to about 306% higher than the GCase activity measured before treatment has begun.

[0073] In some embodiments, when the subject is administered 60 mg of Compound A per day, the minimum value of the subject’s GCase activity measured at steady state after treatment has begun is from about 250% to about 380% higher, or from about 255% to about 376% higher than the GCase activity measured before treatment has begun.

[0074] Methods of determining GCase activity are known to the skilled person. Any suitable method can be used to measure the GCase activity of a subject. An overview of possible methods is laid out in Ysselstein, 2021. Possible methods for measuring GCase activity are summarized in Table 1 below. Each method can yield slightly different results. Therefore, it is preferred that the same measurement method is used when comparing the GCase activity of a subject who can be suitable for treatment, a GBA-PD subject, and a healthy subject.

[0075]

[0076] Table 1: Summary of methods that can be used to measure GCase activity.

[0077] Another aspect of the application provides Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease in a subject carrying an altered lysosomal activity.

[0078] Another aspect of the application provides a method of treating Parkinson's disease in a subject in need of such treatment and carrying an altered lysosomal activity, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0079] Another aspect of the application provides Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the clinical motor progression in a subject having Parkinson's disease and carrying an altered lysosomal activity.

[0080] Another aspect of the application provides a method of preventing or limiting the clinical motor progression in a subject having Parkinson's disease and carrying an altered lysosomal activity, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0081] One aspect of the application 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 carrying an altered lysosomal activity. According to one embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0082] One related aspect of the application provides a method of preventing or delaying cognitive impairment in a subject having Parkinson's disease and carrying an 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 one embodiment, cognitive impairment is assessed using the Parkinson's Disease Cognitive Rating Scale (PD-CRS).

[0083] According to another aspect of the application, there is described Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing motor or non-motor complications, limiting the clinical motor progression and / or reducing the clinical motor impairment in a subject having Parkinson's disease and carrying an altered lysosomal activity.

[0084] In one related aspect of the application, there is described a method for preventing motor or non-motor complications, limiting the clinical motor progression and / or reducing the clinical motor impairment in a subject having Parkinson's disease and carrying an altered lysosomal activity, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0085] Methods of determining lysosomal activity are known to the skilled person. Any suitable method can be used to measure lysosomal activity in a subject. In some embodiments, modulated levels of the GCase substrate glucosylceramide (GluCer) and / or glucosylsphingosine (GluSph) can be used to determine lysosomal activity, in particular 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); and studies have shown that GluSph levels are increased in GBA-PD patients compared to healthy controls (Pires et al., 2023).

[0086] According to embodiments of the above aspects of the application, the patient with Parkinson’s disease has increased or high levels of GluSph prior to starting treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0087] Increased or high levels of GluSph means that the GluSph levels of the patient are higher than the GluSph levels measured in healthy subjects or in a representative sample of healthy subjects. Alternatively, increased or high levels of GluSph means that the GluSph levels of the patient prior to the start of treatment (e.g., at baseline) are higher than the GluSph levels measured in the same patient after long-term administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., after 12 weeks, 26 weeks, 39 weeks, 52 weeks, 65 weeks, 78 weeks or more of continuous once-daily administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof).

[0088] According to embodiments of the above aspects of the application, administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof reduces the GluSph levels in a patient with Parkinson’s disease (e.g., GBA-PD).

[0089] Reduced GluSph levels means that the GluSph levels of the patient are lower after long-term administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., after 12 weeks, 26 weeks, 39 weeks, 52 weeks, 65 weeks, 78 weeks or more of continuous once-daily administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof) than the GluSph levels measured in the same patient prior to administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., at baseline).

[0090] Further, baseline levels of GluSph and / or GluCer can be used as a baseline predictor of treatment response to chronic administration of Compound A or a pharmaceutically acceptable salt thereof (e.g., after 12 weeks, 26 weeks, 39 weeks, 52 weeks, 65 weeks, 78 weeks, or more of daily once administration of a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof), e.g., patient response can depend on GluSph and / or GluCer levels at baseline.

[0091] Methods for measuring both GluCer and GluSph are described in Heijer et al. (2021), which is incorporated herein by reference in its entirety. Briefly: LC-MS / MS (liquid chromatography-tandem mass spectrometry) methods can be used to measure GluCer and GluSph in K2EDTA plasma. The carbon chain of the ceramide group as in GluCer can have different lengths and degrees of saturation. Concentrations of GluCer C16:0, C18:0, C22:0, C24:0, and C24:1 are measured. For GluCer, the assay range is 1.00 pmol to 2500 pmol. For GluSph, the assay range is 0.0500 pmol to 10.0 pmol.

[0092] Possible methods for measuring lysosomal activity can produce slightly different results. Thus, it is preferred that the same measurement method is used when comparing lysosomal activity in subjects who can be suitable for treatment, GBA-PD subjects, and / or healthy subjects.

[0093] Another aspect of the application provides Compound A for use in preventing or reducing the risk of Parkinson’s disease in a subject determined to be at risk of Parkinson’s disease, e.g., a subject not diagnosed with Parkinson’s disease but determined to carry a GBA1 pathogenic variant for PD.

[0094] A related aspect of the application provides a method for preventing or reducing the risk of Parkinson’s disease in a subject determined to be at risk of Parkinson’s disease, e.g., a subject not diagnosed with Parkinson’s disease but determined to carry a GBA1 pathogenic variant for PD, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0095] Another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a pathogenic variant in LRRK2 associated with PD. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0096] A related aspect of the application describes a method for preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a pathogenic variant in LRRK2 associated with PD, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0097] Another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not having Gaucher disease. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0098] A related aspect of the application describes a method for preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not having Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0099] Yet another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), not carrying a pathogenic variant in LRRK2 associated with PD, and not having Gaucher disease. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0100] A related aspect of the application describes a method for preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), not carrying a pathogenic variant in LRRK2 associated with PD, and not having Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0101] Another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a pathogenic variant in LRRK2 associated with PD, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease. According to one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0102] Another aspect of the application describes a method for preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a pathogenic variant in LRRK2 associated with PD, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote 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 one embodiment, cognitive impairment is assessed using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0103] According to another aspect of the application, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in preventing motor or non-motor complications, limiting the clinical motor progression, and / or improving the clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD).

[0104] A related aspect of the application provides a method of treating motor or non-motor complications, limiting the clinical motor progression, and / or reducing the clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0105] Another aspect of the application provides Compound A for use in treating motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD).

[0106] Another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a PD-associated pathogenic variant in LRRK2.

[0107] A related aspect of the application describes a method of treating motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not carrying a PD-associated pathogenic variant in LRRK2, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0108] Another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not having Gaucher disease.

[0109] A related aspect of the application describes a method of treating motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), and not having Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0110] Yet another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor or non-motor complications, limiting clinical motor progression, and / or reducing clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), not carrying a PD-associated pathogenic variant in LRRK2, and not having Gaucher disease.

[0111] A related aspect of the application describes a method for treating motor complications or non-motor complications, limiting the clinical motor progression and / or reducing the clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson’s disease (GBA-PD), not carrying a pathogenic variant in LRRK2 associated with PD and not suffering from Gaucher disease, comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0112] Another aspect of the application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in treating motor complications or non-motor complications, limiting the clinical motor progression and / or reducing the clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson’s disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease.

[0113] Another aspect of the application describes a method for treating motor complications or non-motor complications, limiting the clinical motor progression and / or reducing the clinical motor impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson’s disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD, who is neither a homozygote for a pathogenic variant in GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, comprising administering to said subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0114] Motor complications can be assessed using any method known to the skilled person. For example, using MDS-UPDRS Part II, Part III or Part IV. Preferably, MDS-UPDRS Part IV is used to assess motor complications. Non-motor complications can be assessed using any method known to the skilled person. For example, non-motor complications can be assessed using MDS-UPDRS Part I. “Non-motor complications” can also be referred to as “non-motor symptoms” and can be assessed using MDS-UPDRS Part I.

[0115] In another aspect of the application, Compound A, or a pharmaceutically acceptable salt thereof, is described for use in preventing or limiting the deterioration of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson’s disease (GBA-PD).

[0116] One related aspect of the present application provides a method for preventing or limiting the worsening of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD), the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0117] Another aspect of the present application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the worsening of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD.

[0118] One related aspect of the present application describes a method for preventing or limiting the worsening of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD) and not carrying a pathogenic variant in LRRK2 associated with PD, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0119] Another aspect of the present application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the worsening of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD) and not having Gaucher disease.

[0120] One related aspect of the present application describes a method for preventing or limiting the worsening of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD) and not having Gaucher disease, the method comprising administering to the subject a therapeutically acceptable amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0121] Yet another aspect of the present application describes Compound A, or a pharmaceutically acceptable salt thereof, for use in preventing or limiting the worsening of the quality of life and / or improving the quality of life in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, having Parkinson’s disease (GBA-PD), not carrying a pathogenic variant in LRRK2 associated with PD and not having Gaucher disease.

[0122] A related aspect of the application describes a method for preventing or limiting the deterioration of the quality of life and / or improving the quality of life of a subject carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson's disease (GBA-PD), not carrying a pathogenic variant of LRRK2 associated with PD and not suffering from Gaucher disease, comprising administering to said subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0123] Another aspect of the application describes Compound A or a pharmaceutically acceptable salt thereof for use in preventing or limiting the deterioration of the quality of life and / or improving the quality of life of a subject carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson's disease (GBA-PD) and not carrying a pathogenic variant of LRRK2 associated with PD, who is neither a homozygote for a GBA1 pathogenic variant known to be associated with Gaucher disease nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease.

[0124] Another aspect of the application describes a method for preventing or limiting the deterioration of the quality of life and / or improving the quality of life of a subject carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene, suffering from Parkinson's disease (GBA-PD) and not carrying a pathogenic variant of LRRK2 associated with PD, who is neither a homozygote for a GBA1 pathogenic variant known to be associated with Gaucher disease nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, comprising administering to said subject a therapeutically acceptable amount of Compound A or a pharmaceutically acceptable salt thereof.

[0125] The quality of life can be assessed using any method known to the skilled person. For example, using the five-level five-dimensional health scale (EQ-5D-5L) score and / or the Parkinson's Disease Questionnaire (PDQ-39).

[0126] The PDQ-39 is the most fully validated and widely applied self-report measure for assessing health-related quality of life in PD patients. The EQ-5D-5L is a patient-reported outcome that measures health status in 5 dimensions.

[0127] In one embodiment, the effect of the use or treatment of the use or treatment of any one of the above aspects on the quality of life is assessed using the 39-item Parkinson's Disease Questionnaire (PDQ-39) score and / or the five-level five-dimensional health scale (EQ-5D-5L) score.

[0128] In one embodiment, the use or treatment of any of the above aspects achieves a prolongation of the time to an increase of >2 points in MDS-UPDRS Part II score, and no improvement (i.e., score of zero or higher) in Part III score, compared to subjects treated with placebo. In another embodiment, the use or treatment of any of the above aspects achieves a prolongation of the time to clinically meaningful progression in motor aspects of daily life experience from baseline, as assessed by an increase of >2 points in MDS UPDRS Part II score, and no improvement (i.e., difference from baseline of zero or higher) in Part III score, compared to subjects treated with placebo.

[0129] In one embodiment, the use or treatment of any of the above aspects achieves a prolongation of the time to an increase of >5 points in MDS-UPDRS Part III total score, compared to subjects treated with placebo.

[0130] MDS-UPDRS scores range from 0 to 132, with 32 points and below being mild, and 59 points and above being severe. An increase of greater than or equal to 5 points in MDS-UPDRS Part III is considered measurable motor function deterioration.

[0131] In one embodiment, the use or treatment of any of the above aspects achieves a prolongation of the time to an increase of >3 points in MDS-UPDRS Part III total score, considered a potential minimal measure of motor function deterioration, compared to subjects treated with placebo.

[0132] In one embodiment, the use or treatment of any of the above aspects achieves a prolongation of the time to an increase of >2 points in MDS-UPDRS Part II score, and is confirmed by an increase of >5 points in MDS-UPDRS Part III score, compared to subjects treated with placebo.

[0133] In one embodiment, the use or treatment of any of the above aspects delays the time to the occurrence of any worsening in at least one measure selected from CGI-C, PGI-C, CGI-S (clinical global impression–severity), or PGI-S (patient global impression–severity), compared to subjects treated with placebo.

[0134] In one embodiment, the use or treatment as described above achieves a delay in the time to the occurrence of:

[0135] i) first levodopa-equivalent daily dosage (LEDD) increase;

[0136] ii) any worsening on the Clinical Global Impression-Change (CGI-C) scale;

[0137] iii) any worsening on the Patient Global Impression-Change (PGI-C) scale;

[0138] iv) any worsening on the Clinical Global Impression-Severity (CGI-S) scale; or

[0139] v) any worsening on the Patient Global Impression-Severity (PGI-S) scale.

[0140] In one embodiment, the use or treatment described above results in a reduction in the change from baseline in one or more of the following scales compared to subjects treated with placebo:

[0141] i) MDS-UPDRS total (Part I to Part IV) score;

[0142] ii) MDS-UPDRS Part I score;

[0143] iii) MDS-UPDRS Part II score;

[0144] iv) MDS-UPDRS Part III score;

[0145] v) MDS-UPDRS Part IV score;

[0146] vi) MDS-UPDRS Part II + Part III score;

[0147] vii) bradykinesia as measured by MDS UPDRS Part III total motor spontaneity;

[0148] viii) modified Hoehn and Yahr score; and / or

[0149] ix) PD-CRS score.

[0150] In one embodiment, the use or treatment described above can improve gait speed compared to subjects treated with placebo. In some embodiments, the use or treatment described above can prevent, limit, or delay a decrease in gait speed.

[0151] Motor symptoms such as bradykinesia, postural instability, resting tremor, rigidity and slowness of movement are commonly present in PD. These symptoms contribute to changes in gait parameters. People with PD have a decreased self-selected walking speed (SSWS). Notably, individuals with PD walk with a higher step frequency, shorter stride length, and more time spent in double limb support.

[0152] Thus, an improved gait speed is indicative of an improvement in clinical motor function.

[0153] Gait speed can be measured by any method known to the skilled person. For example, a pedometer or a “smart” watch.

[0154] In one embodiment, the use or treatment as described above results in an improvement in cerebral blood flow, as measured using arterial spin labelling and / or MRI (magnetic resonance imaging) free water imaging.

[0155] Patients with Parkinson’s disease have abnormal cardiovascular regulation due to autonomic nervous system (ANS) dysfunction, and can experience sudden drops in blood pressure (BP) when standing, sitting or performing activities / movements. Cerebral blood flow or perfusion is a measure of the rate at which arterial blood is delivered to the tissue capillary bed and is indicative of cardiovascular health.

[0156] In one embodiment, the use or treatment as described in any of the above aspects results in a reduction in neurofilament light chain concentration.

[0157] Neurofilament light chain (NfL) is a neuronal cytoplasmic protein that is highly expressed in large-diameter myelinated axons. Levels of neurofilament light chain in cerebrospinal fluid (CSF) and blood increase in proportion to the extent of axonal damage in neurodegenerative diseases and Parkinson’s disease. New immunoassay methods enable detection of the biomarker at ultra-low levels, which has made it possible to measure NfL in blood, which can be easily and repeatedly detected for monitoring the course of Parkinson’s disease.

[0158] In one embodiment, the use or treatment as described in any of the above aspects comprises administering to the subject Compound A at a dose of about 10 mg per day.

[0159] In one embodiment, the use or treatment as described in any of the above aspects comprises administering to the subject Compound A at a dose of about 30 mg per day.

[0160] In one embodiment, the use or treatment of any of the above aspects comprises administering to the subject Compound A at a dose of about 60 mg per day.

[0161] In one embodiment, the use or treatment of any of the above aspects results in a minimum activation of GCase activity in the subject at steady state of about 50% to about 125%, or about 69.7% to about 123%, when 10 mg of Compound A is administered to the subject per day.

[0162] In one embodiment, the use or treatment of any of the above aspects results in a minimum activation of GCase activity in the subject at steady state of about 150% to about 310%, or about 163% to about 306%, when 30 mg of Compound A is administered to the subject per day.

[0163] In one embodiment, the use or treatment of any of the above aspects results in a minimum activation of GCase activity in the subject at steady state of about 250% to about 380%, or about 255% to about 376%, when 60 mg of Compound A is administered to the subject per day.

[0164] In one embodiment, the use or treatment of any of the above aspects results in a minimum activation of GCase activity in the subject at steady state of more than about 20%, more than about 30%, more than about 40%, or more than about 50%.

[0165] In one embodiment, the use or treatment of any of the above aspects results in a minimum activation of GCase activity in the subject at steady state of 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%.

[0166] GCase activity can be measured by any of the methods discussed above. Suitable methods include measuring GCase plasma activity or GCase whole blood activity.

[0167] In any of the above aspects, Compound A, or a pharmaceutically acceptable salt thereof, can be used or administered to the subject over an extended period of time. The extended period of time can last for 12 or more weeks, 26 or more weeks, 39 or more weeks, 52 or more weeks, 65 or more weeks, or 78 or more weeks.

[0168] Preferably, in any of the aspects or embodiments described herein, Compound A is administered once daily. Preferably, Compound A is administered orally.

[0169] In one embodiment, the use or treatment of any one of the above aspects comprises administering to a subject carrying at least one major / severe GBA1 mutation (e.g., GBA1 mutation is N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, or R120W heterozygote, or T369M or E326K homozygote).

[0170] In one embodiment, the use or treatment of any one of the above aspects comprises administering to a subject carrying at least one minor / mild GBA1 mutation (e.g., GBA1 mutation is T369M or E326K heterozygote).

[0171] Further, the use or treatment of any of the above aspects can comprise administering to a subject carrying at least one pathogenic / disease-causing GBA1 mutation, for example, the mutation is 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.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.l_2344del. In some embodiments, the at least one pathologic / disease-causing GBA1 mutation can 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.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, and NM_001005741.3: c.1505+1G>T.

[0172] Alternatively, the use or treatment of any of the above aspects can include administering to a subject carrying at least one pathogenic / cause of disease GBA1 mutation in the amino acid sequence of the GCase enzyme 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, 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 can be selected from 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.

[0173] Further information regarding the group of subjects to which Compound A can be administered, e.g., regarding the heterozygous / homozygous nature of the pathological / pathogenic GBA1 variation, can be found above.

[0174] In some embodiments, the use or treatment of any one of the above aspects comprises administering to a subject clinically diagnosed with PD for at least 1 year and no more than 7 years using the Parkinson’s Disease MDS (movement disorder society) criteria.

[0175] In some embodiments, the use or treatment of any one of the above aspects comprises administering to a subject having a modified Hoehn and Yahr score of < 2.5.

[0176] In some embodiments, the use or treatment of any one of the above aspects comprises administering to a subject having a MoCA (Montreal Cognitive Assessment) scale score of > 22.

[0177] In some embodiments, the use or treatment of 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 in any of the sub-items of MDS-UPDRS Part IV. In some embodiments, the subject does not have, has mild, or has mild motor complications, as assessed by a score of <3 (such as a score of 0, 1, or 2) in any of the sub-items of MDS-UPDRS Part IV.

[0178] In some embodiments, the use or treatment of any of the above aspects comprises administering to a subject who does not suffer from psychosis of clinical significance.

[0179] Compound A can be administered in combination with a therapeutically effective amount of one or more of the following concomitant medications: dopaminergic agents (e.g., levodopa, levodopa / dopa decarboxylase inhibitor (DOPA (dihydroxyphenylalanine, also known as dopa) decarboxylase inhibitor, DDCI) preparations, such as levodopa / carbidopa, levodopa / benserazide, and levodopa / carbidopa / entacapone). The levodopa or levodopa preparations can be formulated as immediate-release, controlled-release, or sustained-release formulations; dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine); monoamine oxidase B inhibitors (e.g., rasagiline, safinamide, selegiline); catechol-O-methyl transferase inhibitors (e.g., entacapone, tolcapone, opicapone); N-methyl-D-aspartate receptor antagonists (e.g., amantadine); adenosine receptor antagonists (e.g., istradefylline); anticholinergic agents (e.g., benztropine, biperiden, trihexphenidyl), and neuroprotective agents (e.g., ambroxol).

[0180] When such a combination is used, the administration time of Compound A and the concomitant medication is not limited, and Compound A or a pharmaceutical composition thereof, or the concomitant medication or a pharmaceutical composition thereof can be administered to the administration subject simultaneously, or can be administered at different times. The dose of the concomitant medication can be determined according to the dose used clinically, and can be appropriately selected according to the administration subject, the administration route, the disease, the combination, and the like.

[0181] In some embodiments of the use or treatment of any of the above aspects, Compound A is administered in combination therapy with levodopa or levodopa / DDCI preparations.

[0182] Studies have found that Compound A can be administered simultaneously with levodopa or levodopa / DDCI preparations; however, potential DDI (drug-drug interaction) of clinical significance in PD patients cannot be ruled out.

[0183] Accordingly, when used in combination, the dosing regimen of Compound A and levodopa (or levodopa / DDCI formulation) can differ: each can be administered simultaneously (at the same time) or at different times (e.g., one before or after the other). The skilled person can readily determine when it can be desirable to administer Compound A and levodopa (or levodopa / DDCI formulation) simultaneously or at different times. For example, if Compound A is administered simultaneously with levodopa (or levodopa / DDCI formulation) would result in an undesirable effect (e.g., dyskinesia and / or dopaminergic side effects such as nausea, vomiting, hallucinations, dizziness, or hypotension) due to an undesirable increase in levodopa systemic exposure, Compound A and levodopa (or levodopa / DDCI formulation) are preferably administered at different times.

[0184] In some embodiments, the use or treatment as described in any of the above aspects comprises administering Compound A, or a pharmaceutically acceptable salt thereof, simultaneously with daily dosing of levodopa or levodopa / DDCI formulation. For example, Compound A is administered simultaneously with daily administration of levodopa or levodopa / DDCI formulation, or is administered sequentially within less than 30 minutes, preferably less than 20 minutes, more preferably less than 10 minutes between administration of Compound A and daily administration of levodopa or levodopa / DDCI formulation.

[0185] In some embodiments, the use or treatment as described in any of the above aspects comprises administering Compound A, or a pharmaceutically acceptable salt thereof, prior to or after daily dosing of levodopa or levodopa / DDCI formulation. In some embodiments, Compound A is administered at least 30 minutes to 50 minutes, preferably at least one hour, prior to or after daily administration of levodopa or levodopa / DDCI formulation. In other embodiments, Compound A is administered 30 minutes to 150 minutes prior to or after daily administration of levodopa (or levodopa / DDCI formulation).

[0186] When Compound A is administered after daily administration of levodopa (or levodopa / DDCI formulation), it is preferred that the subsequent administration of levodopa (or levodopa / DDCI formulation) is administered at least 30 minutes, preferably at least 50 minutes, more preferably at least one hour after administration of Compound A.

[0187] When Compound A is administered prior to daily administration of levodopa (or levodopa / DDCI formulation), it is preferred that the previous administration of levodopa (or levodopa / DDCI formulation) is administered at least 30 minutes, preferably at least 50 minutes, more preferably at least one hour prior to administration of Compound A.

[0188] In some embodiments, the use or treatment of any one of the above aspects comprises administering Compound A, or a pharmaceutically acceptable salt thereof, in the morning, in the afternoon, in the evening, before bedtime, before retiring, or at bedtime.

[0189] In still other embodiments, the use or treatment of any one of the above aspects comprises administering Compound A, or a pharmaceutically acceptable salt thereof, in the morning, in the afternoon, in the evening, before bedtime, before retiring, or at bedtime.

[0190] In still other embodiments, the use or treatment of any one of the above aspects comprises administering Compound A, or a pharmaceutically acceptable salt thereof, in the morning, in the afternoon, in the evening, before bedtime, before retiring, or at bedtime.

[0191] In still other embodiments, the use or treatment of any one of the above aspects comprises administering Compound A, or a pharmaceutically acceptable salt thereof, in the morning, in the afternoon, in the evening, before bedtime, before retiring, or at bedtime.

[0192] The term “before bedtime” (i.e., before going to bed) means, in particular, less than 90 minutes before going to bed, in particular less than 60 minutes before going to bed or less than 30 minutes before going to bed. The term “at bedtime” means less than 5 minutes before bedtime, e.g., at the time of going to bed.

[0193] The term “before bedtime” (i.e., before going to bed) means, in particular, less than 90 minutes before going to bed, in particular less than 60 minutes before going to bed or less than 30 minutes before going to bed. The term “at bedtime” means less than 5 minutes before bedtime, e.g., at the time of going to bed.

[0194] In other words, Compound A is taken from the patient before the patient goes to bed (i.e., before bedtime or at bedtime), e.g., less than 90 minutes before bedtime, in particular less than 60 minutes before bedtime, less than 30 minutes before bedtime or less than 5 minutes before bedtime.

[0195] As will be clear in the context of the present application, the term “before bedtime” or “before retiring” does not mean any time of the day before bedtime or before going to bed, and in particular does not include, e.g., 12 hours before bedtime or before going to bed. Rather, the term means taking the drug in a time period close to the patient’s sleep, and most likely as part of the patient’s bedtime routine.

[0196] The mode of administration of the concomitant drug is not particularly limited, and Compound A and the concomitant drug only need to be combined by administration. Examples of such modes of administration include the following:

[0197] (1) administration of a single preparation obtained by mixing the compound of the present application and the concomitant drug at the same time, (2) administration of two preparations separately prepared for the compound of the present application and the concomitant drug at the same time through the same route of administration, (3) administration of two preparations separately prepared for the compound of the present application and the concomitant drug in an alternating manner through the same route of administration, (4) administration of two preparations separately prepared for the compound of the present application and the concomitant drug at the same time through different routes of administration, (5) administration of two preparations separately prepared for the compound of the present application and the concomitant drug in an alternating manner through different routes of administration (for example, administration in the order of the compound of the present application and the concomitant drug, or administration in the reverse order), and the like.

[0198] The dose of the concomitant drug can be appropriately determined based on the dose employed in the clinical situation. The mixing ratio of the compound of the present application to the concomitant drug can be appropriately determined depending on the administration subject, the route of administration, the target disease, the symptoms, the combination, and the like.

[0199] The compound A can be used as it is or in the form of a pharmaceutical composition (also referred to as a medicament) by mixing with a pharmacologically acceptable carrier or the like. As the pharmacologically acceptable carrier, various organic or inorganic carrier substances generally used as formulation materials can be used. They are used as excipients, lubricants, binders, and disintegrants for solid preparations; or solvents, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents, and the like for liquid preparations; and formulation additives such as preservatives, antioxidants, coloring agents, sweetening agents, and the like can be added as necessary.

[0200] Examples of the dosage form of the above-mentioned pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, oral disintegrating tablets, buccal tablets), capsules (including soft capsules, microcapsules), pills, granules, powders, troches, syrups, liquids, emulsions, suspensions, aerosols, films (for example, oral disintegrating films, oral mucosal-adhesive films), and the like; and parenteral preparations such as injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external preparations (for example, transdermal absorption type preparations, ointments, lotions, adhesive preparations), suppositories (for example, rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalants), eye drops, and the like. The compound of the present application and the medicament can be safely administered orally or parenterally (for example, intrarectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorganally, intranasally, intradermally, drip infusion, intracerebrally, intravaginally, and intraperitoneally) respectively.

[0201] These preparations can be controlled release preparations (for example, sustained release microcapsules) such as immediate release preparations, sustained release preparations, and the like.

[0202] The pharmaceutical composition can be prepared according to the methods conventionally used in the field of pharmaceutical preparations.

[0203] The various aspects and embodiments of the application as described above relate to uses and methods involving Compound A or a pharmaceutically acceptable salt thereof. The skilled person will appreciate that these aspects and embodiments can also be expressed as uses of Compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the uses, methods and treatments described. BRIEF DESCRIPTION OF DRAWINGS

[0204] FIG. 1 Percent change from pre-dose over time for GluCer and LacCer isomers (all dose combinations).

[0205] FIG. 2 Percent change from pre-dose over time for GluCer and LacCer in GBA-PD subjects carrying a Gaucher disease mutation versus GBA-PD subjects without a Gaucher disease mutation.

[0206] FIG. 3 Concentration data for Compound A in human brain at three dose ranges (10 mg, 30 mg, and 60 mg) overlaid with a change profile (delta profile) for the effect of Compound A on CGase activity in human brain homogenates in vitro. DETAILED DESCRIPTION

[0207] The practice of the present application employs, unless otherwise indicated, conventional techniques of formulation chemistry, organic chemistry, pharmacology, cell biology, and biochemistry.

[0208] The various aspects of the present application are set forth in the following sections; however, aspects of the present application described in one particular section are not limited to that section.

[0209] DEFINITIONS

[0210] To facilitate the understanding of this application, a number of terms and phrases are defined below.

[0211] The terms "a" and "an," as used herein, mean "one or more" and include the plural unless the context dictates otherwise.

[0212] The term "solid dosage form," as used herein, refers to a combination of an active agent with at least one inert or active carrier or excipient, such that the combination is particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0213] As used herein, "treat" or "treatment" of a disease includes: (1) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; and / or (2) relieving the disease, i.e., causing the regression of the disease or its clinical symptoms.

[0214] As used herein, "treat" or "treatment" of Parkinson's disease in a subject suffering from Parkinson's disease (when compared to a subject administered placebo or not administered Compound A (i.e., not treated)) includes:

[0215] (1) preventing, limiting or delaying clinical motor progression;

[0216] (2) preventing, limiting or delaying worsening of motor impairment;

[0217] (3) preventing or delaying the onset and / or development of Parkinson's disease;

[0218] (4) preventing, limiting or delaying worsening of cognitive impairment;

[0219] (5) preventing, limiting or delaying a decrease in quality of life;

[0220] (6) improving gait speed;

[0221] (7) preventing, limiting or delaying a decrease in gait speed;

[0222] (8) preventing, limiting or delaying progression of non-motor symptoms;

[0223] (9) deferring late motor complications;

[0224] (10) limiting or delaying impairment caused by Parkinson's disease;

[0225] (11) slowing or decelerating disease progression; preventing;

[0226] (12) affecting or modifying the course of the disease; and / or;

[0227] (13) preventing, limiting and / or delaying the rate of disease progression.

[0228] As used herein, the term "clinical motor progression" refers to, but is not limited to, worsening of the cardinal motor features (such as rigidity, bradykinesia and tremor).

[0229] The term "suffering from" or "afflicted with" in connection with the term "treatment" refers to a patient or individual who has been diagnosed with a disease or is predisposed to the disease. The patient can also be referred to as "at risk of suffering from Parkinson's disease" either because of a history of the disease in the patient's family lineage, or the presence of a genetic mutation associated with the disease in their body.

[0230] 5,7-Dimethyl-N-((1S*,4S)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound A, also known as LTI-291 or BIA 28-6156) has the following structure:

[0231]

[0232] Compound A exists in four polymorphic forms: Form A, Form B (thermodynamically most stable form at room temperature), Form C (metastable form) and Form D (hydrated form), which can be prepared by the methods described in WO2019 / 126776.

[0233] The following scales and measures can be used to assess PD. The MDS-UPDRS (Goetz, 2008), the Parkinson’s Disease Cognitive Rating Scale (PD-CRS) (Pagonabarraga, 2008), the Modified Hoehn and Yahr Scale (Goetz, 2004), and the 39-item Parkinson’s Disease Questionnaire (PQD-39) (Peto, 1998) are scales specifically developed to track the longitudinal course of PD and its response to treatment. These scales have reliable measurability; are meaningful to clinicians, patients, and caregivers; and effectively assess the “core” symptoms of PD. The EQ-5D-5L scale (five-level five-dimensional health scale) (Herdman, 2011) is a widely used patient-rated survey instrument for measuring economic preferences for health states that 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.

[0234] The Modified Hoehn and Yahr Scale is used to assess the staging of functional impairment associated with Parkinson’s disease. It helps to describe the progression of the disease between stages, thus enabling the measurement of the severity of the case. The clinical signs are as follows:

[0235]

[0236]

[0237] The MDS-UPDRS (Goetz, 2008) is a multidimensional scale that assesses the impact of PD on motor and non-motor aspects in 4 parts. The scale is completed using a combination of physician and patient assessments and information collection from the patient or caregiver:

[0238] • Part I, Non-Motor Aspects of Experiences of Daily Living, includes 13 items, 6 of which are rated by the physician (Part IA) and 7 of which are rated by the patient (Part IB).

[0239] • Part II, Motor Aspects of Experiences of Daily Living, includes 13 items rated by the patient and / or caregiver. The 13 items in Part II and the 7 items in Part IB make up the patient questionnaire portion of the MDS-UPDRS.

[0240] • Part III, Motor Examination, included 18 items assessed by the investigator (yielding 33 scores by division and laterality).

[0241] • Part IV, Motor Complications, included 6 items (2 items of dyskinesia, 3 items of fluctuations, and 1 item of "off' dystonia) requiring the physician to use the medical history and objective information to assess dyskinesia and motor fluctuations.

[0242] Each item was scored on a 0 to 4 scale, where: 0 = normal; 1 = slight; 2 = mild; 3 = moderate; 4 = severe.

[0243] The PD-CRS (Pagonabarraga, 2008) is a brief PD-specific questionnaire designed to cover the full spectrum of cognitive deficits associated with PD. The questionnaire includes items assessing subcortical deficits and items assessing cortical dysfunction. The questionnaire includes the following assessment tasks: immediate free recall verbal memory (score range 0 to 12), object naming (score range 0 to 20), sustained attention (score range 0 to 10), working memory (score range 0 to 10), clock drawing without cues (score range 0 to 10), clock drawing to copy (score range 0 to 10), delayed free recall verbal memory (score range 0 to 12), alternating verbal fluency (score range 0 to 20), and action verbal fluency (score range 0 to 30). The score for each task is based on the number of correct responses. The subcortical (score range 0 to 114) and cortical (score range 0 to 20) PD-CRS scores were obtained by adding the raw scores of the items within each group. The total score for the PD-CRS was calculated by adding the subcortical and cortical PD-CRS scores.

[0244] The CGI-C is a 7-point scale that asks the clinician to assess the degree of improvement or worsening of the patient's illness compared to the baseline status at the start of the intervention (Guy, 1976). The rater selects one response based on the following question: "Compared to your patient's condition at the start of treatment, how has your patient's condition changed?" The scores are as follows: 1 = marked improvement; 2 = much improved; 3 = a little improved; 4 = no change; 5 = a little worse; 6 = much worse; 7 = marked worsening.

[0245] CGI-S is a 7-point scale that asks the clinician to rate the severity of the patient's illness at the time of evaluation relative to the clinician's past experience with patients who have the same diagnosis (Guy, 1976). The clinician is asked, "Considering your total clinical experience with this particular population, how ill would you rate the patient at this time?" 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.

[0246] PGI-S is a patient-reported scale corresponding to CGI-S (Guy, 1976). PGI-S is a 1-item questionnaire designed to assess the patient's impression of the severity of their illness. The PGI-S item asks respondents to describe their symptoms most accurately according to the following 4-point scale: 1 = Normal, 2 = Mild, 3 = Moderate, or 4 = Severe.

[0247] PGI-C is a patient-reported outcome corresponding to CGI-C. Patients answer the question "Compared to how you felt at the start of treatment, how have you felt since?" based on their own perception of their condition to qualitatively assess meaningful change. Scores are as follows: 1 = Much improved; 2 = Moderately improved; 3 = Slightly improved; 4 = No change; 5 = Slightly worse; 6 = Moderately worse; and 7 = Much worse.

[0248] PDQ-39 is the most fully validated and widely used self-report measure of health-related quality of life in PD patients. The questionnaire measures 39 items assessing 8 domains of health: mobility (10 items), ADLs (6 items), emotional well-being (6 items), stigma (4 items), social support (3 items), cognition (4 items), communication (3 items), and bodily discomfort (3 items) (Peto, 1998). The scoring scale for each item is as follows: 0 = Never, 1 = Occasionally, 2 = Sometimes, 3 = Often, 4 = Always. Items in each subscale and the total scale can be summarized into an index and linearly transformed to a scale from 0 (perfect health status as assessed by the measure) to 100 (worst health status as assessed by the measure).

[0249] EQ-5D-5L (Herdman, 2011) is a patient-reported outcome that measures health status in 5 dimensions. It is a widely used survey instrument for measuring economic preference for health status that 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. The EQ-5D-5L consists of a descriptive system and a visual analog scale (VAS).

[0250] The descriptive system includes 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 5 levels: no problem, slight problem, moderate problem, severe problem, and extreme problem. Patients are asked to indicate their health state by ticking the box that best describes them in each of the 5 dimensions. This decision results in a single digit number that represents the level chosen for that dimension. The numbers corresponding to the 5 dimensions are combined into a 5-digit number that describes the patient's health state.

[0251] The EQ-5D-5L VAS records the patient's self-rated health state on a vertical VAS on which the endpoints are labeled "Best Health State You Can Imagine" and "Worst Health State You Can Imagine." The VAS can be used as a quantitative measure of health outcome reflecting the patient's own judgment.

[0252] The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It was validated in the context of mild cognitive impairment (MCI) and subsequently applied to many other clinical settings. The test consists of 30 points and includes an assessment of short-term memory, executive function, attention, and concentration. The MoCA score ranges from 0 to 30.

[0253] It should be understood that elements and / or features of the various aspects, methods, uses, etc. described herein can be combined with each other in various ways unless explicitly stated otherwise. For example, where reference is made to a particular subject population (optionally defined by genetic characteristics), test criteria, or treatment options, such features apply to and can be used in various embodiments of the application unless otherwise understood from the context. In other words, in this application, embodiments have been described and depicted in a way that enables a clear and concise disclosure and that provides those skilled in the art with an enabling description and the best understanding of how to make and use the embodiments. However, the application should not be understood as limited to the particular embodiments described herein. In another word, all features described and depicted herein are applicable to all aspects of the application described and depicted herein, mutatis mutandis.

[0254] EMBODIMENTS

[0255] The following examples are provided to illustrate various embodiments of the application and should not be considered to be limiting. The use of "LTI-291" and "BIA-28" in the study numbers indicates that the study was conducted with Compound A.

[0256] Example 1 - Human clinical study

[0257] Compound A has been evaluated in two Phase 1 studies to assess the safety, tolerability, PK (pharmacokinetic) and pharmacodynamic effects of single and multiple doses of Compound A in healthy volunteers, and in two Phase lb studies to assess the safety, tolerability, PK and pharmacodynamic effects of Compound A in subjects carrying GBA1 gene mutations and having Parkinson’s disease (GBA-PD). In addition, Compound A has been evaluated in a Phase 1 mass balance recovery study, a Phase 1 comprehensive QTc (corrected QT interval) study, and a Phase 1 drug-drug interaction study. Design features of these studies are summarized in Table 2 below.

[0258] Table 2: Summary of clinical studies

[0259]

[0260]

[0261]

[0262] Abbreviations: CNS = central nervous system; CSF = cerebrospinal fluid; FDG-PET = fluorodeoxyglucose-positron emission tomography; fMRI = functional magnetic resonance imaging; GBA1 = human acid beta glucosidase gene, also known as glucocerebrosidase (GCase); GBA-PD = Parkinson’s disease carrying GBA1 gene mutations; GluCer = glucosylceramide; GluSph = glucosylsphingosine; LacCer = lactosyl-ceramide; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetic.

[0263] In the Phase lb studies, 40 subjects (20 males and 20 females, aged 40 to 80 years) with GBA-PD received multiple doses of 10 mg, 30 mg, or 60 mg Compound A or placebo once daily for up to 28 days (Study LTI-291-003), and 14 subjects (13 males and 1 female) received multiple doses of 10 mg or 60 mg Compound A or placebo once daily for up to 28 days (Study LTI-291-004).

[0264] PK of Compound A was similar between healthy subjects and subjects with GBA-PD. Geometric mean CSF concentrations increased with increasing dose, and the CSF-to-plasma concentration ratios were similar across the different dose levels after the 28th daily dose. The mean of this ratio and the unbound Compound A distribution in plasma versus CSF of approximately 1 : 1 corresponded to Compound A being present in the CSF and the compound being able to cross the blood-brain barrier to reach GCase in brain tissue.

[0265] LTI-291-001 - Single ascending dose study

[0266] This study was a first-in-human, Phase 1, randomized, double-blind, placebo-controlled, single-dose escalation study designed to evaluate the safety and tolerability, PK, and PD of single oral doses of Compound A (3 mg, 10 mg, 30 mg, and 90 mg) at four cohorts of healthy subjects. A total of 32 subjects received single oral doses of Compound A (8 subjects per dose cohort), and 8 subjects received placebo. The effect of food on the PK of Compound A was evaluated by administering a second single oral dose of 10 mg Compound A to subjects in Cohort 2 at a separate occasion after the subjects had consumed a high-fat breakfast. Blood samples were collected for up to 48 hours after each dose for Compound A PK.

[0267] Pharmacodynamic evaluations were made from a battery of CNS assessments, including saccadic eye movements, smooth pursuit eye movements, adaptive tracking, body sway, visual-verbal learning test, and EEG (Electroencephalogram). GluCer was measured in plasma and PBMCs as a biomarker of pharmacological effect.

[0268] Pharmacokinetic results

[0269] Median T max occurred within 1 hour to 3 hours (median) after single dose under fasting conditions and ranged from 1.0 to 8.2. No T max max was observed. There was no relationship between dose level and T 1 / 2 was similar in fasted and fed subjects, and ranged from 21.2 hours to 23.4 hours across dose. Total exposure (C max and AUC 0-inf ) increased in a dose-proportional manner across the dose range, and dose-normalized AUC (area under the plasma concentration versus time curve) and Cmax The values ​​are similar. Compared to administration during fasting, administration of 10 mg during eating resulted in T... max Delay (median 8.0 hours, compared to 1.0 hour under fasting conditions), C max Decrease, but t 1 / 2 Similar to AUC.

[0270] The pharmacokinetic parameters of LTI-291 after a single oral administration in healthy participants under both eating and fasting conditions are summarized in Table 3 below:

[0271] Table 3: Summary of plasma pharmacokinetic parameters of compound A in healthy subjects after a single oral administration of compound A in the LTI-291-001 study.

[0272]

[0273]

[0274] Abbreviation: AUC 0-inf =Area under the plasma concentration-time curve extrapolated to infinity (AUC); AUC 0-last = AUC from time zero to the last measurable concentration; CL / F = Apparent total clearance; C max =Highest observed plasma drug concentration; t 1 / 2 =Terminal elimination half-life; T max =Time to observe peak plasma drug concentration; V z / F = Apparent distribution volume of the terminal phase.

[0275] In a comparison between feeding therapy and fasting therapy, C max The percentage (90% CI) of the geometric mean was 71.3% (ranging from 54.2% to 93.6%). AUC 0-last and AUC 0-inf The ratios were 103% and 111%, and the 90% CI fell entirely within the range of 80.0% to 125.0%.

[0276] Pharmacodynamic results

[0277] Compound A showed no dose-dependent effect on any CNS (Neurocart) test. No significant overall treatment effect was observed in GluCer variables tested in plasma. Differences between treatment with compound A and placebo were observed in some GluCer variables measured in PBMCs, suggesting that treatment with compound A increased glucose and lipid flux.

[0278] Safety results

[0279] No deaths, other SAEs (serious adverse events), severe AEs (adverse events), or discontinuations due to AEs were reported. The most common AEs after taking Compound A were fatigue (3 subjects, 7.5%), headache (5 subjects, 12.5%), and somnolence (4 subjects, 10%), while the most common AE after taking placebo was somnolence (2 subjects, 25%). Three subjects (7.5%) in the Compound A treatment group reported at least one AE in the GI (gastroenterology intestine) system organ class, while none of the subjects in the placebo group reported any GI AEs. The intensity of most AEs was mild, with only 1 moderate AE reported (unrelated to Compound A).

[0280] No clinically meaningful safety observations were found from vital sign measurements, laboratory safety assessments, or ECG parameters.

[0281] Multiple ascending dose study

[0282] This study was a Phase 1, randomized, double-blind, placebo-controlled, multiple-dose escalation study of Compound A in 4 cohorts of healthy middle-aged to elderly participants (ages 52 to 75 years). The goal of the study was to investigate the safety, tolerability, and PK of multiple-dose escalation of Compound A, which had been shown to be well-tolerated in a single-dose escalation study (LTI-291-001), and to explore its pharmacodynamics. A total of 39 healthy subjects were enrolled in 4 consecutive cohorts. Subjects in each cohort received oral Compound A or placebo at a frequency of once daily for 14 days at 3 mg (n=7), 10 mg (n=8), 30 mg (n=8), or 60 mg (n=8). Pharmacokinetic parameters were determined on Day 1, Day 7, and Day 14 for each dose. For each dose level, Compound A concentrations were measured in cerebrospinal fluid samples before the first dose and 4 hours after the last dose. GluCer, GluSph, and LacCer were measured in plasma, PBMCs, and CSF as biomarkers of pharmacology. Pharmacodynamic measures were derived from a battery of CNS Assessments included saccadic eye movements, smooth pursuit eye movements, adaptive tracking, body sway, visual-verbal learning test, and drug-EEG.

[0283] Pharmacokinetic results

[0284] The peak plasma concentration occurred within 1 to 4 hours (median) and ranged from 1.0 to 8.12 hours after the first, seventh, and fourteenth daily oral doses of 3 mg, 10 mg, 30 mg, and 60 mg of Compound A. No trends were observed in the values of t max values with increasing dose level or number of doses. The t 1 / 2 values 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 fourteenth dose. No trends were observed in the values of t 1 / 2 with increasing dose. Accumulation results indicated that steady-state conditions were achieved at the seventh daily dose with the exception of the 30 mg dose level (accumulation index = 5.22), and the accumulation index values ranged from 2.11 to 2.72 after the seventh daily dose and 2.49 to 2.78 after the fourteenth daily dose. No trends were observed in the accumulation index with increasing dose or number of doses. Over the dose range of 3 mg to 60 mg, it was seen that total exposure (AUC max and AUC 0-24 ) increased in a dose-proportional manner after each of the first, seventh, and fourteenth daily oral doses, and the values of dose-normalized AUC and C max were similar across the different dose levels.

[0285] The geometric mean CSF concentration increased with increasing dose. The CSF-to-plasma concentration ratios were similar across the different dose levels after the fourteenth daily dose, with a mean value ranging from 0.0122 to 0.0128. These values corresponded to an approximately 1 : 1 distribution of unbound Compound A in plasma and CSF and indicated that Compound A was able to cross the blood-brain barrier at all doses.

[0286] The PK parameters for LTI-291 following single oral administration in fed and fasted healthy participants are summarized in Table 4.

[0287]

[0288]

[0289] Pharmacodynamic results

[0290] Compound A had no dose-dependent effects on any of the CNS (Neurocart) tests. A significant increase in saccadic inaccuracy was observed in the 10 mg and 30 mg Compound A groups compared to placebo. No changes in saccadic peak velocity or reaction time were observed. A significant decrease in EEG alpha-power Pz-Oz (in μν) under ocular closed conditions was observed at the 3 mg dose compared to placebo.

[0291] Sparse statistically significant increases were observed in some GluCer and LacCer variables in plasma and PBMCs, and sparse statistically significant decreases were observed in some GluCer and LacCer variables in CSF. Overall, no consistent pharmacodynamic effects of Compound A on glycolipids were observed in healthy subjects over the 14-day dosing period.

[0292] Safety results

[0293] No deaths, other SAEs, severe AEs, or discontinuations due to AEs were reported. All AEs were mild or moderate and were self-limited, and no specific pattern of AEs related to Compound A administration was found. The most common AEs after multiple oral doses of Compound A at a frequency of once daily for 14 days were headache (12 subjects, 39%), somnolence (5 subjects, 16%), myalgia (5 subjects, 16%), and back pain (4 subjects, 13%), while the most common AEs after administration of placebo were back pain (2 subjects, 25%) and dizziness (2 subjects, 25%).

[0294] Somnolence 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 the placebo group (13%). Of the 5 subjects who reported somnolence during the study (including placebo subjects), the AEs resolved within hours of onset for 4 subjects. The AE for 1 subject occurred intermittently over a 24-day period. Somnolence was considered possibly related to Compound A administration by the study, although no effects were observed in NeuroCart measures.

[0295] The frequency of myalgia was higher 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 the placebo group (13%). All AEs in subjects occurred on Day 1 through Day 4, and the symptoms in 5 of 6 subjects persisted for 3 to 10 days, and the symptoms in 1 subject (3 mg group) resolved within 8 hours. No clinically significant creatine kinase abnormalities were found in the 60 mg group, thus ruling out rhabdomyolysis. No clinically significant safety observations were found from vital sign measurements, laboratory safety assessments (including creatine kinase), or ECG parameters.

[0296] Compound A - Multiple dose study in subjects with PD and carrying GBA1 gene mutation (LTI-291- 003)

[0297] This study was a Phase lb, randomized, double-blind, placebo-controlled, multiple oral dose study of Compound A in 40 subjects with GBA-PD, aged 40 to 80 years. Approximately 50% of the enrolled subjects carried a major mutation in GCase (total activity loss 30-50%) and 50% carried a polymorphic mutation in GCase (total activity loss 10-20%). The objective of the study was to investigate the safety, tolerability, and PK of Compound A with multiple-oral dosing at once-daily frequency and to explore the concomitant pharmacodynamic changes in subjects with GBA-PD carrying major and polymorphic mutations. Subjects received oral dosing 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) at once-daily frequency for 28 days.

[0298] Blood samples were collected for detection of Compound A concentrations up to 6 hours after the first and last dose. For each dose level, CSF samples were taken for detection of Compound A concentrations before the first dose and 4 hours after the last dose.

[0299] GluCer, GluSph, and LacCer were measured in plasma, PBMCs, and CSF as biomarkers of pharmacology. Pharmacodynamic evaluation also consisted of a series 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 (mini-mental state examination)); and pharmacologic EEG.

[0300] Pharmacokinetic results

[0301] Peak plasma concentrations occurred at 2.0 hours (median) after the first and the twenty-eighth daily dose of Compound A, and the range of plasma peak concentrations was 2.0 hours to 6.0 hours for different dosing days and dose levels. Due to the limited sampling schedule, it was not possible to estimate t 1 / 2 . Accumulation of Compound A over the study period was assessed by calculating the ratios of C max , AUC 0-last , and AUC 0-6 after the twenty-eighth dose to the corresponding parameters after the first dose. When the data were grouped by dose level, the median ratios for these three parameters were between 1.93 and 2.47, and were consistent with the results observed in healthy subjects. Over the dose range of 10 mg to 60 mg, it was seen that total exposure (AUC max and AUC 0-last ) increased in a dose-proportional manner after the first and the twenty-eighth dose, and the values of dose-normalized AUC and C max were similar across the different dose levels.

[0302] Table 5: LTI-291-003 Study: Summary of Compound A Plasma Pharmacokinetic Parameters in Subjects Carrying GBA1 Gene Mutations and Having Parkinson’s Disease

[0303]

[0304] Abbreviations: AUC 0-last = Area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration time; AUC 0-6 = AUC from time zero to 6 hours; C max = Observed maximum plasma drug concentration; C min = Observed minimum plasma drug concentration; T max = Time of observed maximum plasma drug concentration; T min = Time of observed minimum plasma drug concentration.

[0305] Geometric mean CSF concentrations increased with increasing dose, and the CSF-to-plasma concentration ratios were similar across the different dose levels after the 28th daily dose. For the 10 mg dose, the mean (SD) value of the ratio was 0.0113 (0.00233); for the 30 mg dose, the mean (SD) value of the ratio was 0.0122 (0.0036), and for the 60 mg dose, the mean (SD) value of the ratio was 0.0115 (0.00305). These results were similar to those observed in the 14-day multiple-dose study in healthy subjects (Study LTI-291-002) and corresponded to the approximately 1 : 1 distribution of unbound Compound A in plasma and CSF determined in preclinical studies.

[0306] Pharmacodynamic results

[0307] Compound A had no dose-dependent effects on any of the NeuroCart test, MMSE, MDS-UPDRS, or EEG.

[0308] In subjects with GBA-PD treated in all dose groups (10 mg / day, 30 mg / day, and 60 mg / day), a significant trend over time was observed in intracellular PBMC glycolipid levels (GluCer and LacCer), indicating a change in glycolipid flux due to the effect of Compound A FIG. 1 ). This phenomenon manifested as a statistically significant increase in GluCer and LacCer in PBMCs at treatment days 7 and 14, with a smaller increase observed at treatment day 28.

[0309] These effects did not show a clear dose-response or exposure-response relationship, although responder analysis showed that the largest changes occurred in the 60 mg GluCer PBMC group (no sharp dose-response was expected, as exposure was exceeded for all 3 doses for doubling GCase activity in vitro). Severity of GBA1 mutation (i.e., degree of loss of function and relative risk of PD) was a statistically significant covariate in the ANCOVA (analysis of covariance) analysis, indicating that subjects with Parkinson’s disease carrying “Gaucher” or major mutations (30-50% total activity loss) were generally more affected than subjects carrying polymorphic GBA1 mutations (10-20% total activity loss) FIG. 2

[0310] ​This relationship is consistent with the expectation that the GSL (glycosphingolipid) pathway would be more significantly altered in patients with low GCase activity than in patients with moderate GCase activity. No GSL pathway changes were observed in healthy older subjects. Overall, these changes suggest that Compound A increases GCase activity, increases GSL "flux" through GCase, and alters the levels of key elements in this pathway (GluCer and LacCer).

[0311] Intracellular GluSph in PBMC did not show a clear response to Compound A compared to placebo, and there were no clear changes in glycolipid levels in plasma or CSF.

[0312] Safety results

[0313] No deaths, other SAEs, severe AEs, or discontinuations due to AEs were reported. The most common AEs in subjects with GBA-PD after multiple oral doses of Compound A 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%). One subject (10%) in the placebo group reported worsening of Parkinson’s disease symptoms. Worsening of Parkinson’s disease symptoms was considered unlikely to be related to Compound A given the natural fluctuation in Parkinson’s disease symptom severity and the progressive nature of the disease course.

[0314] The intensity of most AEs was mild, with only 3 moderate AEs reported (none related to Compound A); no severe AEs were reported. No clinically meaningful safety observations were found from vital sign measurements, laboratory safety assessments, or ECG parameters.

[0315] Multiple dose imaging study in subjects with Parkinson's disease carrying GBA1 gene mutation (GBA-PD) (LTI-291-004)

[0316] This study was a Phase 1B, randomized, double-blind, placebo-controlled, multiple oral dose study of Compound A in 14 subjects (ages 51 to 81) with GBA-PD. The objective of the study was to investigate the safety, tolerability, and PK of Compound A administered multiple-oral doses at a once-daily frequency, and to explore concomitant pharmacodynamic changes. Subjects received oral doses of 10 mg (n=6) or 60 mg (2 x 30 mg capsules) (n=6) of Compound A or placebo (n=2) at a once-daily frequency for 28 days. PK samples were measured once on Days 7 and 14, and 4 times after the last dose on Day 28. Plasma concentrations were summarized at each time point, and PK parameters were not estimated. PD assessments included fMRI measurements; FDG-PET to determine glucose metabolic rate in specific regions of the brain; and functional outcome measures (MDS-UPDRS Part III and MMSE). GluCer, GluSph, and LacCer as biomarkers of pharmacological effect, as well as other sphingolipids, were measured in PBMCs and plasma.

[0317] Pharmacokinetic results

[0318] At all time points (Day 7, Day 14, pre-dose on Day 28, and 1.5 hours, 3 hours, and 6 hours post-dose on Day 27), the mean plasma concentrations following the 60 mg dose were higher than those following the 10 mg dose.

[0319] Pharmacodynamic results

[0320] The fMRI and FDG-PET results generally supported a pharmacodynamic effect of Compound A in subjects with GBA-PD. Compound A improved the default mode network (DMN), a large-scale network of different regions of the brain, as assessed by fMRI. The intergroup differences were not statistically significant due to the small sample size.

[0321] 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 compared to the 10 mg dose group. Some changes in imaging measures (fMRI analysis) suggested that Compound A produced a physiological effect in subjects with GBA-PD. There was a trend for decreased plasma LacCer following treatment with Compound A, although no related effect was observed in plasma GluCer or GluSph. Overall, the results suggest that administration of Compound A for 28 days transiently increased the abundance of intermediates in the glycosphingolipid pathway measured in PBMCs compared to placebo, which can indicate an increase in GCase activity.

[0322] On Day 28, there were no changes in MDS-UPDRS III and MMSE scores in all subjects compared to Day -1.

[0323] Safety results

[0324] No deaths, other SAEs, or severe AEs were reported. Most AEs were transient, resolved without sequelae. One subject in the 10 mg group withdrew from the study on Day 25 due to moderate back pain, which the investigator considered unrelated to study drug. No other moderate AEs were reported. Muscle spasm (2 events, 1 subject each in the dose groups) and frequent urination (2 events, 2 subjects in the 60 mg dose group) were reported in only more than one subject. All other AEs were reported by only 1 subject. All AEs were considered unrelated to study treatment.

[0325] No clinically meaningful safety observations were found from vital sign measurements, laboratory safety assessments, physical examinations, or ECG parameters.

[0326] Pharmacokinetic and pharmacodynamic summary of GBA-PD patient phase 1 study

[0327] In 2 Phase lb, 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 the CSF to plasma unbound drug concentration ratio was similar across dose levels after the 28th daily dose. There was an equivalent amount of unbound Compound A in plasma compared to CSF, indicating that Compound A can penetrate into the CSF and cross the blood-brain barrier to reach GCase in brain tissue. Significant changes in PBMC glycolipid levels were observed in all dose groups of treated GBA-PD subjects (10 mg / day, 30 mg / day, and 60 mg / day), indicating that glycolipid flux changed due to Compound A treatment. Subjects carrying major mutations were generally more affected than subjects carrying polymorphic GBA1 mutations. These changes reached a maximum at 2 weeks of treatment, and by 4 weeks, the magnitude of the effect decreased, which can indicate that ceramide flux has established a new equilibrium. Some changes in imaging measures, such as functional magnetic resonance imaging (fMRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET), indicated that Compound A produced a standardized physiological effect in some subjects with GBA-PD. Overall, these data support the hypothesis that Compound A binds to the GCase target and elicits secondary changes in key glycosphingolipids by increasing flux in this system.

[0328] Compound A - Comprehensive QTc study (BIA28-6156-105)

[0329] This was a Phase 1, randomized, double-blind, placebo-controlled, single-dose, 4-period crossover design study to evaluate the effects of Compound A on cardiac repolarization in healthy male and female subjects (aged 20 to 55 years). A total of 37 subjects (20 males and 17 females) were randomized to 1 of 12 treatment groups and received a single oral dose of 60 mg Compound A (n=34), 150 mg Compound A (n=36), placebo (as a placebo control; n=35), and 400 mg moxifloxacin (as a positive control; n=34) under fed conditions in a 4-way crossover design. Objectives of the study included evaluating the effects of single treatment (60 mg) and single supra-treatment (150 mg) oral doses of Compound A on the heart rate-corrected QT interval (HR[QTc]) based on Fridericia correction (QTcF), evaluating the PK, safety, and tolerability of Compound A, correlating any observed effects on QTcF with plasma concentrations of Compound A, and confirming the effects of moxifloxacin on QTcF in healthy subjects for comparison with Compound A. Blood samples for PK measurements were collected within 72 hours post-dose in each period, and continuous Holter monitoring was performed for 24 hours post-dose of each administration.

[0330] Pharmacokinetic results

[0331] Median T max Similar to plasma Compound A, the median T 1 / 2 and was higher following administration of 150 mg Compound A compared to 60 mg Compound A (Table 6). Median T max was 3.0 hours, and the moxifloxacin geometric mean t 1 / 2 was 13.1 hours.

[0332] Table 6: Geometric mean values (range) for Compound A and moxifloxacin plasma pharmacokinetic parameters (PK set)

[0333]

[0334] Abbreviations: AUC 0-last = area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration time; AUC inf = AUC extrapolated from time zero to infinity; C max= Observed maximum plasma drug concentration; T max = Time of observed maximum plasma drug concentration; t 1 / 2 = Terminal elimination half-life.

[0335] Continuous cardiac monitoring and safety results

[0336] BIA-28 did not produce clinically meaningful related effects on cardiac ECG parameters at the study doses of 60 mg and 150 mg. Concentration-QTc analysis results indicated that the effect on AQTcF did not exceed 10 ms across the full range of observed plasma concentrations of Compound A up to approximately 7150 ng / mL. As shown by the concentration-QTc analysis, the positive control, moxifloxacin, exhibited a statistically significant effect on AQTcF of more than 5 milliseconds, demonstrating the sensitivity of the study to detect positive effects on cardiac conduction parameters.

[0337] During the study, 24 of 37 subjects (64.9%) reported a total of 90 TEAEs (treatment emergent adverse events), of which 88 were transient and had resolved with no sequelae at the subsequent visit. The severity of the two ongoing TEAEs was mild and were considered unrelated to Compound A or moxifloxacin. No deaths or other SAEs were reported.

[0338] Of the 90 TEAEs reported, a total of 4 TEAEs occurring in 2 subjects were considered related to Compound A at 150 mg (1 subject reported headache and nausea, and the other subject reported ALT (alanine aminotransferase) elevation and GGT (gamma-glutamyltransferase) elevation). The severity of most TEAEs was mild, 1 TEAE was of grade 2 (moderate) (pulpitis was considered unrelated to study drug), and 1 TEAE was of grade 3 (severe) (hypersensitivity was considered related to moxifloxacin). Two subjects withdrew from the study due to TEAEs: 1 subject withdrew due to ALT elevation and GGT elevation after receiving Compound A at a dose of 150 mg, which was considered of grade 1 severity and related to Compound A; and the other subject withdrew due to hypersensitivity (grade 3 severity), urinary frequency (grade 1 severity), and nervousness (grade 1 severity) after receiving 400 mg moxifloxacin.

[0339] No clinically meaningful safety observations were found from vital sign measurements, physical examinations, safety ECG parameters, or laboratory values reported during the study and considered related to Compound A, with the exception of one subject who experienced an ALT elevation and GGT elevation after administration of 150 mg Compound A.

[0340] Compound A - Mass balance recovery and metabolite analysis study (BIA 28-6156-106)

[0341] This was a Phase 1, single-dose, mass balance recovery study of Compound A in 1 group of healthy male subjects aged 30 to 65 years. 14 Six subjects in total received a single oral dose of 60 mg Compound A under fasted conditions containing no more than 3.7 MBq of 14 C. The objectives of this study included determining 14 the route and rate of excretion of Compound A-C, identifying the structures of metabolites that account for more than 10% of the total radioactivity in plasma and more than 10% of the total radioactivity dose in urine and feces, exploring the PK of Compound A, assessing the extent of distribution of the TR (test radiotracer) in blood cells, and collecting additional safety and tolerability information for Compound A.

[0342] Mass balance and metabolite analysis results

[0343] The mean recovery of radioactive material from excreta over the 288-hour sampling period was approximately 93% (range: 84.00% to 96.25%). The majority of the total recovery (mean: approximately 71%; range: 66.64% to 80.77%) was present in urine. Approximately 21% of the total recovery (range: 15.24% to 27.20%) was present in feces. Based on AUC 0-inf , Compound A accounted for approximately 92% of the total recovery in circulating plasma, indicating that Compound A was the predominant circulating species in plasma following oral administration.

[0344] Metabolite analysis and identification indicated that there were no systemic metabolites of Compound A that accounted for >10% of the drug-related exposure AUC.

[0345] Pharmacokinetic results

[0346] Following a single oral dose of 60 mg 14 Compound A BIA-28, the geometric mean plasma half-life of Compound A was 21.5 hours (range: 10.7 hours to 34.1 hours). The median T max was 1.5 hours (range: 1.00 hour to 8.00 hours). The plasma C max , AUC0-last and AUC 0-inf The geometric mean (CV%) for AUCo-24, AUCo-12, and AUCo-24 were 1750 ng / mL (38.3%), 41,700 ng.h / mL (10.4%), and 42,100 ng.h / mL (10.5%), respectively.

[0347] The geometric mean (geometric mean CV%) of the ratio of whole blood to plasma total radioactivity concentration ranged from 0.542 (5.6%) to 0.562 (3.1%), indicating that the total recoveries did not exhibit preferential distribution in the cellular components of whole blood.

[0348] Safety results

[0349] No deaths, other SAEs, severe AEs, or discontinuations due to AEs were reported. A total of 3 subjects (50.0%) reported a total of 4 AEs. 2 subjects (33.3%) reported mild headache; and 1 subject (16.7%) reported moderate tinea cruris. All AEs reported were assessed by the investigator as not related to the IMP (investigational medicinal product), were self-limiting, and had resolved by the end of the study. No clinically meaningful safety observations were found from vital sign measurements, laboratory safety assessments, or ECG parameters.

[0350] Drug-drug interaction study (study BIA-6156-107) (Compound A)

[0351] In a Phase 1, non-randomized, open-label, crossover design, drug-drug interaction study of multiple oral doses of carbamazepine (CYP3A4 inducer) on the single dose PK of oral Compound A, 12 male and female subjects, aged 24 to 69 years, received the following two treatments: 1) single oral dose of 60 mg Compound A alone, and single oral dose of Compound A while on oral carbamazepine ER (titrated to 300 mg, twice daily).

[0352] Alternatively, in a Phase 1, non-randomized, open-label, crossover design, drug-drug interaction study of single oral dose of Compound A on the single dose PK of oral carbidopa-levodopa, 12 male and female subjects, aged 24 to 69 years, received the following two treatments: single oral dose of carbidopa-levodopa 25 mg / 100 mg (25 mg carbidopa and 100 mg levodopa) IR alone, and single oral dose of carbidopa-levodopa while on single oral dose of 60 mg Compound A.

[0353] The results of the study of Compound A, BIA 28-6156-107, are summarized below.

[0354] Effect of multiple-dose oral carbamazepine on single dose PK of Compound A

[0355] Median T of Compound A concentration max The post-dose 1 hour extension from Compound A administered alone to Compound A coadministered with carbamazepine was observed for 2 hours. A decrease in systemic exposure of Compound A was observed when Compound A was coadministered with CYPP3A4 inducer carbamazepine relative to Compound A administered alone. Based on the ratio of the geometric least square means of the test group compared to the reference treatment group and the associated 90% confidence interval, the point estimate and 90% CI for Compound A C max decreased by approximately 12% (point estimate: 0.877; 90% CI: 0.672 to 1.146), AUC 0-last decreased by 63% (point estimate: 0.367; 90% CI: 0.333 to 0.405), and AUC 0-inf decreased by 64% (point estimate: 0.363; 90% CI: 0.328 to 0.402). The geometric mean t 1 / 2 for Compound A administered alone was 28 hours and the geometric mean t 1 / 2 for Compound A coadministered with carbamazepine was 12 hours.

[0356] Effect of single dose Compound A on single dose PK of carbidopa-levodopa

[0357] Levodopa

[0358] The median T of levodopa concentration was observed at 0.5 hours post-dose when carbidopa-levodopa was administered alone max and at 1 hour post-dose when carbidopa-levodopa was coadministered with Compound A max .Similar systemic exposure of levodopa was observed when carbidopa-levodopa was coadministered with Compound A and when carbidopa-levodopa was administered alone. Based on the ratio of the geometric least square means of the test group compared to the reference treatment group and the associated 90% CI, the point estimate and 90% CI for levodopa exposure value parameters were 1.061 (0.918 to 1.227) for C max , 1.048 (0.954 to 1.152) for AUC 0-last , and 1.035 (0.945 to 1.132) for AUC 0-inf . The geometric mean t 1 / 2 for levodopa was similar under both treatment conditions (1.7 hours after carbidopa-levodopa administered alone and 1.4 hours after carbidopa-levodopa coadministered with Compound A).

[0359] Carbidopa

[0360] The median Tmaxfor carbidopa concentration was observed at 2.5 hours post-dose when carbidopa-levodopa was administered alone max and at 2 hours post-dose when carbidopa-levodopa was co-administered with Compound A max Relative to carbidopa-levodopa administered alone, a slight increase (approximately 3%) in the maximum exposure and a slight decrease (approximately 9%) in the systemic exposure of carbidopa was observed when carbidopa-levodopa was co-administered with Compound A. Based on the ratio of the geometric least square means of the test group compared to the reference treatment group and the associated 90% CI, the point estimate and 90% CI for the carbidopa exposure value parameters were 1.031 (0.777 to 1.368) for Cmax max and 0.909 (0.630 to 1.313) for AUC 0-last The geometric mean t 1 / 2 was similar under both treatment conditions (2.3 hours).

[0361] The metabolite 3-O-methyl dopa (3-OMD)

[0362] The median Tmaxfor 3-OMD concentration was observed at 6 hours post-dose when carbidopa-levodopa was administered alone and when carbidopa-levodopa was co-administered with Compound A max Similar 3-OMD systemic exposure was observed when carbidopa-levodopa was co-administered with Compound A and when carbidopa-levodopa was administered alone. Based on the ratio of the geometric least square means of the test group compared to the reference treatment group and the associated 90% CI, the point estimate and 90% CI for the 3-OMD exposure value parameters were 1.056 (0.993 to 1.123) for Cmax max and 1.060 (1.010 to 1.112) for AUC 0-last The geometric mean t 1 / 2 was not calculable for 3-OMD as the 12-hour PK profile did not have a terminal phase for most subjects.

[0363] Safety results

[0364] Some TEAEs were observed. All TEAEs were transient and had resolved with no sequelae at subsequent visits.

[0365] After administration of 60 mg of Compound A alone, 2 of 12 subjects (16.7%) reported a total of 2 AEs (mild back pain, n = 1; mild headache, n = 1), and after co-administration of 60 mg of Compound A with 300 mg of extended-release carbamazepine, 3 of 12 subjects (25.0%) reported a total of 3 AEs (mild myalgia, n = 1; mild headache, n = 2). No AEs were reported after co-administration of 60 mg of Compound A with 25 mg / 100 mg immediate-release carbidopa-levodopa. No SAEs were reported, and no TEAEs of severity > Grade 3 were reported. The majority of TEAEs were of Grade 1 (mild) severity. Only 4 TEAEs were of Grade 2 (moderate) severity: abdominal pain (considered related to Compound A or carbamazepine), hepatobiliary disease (considered related to Compound A, carbamazepine, or carbidopa-levodopa), fall (considered unrelated to any study drug), and constipation (considered related to carbamazepine but unrelated to Compound A or carbidopa-levodopa).

[0366] Two subjects discontinued study treatment due to TEAEs. One subject prematurely discontinued the study due to a decreased platelet count, which was reported as a Grade 1 (mild) TEAE and considered related to carbamazepine. One subject prematurely discontinued the study due to a viral infection (primary reason) and abdominal pain. The viral infection was of Grade 1 (mild) severity and considered unrelated to any study drug. The abdominal pain was of Grade 2 (moderate) severity and considered related to Compound A or carbamazepine, although the subject was only receiving carbamazepine at the time of the event.

[0367] No safety observations of clinical significance were found from vital sign measurements, physical examinations, ECG parameters, or C-SSRS (columbia-suicide severity rating scale) (Posner 2011). No other laboratory values of clinical significance were reported during the study, except for a decreased platelet count in one subject and a transient elevation of liver enzymes in one subject.

[0368] Drug-drug interaction study (BIA-28-6156-109)

[0369] This was a Phase 1, nonrandomized, open-label, 2-cohort, crossover design, DDI study in healthy male and female subjects. The study evaluated the effect of multiple doses of Compound A on the single-dose PK and safety of levodopa-carbidopa and levodopa-benserazide.

[0370] In Cohort 1, a single oral dose of 100 mg / 25 mg levodopa-carbidopa was administered alone on Day 1 IR. On Days 2-6, a single dose of 60 mg Compound A was administered. On Day 7, a single dose of 60 mg Compound A and a single dose of 100 mg / 25 mg levodopa-carbidopa IR.

[0371] In Cohort 2, a single oral dose of 100 mg / 25 mg levodopa-benserazide was administered alone on Day 1 IR. On Days 2-6, a single dose of 60 mg Compound A was administered. On Day 7, a single dose of 60 mg Compound A and a single dose of 100 mg / 25 mg levodopa-benserazide IR.

[0372] For For Part, analysis of carbidopa plasma PK samples was conducted outside of a validated stability period, and the resulting sample reproducibility assessment did not meet acceptable standards. Therefore, carbidopa results are not described in this CSR (clinical study report).

[0373] For In this section, plasma PK results for benserazide are not described because all benserazide concentrations measured in this study (except for two concentrations) were below the LLOQ (lower limit of quantification). Statistical analyses of the DDIs performed were for exploratory purposes only. Therefore, the application of the default bioequivalence range should be interpreted in this context. In both sections, the effect of multiple-dose compound A on the PK of a single-dose levodopa cannot be ruled out because the upper limit of the 90% CI for the AUC ratio did not fall within the 80% to 125% of the default no-effect boundary. Further studies may be needed to confirm the potential clinical DDIs. However, it can be seen that the potential effect of compound A on the PK of levodopa is limited (the AUC increased by approximately 13% and 24% in cohort 1 and cohort 2, respectively). According to the U.S. Food and Drug Administration's (FDA) guidance on drug interactions ("Clinical Drug Interaction Studies—Cytochrome P450 Enzyme-and Transporter-Mediated Drug Interactions, Guidance for Industry"), issued January 2020 by the Center for Drug Evaluation and Research (CDER), U.S. Department of Health and Human Services, FDA, and Clinical Pharmacology, this would be the minimum effect, as an increase in AUC >1.25-fold to <2-fold is considered a weak DDI effect.

[0374] Levodopa - Section: Effect of multiple doses of Compound A on single dose

[0375] Plasma Comparison of Levodopa and 3-OMD

[0376] Compared with single application In comparison, in joint application / After compound A, for levodopa, the ratio of the geometric least squares mean CI to C is 90%. max For AUC, it is 1.231 (from 1.006 to 1.508). 0-t It is 1.130 (from 1.004 to 1.272), and for AUC 0-inf The values ​​were 1.132 (from 1.007 to 1.272). These results indicate that compared to application alone... In comparison, the maximum exposure of levodopa was increased by approximately 23% for Cmax (based on the estimate of 1.231), and the systemic exposure of levodopa was increased by approximately 13% for AUCo-t (based on the estimate of 1.130) and AUCo-inf (based on the estimate of 1.132).

[0377] However, based on the 90% CI for the ratio of geometric means for Cmax (estimate of 1.077; 90% CI range of 0.980 to 1.184) and AUCo-t (estimate of 1.065; 90% CI range of 0.979 to 1.159), Compound A had no effect on the 3-OMD PK. The geometric mean t½ value for levodopa after the combination administration of Compound A and (1.59 hours) was similar to the geometric mean t½ value for levodopa after administration of (1.69 hours), indicating that the clearance of levodopa was not affected by the co-administration of Compound A. It is expected that the steady state concentration of Compound A will be reached after 6 days of dosing, since the t½ after multiple doses in trial LTI-291-002 was 25 hours to 35 hours. However, based on visual inspection of the geometric mean trough plasma concentration-time curve, it can be seen that the steady state concentration of Compound A has not yet been reached after 6 days of dosing with 60 mg of Compound A (Days 2 to 7), since the trough concentrations for these days are still increasing. However, the curve levels off by Day 7, indicating that the steady state concentration of Compound A will be reached soon.

[0378] Summary Statistics (Geometric Mean [Range]) for Levodopa and 3-OMD Plasma PK Parameters (PK Set)

[0379]

[0380]

[0381] % AUC extra = percentage of the estimated portion of AUCo-inf;

[0382] 3-OMD = 3-O-methyl dopa; N = number of subjects; n = number of subjects for this parameter;

[0383] PK = pharmacokinetics;

[0384] n is 12, unless otherwise specified;

[0385] a : For tmax, the median (range) is presented instead of the geometric mean (range);

[0386] b : 3 subjects did not meet the criteria of %AUCextra < 20% and 9 subjects had AUC0-inf that could not be estimated;

[0387] c : 6 subjects did not meet the criteria of %AUCextra < 20% and 6 subjects had AUC0-inf that could not be estimated;

[0388] d : These half-life data should be considered unreliable due to the actual values being much greater than the calculated range.

[0389] Part: Statistical analysis of drug-drug interactions (PK set) between Compound A and

[0390]

[0391] 3-OMD = 3-O-methyl dopa; AUC = area under the plasma concentration-time curve; CI = confidence interval; ln = natural logarithm; PK = pharmacokinetics.

[0392] Note: Cmax and AUC analyses were performed on the natural log-transformed parameters using a linear mixed effects model with treatment as a fixed effect and subject as a random effect.

[0393] a : AUC0-inf could not be estimated or accurately estimated for 3-OMD.

[0394] Part: Summary statistics (geometric mean [range]) for Compound A plasma PK parameters (PK set)

[0395]

[0396] N = number of subjects; PK = pharmacokinetics;

[0397] a : For tmax, the median (range) is presented instead of the geometric mean (range).

[0398] Levodopa - Section: Effect of multiple doses of Compound A on single dose

[0399] Plasma PK of levodopa and 3-OMD

[0400] Compared to Compound A administered alone Compared to Compound A administered alone ​Following Compound A, the 90% CI for the ratio of the geometric mean for levodopa was 1.330 (1.124 to 1.575) for Cmax, 1.238 (1.146 to 1.337) for AUCo-t, and 1.237 (1.146 to 1.335) for AUCo-inf. These results indicate that, compared to administration of levodopa alone, the maximum exposure of levodopa was increased by about 33% for Cmax (based on the estimate of 1.330), and the systemic exposure of levodopa was increased by about 24% for both AUCo-t (based on the estimate of 1.238) and AUCo-inf (based on the estimate of 1.237).

[0401] However, based on the 90% CI for the ratio of the geometric mean for Cmax (estimate of 1.131; 90% CI range of 1.086 to 1.178) and AUCo-t (estimate of 1.115; 90% CI range of 1.075 to 1.158), Compound A had no effect on the 3-OMD PK. The geometric mean t½ value for levodopa following the combined administration of Compound A and (2.45 hours) was similar to the geometric mean t½ value for levodopa following the administration of (2.26 hours) alone, indicating that the clearance of levodopa was not affected by the co-administration of Compound A.

[0402] It was expected that, since the t½ following multiple doses in trial LTI-291-002 was 25 to 35 hours, the steady state concentration of Compound A would be reached after 6 days of dosing. However, based on visual inspection of the geometric mean trough plasma concentration-time curve, it appeared that the steady state concentration of Compound A had not been reached after 6 days of dosing with 60 mg of Compound A (Days 2 to 7), since the trough concentrations were still increasing on these days. However, the curve leveled off by Day 7, indicating that the steady state concentration of Compound A would soon be reached.

[0403] Based on the statistical analysis, compared to administration of levodopa alone, the maximum systemic exposure of levodopa was increased by about 23% for Cmax, and the systemic exposure of levodopa was increased by about 13% for both AUCo-t and AUCo-inf following the combined administration of Compound A and However, based on the plasma exposure PK parameters for 3-OMD, Compound A had no effect.

[0404] Based on the statistical analysis, compared to administration of levodopa alone, the maximum systemic exposure of levodopa was increased by about 23% for Cmax, and the systemic exposure of levodopa was increased by about 13% for both AUCo-t and AUCo-inf following the combined administration of Compound A and ​Afterwards, the maximum systemic exposure of levodopa increased approximately 33% for Cmax, and the systemic exposure of levodopa increased approximately 24% for both AUCo-t and AUCo-inf. However, based on the plasma exposure PK parameters of 3-OMD, Compound A had no effect on No effect.

[0405] The geometric mean t½ values of levodopa after co-administration of Compound A and were similar to the geometric mean t½ values after administration of levodopa alone, indicating that the clearance of levodopa was not affected by Compound A. The geometric mean t½ values of levodopa after co-administration of Compound A and were similar to the geometric mean t½ values after administration of levodopa alone, indicating that the clearance of levodopa was not affected by co-administration of Compound A.

[0406] It can be seen that steady state concentrations of Compound A were not yet reached when Compound A was co-administered with / Compound A on Day 7 or Compound A was co-administered with / Compound A on Day 7.

[0407] Summary Statistics (Geometric Mean [Range]) of Levodopa and 3-OMD Plasma PK Parameters (PK Set)

[0408]

[0409] % AUC extra = percentage of the estimated portion of AUCo-inf;

[0410] 3-OMD = 3-O-methyl dopa; N = number of subjects; n = number of subjects for this parameter; PK = pharmacokinetics;

[0411] For Compound A alone Unless otherwise specified, n is 12;

[0412] For Compound A + levodopa, unless otherwise specified, n is 11;

[0413] a : For tmax, the median (range) is presented instead of the geometric mean (range);

[0414] b : 8 subjects did not meet the criteria of %AUC extra < 20% and 4 subjects had an AUCo-inf that could not be estimated;

[0415] c ​: 9 subjects did not meet the criteria of %AUCextra < 20% and AUCo-inf was not estimable for 2 subjects;

[0416] d : Since the actual values of the half-lives were much greater than the calculated range, these half-life data should be considered unreliable.

[0417] Part: Statistical analysis of the drug-drug interaction (PK set) between Compound A and

[0418] 3-OMD = 3-O-methyl dopa; AUC = area under the plasma concentration-time curve; CI = confidence interval; CI = confidence interval; ln = natural logarithm; PK = pharmacokinetics;

[0419] Note: C max and AUC analysis using linear mixed effects model on the natural log-transformed parameters with treatment as a fixed effect and subjects as random effects;

[0420] a : For 3-OMD, AUC 0-inf could not be estimated or could not be accurately estimated.

[0421] Part: Summary statistics (geometric mean [range]) for Compound A plasma PK parameters (PK set)

[0422]

[0423] N = number of subjects; PK = pharmacokinetics;

[0424] a : For tmax, the median (range) is presented instead of the geometric mean (range).

[0425] Overall, the results of this study indicate that Compound A can be co-administered with levodopa-carbidopa or levodopa-benserazide; however, potential clinically meaningful DDIs in PD patients cannot be excluded.

[0426] Drug-drug interaction study (BIA 28-6156-110)

[0427] This was a Phase 1, non-randomized, open-label, 2-cohort, crossover design, DDI study in healthy male and female subjects. This study evaluated the effect of multiple doses of Compound A on the single dose PK and safety of rosuvastatin and metformin.

[0428] ​In Cohort 1, a single oral dose of 10 mg rosuvastatin was administered alone on Day 1. No drug was administered on Day 2. From Day 3 to Day 8, a single daily dose of 60 mg Compound A was administered. On Day 9, a single dose of 60 mg Compound A and a single dose of 10 mg rosuvastatin were administered.

[0429] In Cohort 2, a single oral dose of 500 mg metformin was administered alone on Day 1. From Day 2 to Day 7, a single daily dose of 60 mg Compound A was administered. On Day 8, a single dose of 60 mg Compound A and a single dose of 500 mg metformin were administered.

[0430] Statistical analysis of the DDI was performed for exploratory purposes only. Therefore, the following application of default bioequivalence ranges should be interpreted in this context.

[0431] In the rosuvastatin part, the effect of multiple doses of Compound A on the PK of a single dose of rosuvastatin could not be ruled out as both the upper and lower limits of the 90% CI for the AUC ratio fell outside the default no-effect boundary of 80% to 125%. The effect of Compound A on the PK of rosuvastatin appeared to be an increase of about 3-fold, with AUC increasing from 304% to 344%. In the metformin part, the 90% CI for the metformin AUC ratio fell within the default no-effect boundary of 80% to 125%, indicating that multiple oral doses of Compound A had no effect on the PK of metformin following a single oral dose of metformin.

[0432] The truncated PK profile of rosuvastatin over 48 hours and the truncated PK profile of metformin over 24 hours were considered sufficient to effectively characterize and compare the rate and extent of absorption when administered in combination with Compound A or alone. However, the parameters related to excretion had a higher degree of uncertainty and should be treated with caution when interpreting.

[0433] Rosuvastatin Section: Effect of multiple doses of Compound A on single dose plasma pharmacokinetics of rosuvastatin Metformin Section: Effect of multiple doses of Compound A on single dose plasma pharmacokinetics of metformin

[0434] The 90% CI for the ratio of rosuvastatin geometric mean least squares mean Cmax(estimated value of 3.467; 90% CI range of 3.141 to 3.826), AUCo-t(estimated value of 3.437; 90% CI range of 3.151 to 3.750), and AUCo-inf(estimated value of 3.041; 90% CI range of 2.759 to 3.352) did not fall within the 80% to 125% of the default no effect boundary. Thus, compared to rosuvastatin administered alone, an increase of 347% in the maximum exposure of rosuvastatin (based on the estimated value of 3.467), an increase of 344% in the systemic exposure of rosuvastatin (based on the estimated value of 3.437), and an increase of 304% in the systemic exposure of rosuvastatin (based on the estimated value of 3.041) was observed following co-administration with Compound A. It is expected that steady state concentrations of Compound A will be reached after 6 days of dosing. However, based on visual inspection of the geometric mean trough plasma concentration-time profile, it appears that steady state concentrations of Compound A have not been reached after 6 days (Days 3 to 9) of Compound A dosing at 60 mg, as the trough concentrations for these days are still increasing.

[0435] EMBODIMENTS FIG. 3

[0436] The 90% CI for the ratio of metformin geometric mean least squares mean Cmax(estimated value of 0.950; 90% CI range of 0.877 to 1.028), AUCo-t(estimated value of 0.938; 90% CI range of 0.881 to 1.000), and AUCo-inf(estimated value of 0.940; 90% CI range of 0.882 to 1.002) fell within the 80% to 125% of the default no effect boundary, indicating that multiple oral doses of Compound A had no effect on metformin PK following a single oral dose of metformin. It is expected that steady state concentrations of Compound A will be reached after 6 days of dosing. However, based on visual inspection of the geometric mean trough plasma concentration-time profile, it appears that steady state concentrations of Compound A have not been reached after 6 days (Days 2 to 8) of Compound A dosing at 60 mg, as the trough concentrations for these days are still increasing.

[0437] EMBODIMENTS

[0438] In vitro measurement of GCase activity in human brain homogenate was used to correlate exposure with GCase activity and to estimate the GBA-PD patient steady state C min (C b,min,ssincrease in GCase activity in the brain under the conditions described below. The brain concentration of Compound A in humans was obtained using the concentration relationship observed in the brain and CSF of rats and assuming that this concentration relationship is conserved across mammalian species. The human in vivo estimated C b,min,ss The range was overlaid with the corresponding concentrations from the in vitro human brain homogenate study to assess the activation of GCase by Compound A.

[0439] It was found that the minimum GCase activity in GBA-PD patients should reach 69.7% to 123%, 163% to 306%, and 255% to 376% of the normal control value at the dose range of 10 mg, 30 mg, and 60 mg, respectively. Efficacy results Based on the GCase activity, it was concluded that all three dose levels should be associated with an effect since the minimum GCase activity in GBA-PD patients (69.7%) at a dosing interval of 10 mg (24 h) is approximately 2-fold the effective GCase activity.

[0440] In vitro GCase brain homogenate activity assay

[0441] In the GCase assay, the activity of Compound A was determined using 4-MUG (1 mM) as the substrate and brain homogenate (5 pg / well) as the enzyme source.

[0442] A 500 pl aliquot of 1.0 mg / ml phosphatidylserine (PS, Sigma P7769) in chloroform was evaporated under a stream of nitrogen for 1 h. The lipid membrane was dissolved in 41 mL of 176 mM K2HPO4 / 50 mM citric acid (pH 4.7) containing 7.7 pL triton X-100, vortexed vigorously for 4 min, to give a mixed micelle preparation consisting of 0.32 mM triton and 4.6 mol% PS.

[0443] 4-methylumbelliferyl-beta-D-glucopyranoside (4-MUG, ACROS-337025000) was dissolved in the micelle solution, formulated to a final concentration of 2 mM, and used as the reaction substrate.

[0444] The micelle / homogenate solution was prepared by adding 3.2 ml Triton X-100 / phosphatidylserine mixed micelles containing 400 pg / mL brain homogenate. A 1.6 mL portion of this mixture received 32 pi of conduritol B epoxide (CBE, 100 mM stock in DMSO) such that the final concentration was 2 mM CBE. The remaining 1.6 mL portion received 32 pL of DMSO as a solvent control. Compound A was diluted from a 10 mM stock in DMSO to the desired assay concentration with DMSO, and 0.45 pL of the compound DMSO solution was added to 75 pL of the micelle / homogenate solution (+ / - CBE).

[0445] After a 30-minute pre-incubation at room temperature, the reaction was initiated by combining 25 pL of substrate solution with 25 pL of compound / GCase / homogenate mixture. The reaction was allowed to proceed for 30 minutes at room temperature for rat brain homogenate, cynomolgus monkey brain homogenate, and dog brain homogenate, and for 60 minutes at room temperature for mouse brain homogenate and human brain homogenate. The reaction was stopped by the addition of 150 pL of 1 M glycine (pH 12.5). The endpoint fluorescence intensity of the reaction was measured on a SpectraMax i3 instrument (Molecular Devices) at 365 nm excitation, 440 nm emission. Compound activity was expressed with reference to the DMSO solvent control. GBA1 activity was obtained by subtracting the GCase activity in the CBE-containing samples from the GCase activity in the DMSO-containing samples and plotted on a dose-response curve.

[0446] Method for quantifying Compound A in human CSF

[0447] To measure the amount of Compound A in CSF, the CSF was diluted 1 : 1 (v / v) with 0.2% bovine serum albumin and sample handling was performed using a protein precipitation / dilution method: a sample volume of 50.0 pL was used and Compound A was used as an internal standard. Separation of metabolite from interfering endogenous compounds was achieved by HPLC: a Shim-pack XR-ODS column (3.0 x 50 mm, 2.2 pm particles) was used at a temperature of 60 °C using 0.1% formic acid in water as mobile phase A, acetonitrile as mobile phase B, and an isocratic run at 55% B followed by a stepwise gradient run at 85% B at a flow rate of 0.900 mL / min.

[0448] Detection was performed using an API4000 mass spectrometer equipped with a turbo ion spray source in positive ion mode. Quantitation was performed based on multiple reaction monitoring (MRM) of transitions of m / z 359.2-174.2 for LTI-291 and m / z 365.3-180.2 for its internal standard. A linear calibration curve with a 1 / x2 weighting factor was used to determine the range of LTI-291 in CSF from 0.0500 ng / mL to 100 ng / mL (0.0250 ng / mL to 50.0 ng / mL in CSF: 0.2% BSA 1:1 (v / v)).

[0449] Results were plotted and analyzed using Analyst version 1.6.2 (AB Sciex, Concord, Canada).

[0450] Pharmacokinetic results

[0451] This study was a Phase 2, randomized, double-blind, placebo-controlled, multiple oral dose study of Compound A in subjects with GBA-PD, aged 35 to 80 years, inclusive. Subjects had been clinically diagnosed with PD for at least 1 year and no more than 7 years, had a modified Hoehn and Yahr score of <2.5 and a Montreal Cognitive Assessment (MoCA) score of >22, as confirmed by a neurologist using the Parkinson Disease MDS Scale, and were on symptomatic treatment for PD prior to the start of screening (for Part A). In some embodiments, subjects did not have moderate (or severe) motor complications, as assessed by a score of >3 on any sub-item of the MDS-UPDRS Part IV, and subjects did not have clinically meaningful psychosis, per investigator clinical judgment. The objective of the study was to investigate the efficacy, safety, tolerability, pharmacodynamics, and PK of Compound A for oral administration at a once-daily frequency.

[0452] Subjects were genetically screened using blood collected (preferably whole blood samples). Subjects were screened by sequencing the entire GBA1 gene, with any PD risk-related variants identified detailed. Subjects were also screened for the presence of PD risk-related variants in the LRRK2 (leucine-rich repeat kinase 2) gene. Subjects carrying LRRK2 pathogenic variants were not eligible for inclusion in Part B (double-blind treatment) of the study.

[0453] Subjects carrying pathogenic variants of the glucocerebrosidase 1 (GBA1) gene (i.e. GBA-PD) (e.g. see Appendix 1) and who have been on a stable dose of PD medication for at least 30 days prior to treatment initiation (at least 60 days if rasagiline is used) will enter the next phase of the trial. In addition, subjects who present with the following will be discontinued from subsequent treatment:

[0454] • The subject has Gaucher disease (GD) as defined by clinical signs and symptoms (i.e. hepatosplenomegaly, cytopenias, skeletal disease), and / or has a history of marked deficiency in GCase plasma activity (preferably GCase whole blood activity) consistent with GD.

[0455] • The subject is homozygous for a GBA1 pathogenic variant known to be associated with GD, or is a compound heterozygote for 2 alleles known to be associated with GD.

[0456] • The subject carries a LRRK2 pathogenic variant known to be associated with PD (e.g. see Appendix 2).

[0457] • The subject is considered to have atypical parkinsonism or secondary parkinsonism according to the medical history or the investigator’s opinion. Atypical parkinsonism includes, but is not limited to, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy diagnosed. Secondary parkinsonism includes drug-induced parkinsonism, toxin-induced parkinsonism, post-infectious parkinsonism, post-traumatic parkinsonism or vascular parkinsonism.

[0458] • The subject is using a potent CYP3A4 modulator at the time of screening for Part B.

[0459] • The subject is using a breast cancer resistance protein (BCRP) substrate (e.g. pravastatin, rosuvastatin, glibenclamide) at the time of screening for Part B.

[0460] • (Optionally) The subject has used any of the following medications within 60 days prior to baseline: typical or atypical antipsychotic drugs (including but not limited to clozapine, pimavanserin, olanzapine, quetiapine, risperidone and aripiprazole); metoclopramide; prochlorperazine; methyldopa; tetrabenazine; deutetrabenazine;

[0461] valbenazine; reserpine; or has a history of ambroxol use (dose > 120 mg / day), ongoing use or new initiation of ambroxol during the study.

[0462] Subjects are randomized into three groups to receive i) 10 mg Compound A, orally administered once daily; ii) 60 mg Compound A, orally administered once daily; or iii) placebo, orally administered once daily. Subjects are also to receive their usual PD medication throughout the study. Randomization is stratified by major / severe (e.g., heterozygotes for N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, R120W; homozygotes for T369M or E326K) or minor / mild (e.g., heterozygotes for T369M or E326K) PD risk-associated variants. Alternatively, randomization is stratified by severity of mild or severe GBA1 variants as described in Parlar, 2023 (see also Appendix 1). Based on emerging data, subjects carrying other PD risk-associated variants are classified as major / severe or minor / mild and randomized accordingly.

[0463] Subjects receive treatment for up to 78 weeks, followed by a 30-day (or 4-week) safety follow-up. Efficacy, safety, tolerability, pharmacodynamics, and PK are assessed at study visits at baseline and at Week 4, Week 12, Week 26, Week 39, Week 52, Week 65, and Week 78. Study personnel contact subjects prior to each scheduled study visit to remind them to take their last dose of non-study PD medication > 10 hours prior to each study visit. After completion of study visit assessments, subjects can resume taking their non-study PD medication. For subjects who take non-study PD medication < 10 hours prior to a scheduled study visit, the study visit is rescheduled.

[0464] Study visits are scheduled at approximately the same time each day to ensure that assessment scales are completed at a consistent time during the study. Throughout the study, every effort is made to have the same rater perform the same assessments for individual subjects. Where possible, efficacy assessments are performed first, followed by safety assessments, and then blood is drawn.

[0465] Subjects can require unscheduled visits for any adjustments to non-study PD medication. In such cases, the last dose of non-study PD medication is taken > 10 hours prior to each unscheduled visit, and assessments of MDS-UPDRS Part I to Part IV, CGI-C, and PGI-C are performed prior to any adjustments to non-study PD medication. After completion of study visit assessments, subjects can resume taking their non-study PD medication.

[0466] The following criteria are assessed periodically throughout the study:

[0467] • Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Part I, II, III, and IV.

[0468] • Clinical Global Impression-Change (CGI-C) and Clinical Global Impression- Severity (CGI-S).

[0469] • Patient Global Impression-Change (PGI-C) and Patient Global Impression- Severity (PGI-S).

[0470] • Levodopa Equivalent Daily Dose (LEDD).

[0471] • Modified Hoehn and Yahr score.

[0472] • Parkinson’s Disease Cognitive Rating Scale (PD-CRS).

[0473] • 39-item Parkinson’s Disease Questionnaire (PDQ-39).

[0474] • EuroQol-5D-5L (EQ-5D-5L).

[0475] • Gait speed.

[0476] In addition, PD biomarkers and GCase activity in whole blood samples are measured at baseline and Week 78 (preferably baseline and Weeks 4, 26, 52, and 78). This can include biomarkers of lysosomal activity (e.g., glucosylsphingosine (GluSph) and / or glucosylceramide (GluCer)). Methods of measuring lysosomal activity (e.g., GluSph and / or GluCer) are described above. Methods of measuring GCase activity are described below. A subset of GBA-PD subjects undergoes magnetic resonance imaging (MRI) scans at baseline and Week 78.

[0477] At study visits at baseline and Weeks 4, 12, 26, 39, 52, 65, and 78, efficacy, safety, tolerability, and pharmacodynamic assessments are performed. A telephone contact is made at Week 8 to inquire about the occurrence of any adverse events (AEs) and any changes in concomitant medications.

[0478] At the baseline visit and during the Week 4, 12, 26, 39, 52, 65, and 78 visits, blood is collected from all subjects for population PK analysis to determine plasma concentrations of Compound A at the study site prior to administration of the first dose of IMP. Subjects are reminded to take their IMP in the morning prior to the Week 4, 12, 26, 39, 52, 65, and 78 visits. The time of collection of the PK blood samples is recorded.

[0479] During screening, subjects who are assessed to meet the inclusion criteria and agree to participate in the optional MRI sub-study will have their baseline magnetic resonance imaging (MRI) scan obtained. The baseline MRI is obtained within a 35-day screening window and after all other screening assessments have confirmed that the subject meets the study inclusion criteria. For subjects participating in the MRI sub-study, their post-treatment MRI is obtained at Week 78; the MRI at Week 78 allows for completion within a -2 weeks to +1 day window.

[0480] Plasma concentrations at each time point are summarized, and PK parameters are not estimated. PD assessments include fMRI measures; FDG-PET for determination of glucose metabolic rate in specific regions of the brain; and functional outcome measures (MDS-UPDRS Part III and MMSE). GluCer, GluSph, and LacCer, as well as other sphingolipids, are measured in PBMCs and plasma as biomarkers of pharmacological effect.

[0481] The preferred method for measuring GCase activity in whole blood is described below and is also described in Totorelli, 2016, which is incorporated by reference herein:

[0482] A 5plex mixture assay for GCase, acid a-glucosidase (GAA), galactocerebrosidase (GALC), a-galactosidase A (GLA), and a-L-iduronidase (IDUA) activity was prepared. Vials containing substrate (S) and internal standard (IS) for GCase and GAA were reconstituted with methanol and transferred to a GALC S+IS vial, followed by evaporation. The GLA S+IS vial was reconstituted with 1.8 mL of a 96 g / L aqueous sodium taurocholate solution, then transferred to the dry GALC S+IS vial, which was then heated to 60 °C to dissolve all solids. To the GALC S+IS vial was added the following reagents: 0.3 mL of a 0.8 mmol / L aqueous acarbose solution (GAA inhibitor) and 2.88 mL of a 1 mol / L N-acetylgalactosamine (GLA inhibitor) solution in buffer (0.2 mol / L sodium phosphate + 0.1 mol / L sodium citrate, pH = 4.4). The IDUA S+IS vial was 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 a 3 mmol / L aqueous D-glycero-1,4-lactone solution. The reconstituted IDUA S+IS vial was transferred to the GALC S+IS vial. The acid sphingomyelinase (ASM) mixture was prepared separately by reconstituting the ASM S+IS vial with 0.15 mL of a 96 g / L aqueous sodium taurocholate solution, followed by 17.85 mL of buffer (0.85 mol / L sodium acetate + 0.604 mmol / L zinc chloride, pH = 5.7). After mixing, 1 mL aliquots of these reagents were stored at -20 °C for up to 2 months.

[0483] Three 3 mm discs were cut from dried blood spots (DBS) prepared by spotting blood on Whatman 903 filter paper and allowing it to dry at ambient conditions for at least 3 hours and placed in individual microtiter plates. For GCase, GAA, GLA, GALC, and IDUA, the first disc was treated with 30 pL of ASM mixture and the second disc was treated with 30 pL of the 5plex mixture containing S and IS. The 2 enzyme plates were sealed, centrifuged at 493 g for 2 minutes, and incubated at 37 °C for 19 hours. The enzyme reactions were quenched with 300 pL of a 12 ng / mL d4-C 26Lysophosphadildicholine (LPC) was extracted from the third plate in methanol. The extract was then evaporated under heated nitrogen, reconstituted with 130 μΐ^ of mobile phase (800 mL methanol / 200 mL water with 5 mmol / L ammonium formate) and stored cold. After 19 hours of incubation, the 5-reaction and ASM reactions were terminated by adding 200 μΐ^ of ethyl acetate:methanol in a 1 : 1 ratio to each plate. The 5-reaction and ASM plates were combined into a single deep well plate and liquid-liquid extraction was performed by adding 400 μΐ^ of ethyl acetate to each well, followed by 400 μΐ^ of water. The plate was sealed and centrifuged at 493 g for 2 minutes and 150 μΐ^ of the organic layer was transferred to a new plate, evaporated under nitrogen and reconstituted with 150 μΐ^ of ethyl acetate:methanol in a 19: 1 ratio. The reconstituted extract was added to a silica-containing filter plate that had previously been washed with 200 μΐ^ of ethyl acetate in a 19: 1 ratio. The sample was moved through the filter plate by positive pressure and the plate was eluted with an additional 200 μΐ^ of ethyl acetate in a 19: 1 ratio. The collected 350 μΐ^ of eluate was evaporated under a stream of nitrogen and then reconstituted with a stored (X- adrenoleukodystrophy) ALD (adrenoleukodystrophy) plate. The samples were analyzed by flow injection tandem mass spectrometry (FIA-MS / MS). The total time to process the plate of 96 samples was 60 minutes and 70 minutes before and after incubation for 19 hours, respectively.

[0484] MS / MS (tandem mass spectrometry) procedure. A triple quadrupole MS / MS system operating in positive ion mode (source voltage, 5500 V) was used. The mass calibration and resolution of both resolving quadrupoles were optimized by infusion of a poly(propylene glycol) solution. Method optimization was performed by infusing a solution containing the enzyme product under test, LPC species and IS at a flow rate of 0.6 mL / h. The instrument was optimized to monitor the transitions. Single reaction monitoring experiments (100 ms dwell time per experiment) were added to the MS / MS method. Sample introduction into the atmospheric pressure ionization source was achieved by an autosampler and HPLC system. Without the use of a chromatographic column, the autosampler injected 20 pL of each sample into the liquid chromatography (LC) mobile phase (800 mL methanol / 200 mL water containing 5 mmol / L ammonium formate) at a flow rate of 0.250 mL / min. Between injections, the analysis time for each sample was 1 minute. Each prepared C 26 - samples with a significant increase in LPC concentration to minimize false positive results. This is because unknowns inconsistently present in DBS can interfere with the C 26 - accurate quantification of LPC.

[0485] Preparation of calibrators and controls. The skilled person will know which controls are suitable for comparison of interest and will select these for use in the GCase activity protocol.

[0486] For example, controls for enzyme activity levels can be prepared and provided by the centers for disease control and prevention (CDC). These controls include a base pool control with no enzyme activity (CDC base pool), a low control with reduced enzyme activity (CDC low), a medium control with moderate enzyme activity (CDC medium (med)), and a high control with normal enzyme activity (CDC high). The CDC can provide liquid calibrators with a product (P) to IS ratio (P / IS) of 0.00, 0.05, 0.5, 1.0, 2.0, and 5.0 for each enzyme, as well as 0.00 mg / L, 0.58 mg / L, 0.97 mg / L, 1.16 mg / L, 1.74 mg / L, and 2.32 mg / L C 20 - LPC, C 22 - LPC, C 24 - LPC, and C26 - the liquid calibrant corresponding to LPC for linearity study.

[0487] In some embodiments, the control of the level of enzyme activity can be prepared from a sample taken from the patient before the start of the treatment or from a sample taken from the patient at an earlier time point before the treatment.

[0488] It can also be useful to provide a control prepared from a baseline pool lacking enzyme activity, a baseline pool with low activity, and / or a baseline pool of healthy subjects.

[0489] Pharmacodynamic results

[0490] For at least one of the measurements described herein, some subjects treated with Compound A exhibit an extended time to worsening compared to subjects treated with placebo. Clinical worsening can be defined as an increase in the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II total score of >2 points and no improvement in motor exam as assessed by an increase in the MDS-UPDRS Part III total score of >0 points.

[0491] Alternatively or additionally, the time to worsening can be defined as the time to an increase in the MDS-UPDRS Part III total score of >5 points, or the time to an increase in the MDS-UPDRS Part III total score of >3 points, and / or the time until an increase in the MDS-UPDRS Part II total score of >2 points and an increase in motor exam assessed by the MDS-UPDRS Part III total score of >5 points.

[0492] Alternatively or additionally, subjects treated with Compound A can also exhibit an extended time to any worsening from baseline on the CGI-C, CGI-S, PGI-S, and / or PGI-C scales, and / or an extended time until the first LEEDD increase compared to those subjects treated with placebo.

[0493] Alternatively or additionally, subjects treated with Compound A can exhibit lower changes from baseline to Week 78 in MDS-UPDRS scores (I to IV), Modified H&Y (Hoehn and Yahr) score, PD-CRS score, PDQ-39, EQ-5D-5L score, CGI-C score, and / or PGI-C score compared to those subjects treated with placebo.

[0494] ​

[0495] At all time points of measurement, the mean plasma concentration of Compound A was higher after dosing 60 mg than after dosing 10 mg.

[0496] ​

[0497] The mean change in neurofilament light chain plasma concentration was lower in subjects treated with Compound A compared to those treated with placebo.

[0498] The mean change in GCase activity in whole blood samples was higher in subjects treated with Compound A compared to those treated with placebo.

[0499] The mean change in lysosomal activity was higher in subjects treated with Compound A compared to those treated with placebo. In addition, the mean change in GluSph levels was higher in subjects treated with Compound A compared to those treated with placebo.

[0500] The mean change in cerebral blood flow measured with MRI arterial spin labeling was higher in subjects treated with Compound A compared to those treated with placebo.

[0501] Appendix 1: List of GBA1 mutations (for inclusion in trial)

[0502]

[0503]

[0504] a. Based on emerging data, subjects carrying other GBA-PD risk-related variants will be classified as severe or mild and randomized accordingly.

[0505] b. Fulgent Genetics (likely pathogenic / disease-causing).

[0506] c. National Center for Biotechnology Information.

[0507] d. See Parlar, 2023.

[0508] GBA-PD patients are eligible for inclusion if they meet the following criteria:

[0509] a) carry any listed mutation as a heterozygote, including carrying a listed “risk variant (mild)” mutation as a heterozygote, or

[0510] b) carry a listed “risk variant (mild)” mutation as a homozygote.

[0511] GD patients (for exclusion):

[0512] 1. carry a listed “mild” or “severe” mutation as a homozygote, or

[0513] 2. carry a listed “mild” or “severe” mutation as a compound heterozygote.

[0514] Appendix 2: List of LRRK2 mutations (for exclusion from trial)

[0515]

[0516] a. Fulgent Genetics (likely pathogenic / pathogenic). b. National Center for Biotechnology Information.

[0517] References

[0518] The contents of the following documents and any other documents cited elsewhere in the present disclosure are incorporated herein by reference in their entirety.

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[0550]

[0551]

Claims

1. 5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound A), or a pharmaceutically acceptable salt thereof, characterized in that, For use in preventing or limiting clinical motor progression in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD).

2. A method for preventing or limiting the clinical motor progression of a subject carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD), characterized in that, The method comprises administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof.

3. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[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 (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not carrying a PD-associated LRRK2 pathogenic variant.

4. A method for treating or preventing Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not carrying a pathogenic variant in LRRK2 associated with PD (GBA-PD), characterized in that, The method comprises administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof.

5. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[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 (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not having Gaucher disease.

6. A method for treating or preventing Parkinson’s disease in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and not suffering from Gaucher disease (GBA-PD), characterized in that, The method comprises administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof.

7. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[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 (GBA-PD) in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene, who is neither a homozygote for a GBA1 pathogenic variant known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease.

8. A method for treating or preventing Parkinson’s disease in a subject carrying a pathogenic variant of the glucocerebrosidase 1 (GBA1) gene (GBA-PD), which is neither homozygous for a pathogenic variant of GBA1 known to be associated with Gaucher disease, nor a compound heterozygote for two alleles of GBA1 known to be associated with Gaucher disease, characterized in that, The method comprises administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof.

9. A method for preventing or delaying cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD), characterized in that, The method comprises administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof. The method comprises administering to the subject a therapeutically effective amount of 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound A), or a pharmaceutically acceptable salt thereof.

10. 5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound A), or a pharmaceutically acceptable salt thereof, for use in the prevention or delay of cognitive impairment in a subject carrying a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene and having Parkinson’s disease (GBA-PD).

11. A method of treating Parkinson's disease in a subject carrying reduced, decreased or low glucocerebrosidase activity, characterized in that, The method comprises 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)pyrazolo[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 carrying reduced, decreased or low glucocerebrosidase activity.

13. The method of treatment or use of any one of the preceding claims, wherein, Treatment or clinical motor progression 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. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment achieves a prolongation of the time to an increase of >2 points in the MDS-UPDRS Part II score and no improvement (i.e. a score of zero or higher) in the Part III score compared to subjects treated with placebo.

15. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment achieves a prolongation of the time to an increase of >2 points in the MDS-UPDRS Part II score and no improvement (i.e. a difference of zero or higher compared to baseline) in the Part III score compared to subjects treated with placebo.

16. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment achieves a prolongation of the time to an increase of >5 points in the total MDS-UPDRS Part III score compared to subjects treated with placebo.

17. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment achieves a prolongation of the time to an increase of >3 points in the total MDS-UPDRS Part III score compared to subjects treated with placebo.

18. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment achieves a prolongation of the time to an increase of >2 points in the MDS-UPDRS Part II score and is evidenced by an increase of >5 points in the MDS-UPDRS Part III score compared to subjects treated with placebo.

19. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment achieves a delay in the time to occurrence of: i) first levodopa equivalent daily dose increase (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 on the Patient Global Impression-Change (PGI-S) scale.

20. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment results in an improvement in gait speed, or the use or treatment prevents, limits or delays a decrease in gait speed.

21. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment results in an improvement in cerebral blood flow, as measured using arterial spin labeling and / or MRI free water imaging.

22. The method of treatment or use of any one of the preceding claims, The use or treatment results in a decrease in neurofilament light chain concentration.

23. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment prevents or limits deterioration in quality of life.

24. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment results in an improvement in quality of life.

25. The method of treatment or use of any one of the preceding claims, wherein, The glucocerebrosidase activity in the cerebrospinal fluid (CSF) of the subject is thereby at least doubled.

26. The method of treatment or use of any one of the preceding claims, wherein, The subject has been clinically diagnosed with Parkinson’s disease, e.g., GBA-PD.

27. The method of treatment or use of any one of the preceding claims, wherein, The subject has been clinically diagnosed with PD for at least 1 year and no more than 7 years prior to the start of treatment, the subject has a modified Hoehn and Yahr score of < 2.5, and the subject is receiving symptomatic treatment for PD.

28. The method of treatment or use of any one of the preceding claims, wherein, The subject has been diagnosed with Parkinson’s disease and carries reduced, decreased, or low glucocerebrosidase activity.

29. The method of treatment or use of any one of the preceding claims, wherein, Compound A is administered in combination with a therapeutically effective amount of one or more of the following concomitant medications: a dopaminergic agent, a dopamine receptor agonist, a monoamine oxidase B inhibitor, a catechol-O-methyl transferase inhibitor, an N-methyl-D-aspartate receptor antagonist, an adenosine receptor antagonist, and an anticholinergic agent.

30. The method of treatment or use of any one of the preceding claims, wherein, Compound A, or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of a dopaminergic agent.

31. The method of treatment or use according to 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 formulation.

32. The method of treatment or use according to claim 31, wherein, Compound A, or a pharmaceutically acceptable salt thereof, is administered simultaneously with levodopa or a levodopa / DDCI formulation, or is administered sequentially within less than 30 minutes.

33. The method of treatment or use according to claim 32, wherein the compound is administered in combination with a second therapeutic agent. Compound A, or a pharmaceutically acceptable salt thereof, is administered separately from levodopa or a levodopa / DDCI formulation, with at least 30 minutes separation. 34.5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (Compound A), or a pharmaceutically acceptable salt thereof, is characterized for use in preventing or reducing the risk of developing Parkinson’s disease in a subject determined to be at risk for Parkinson’s disease, e.g., a subject not diagnosed with Parkinson’s disease but determined to carry a GBA1 pathogenic variant for PD.

35. A method for preventing or reducing the risk of developing Parkinson’s disease in a subject determined to be at risk of developing Parkinson’s disease, e.g., a subject not diagnosed with Parkinson’s disease but determined to carry a PD-associated GBA1 pathogenic variant, characterized in that, The method comprises administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

36. The method of treatment or use according to claim 34 or 35, wherein, The subject has been determined to carry reduced, decreased, or low glucocerebrosidase activity.

37. The method of treatment or use according to any one of claims 34 to 36, wherein the compound is administered in combination with a second therapeutic agent. The glucocerebrosidase activity in the cerebrospinal fluid (CSF) of the subject is thereby at least doubled.

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

39. The method of treatment or use according to any one of claims 34 to 38, wherein, The use or treatment prevents or delays the onset of Parkinson’s disease.

40. The method of treatment or use of any one of claims 34 to 39, wherein, The use or treatment prevents, limits, or delays deterioration in quality of life.

41. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment comprises administering to the subject Compound A at a dose of about 10 mg to about 60 mg per day.

42. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment comprises administering to the subject Compound A at a dose of about 10 mg per day.

43. The method of treatment or use of any one of the preceding claims, wherein, The use or treatment comprises administering to the subject Compound A at a dose of about 60 mg per day.

44. The method of treatment or use of any one of the preceding claims, wherein, Compound A, or a pharmaceutically acceptable salt thereof, is used or administered to a subject over an extended period of time, e.g., 52 weeks or more.

45. The method of treatment or use of any one of the preceding claims, wherein, Compound A, or a pharmaceutically acceptable salt thereof, is used or administered to a subject at a frequency of once per day.

46. The method of treatment or use of any one of claims 1 to 10 and 13 to 45, wherein, The pathogenic variant of the GBA1 gene is selected from 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_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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