Method for the stratification of a subject with parkinson's disease

Abstract

The present invention provides a method for the stratification of a subject with Parkinson's disease or at risk of developing Parkinson's disease, into genetic subgroups as well as a method of treating or preventing Parkinson's disease in a subject. Methods of conducting or analysing clinical trials in which subjects are stratified into subgroups are also disclosed.

Description

[0001] METHOD

[0002] The present invention concerns a method for the stratification of Parkinson’s disease patients (and subgroups of said patients), methods of treating an individual with Parkinson’s disease based on said stratification, and methods of conducting or analysing the results of a clinical trial for the treatment of Parkinson’s disease based on said stratification.

[0003] Parkinson’s disease (PD) is a neurodegenerative condition currently impacting 10 million patients with a projected increase to 12 million people by 2040, driven primarily by an increasingly aged population (Dorsey et al., 2018). PD is chronic and progressive, with a wide range of features including multiple motor and non-motor symptoms, with varying onset of symptoms and progression rates between affected individuals. Currently there is neither a cure for PD nor treatments proven to slow disease progression despite substantial efforts to identify effective therapeutics.

[0004] PD comprises a significant genetic component with 5-10% of PD patients following a single gene inheritance pattern (monogenic) (Lesage and Brice, 2009), creating an opportunity for targeted therapies to slow progression in these patients. However, such targeted approaches do not currently exist for the >85% of PD patients for whom the disease aetiology is unknown (idiopathic).

[0005] A challenge in identifying the disease biology underpinning idiopathic PD is that PD may represent several different disorders, driven by different biological mechanisms, but which converge on a similar clinical presentation. Individual PD patients may therefore have dysfunction in different biological pathways which are primary drivers of their cell dysfunction and disease (Espay et al., 2017). A diverse range of disease mechanisms have been proposed for PD that include lysosomal dysfunction, synaptic failure, immune activation and neuroinflammation, mitochondrial dysfunction, oxidative stress, impaired autophagy / mitophagy, calcium overload / dysregulation and pathogenic forms of alpha-synuclein (Maiti etal., Transl NeurodegenerQ, 28 (2017)). However, it remains unclear which of these potential disease mechanisms directly or primarily contribute to PD, and just as critically, in which individual patients the affected disease mechanism is present.

[0006] Therefore, the lack of efficacy outcomes in PD disease modification clinical trials may not be solely due to the overall lack of drug efficacy, but instead may reflect that only a subgroup oftrial participants were affected by the disease biology that the drug targeted, resulting in a nonsignificant signal of efficacy across the entire PD population enrolled in the study.

[0007] Previous efforts to identify subtypes have focused on clinical features including, for example tremor dominant (TD) and postural instability and gait disorder (PIGD), as well as age of onset, and motor or cognitive phenotypes. However, these symptom-based approaches have not defined the disease mechanism and have thus far not led to a determination of targets and treatments.

[0008] Amongst the monogenic forms of PD, differing disease biology mechanisms that converge on the clinical symptoms of PD have been identified and include vacuolar protein sorting 35 (VPS35), and parkin (PRKN; PARK2) as well as glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) risk variant carriers.

[0009] Genomic analyses have provided limited insights into the disease biology of PD, both in identifying monogenic forms of the disease but also independent risk signals identified by genome-wide association studies (GWAS) as associated with PD (Nalls et al., 2019). Of the 90 risk signals identified, 38 were novel genome-wide significant Parkinson’s disease variants.

[0010] Previous genomic analysis has predominantly focused on SNP mutations and / or risk variants in specific genes. However, to the inventors’ knowledge, none of these approaches have identified loci which robustly correspond to therapeutic response outcomes.

[0011] Summary of the Invention

[0012] The present invention therefore aims to provide methods that use genomic stratification methods for individuals with Parkinson’s disease that can be used to group patients into subgroups which demonstrate more consistency in terms of responses to specific treatments. By doing so, treatments for PD patients can be tailored to include therapies known to have improved response rates across the subgroups to which they belong, as compared to the PD population as a whole.

[0013] These methods can also be used in the performance of clinical trials, to establish variations in response rates across different PD subgroups and I or to investigate response rates in specific PD subgroups. Additionally, these methods can be used in clinical trial rescue, to retrospectively correlate response rates from a failing or failed clinical trial to specific PDsubgroups with a view to identifying a strong response signal in one or more specific subgroups.

[0014] The methods of the invention may additionally be used to identify PD subgroups which do not exhibit a meaningful response signal to a given therapeutic, and therefore will avoid unnecessary treatments and I or disease progression owing to ineffective treatment.

[0015] The methods of the invention may additionally be used to identify appropriate drug combinations by identifying overlapping PD subgroups responding to different therapies.

[0016] According to a first aspect of the present invention, there is provided a method for the stratification of a subject with Parkinson’s disease or at risk of developing Parkinson’s disease, comprising:

[0017] a) obtaining genetic data from the subject comprising at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,

[0018] b) analysing the first and second chromosomes or the parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present, and

[0019] c) stratifying the subject into one of three subgroups, namely N / N, N / l or l / l.

[0020] As will be demonstrated by the accompanying description and examples herein, the inventors have identified that the inversion haplotype status of chromosome 8 is of predictive value to drug response.

[0021] Thus, according to a further aspect of the present invention, there is provided a method of treating Parkinson’s disease in a subject or preventing Parkinson’s disease in a subject at risk of developing Parkinson’s disease, comprising stratifying the subject into one of the three subgroups as discussed above, and administering a therapeutic to the subject which is efficacious in the prevention or treatment of Parkinson’s disease in patients in the respective subgroup.Additionally, the stratification of Parkinson’s disease patients or subjects at risk of developing Parkinson’s disease into the three subgroups mentioned above can assist with clinical trial performance and analysis which advantageously reduces the risk of a drug failing to show a sufficient signal of efficacy across an unstratified Parkinson’s disease patient cohort when it is effective in one (or possibly two) of the subgroups described herein.

[0022] Thus, according to a further aspect of the present invention, there is provided a method of conducting a clinical trial in which subjects enrolled in the clinical trial are stratified in accordance with the first aspect of the invention, discussed above, and are administered a study drug.

[0023] Additionally, there is also provided a method of analysing the results of an ongoing or completed clinical trial in which the achievement of at least one effect indicative of efficacy of the study drug has been assessed in which the subjects enrolled in the clinical trial are stratified in accordance with the first aspect of the invention, discussed above, and the achievement of the at least one effect indicative of efficacy is assessed for each different subgroup. The stratification may utilise genetic data provided by the subjects prior to, during or following the clinical trial.

[0024] Brief Description of the Drawings

[0025] The invention will now be more particularly described with reference to the following figures, which are not intended to be limiting on the scope of protection provided, in which;

[0026] Figure 1 is a principal component analysis (PCA) plot of the initial discovery of the PD genetic subgroups underlying the stratification methodology of the invention.

[0027] Figure 2 illustrates a Manhattan plot showing the genomic signal driving PD genetic subgroup separation.

[0028] Figure 3 illustrates a schematic diagram of applying genetic subgrouping based on the method of the invention to identify participants in a trial that are more likely to respond to the trial drug.

[0029] Detailed Description of the InventionAs noted above, according to a first aspect of the present invention, there is provided a method for the stratification of a subject with Parkinson’s disease or at risk of developing Parkinson’s disease, comprising:

[0030] a) obtaining genetic data from the subject comprising at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,

[0031] b) analysing the first and second chromosomes or the parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present, and

[0032] c) stratifying the subject into one of three subgroups, namely N / N, N / l or l / l.

[0033] As explained in the accompanying disclosure, the inventors have identified inversion status in chromosome 8 as being particularly useful for stratifying subjects with, or at risk of developing, Parkinson’s disease into subgroups in which subjects are more or less likely to respond to given therapies.

[0034] This advantageously allows individuals, once stratified, to receive treatment which is most likely to result in a clinically positive outcome and to avoid negative outcomes. Without wishing to be bound by theory, it is believed that the molecular mechanisms underlying the chromosome 8 (chr8) inversion haplotype leading stratification of PD patients into the three subgroups are most likely responsible for altered gene expression and / or gene disruption. Therefore, it is suggested that the subgroups defined herein identify distinct genetic and / or molecular subgroups of individuals with PD, and these subgroups will exhibit material differences in response to therapeutic interventions.

[0035] Parkinson’s Disease

[0036] Parkinson's disease is a common neurodegenerative disease neuropathologically characterised by degeneration of heterogeneous populations of neural cells (dopamine-producing cells). The clinical diagnosis of Parkinson's disease requires bradykinesia and at least one of the following core symptoms: resting tremor; muscle rigidity and postural reflex impairment. Other signs and symptoms that may be present or develop during the progression of the disease are autonomic disturbances (sialorrhoea, seborrhoea, constipation, micturitiondisturbances, sexual function disturbances, orthostatic hypotension, hyperhydrosis), sleep disturbances and disturbances in the sense of smell or sense of temperature.

[0037] Other symptoms of PD include depressive symptoms, reduced verbal memory and / or executive functions, impaired attention, impaired working memory, impaired verbal fluency, increased anxiety, cognitive dysfunction, motor complications, motor fluctuations, neuronal loss, Parkinson's disease dementia (PDD), impaired dopaminergic neurotransmission, a loss of dopaminergic cells in the substantia nigra, the degeneration of dopaminergic neurons in the substantia nigra pars compacta, the loss of nerve fibres in the striatum, loss of nigrostriatal dopaminergic neurons, reduced dopamine levels, reduced 3,4-dihydroxyphenylacetic acid (DOPAC) levels, impaired signalling in the central, autonomic and enteric nervous systems, impaired activity of the hypothalamic-pituitary-adrenal (HPA) axis, impaired function of the neuroendocrine and / or neuroimmune pathways, and increased gastrointestinal permeability.

[0038] Each of bradykinesia, the core symptoms of PD and the other symptoms listed herein are considered to be symptoms of PD. A patient at risk of developing PD may exhibit one or more of these symptoms. A patient having PD may exhibit one or more of these symptoms.

[0039] A patient having PD may have prodromal Parkinson’s disease. A patient at risk of developing PD may have prodromal PD.

[0040] In embodiments, therapeutics, e.g. therapeutic interventions or therapeutic compositions which may be employed in aspects of the invention to treat PD may prevent, reduce or alleviate one or more, two or more, three or more, four or more or five or more of the symptoms of PD detailed herein. In specific embodiments, the therapeutic, e.g. therapeutic intervention or composition may prevent, reduce or alleviate one or more of the symptoms of PD detailed herein. In certain embodiments, the therapeutic, e.g. therapeutic intervention or composition may prevent, reduce or alleviate one or more of the core symptoms listed herein. In some embodiments, the therapeutic, e.g. therapeutic intervention or composition may prevent, reduce or alleviate bradykinesia and one or more of the core symptoms listed herein. In preferred embodiments, the therapeutic, e.g. therapeutic intervention or composition may prevent, reduce or alleviate PD progression.

[0041] In embodiments of the invention, a therapeutic, e.g. a therapeutic intervention, composition or agent, a study drug, or a combination thereof may be considered to prevent, reduce or alleviate a symptom of PD if the observed effect on the symptom, test or disease scale is animprovement of about 10% or greater, about 20% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater or about 90% or greater, optionally as compared to baseline.

[0042] Those skilled in the art will be familiar with scales used to grade PD symptoms or disease progression. Examples of such scales include the Unified Parkinson's Disease Rating Scale. In particular, UPDRS II considers the activity of daily life and UPDRS III considers motor examination.

[0043] Further examples of tests or scales include the Hopkins Verbal Learning Test - Revised (HVLT-R); the Delis-Kaplan Executive Function System (D-KEFS) Colour-Word Interference Test; the Hamilton Depression Rating Scale (HAM-D 17; depression); the Hamilton Anxiety Rating Scale (HAM-A; anxiety), and the Clinical Global Impression - Global Improvement (CGI- 1) scale for assessing psychiatric and neurological disorders.

[0044] In embodiments, a patient at risk of developing PD may have progressed over time on one or more of these scales. A patient having PD may have progressed over time on one or more of these scales.

[0045] In some embodiments, the therapeutic, e.g. therapeutic intervention or composition employed in aspects of the invention may improve the symptoms associated with PD according to a symptomatic or diagnostic test and / or scale.

[0046] Those skilled in the art of the diagnosis and treatment of PD will be familiar with biomarkers which are indicative of the presence or progression of that disease, for example serum urate and alpha-synuclein. In embodiments of the invention, reduced serum urate or increased alpha-synuclein may be symptoms of PD or the progression of that disease. Compositions useful in aspects of the invention may be effective to increase serum urate or reduce alpha-synuclein levels.

[0047] The methodology discussed herein may be utilised to stratify patients with Parkinson’s disease or who are at risk of developing Parkinson’s disease. As used herein, a patient with Parkinson’s disease may have been diagnosed with Parkinson’s disease.In other embodiments, the subject may not have been diagnosed with Parkinson’s disease but may exhibit one or more symptoms of Parkinson’s disease as described herein. Such patients can also be considered to be at risk of Parkinson’s disease.

[0048] In certain embodiments of the invention, the subject may have idiopathic Parkinson’s disease.

[0049] In some embodiments, a subject may be at risk of developing Parkinson’s disease, e.g. owing to age, risk factors (such as exposure to environmental causes or head trauma) or hereditary likelihood.

[0050] In some embodiments, the subject may be at least about 40, at least about 50, at least about 60, or at least about 70 years old. In certain embodiments, the subject may have first been diagnosed with Parkinson’s disease at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 1.5 years, at least about 2 years at least about 3 years, at least about 5 years, at least about 10 years or at least about 15 years prior to being stratified according to the method of the present invention.

[0051] Additionally, the subject may be at any stage of the Hoehn & Yahr scale of Parkinson’s disease development. For example, the subject may be at stage 1 or higher, at stage 2 or higher, at stage 3 or higher, at stage 4 or higher or at stage 5.

[0052] The subject may be of any ethnic background, for example, they may be of African, Asian, European, Middle Eastern or North African descent.

[0053] Obtaining Genetic Material

[0054] Genetic data from the subject may be isolated from a bodily sample provided by the subject, including blood, saliva, cells (e.g. cheek cells, skin cells or similar), cerebrospinal fluid, synovial fluid, serous fluid, mucus, urine, lymph or similar. The bodily sample may be collected using conventional means familiar to one skilled in the art. In embodiments of the invention, the collection of the bodily sample is non-invasive. In certain embodiments, the collection of the bodily sample involves a minor intervention and no substantive health risks. In some embodiments of the invention, the stratification method is ex vivo. Advantageously, through the non-invasive collection of genetic data from subjects, the need to conduct invasive biopsies or complex scanning techniques in specialist centres can be avoided.In embodiments in which genetic material is isolated from a bodily sample, this may be achieved using any technique and apparatus known to those skilled in the art. For example, genetic material may be extracted from a bodily sample using chromatography (optionally SEC or I EC), centrifugation, Chelex extraction, phenol-chloroform based extraction, protease mediated extraction, spin-column extraction, magnetic bead-based DNA extraction, anionic resin-based extraction and guanidine thiocyanate extraction.

[0055] In certain embodiments, genetic material may be provided for use in the stratification methodology of the present invention by a third party, e.g. a commercial provider, laboratory, clinic, hospital or the like.

[0056] Inversion Haplotypes

[0057] Inversions are segments of DNA in a chromosome which break off and reattach in the opposite direction. Inversion haplotypes are known in the art. While various chromosomal defects have been linked to chromosome inversions, to the inventors’ knowledge, no link has been made between inversion haplotypes in chromosome 8 and neurodegenerative disorders, particularly PD.

[0058] Chromosome Analysis

[0059] As part of the process of the present invention, the first and second chromosomes from pair 8 (or parts thereof) are analysed. If an inversion haplotype is identified on both chromosomes, then the subject is stratified into the subgroup l / l. If an inversion haplotype is identified on one of the chromosomes but not the other, then the subject is stratified into the subgroup N / l. If no inversion haplotype is identified on either chromosome, the subject is stratified into the N / N subgroup.

[0060] Those skilled in the art will be familiar with techniques that may be employed in the present invention to identify genomic inversions. In some embodiments, the method used to analyse the first and second chromosomes (or parts thereof) may be any technique to identify and map chromosomal inversions, for example G-banding karyotypes, fluorescent in-situ hybridisation (FISH), Southern blot hybridisation, pulsed-field gel electrophoresis or whole genome sequencing e.g. using next-generation sequencing technology. In addition to PCA analysis, clustering algorithms such as K-means can be used to identify inversions in large sets of genetic data.In embodiments of the invention, specific regions of the first and second chromosomes from pair 8 (or parts thereof), for example, the p arms (short arms), the 8p23 regions and I or the 8p23.1 regions are analysed.

[0061] In more detail, in embodiments of the invention, if an inversion haplotype is identified in the p arm (short arm) of both chromosomes, then the subject is stratified into the subgroup l / l. If an inversion haplotype is identified in the p arm (short arm) of one of the chromosomes but not in the p arm (short arm) of the other chromosome, then the subject is stratified into the subgroup N / l. If no inversion haplotype is identified in the p arm (short arm) on either chromosome, the subject is stratified into the N / N group.

[0062] In embodiments of the invention, if an inversion haplotype is identified in the 8p23 region of both chromosomes, then the subject is stratified into the subgroup l / l . If an inversion haplotype is identified in the 8p23 region of one of the chromosomes but not the 8p23 region of the other chromosome, then the subject is stratified into the subgroup N / l. If no inversion haplotype is identified in the 8p23 region on either chromosome, the subject is stratified into the N / N group.

[0063] In embodiments of the invention, if an inversion haplotype is identified in the 8p23.1 region of both chromosomes, then the subject is stratified into the subgroup l / l . If an inversion haplotype is identified in the 8p23.1 region of one of the chromosomes but not the 8p23.1 region of the other chromosome, then the subject is stratified into the subgroup N / l. If no inversion haplotype is identified in the 8p23.1 region on either chromosome, the subject is stratified into the N / N group.

[0064] In embodiments of the invention, the inversion haplotype has a length of about 1Mb to about 10Mb. In some embodiments, the inversion haplotype has a length of about 3Mb to about 7Mb. In certain embodiments, the inversion haplotype has a length of about 4Mb to about 5Mb, for example about 4.5Mb. The inversion haplotype may comprise flanking regions.

[0065] In certain embodiments, at least about 10% of the inversion haplotype in chromosome 8 is located within the region with GRCh38 coordinates chr8:7, 600, 000-12, 100, 000. In some embodiments, at least about 50% of the inversion haplotype in chromosome 8 is located within the region with GRCh38 coordinates chr8:7, 600, 000-12, 100,000. In embodiments, at least about 90% of the inversion haplotype in chromosome 8 is located within the region with GRCh38 coordinates chr8:7, 600, 000-12, 100,000. In certain embodiments, at least about

[0066]

[0067] coordinates chr8:7, 600, 000-12, 100, 000.

[0068] In some embodiments, the inversion haplotype has at least about 70% sequence identity to the chr8p23.1 inversion haplotype [GRCh38: chr8:7, 600, 000-12, 100,000], referenced for example in the University of California Santa Cruz Genomics Institute Genome Browser as https: / / genome-euro.ucsc.edu / cgi- bin / hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType= default&virtMode=0&nonVirtPosition=&position=chr8%3A7600000%2D12100000&hgsid=34 7347329_Ym4UzYQbvd2hOsxJygd196IVbyOs.

[0069] In certain embodiments, the inversion haplotype has at least about 80% sequence identity to the chr8p23.1 inversion haplotype [GRCh38: chr8:7, 600, 000-12, 100,000], In embodiments, the inversion haplotype has at least about 90% sequence identity to the chr8p23.1 inversion haplotype [GRCh38: chr8:7, 600, 000-12, 100,000], In some embodiments, the inversion haplotype has at least about 95% sequence identity to the chr8p23.1 inversion haplotype [GRCh38: chr8:7, 600, 000-12, 100, 000], In certain embodiments, the inversion haplotype has at least about 98% sequence identity to the chr8p23.1 inversion haplotype [GRCh38: chr8:7, 600, 000-12, 100,000],

[0070] The inventors have surprisingly found that the inversion haplotype as a whole rather than a specific feature within it is most relevant to the difference in subgroups identified in the current invention. The inventors analysed databases containing information about both healthy people and people with Parkinson’s disease. Importantly, the databases contained genetic information on each individual in the form of single nucleotide variants (SNPs) in the person’s genome. The difference in SNP pattern between healthy people and people with Parkinson’s disease (called control and case groups respectively) was examined using PCA to reduce the dimensionality of the genetic data. The output of the PCA analysis is a set of principal components which identify the variants which best differentiate cases and controls. The relative contribution of each SNP to the case-control difference is indicated by the loading which is calculated by the PCA algorithm. By plotting the loadings of each SNP, the inventors were able to gain insight into the genetic drivers of Parkinson’s disease. Figure 1 shows an example of this type of plot which shows 3 genetically distinct groups present in both the cases and controls. This was then examined further as described in Example 1. The relevant principal component loadings of the chr8p23.1 stratification signal were plotted to identify any peaks or enriched regions, corresponding to genes or loci, in the reference cohorts. Thisdemonstrated a mostly uniform signal across the inversion region, suggesting the relevance of the inversion haplotype as a whole rather than a specific feature within it. In addition, the recombination rate showed many active recombination hotspots across the region suggesting that multiple genes relevant to Parkinson’s disease within this region could be affected by the inversion haplotype, which could have a propagating effect on different pathways in diverse cell types. Example 1 has a detailed explanation of the methodology used by the inventors.

[0071] The subgroups based on the identified inversion haplotypes may be distinct diplotype subgroups. The subgroups may be based on the overall haplotype inversion. A single subgroup may contain an overall haplotype inversion but contain multiple different mutations and recombination hotspots across the inversion region of the haplotype. The subgroups may be based on a strong stratifying signal corresponding to the inversion diplotypes, rather than 3 distinct haplotype clusters.

[0072] A key step of the stratification method of the present invention is the assessment of whether the chromosome (or region thereof) being considered comprises an inversion haplotype or not. The inversion haplotype as a whole rather than a specific feature within it is used to stratify individuals into subgroups. The identification of inversion haplotypes may comprise determining the orientation of the haplotype region and comparing it to the known orientation at that locus.

[0073] In embodiments of the invention, the step of analysing the first and second chromosomes may be conducted on the full first and second chromosomes of pair 8, or parts thereof. In such embodiments, the parts of the first and I or second chromosome of pair 8 which are analysed may comprise at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% of the full chromosome.

[0074] In embodiments in which the inversion haplotype is located within a specific region of the first and I or second chromosome of chromosome pair 8, only that region or a fragment thereof may be analysed.

[0075] As mentioned above, in embodiments of the invention, chromosome 8 inversion haplotypes could be identified using fluorescent in situ hybridisation (FISH), by long read DNA sequencing, by optical genome mapping, or by using quantitative polymerase chain reaction with multiple primers (multiplexed qPCR).In another embodiment of the invention, the inversion haplotype may be identified from analysis of the single nucleotide polymorphisms (SNPs) in the genetic data. Techniques for such approaches would be familiar to the skilled person and include using computer programs such as ScorelnvHap in the R language. SNPs may be measured from whole genome sequencing of the genetic material or by using a microarray.

[0076] In embodiments of the invention, the genetic data comprises genomic data. The genomic data may comprise whole genome sequencing data. The subgroups may represent diplotype groups. The diplotype groups may represent haplotype pairs on homologous chromosomes.

[0077] Specific methodology regarding the identification of inversion haplotypes in chr8 is described in the accompanying example. Additionally, further guidance regarding the identification of inversion haplotypes in chromosome 8 can be found in Secolin etal., Sci Rep 9, 13900 (2019), the contents of which are incorporated herein by reference. In that paper, the authors postulated a potential link between inversion haplotypes in chr8 and metabolic disorders, primarily diabetes. No mention of neurodegenerative disorders, let alone Parkinson’s disease was made.

[0078] Methods of Treatment

[0079] As explained herein, the subgroups into which patients are stratified according to the method of the present invention correlate to clinical responses to specific therapeutic interventions. Thus, according to the present invention, there is provided a method of treating Parkinson’s disease in a subject or preventing Parkinson’s disease in a subject at risk of developing Parkinson’s disease, comprising:

[0080] a) obtaining genetic data from the subject comprising at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,

[0081] b) analysing the first and second chromosomes or parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,

[0082] c) stratifying the subject into one of three subgroups, namely N / N, N / l or l / l, andd) administering a therapeutic to the subject which is efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the subject has been stratified.

[0083] A therapeutic, e.g. therapeutic intervention, composition or agent or is considered to be efficacious in the treatment of Parkinson’s disease in a given subgroup if it has been demonstrated (e.g. preferably through extensive clinical practice or in a sufficiently powered clinical study, e.g. a phase II or a phase III study) as having a greater therapeutic effect in that subgroup than in a placebo comparator cohort within the same subgroup and I or at least one of the other two subgroups. Those skilled in the art of treating Parkinson’s disease will recognise the provision of a therapeutic effect in the treatment of that condition. Further guidance on the therapeutic effects that may be achieved by compositions employed in this aspect of the invention is provided herein.

[0084] For example, efficacy may be an improvement in or amelioration of one or more of the Parkinson’s disease symptoms described herein (e.g. bradykinesia, one of the core symptoms or one of the other symptoms detailed herein).

[0085] Alternatively, efficacy may be a reduction in disease progression or a reversal of disease progression, (e.g. an improvement, amelioration, prevention, reduction) in one of the symptoms or scales disclosed herein.

[0086] Greater efficacy could be a broader improvement across the subgroup in question as compared to in another subgroup (i.e. administration of the therapeutic resulted in efficacy in a greater proportion of subjects in that subgroup than in subjects in a different subgroup). Additionally or alternatively, greater efficacy could be an improvement of the average magnitude of improvement in the subgroup in question as compared to another subgroup (i.e. on average administration of the therapeutic resulted in a greater magnitude of efficacy, where this is quantifiable, for the subgroup in question than in another subgroup).

[0087] In embodiments of the invention, the therapeutic, e.g. therapeutic intervention, composition or agent administered in step d) above may be efficacious in the treatment of Parkinson’s disease in one of the subgroups. For example, in some embodiments, the therapeutic may be efficacious in the N / N subgroup and optionally not in the N / l and I or the l / l subgroups. In certain embodiments, the therapeutic may be efficacious in the N / l subgroup and optionallynot in the N / N and I or l / l subgroups. In other embodiments, the therapeutic may be efficacious in the l / l subgroup and optionally not in the N / l and / or the N / N subgroups.

[0088] In certain embodiments of the invention, the therapeutic, e.g. therapeutic intervention, composition or agent may be efficacious in the treatment of Parkinson’s disease in two of the subgroups. For example, in some embodiments, the therapeutic may be efficacious in the N / N and the N / l subgroups and optionally not in the l / l subgroup. In other embodiments, the therapeutic may be efficacious in the N / N and the l / l subgroups and optionally not in the N / l subgroup. In certain embodiments, the therapeutic may be efficacious in the N / l and the l / l subgroups and optionally not in the N / N subgroup.

[0089] In certain variant embodiments, step d) does not comprise the administration of a therapeutic to the subject which is efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the subject has been stratified, but instead comprises ceasing administration of a therapeutic to the subject which is not efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the patient has been stratified.

[0090] In some embodiments, the therapeutic may be selected from the following group: levodopa, carbidopa, dopamine agonists (e.g. pramipexole, ropinirole, tavapadon), MAO-B inhibitors (e.g. rasagiline, selegiline), benserazide, COMT inhibitors (e.g. entacapone, opicapone), amantadine, urate increasing agents (e.g. inosine), anticholinergics (e.g. procyclidine, trihexyphenidyl), apomorphine, rotigotine, foscarbidopa / foslevodopa, calcium channel blockers (e.g. isradipine), AMPA receptor antagonists (e.g. perampanel), glucosylceramide synthase inhibitors (e.g. venglustat), mGluR5 antagonists (e.g. mavoglurant), mixed lineage kinase inhibitors (e.g. CEP-1347), Bcr-Abl kinase inhibitors (e.g. vodobatinib), tetracycline antibiotics (e.g. doxycycline), GCase modulators (e.g. ambroxol), LRRK2 inhibitors (e.g. BIIB122), glucocerebrosidase activators, neurotrophic factors (e.g. GDNF and CNTF), alphasynuclein targeting agents, e.g. antibodies such as prasinezumab, and GLP-1 agonists (e.g. exenatide).

[0091] In some embodiments, the therapeutic may be a repurposed therapeutic and / or a therapeutic currently in development. For example, the therapeutic may be selected from the following: ambroxol, cannabidiol, azathioprine, exenatide, rivastigmine, escitalopram, nortriptyline, ursodeoxycholic acid, deferiprone, simvastatin, doxazosin, donepezil, topiramate, celecoxib, memantine, sildenafil, quetiapine, exidavnemab, perampanel, acamprosate, pimavanserin, agomelatine, dalfampridine, aripiprazole, atomoxetine, pitolisant, buspirone, cilostazol,clozapine, dipraglurant, docosahexaenoic acid, fipamezole, istradefylline, talampanel, ketamine, levetiracetam, methylphenidate, minzasolmin, mirtazapine, nabilone, N-acetylcysteine, ondansetron, pardoprunox, foliglurax, clonidine, pridopidine, psilocybin, ropinirole, rotigotine, sargramostim, sarizotan, sumanirole, tozadenant, BIIB122 (DNL151), CDNF, cogane, emrusolmin, GDNF, inosine, lixisenatide, mesdopetam, mevidalen, nelotanserin, nilotinib, NLY01, NPT088, P2B001, prasinezumab, rytary, verdiperstat, or VY-AADC02.

[0092] In such embodiments, the term ‘therapeutic’ is used to describe a therapeutic agent or a therapeutic composition comprising such an agent. However, as used herein, the term ‘therapeutic’ also encompasses therapeutic interventions such as stimulation techniques, e.g. e.g. brain stimulation treatments such as DBS or IR stimulation.

[0093] In some embodiments, the method may comprise administering one or more (e.g. 1, 2, 3, 4 or more than 4) additional therapeutics, e.g, therapeutic interventions, agents and I or compositions to the subject which is I are efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the subject has been stratified. In such embodiments, combination therapies can be employed which are tailored to patients belonging to one of the PD subgroups described therein and thus have an improved likelihood of providing a therapeutic effect. The therapeutic may be administered simultaneously, sequentially or separately from the one or more additional therapeutic.

[0094] Also disclosed are compositions for use in the treatment of Parkinson’s disease and I or in the methods of treatment disclosed above. Further disclosed is the use of an active pharmaceutical ingredient, optionally one disclosed herein, in the manufacture of a medicament to treat Parkinson’s disease and I or for use in the methods of treatment described herein. The active pharmaceutical ingredient may be one as described herein.

[0095] The composition and I or medicament may comprise one or more pharmaceutically acceptable excipients, diluents, carriers and I or fillers.

[0096] The pharmaceutical compositions may be formulated based on the mode of delivery. For example, the compositions may be formulated for systemic administration via parenteral delivery, e.g., by intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or the composition may be formulated for direct delivery into the brain parenchyma, e.g., by infusion into the brain, such as by continuous pump infusion; or thecomposition may be formulated for intrathecal, intraventricular or intrahepatic administration. Alternatively, the compositions may be formulated for oral; topical (e.g., by a transdermal patch); pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal; intranasal; epidermal; or transdermal administration.

[0097] Compositions and formulations for parenteral, intraparenchymal (into the brain), intrathecal, intraventricular or intrahepatic administration may include, but are not limited to, sterile aqueous solutions which can also contain buffers, diluents and other suitable additives such as penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Compositions and formulations for oral administration may include, but are not limited to, powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets.

[0098] Thickeners, flavouring agents, diluents, emulsifiers, dispersing aids or binders may also be used.

[0099] Pharmaceutical compositions and formulations for topical administration may include, but are not limited to, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Pharmaceutical compositions of the present invention may also include, but are not limited to, solutions, emulsions, and liposome-containing formulations. The compositions may be formulated into various forms including, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas.

[0100] The therapeutic agent, intervention, composition or medicament may be administered to a subject using any mode of administration known in the art, including, but not limited to subcutaneous, intravenous, intramuscular, intraocular, intrabronchial, intrapleural, intraperitoneal, intraarterial, lymphatic, cerebrospinal, and any combinations thereof. In preferred embodiments, the agent is administered subcutaneously.

[0101] In some embodiments, the administration is via a depot injection. Depot injections may include subcutaneous injections or intramuscular injections. In certain embodiments, the depot injection is a subcutaneous injection.

[0102] In some embodiments, the administration is via a pump. The pump may be an external pump or a surgically implanted pump. In certain embodiments, the pump is a subcutaneously implanted osmotic pump. In other embodiments, the pump is an infusion pump. An infusionpump may be used for intravenous, subcutaneous, arterial, or epidural infusions. In certain embodiments, the infusion pump is a subcutaneous infusion pump. In other embodiments, the pump is a surgically implanted pump that delivers the therapeutic agent, composition or medicament to the liver.

[0103] The therapeutic agent, intervention, composition or medicament may be administered to a subject as a fixed dose. A "fixed dose" (e.g., a dose in mg) is a dose that is used for all subjects regardless of any specific subject- related factors, such as weight. Alternatively, the therapeutic agent, intervention, composition or medicament may be administered to a subject as a weightbased dose (e.g., a dose in mg / kg), which is a dose of the therapeutic agent, intervention, composition or medicament that will change depending on the subject's weight. In embodiments in which a subject receives multiple doses, the therapeutic agent, intervention, composition or medicament may be administered as a combination of fixed doses and weightbased doses.

[0104] In certain embodiments, a therapeutic agent, composition or medicament is administered to the subject as a fixed dose of about 50 mg to about 800 mg, about 100 mg to about 800 mg, about 150 mg to about 800 mg, about 200 mg to about 800 mg, about 250 mg to about 800 mg, about 300 mg to about 800 mg, about 350 mg to about 800 mg, about 400 mg to about 800 mg, about 450 mg to about 800 mg, about 500 mg to about 800 mg, about 550 mg to about 800 mg, about 600 mg to about 800 mg, about 650 mg to about 800 mg, about 700 mg to about 800 mg, about 750 mg to about 800 mg, about 50 mg to about 750 mg, about 100 mg to about 750 mg, about 150 mg to about 750 mg, about 200 mg to about 750 mg, about 250 mg to about 750 mg, about 300 mg to about 750 mg, about 350 mg to about 750 mg, about 400 mg to about 750 mg, about 450 mg to about 750 mg, about 500 mg to about 750 mg, about 550 mg to about 750 mg, about 600 mg to about 750 mg, about 650 mg to about 750 mg, about 700 mg to about 750 mg, about 50 mg to about 700 mg, about 100 mg to about 700 mg, about 150 mg to about 700 mg, about 200 mg to about 700 mg, about 250 mg to about 700 mg, about 300 mg to about 700 mg, about 350 mg to about 700 mg, about 400 mg to about 700 mg, about 450 mg to about 700 mg, about 500 mg to about 700 mg, about 550 mg to about 700 mg, about 600 mg to about 700 mg, about 650 mg to about 700 mg, about 50 mg to about 650 mg, about 100 mg to about 650 mg, about 150 mg to about 650 mg, about 200 mg to about 650 mg, about 250 mg to about 650 mg, about 300 mg to about 650 mg, about 350 mg to about 650 mg, about 400 mg to about 650 mg, about 450 mg to about 650 mg, about 500 mg to about 650 mg, about 550 mg to about 650 mg, about 600 mg to about 650 mg, about 50 mg to about 600 mg, about 100 mg to about 600 mg, about 150 mg to about600 mg, about 200 mg to about 600 mg, about 250 mg to about 600 mg, about 300 mg to about 600 mg, about 350 mg to about 600 mg, about 400 mg to about 600 mg, about 450 mg to about 600 mg, about 500 mg to about 600 mg, about 550 mg to about 600 mg, about 50 mg to about 550 mg, about 100 mg to about 550 mg, about 150 mg to about 550 mg, about 200 mg to about 550 mg, about 250 mg to about 550 mg, about 300 mg to about 550 mg, about 350 mg to about 550 mg, about 400 mg to about 550 mg, about 450 mg to about 550 mg, about 500 mg to about 550 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, about 450 mg to about 500 mg, about 50 mg to about 450 mg, about 100 mg to about 450 mg, about 150 mg to about 450 mg, about 200 mg to about 450 mg, about 250 mg to about 450 mg, about 300 mg to about 450 mg, about 350 mg to about 450 mg, about 400 mg to about 450 mg, about 50 mg to about 400 mg, about 100 mg to about 400 mg, about 150 mg to about 400 mg, about 200 mg to about 400 mg, about 250 mg to about 400 mg, about 300 mg to about 400 mg, about 350 mg to about 400 mg, about 50 mg to about 350 mg, about 100 mg to about 350 mg, about 150 mg to about 350 mg, about 200 mg to about 350 mg, about 250 mg to about 350 mg, about 300 mg to about 350 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 150 mg to about 300 mg, about 200 mg to about 300 mg, or about 250 mg to about 300 mg, e.g., a fixed dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg.

[0105] Values and ranges intermediate to the foregoing recited values are also intended to be part of this invention.

[0106] The therapeutic agent, composition or medicament may be administered as multiple doses that repeat, for example, at regular intervals. For instance, the therapeutic agent, composition or medicament may be administered to the subject at an interval of about one day, about two days, about three days, about four days, about five days, about six days, about a week, about two weeks, about three weeks, about four weeks, about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about 11 months, about 12 months, about one year, about 13 months, about 14 months, about 15 months, about 16 months, about17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, or longer, e.g., chronic administration. In certain embodiments, the fixed dose may be administered to the subject one or more times per year, i.e. , twice, three times, four times, five times, six times, seven times, eight times, nine times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, or more often. In some embodiments, the fixed dose may be administered to the subject once every about four weeks, every about five weeks, every about six weeks, every about seven weeks, every about eight weeks, every about nine weeks, every about 10 weeks, every about 11 weeks, every about 12 weeks, every about 13 weeks, every about 14 weeks, every about 15 weeks, every about 16 weeks, every about 17 weeks, every about 18 weeks, every about 19 weeks, every about 20 weeks, every about 22 weeks, every about 24 weeks, every about 26 weeks, every about 28 weeks, every about 30 weeks, every about 32 weeks, every about 34 weeks, every about 36 weeks, every about 38 weeks, every about 40 weeks, every about 42 weeks, every about 44 weeks, every about 46 weeks, every about 48 weeks, every about 50 weeks, every about 52 weeks, or longer. In certain embodiments, the fixed dose may be administered to the subject once per day, once per about two days, once per about three days, once per about four days, once per about five days, once per about six days, once per about seven days, once per about eight days, once per about nine days, once per about 10 days, once per about 11 days, once per about 12 days, once per about 13 days, once per about 14 days, once per about 15 days, once per about 16 days, once per about 17 days, once per about 18 days, once per about 19 days, once per about 20 days, once per about 30 days, once per about 40 days, once per about 50 days, once per about 60 days, once per about 70 days, once per about 80 days, once per about 90 days, once per about 100 days, once per about 110 days, once per about 120 days, once per about 130 days, once per about 140 days, once per about 150 days, once per about 160 days, once per about 170 days, once per about 180 days, once per about 190 days, once per about 200 days, once per about 210 days, once per about 220 days, once per about 230 days, once per about 240 days, once per about 250 days, once per about 260 days, once per about 270 days, once per about 280 days, once per about 290 days, once per about 300 days, once per about 310 days, once per about 320 days, once per about 330 days, once per about 340 days, once per about 350 days, once per about 360 days, once per about 365 days, or longer.

[0107] Identification of Combination TherapyAs noted above, in embodiments of the invention, combination therapies of therapeutics, e.g. therapeutic agents, compositions and I or interventions efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the subject has been stratified can be used. The stratification methodology of the present invention advantageously also allows combination therapies to be identified. Thus, according to a further aspect of the present invention, there is provided a method of identifying a combination therapy for treating Parkinson’s disease in a subject or preventing Parkinson’s disease in a subject at risk of developing Parkinson’s disease, comprising:

[0108] a) obtaining genetic data from the subject comprising at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,

[0109] b) analysing the first and second chromosomes or parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,

[0110] c) stratifying the subject into one of three subgroups, namely N / N, N / l or l / l, and

[0111] d) identifying a combination of therapeutics which combination is efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the subject has been stratified.

[0112] In embodiments, the therapeutic agents comprised in the combination may be any of the therapeutic agents, compositions or interventions disclosed herein.

[0113] In some embodiments of the invention, the method may further comprise the step of administering the combination of therapeutics to the subject.

[0114] Clinical Trial Design

[0115] As mentioned herein, and as demonstrated in the accompanying examples, the inventors have found that response rates in different subgroups, such as those described herein, may vary when an effective PD stratification methodology is applied. In order to determine whether this is the case, or whether a candidate therapy has a broader effect, i.e. across two or all threesubgroups, it would be advantageous to investigate efficacy of a candidate drug in each of the subgroups described herein.

[0116] Thus, according to a further aspect of the present invention, there is provided a method of conducting a clinical trial in a cohort of subjects diagnosed with PD or exhibiting one or more symptoms of PD comprising:

[0117] a) obtaining genetic data from the cohort of subjects comprising, for each subject in the cohort, at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,

[0118] b) analysing the first and second chromosomes or parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,

[0119] c) stratifying each subject in the cohort into one of three subgroups, namely N / N, N / l or l / l, and

[0120] d) administering the subject a study drug.

[0121] An assessment of the achievement of one or more effects indicative of efficacy may be part of the clinical trial. Thus, in embodiments of the invention, the process may comprise the step of assessing whether an effect indicative of efficacy has been met. The effect indicative of efficacy may comprise any of those discussed herein, in connection with this aspect of the invention or any other. For example, the effect indicative of efficacy may comprise one or more changes (e.g. the improvement, amelioration, prevention, reduction) in one of the symptoms or scales disclosed herein. For example, in embodiments, the effect indicative of efficacy may comprise one or more changes in MDS-UPDRS l-lll scores, the rate of change in the total MDS-UPDRS l-lll score, the time to initiation of anti-Parkinson’s disease therapy (e.g. dopaminergic therapy), mean change in cLED (cumulative Levodopa Equivalent Dose), or the dose required to treat one or more symptoms of Parkinson’s disease as described herein and I or reduce or reverse disease progression. In embodiments, the effect indicative of efficacy may comprise one or more changes in a biomarker indicative of PD or PD progression, for example alpha-synuclein or serum urate.In embodiments of the invention, the cohort comprise a plurality of subjects, for example at least about 10 subjects, at least about 20 subjects, at least about 50 subjects, at least about 100 subjects, at least about 200 subjects, at least about 500 subjects or at least about 1000 subjects. In such embodiments, at least about 3 subjects, at least about 5 subjects, at least about 10 subjects, at least about 20 subjects, at least about 50 subjects, at least about 100 subjects, at least about 200 subjects, or at least about 500 subjects will be stratified into each of the three subgroups. In some embodiments, the clinical trial is a phase I clinical trial, a phase II clinical trial or a phase III clinical trial.

[0122] In such embodiments, where the process of this aspect of the invention is performed on a cohort of subjects such that multiple subjects are stratified into each of the three subgroups, this permits a comparison to be made of the achievement of the effect indicative of efficacy between the three subgroups. Thus, in embodiments of this aspect of the invention, the method may additionally comprise performing an assessment as to the mean achievement of the effect indicative of efficacy for one, two, or more preferably all three of the subgroups. In embodiments in which an assessment is made on the mean achievement of the effect indicative of efficacy in each of the three subgroups, the method may further comprise the step of comparing the mean achievement of the effect for all three subgroups and optionally identifying the subgroup for which the achievement of the effect indicative of efficacy was greatest. This will allow an assessment to be made as to whether the study drug has a greater impact on the effect indicative of efficacy to a greater extent (e.g. whether the study drug is efficacious I has a greater therapeutic effect) in one subgroup as compared to the other two subgroups.

[0123] In embodiments of the invention, the clinical trial may be blinded (e.g. double blinded) and I or placebo controlled. In embodiments in which the clinical trial is placebo controlled, i.e. such that a proportion of the cohort of subjects was administered a placebo rather than the study drug, the process may further comprise identifying the subjects in each subgroup that were administered placebo or the study drug. In such embodiments, the method may additionally comprise discounting the subjects administered placebo from the assessment of the mean achievement of the effect indicative of efficacy for each subgroup. In certain embodiments, the method may comprise comparing the mean achievement of the effect indicative of efficacy for subjects administered the study drug to the mean achievement of the effect indicative of efficacy for subjects administered placebo.Preferably, clinical trials will be sufficiently powered to perform statistically significant analysis of the subgroup data. However, in embodiments, the clinical trial may not be sufficiently powered for subgroup analysis and alternative measures may be used for example, the assessment of effect sizes including Hazard Ratios, 95% Confidence Intervals, or other trends in the data.

[0124] In embodiments of the invention, the clinical trial may comprise the step of assessing the achievement of a plurality of effects indicative of efficacy. In certain embodiments, the clinical trial may comprise the step of assessing the achievement of one or more effects indicative of safety. One, some or all of these effects may be primary endpoints and optionally secondary endpoints. The effects may comprise composite endpoints.

[0125] The assessment of whether an effect indicative of efficacy has been achieved for a given subject will depend on the effect in question. The skilled person will be familiar with assessing the positive achievement of effects indicative of efficacy in PD treatment, e.g. a reduction in one or more of the symptoms described herein. Further, the skilled person will be familiar with determining the mean achievement of the effect indicative of efficacy for subgroups of patients and the statistical techniques and approaches for doing so, for example using intention to treat (ITT) analysis, per-protocol analysis, survival analysis, multivariable regression analysis, subgroup analysis, Bayesian methods and I or meta-analysis.

[0126] An effect indicative of efficacy in the treatment of PD may be observed where administration of the study drug results in an improvement of one of the symptoms, tests or disease scales disclosed herein of about 10% or greater, about 20% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater or about 90% or greater, optionally as compared to baseline or a placebo-treated group.

[0127] In embodiments of the invention, the subject may be stratified (i.e. via steps a) to c) of the process of this aspect of the invention) prior to administration of the study drug (i.e. step d)). Alternatively, the study drug may be administered prior to stratification of the subject.

[0128] Identifying if the treatment results in positive, neutral or negative outcomes for each subgroup may be based on an overall outcome determined from the one or more treatment measures employed. This may be a statistically significant outcome or may be a trend, e.g. if the number of subjects in the trial was not originally powered for subgroup analysis.The method of this aspect of the invention may further comprise ceasing administering the study drug for subjects in a subgroup showing neutral or negative responses to the study drug, e.g. a lack of efficacy, acceleration of disease progression, increased frequency of adverse events or similar.

[0129] Clinical Trial Analysis

[0130] A further beneficial application of the stratification methodology of the present invention is that it permits the stratification of subjects into subgroups which subgroups may have differing responses to study drugs. Thus, stratification may permit a signal of efficacy to be identified in a certain subgroup of Parkinson’s disease patients which otherwise would have been unnoticed, or not statistically significant, across an unstratified cohort of Parkinson’s disease patients.

[0131] Accordingly, there is provided a method of analysing the results of an ongoing or completed clinical trial in which the achievement of an effect indicative of efficacy of a study drug in a cohort of subjects diagnosed with PD or exhibiting one or more symptoms of PD has been assessed comprising:

[0132] a) obtaining genetic data from the cohort of subjects enrolled in the clinical trial comprising, for each subject in the cohort, at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,

[0133] b) analysing the first and second chromosomes to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,

[0134] c) stratifying each subject into one of three subgroups, namely N / N, N / l or l / l, and

[0135] d) identifying whether each subject achieved the effect indicative of efficacy in PD following administration of the study drug.

[0136] In step a), genetic data for the cohort of subjects may be obtained from a pre-existing data source, e.g. data storage means and / or from the sponsor of the clinical trial in the event thatgenetic data was collected upon or following enrolment of the subjects into the clinical trial. Alternatively, in step a), genetic data may be obtained, e.g. from the cohort of subjects (directly, e.g. via samples obtained from the subjects, or via an intermediary) during their engagement in the clinical trial or following completion of the clinical trial.

[0137] In some embodiments, steps a) to c) may be conducted during engagement of the subject in the clinical trial or following their completion in the clinical trial.

[0138] Analysis step b) and I or stratification step c) of this aspect of the invention may be carried out as described herein in connection with corresponding steps of other aspects of the invention.

[0139] In embodiments of this aspect of the present invention, the effect indicative of efficacy may be any of those discussed herein, in connection with this aspect of the invention or any other. For example, the effect indicative of efficacy may comprise one or more changes (e.g. the improvement, amelioration, prevention, reduction) in MDS-UPDRS l-lll scores, the rate of change in the total MDS-UPDRS l-lll score, the time to initiation of anti-Parkinson’s disease therapy (e.g. dopaminergic therapy), mean change in cLED (cumulative Levodopa Equivalent Dose), or the dose required to treat one or more symptoms of Parkinson’s disease as described herein and I or reduce or reverse disease progression. In embodiments, the effect indicative of efficacy may comprise one or more changes in a biomarker indicative of PD or PD progression, for example alpha-synuclein or serum urate.

[0140] An effect indicative of efficacy in the treatment of PD may be observed where administration of the study drug results in an improvement of one of the symptoms, tests or disease scales disclosed herein of about 10% or greater, about 20% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater or about 90% or greater, optionally as compared to baseline or a placebo-treated group.

[0141] As used herein, a completed clinical trial may be one which has reached primary completion, in which all patients enrolled in the clinical trial have been dosed with the study drug, which has been terminated early (e.g. as a result of a lack of clinical benefit being observed) or ended for any other reason.

[0142] In embodiments of the invention, cohort of subjects comprises a plurality of subjects. In certain embodiments, the cohort of subjects may comprise at least about 10 subjects, at least about20 subjects, at least about 50 subjects, at least about 100 subjects, at least about 200 subjects, at least about 500 subjects or at least about 1000 subjects. In some embodiments, the clinical trial is a phase I clinical trial, a phase II clinical trial or a phase III clinical trial.

[0143] In some embodiments, at least about 3 subjects, at least about 5 subjects, at least about 10 subjects, at least about 20 subjects, at least about 50 subjects, at least about 100 subjects, at least about 200 subjects, or at least about 500 subjects will be stratified into each of the three subgroups.

[0144] Preferably, the clinical trials will be sufficiently powered to perform statistically significant analysis of the subgroup data. However, in embodiments, the clinical trial may not be sufficiently powered for subgroup analysis and alternative measures may be used for example, the assessment of effect sizes including Hazard Ratios, 95% Confidence Intervals, or other trends in the data.

[0145] In such embodiments, where the process of this aspect of the invention is performed on a cohort of subjects such that multiple subjects are stratified into each of the three subgroups, this permits a comparison to be made of the achievement of the effect indicative of efficacy between the three subgroups. Thus, in embodiments of this aspect of the invention, the method may additionally comprise performing an assessment as to the mean achievement of the effect indicative of efficacy for one, two, or more preferably all three of the subgroups. In embodiments in which an assessment is made on the mean achievement of the effect indicative of efficacy in each of the three subgroups, the method may further comprise the step of comparing the mean achievement of the effect for all three subgroups and optionally identifying the subgroup for which the achievement of the effect indicative of efficacy was greatest. This will allow an assessment to be made as to whether the study drug has a greater impact on the effect indicative of efficacy to a greater extent (e.g. whether the study drug is efficacious I has a greater therapeutic effect) in one subgroup as compared to the other two subgroups.

[0146] In embodiments of the invention, the clinical trial may be blinded (e.g. double blinded) and I or placebo controlled. In embodiments in which the clinical trial is placebo controlled, i.e. such that a proportion of the cohort of subjects was administered a placebo rather than the study drug, the process may further comprise identifying the subjects in each subgroup that were administered placebo or the study drug. In such embodiments, the method may additionally comprise discounting the subjects administered placebo from the assessment of the mean

[0147] T1achievement of the effect indicative of efficacy for each subgroup. In certain embodiments, the method may comprise comparing the mean achievement of the effect indicative of efficacy for subjects administered the study drug to the mean achievement of the effect indicative of efficacy for subjects administered placebo.

[0148] In embodiments of the invention, the clinical trial may comprise the step of assessing the achievement of a plurality of effects indicative of efficacy. In certain embodiments, the clinical trial may comprise the step of assessing the achievement of one or more effects indicative of safety. One, some or all of these effects may be primary endpoints and optionally secondary endpoints. The effects may comprise composite endpoints.

[0149] The identification of whether an effect indicative of efficacy has been achieved for a given subject will depend on the effect in question. The skilled person will be familiar with assessing the positive achievement of effects indicative of efficacy in PD treatment, e.g. a reduction in one or more of the symptoms described herein. Further, the skilled person will be familiar with determining the mean achievement of the effect indicative of efficacy for subgroups of patients and the statistical techniques and approaches for doing so, for example using intention to treat (ITT) analysis, per-protocol analysis, survival analysis, multivariable regression analysis, subgroup analysis, Bayesian methods and I or meta-analysis.

[0150] Identifying if the treatment results in positive, neutral or negative outcomes for each subgroup on the achievement of the effect indicative of efficacy may be based on an overall outcome determined from the study drug administered. This may be a statistically significant outcome or may be a trend, e.g. if the number of subjects in the trial was not originally powered for subgroup analysis.

[0151] In the event that the clinical trial is still ongoing, the method of this aspect of the invention may further comprise ceasing administering the study drug for subjects in a subgroup showing neutral or negative responses to the study drug, e.g. a lack of efficacy, acceleration of disease progression, increased frequency of adverse events or similar.

[0152] Any of the features discussed above in relation to one of the aspects of the present invention can equally apply to the other aspects of the present invention.

[0153] Computer System and Program ProductThe stratification approaches disclosed herein can be implemented as a computer system and / or a computer program product that comprises a computer program mechanism embedded in a computer readable storage medium.

[0154] Further, any of the methods of the present invention can be implemented in one or more computers or computer systems. Further still, any of the methods of the present invention can be implemented in one or more computer program products. Some embodiments of the present invention provide a computer system or a computer program product that encodes or has instructions for performing any or all of the methods disclosed herein. Such methods / instructions can be stored on a CD-ROM, DVD, magnetic disk storage product, electronically erasable programmable read-only memory (EEPROM), or any other computer readable data or program storage product. Such methods can also be embedded in permanent storage, such as ROM, one or more programmable chips, or one or more application specific integrated circuits (ASICs). Such permanent storage can be localized in a server, 802.11 access point, 802.11 wireless bridge / station, repeater, router, mobile phone, or other electronic devices. Such methods encoded in the computer program product can also be distributed electronically, via the Internet or otherwise, by transmission of a computer data signal (in which the software modules are embedded) either digitally or on a carrier wave.

[0155] Some embodiments of the present invention provide a computer system or a computer program product that contains any or all of the program modules as disclosed herein. These program modules can be stored on a CD-ROM, DVD, magnetic disk storage product, EEPROM, or any other computer readable data or program storage product. The program modules can also be embedded in permanent storage, such as ROM, one or more programmable chips, or one or more application specific integrated circuits (ASICs). Such permanent storage can be localized in a server, 802.11 access point, 802.11 wireless bridge / station, repeater, router, mobile phone, or other electronic devices. The software modules in the computer program product can also be distributed electronically, via the Internet or otherwise, by transmission of a computer data signal (in which the software modules are embedded) either digitally or on a carrier wave.

[0156] In some embodiments, the method disclosed herein can be implemented in a networked device selected from the group consisting of a desktop computer, a laptop computer, a cellular phone, a personal digital assistant (PDA), an iPod, a tablet, a mobile device equipped with a network device, a smart phone, a pager, a television, a media player, a digital video recorder (DVR), and any other networked devices.Definitions

[0157] Administration: As used herein, the term “administration” typically refers to the administration of a composition to a subject or system, for example to achieve delivery of an agent that is, or is included in or otherwise delivered by, the composition.

[0158] Agent: As used herein, the term “agent” refers to an entity (e.g., a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or complex, combination, mixture or system [e.g., cell, tissue, organism] thereof).

[0159] Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance, e.g., by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.

[0160] Antagonist: As used herein, the term “antagonist” may refer to an agent, or condition whose presence, level, degree, type, or form is associated with a decreased level or activity of a target. An antagonist may include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that shows the relevant inhibitory activity. In some embodiments, an antagonist may be a “direct antagonist” in that it binds directly to its target; in some embodiments, an antagonist may be an “indirect antagonist” in that it exerts its influence by means other than binding directly to its target; e.g., by interacting with a regulator of the target, so that the level or activity of the target is altered. In some embodiments, an “antagonist” may be referred to as an “inhibitor”.

[0161] Antibody: As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, intact antibodies as produced in nature are approximately 150kD tetrameric agents comprised of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure. Each heavy chain is comprised of at least four domains (each about 110 amino acids long) — an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CH1, CH2, and the carboxy-terminal CH3 (located at the base of the Y's stem). A short region, known as the “switch”, connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody. Each light chain is comprised of two domains — an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. Intact antibody tetramers are comprised of two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another, so that the dimers are connected to one another and the tetramer is formed. Naturally produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as “complement determining regions” (CDR1, CDR2, and CDR3) and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. The Fc region of naturally occurring antibodies binds to elements of the complement system, and also to receptors on effector cells, including for example effector cells that mediate cytotoxicity. As is known in the art, affinity and / or other binding attributes of Fc regions for Fc receptors can be modulated through glycosylation or other modification. In some embodiments, antibodies produced and / or utilized in accordance with the present invention include glycosylated Fc domains, including Fc domains with modified or engineered such glycosylation. For purposes of the present invention, in certain embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and / or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen), or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. Insome embodiments, an antibody has constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, antibody sequence elements are humanized, primatized, chimeric, etc, as is known in the art. Moreover, the term “antibody” as used herein, can refer in appropriate embodiments (unless otherwise stated or clear from context) to any of the art-known or developed constructs or formats for utilizing antibody structural and functional features in alternative presentation. For example, embodiments, an antibody utilized in accordance with the present invention is in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi- or multi-specific antibodies (e.g., Zybodies®, etc); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); Small Modular ImmunoPharmaceuticals (“SMIPs™”); single chain or Tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTE®s; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-like antibodies; Adnectins®; Affilins®; Trans-Bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®; and KALBITOR®s. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload [e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc], or other pendant group [e.g., poly-ethylene glycol, etc.]).

[0162] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cellcontaining body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; faeces; lymph; gynaecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or bronchoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; faeces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, faeces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0163] Combination Therapy: As used herein, the term “combination therapy” refers to a clinical intervention in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g. two or more therapeutic agents, compositions and I or interventions). In some embodiments, the two or more therapeutic regimens may be administered simultaneously. In some embodiments, the two or more therapeutic regimens may be administered sequentially (e.g., a first regimen administered prior to administration of any doses of a second regimen). In some embodiments, the two or more therapeutic regimens are administered in overlapping dosing regimens. In some embodiments, administration of combination therapy may involve administration of one or more therapeutic agents or modalities to a subject receiving the other agent(s) or modality. In some embodiments, combination therapy does not necessarily require that individual agents be administered together in a single composition (or even necessarilyat the same time). In some embodiments, two or more therapeutics, e.g. therapeutic agents compositions or interventions of a combination therapy are administered to a subject separately, e.g., in separate compositions, via separate administration routes (e.g., one agent orally and another agent intravenously), and / or at different time points. In some embodiments, two or more therapeutics may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity), via the same administration route, and / or at the same time.

[0164] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0165] Corresponding to: As used herein, the phrase “corresponding to” refers to a relationship between two entities, events, or phenomena that share sufficient features to be reasonably comparable such that “corresponding” attributes are apparent. For example, in some embodiments, the term may be used in reference to a compound or composition, to designate the position and / or identity of a structural element in the compound or composition through comparison with an appropriate reference compound or composition. For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid “corresponding to” a residue at position 190, for example, need not actually be the 190th amino acid in a particular amino acid chain but rather corresponds to the residue found at 190 in thereference polypeptide; those of ordinary skill in the art readily appreciate how to identify “corresponding” amino acids. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE that can be utilized, for example, to identify “corresponding” residues in polypeptides and / or nucleic acids in accordance with the present disclosure.

[0166] Dosing regimen: As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e. , is a therapeutic dosing regimen).

[0167] Improved, increased or reduced: As used herein, the terms “improved,” “increased,” or “reduced,”, or grammatically comparable comparative terms thereof, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be “improved” relative to that obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest inpresence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.).

[0168] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amounts appropriate for administration in a therapeutic regimen to a relevant subject (e.g., in amounts that have been demonstrated to show a statistically significant probability of achieving a predetermined therapeutic effect when administered), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0169] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0170] Preventing: As used herein, the term “preventing” or “prevention” includes impeding or preventing an underlying mechanism of Parkinson’s disease or one or more symptoms thereof, delaying the onset of Parkinson’s disease or one or more symptoms thereof, or reducing or preventing progression of Parkinson’s disease or one or more symptoms thereof.

[0171] Reference: As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterizedunder comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0172] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” refers to an amount of a substance (e.g., a therapeutic agent, composition, intervention and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance or intervention is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0173] Variant: As used herein, the term “variant” refers to an entity that shows significant structural identity with a reference entity but differs structurally from the reference entity in the presence or level of one or more chemical moieties as compared with the reference entity. In many embodiments, a variant also differs functionally from its reference entity. In general, whether a particular entity is properly considered to be a “variant” of a reference entity is based on its degree of structural identity with the reference entity. As will be appreciated by those skilled in the art, any biological or chemical reference entity has certain characteristic structural elements. A variant, by definition, is a distinct chemical entity that shares one or more such characteristic structural elements. To give but a few examples, a small molecule may have a characteristic core structural element (e.g., a macrocycle core) and / or one or more characteristic pendent moieties so that a variant of the small molecule is one that shares the core structural element and the characteristic pendent moieties but differs in other pendent moieties and / or in types of bonds present (single vs double, E vs Z, etc.) within the core, a polypeptide may have a characteristic sequence element comprised of a plurality of amino acids having designated positions relative to one another in linear or three-dimensional space and / or contributing to a particular biological function, a nucleic acid may have a characteristicsequence element comprised of a plurality of nucleotide residues having designated positions relative to on another in linear or three-dimensional space. For example, a variant polypeptide may differ from a reference polypeptide as a result of one or more differences in amino acid sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, etc.) covalently attached to the polypeptide backbone. In some embodiments, a variant polypeptide shows an overall sequence identity with a reference polypeptide that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. Alternatively or additionally, in some embodiments, a variant polypeptide does not share at least one characteristic sequence element with a reference polypeptide. In some embodiments, the reference polypeptide has one or more biological activities. In some embodiments, a variant polypeptide shares one or more of the biological activities of the reference polypeptide. In some embodiments, a variant polypeptide lacks one or more of the biological activities of the reference polypeptide. In some embodiments, a variant polypeptide shows a reduced level of one or more biological activities as compared with the reference polypeptide. In many embodiments, a polypeptide of interest is considered to be a “variant” of a parent or reference polypeptide if the polypeptide of interest has an amino acid sequence that is identical to that of the parent but for a small number of sequence alterations at particular positions. Typically, fewer than 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% of the residues in the variant are substituted as compared with the parent. In some embodiments, a variant has 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 substituted residue as compared with a parent. Often, a variant has a very small number (e.g., fewer than 5, 4, 3, 2, or 1) number of substituted functional residues (i.e., residues that participate in a particular biological activity). Furthermore, a variant typically has not more than 5, 4, 3, 2, or 1 additions or deletions, and often has no additions or deletions, as compared with the parent. Moreover, any additions or deletions are typically fewer than about 25, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and commonly are fewer than about 5, about 4, about 3, or about 2 residues. In some embodiments, the parent or reference polypeptide is one found in nature.

[0174] The invention will now be more particularly described with reference to the following examples.

[0175] Example 1 - Identification of Stratification Signature for PD Subgroups

[0176] Genetic data and subject metadata were downloaded from EGA (PD-LIK, study ID EGAD00000000057, request ID 12097) and dbGaP (PD-USA, dataset phs001172.v1.p2, project #11139). The PD-LIK cohort comprised 2197 subjects from the Wellcome Trust CaseControl Consortium (WTCCC2) PD cohort and 3000 subjects from the matched National Blood Service (NBS) controls (Wellcome Trust Case Control Consortium, 2007). The PD-LISA cohort combined 2 phases of the National Institute of Neurological Disorders and Stroke (NINDS) PD cohort and neurologically normal controls (Fung et al., 2006) consisting of 929 PD cases and 798 controls.

[0177] The downloaded data were stored and analysed on the Amazon Web Services cloud computing facilities. To ensure security, the data were encrypted, stored behind a HIPAA-compliant firewall, and access to the data was restricted to a defined list of IP addresses. Genotype annotation files for the relevant SNP microarrays were obtained from Illumina (illumina.com).

[0178] Analysis of case-control and stratifying signals in genetic cohort datasets was based on correlations of individualized divergences, referred to as Log Bayes Factors, (LBFs) and their Eigen decomposition. Briefly, for each genotype in a case / control group, the LBF is calculated, and for all subjects, each genotype is replaced by the calculated LBF for that genotype. In this way, the initial genotype data matrix is transformed into a LBF matrix of the same dimensions, representing the information gain provided by each subject and SNP pertaining to the overall case / control distinction. LBFs have additive properties allowing the use of linear algebra tools. Eigen decomposition of correlations of LBFs (Principal component analysis) was the preferred multivariate analysis method as it produces independent sets of correlated variables. To accurately determine how much each variable contributes to case / control distinction, variable loadings were projected on to the observed case / control direction in relevant dimensional space. LBF calculation and eigen decomposition were performed using an implementation of the published, proprietary, Taxonomy3® method.

[0179] Quality control of genetic datasets was performed using proprietary techniques which calculated standard QC parameters from data in PLINK format. Univariate QC was performed on the SNPs and subjects, to identify and remove poor quality and inconsistently annotated data points. Two sets of thresholds were calculated (“classic” and “stringent”). Subjects with high missingness, reported gender that did not match inferred gender or highly related individuals were excluded from the analysis.

[0180] HapMap reference population data were downloaded from the HapMap FTP site (ftp: / / ftp.ncbi.nlm.nih.gov / hapmap / ) Release 3 in PLINK format. The CEU, TSI, JPT, CHB and YRI populations were co-analysed with PD case-control populations to identify heterogeneitydriven by genetic ancestry. The PD-LIK cohort was co-analysed with reference populations from the HapMap consortium (The International HapMap Consortium, 2003). The CEU HapMap population (ancestrally most similar to the majority European test cohorts) were labelled as “controls”, and the TSI, YRI, CHB and JPT populations were labelled as “cases” in relation to the CEU population. The test cohort were labelled as “unknowns” and LBFs were calculated based on the CEU:non-CEU contrast of HapMap populations. Ancestrally homogenous case and control populations were defined probabilistically using the Mahalanobis distance around centres determined by k-means clusters for the population of interest. An appropriate a percentile was selected to retain the most subjects while minimising population heterogeneity, which could bias downstream case-control analyses. Additional inversion haplotyping of subjects using SNP data was performed using the ScorelnvHap R package.

[0181] Additional inversion haplotyping of subjects using SNP data was performed using the ScorelnvHap R package. This package claimed to determine chr8p23 inversion haplotypes with 100% accuracy, and chr17q21 inversion haplotypes with 99.8% accuracy for European populations (Ruiz-Arenas et al., 2019).

[0182] Analyses were conducted with Stata version 18 or GraphPad Prism Version 10.2.1.

[0183] Using an inclusive alpha value of 0.01 to only exclude genetic ancestral outliers (1456 cases and 2443 controls), the strongest signals in the first two components of these analyses stratified the subjects into 6 distinct clusters, 3 for cases and 3 corresponding clusters for controls.

[0184] These 6 distinct clusters are visible in Figure 1, a PCA plot which represents components 1 and 2 (Variable Loading 1 and 2). Cases (patients with PD) and controls are shown to be well separated, with controls forming the top three clusters and PD cases forming the lower three clusters. Both cases and controls display 3 distinct subgroup clusters. The central cluster represents SNPs. The black arrow represents the direction of case-control separation.

[0185] The stratification signal informing the 3 subgroups originated from a single locus on chromosome 8, as represented in Figure 2. That figure is a Manhattan plot showing the genomic signal driving PD genetic subgroup separation. The representative Manhattan plot shows component 1 (Variable Loading 1) of the PD-UK analysis (absolute values) on the y-axis and Chromosomes along the x-axis. The stratifying signal from component 1 represents a single locus on chromosome 8.

[0186] The signal was orthogonal to the case-control axis and corresponding clusters were present in both cases and controls, so this appears to represent population heterogeneity that is not directly related to disease risk.

[0187] To ensure that the chromosome 8 signal was not resulting from a subtle difference in genetic ancestry between cases and controls, an extremely stringent, genetically homogeneous, cluster was selected using alpha=0.7. The reduced subject numbers in this analysis (503 cases and 914 controls) resulted in the case-control signals explaining the most variance in the first component, but the chromosome 8 stratifying signal was present in the second component. This suggests that the stratifying signal from chromosome 8 was not due to subtle differences in genetic ancestry.

[0188] Inversion diplotypes were confirmed independently using the ScorelnvHap tool which has been shown to reliably infer inversion diplotypes using SNP data (Ruiz-Arenas et al., 2019). Chr8p23.1 inversion diplotypes correspond to the 3 clusters formed from the chromosome 8 stratifying signal.

[0189] To explore the potential contribution of the chr8p23.1 signal to disease, the inversion alleles were tested for significant association with PD. The alleles tested were N (non-inverted) and I (inverted) as imputed by ScorelnvHap. Fisher’s exact test showed the N allele was weakly associated with the case population (p=0.011 , OR=1.13) but would not be significant after multiple testing. For comparison, the same test was run for diplotypes of the chromosome 17q21 inversion, which was one of the loci that reached genome-wide significance in the GWAS publication of this dataset (UK Parkinson’s Disease Consortium et al., 2011). The chr17q21 N allele shows a much stronger disease association than the chr8p23 N allele (p=3.15e-8, OR=1.37), which may explain why the chr8p23.1 locus was not revealed by the original GWAS analysis and emphasises the importance of identifying patterns in genetic data, consisting of the contributions of many smaller signals. This suggests that the chr8p23.1 locus may have a small effect on overall disease risk but may represent distinct molecular subtypes of PD affecting disease prognosis.

[0190] T o further validate the robustness of the chr8p23.1 stratifying signal for PD, a validation cohort was analysed. This cohort consisted of the National Institute of Neurological Disorders andStroke (NINDS) PD cohort and neurologically normal controls (Fung et al., 2006). These individuals were genotyped in 2 groups, Group 1 with the Illumina HumanHap250 and HumanHap300v1 platforms and Group 2 with the Illumina HumanHap550v3 platform. This provided an overlap of 548,684 genotypes SNPs for the whole cohort of 929 PD cases and 798 controls, referred to as the “PD-LISA” cohort. Univariate QC was performed on the SNPs and subjects, using the same parameters as the PD-UK cohort.

[0191] The PD-USA cohort was co-analysed with the same HapMap reference populations as for PD-UK. The genetic ancestry of the PD-USA cohort was more diverse than PD-UK. The largest cluster of subjects was proximal to the CEU population, with a smaller cluster closer to the TSI population, and many subjects extending towards the YRI and JPT / CHB populations. To obtain a suitably homogeneous population, an alpha value of 0.1 was used.

[0192] Using proprietary techniques to analyse the PD-USA case-control populations also revealed a strong signal at the chr8p23.1 locus. Due to the smaller population size than PD-UK, the case-control axis explained more variance in the first component and the chr8p23.1 signal dominated the second component. This also resulted in a gradient of diplotypes, rather than 3 distinct clusters, as verified by haplotyping by ScorelnvHap. Nevertheless, a strong stratifying signal was observed corresponding to chr8p23.1 inversion diplotypes, orthogonal to the PD case-control axis.

[0193] To further investigate the chr8p23.1 stratification signal, the relevant principal component loadings were plotted to identify any peaks or enriched regions, corresponding to genes or loci, for the PD-UK and PD-USA cohorts. The signal across the inversion region is not dominated by a peak at any specific locus, suggesting the relevance of the inversion haplotype as a whole rather than a specific feature within it. In addition, this is not simply because of a lack of recombination within the locus, as the recombination rate shows many active recombination hotspots across this region. This may suggest that multiple PD-relevant genes within this region could be affected by inversion haplotype, which could have a propagating effect on different pathways in diverse cell types.

[0194] Therefore, the proprietary analysis has allowed the identification of three distinct genetic PD subgroups based on the inversion haplotype at chromosome 8p23. While the stratification signal was not significantly associated with disease risk, and thus each subgroup was just as likely to develop Parkinson’s disease, the inventors recognised that the subgroups likely represented distinct molecular subtypes of the disease. This was supported by further case-control analysis of each subgroup individually which showed a distinct genetic risk profile for each subgroup, associated with different genes and biological pathways. These pathway differences between the subgroups could manifest clinically as differences in disease progression, interaction with environmental factors or response to disease-modifying therapeutics.

[0195] Figure 3 illustrates a schematic diagram of how the stratification methodology can be applied to identify participants in a failed clinical trial that are more likely to respond to the trial drug. For example, patients in a failed Phase 3 (Ph3) clinical trial for PD may be identified, genetic subgrouping is applied using the methodology of the present invention, whereby the patients are grouped based on their Ch8p23 inversion status, into groups l / l, N / l, or N / N, where I represents an inverted allele and N represents a non-inverted allele. Analysis of the trial treatment may be performed on a subgroup basis and patients in a subgroup that showed positive outcomes from the drug may be identified. In the hypothetical case shown in Figure 3 patients in the l / l subgroup have positive outcomes from the treatment and patients in the N / l and N / N subgroups did not.

[0196] Example 2 - Clinical Trial Rescue Using PD Patient Stratification

[0197] The PD patient stratification signature identified by the inventors and discussed herein including in Example 1, was retrospectively applied to two phase III studies (STEADY PD3 and SURE PD3), as presented in a poster by Hill et al. at the 2024 International Congress of the International Parkinson and Movement Disorder Society and summarised in Abstract 932 (Mov Disord. 2024; 39 (suppl 1)). The contents of the poster and abstract are incorporated herein by reference.

[0198] The STEADY PD3 study (NCT02168842) enrolled 336 patients diagnosed with PD less than 3 years prior to enrolment to investigate the impact of immediate release isradipine on disease progression. Patients participated for three years in the study, with the study unfortunately concluding that long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD.

[0199] The SURE PD3 study (NCT02642393) enrolled 298 recently diagnosed patients to investigate the effects of inosine on disease progression. Again, the study unfortunately concluded with the finding that among patients recently diagnosed as having PD, treatment with inosine,compared with placebo, did not result in a significant difference in the rate of clinical disease progression.

[0200] Whole genome sequencing (WGS) data from the patients enrolled in the STEADY PD3 and SURE PD3 studies was analysed to stratify the patients into the three genetic sub-groups as defined by the chr8p23.1 signal discussed herein and in Example 1 above, and labelled by Hill et al as A (correlating to the l / l subgroup as described herein), B (correlating to the N / l subgroup as described herein) or C (correlating to the N / N subgroup as described herein), and to identify whether there was any correlation between sub-groups and response rates.

[0201] The primary endpoint for the STEADY PD3 clinical trial was a mean change in total UPDRS l-lll score between treatment and placebo from baseline to 36 months. UPDRS l-lll is a clinical rating scale that assesses various aspects of PD. An increase in UPDRS score indicates disease progression. At 36 months the observed total UPDRS l-lll scores of subgroup C participants on placebo had increased from baseline by a mean of 7.7 points, whereas subgroup C participants receiving isradipine increased by 2.7 points, a mean reduction of 5.0 points (p=0.051) associated with isradipine treatment. Subgroup A and B participants receiving isradipine showed little change relative to placebo.

[0202] In the report summarising the findings of the original phase III study (Ann Intern Med, 2020 May 5;172(9):591-598), the adjusted least-squares mean changes in total UPDRS score in over 36 months for isradipine and placebo recipients were 2.99 (95% Cl, 0.95 to 5.03) points versus 3.26 (Cl, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (Cl, -3.02 to 2.48) points (P = 0.85). In other words, across the entire PD cohort treated with isradipine, no material difference in response was observed versus placebo.

[0203] Thus, the finding that a subgroup of patients having a specific genetic signature led to a marked reduction in disease progression compared to placebo is striking. Had the patients in that study been genetically stratified prior to enrolment, the outcome of the study, at least for that subgroup could have been very different.

[0204] Regarding the SURE PD3 study, a major focus of it was the effect of the trial drug (inosine) on serum urate levels. Serum urate had previously been identified (by Schwarzchild et al., Arch Neurol. 2008;65(6):716-723) as a predictor of disease progression in PD, with urate levels being decreased in PD patients, and higher urate levels in blood in early PD patients being found to predict a slower rate of disease progression.When the effects on serum urate levels achieved by inosine treatment of patients enrolled in the SURE PD3 study were correlated against their stratification into subgroups A, B and C, again, one subgroup was observed to show strikingly different results to the others.

[0205] More specifically, in time-to-event analyses (time to decision to requiring anti-PD therapy) participants from each subgroup who achieved a higher urate exposure were compared to those who did not achieve the target level. Subgroup A participants who achieved higher urate levels were delayed in their time before requiring anti Parkinson’s therapy (p=0.049), relative to A participants with lower urate levels. Subgroup B and C participants did not show any benefit.

[0206] The mean cumulative LEDD (Levodopa-Equivalent Daily Dosage) from baseline to 1 year of treatment for each subgroup was investigated. Subgroup A participants with higher urate levels had a mean cLEDD 76% less (p=0.0003) than those of A participants with lower urate levels. Subgroup B or C participants did not show a difference in the equivalent comparison.

[0207] These findings demonstrate that the genetic signatures and corresponding stratification method of the present invention can be used to stratify PD patients into subgroups having significantly different responses to therapeutic interventions. Strikingly, in this example, different subgroups responding positively to different agents (in the STEADY PD3 study, subgroup C showed a positive response trend to isradipine treatment, whereas in the SURE PD3 study, subgroup A showed the strongest response signal).

Claims

Claims1. A method for the stratification of a subject either with Parkinson’s disease or at risk of developing Parkinson’s disease, comprising:a) obtaining genetic data from the subject comprising at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,b) analysing the first and second chromosomes or the parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present, andc) stratifying the subject into one of three subgroups, namely N / N, N / l or l / l.

2. The method of Claim 1 wherein, the inversion haplotype is located within the p arm regions of the first and second chromosomes or parts thereof.

3. The method of Claim 1 or 2 wherein, the inversion haplotype includes an inversion of the entire 8p23.1 region.

4. The method of Claim 2 wherein, the inversion further includes the flanking regions at the inversion boundaries.

5. A method of treating Parkinson’s disease in a subject or preventing Parkinson’s disease in a subject at risk of developing Parkinson’s disease, comprising:a) obtaining genetic data from the subject comprising at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,b) analysing the first and second chromosomes or parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,c) stratifying the subject into one of three subgroups, namely N / N, N / l or l / l, and d) administering a therapeutic agent to the subject which is efficacious in the treatment of Parkinson’s disease in patients in the subgroup into which the subject has been stratified.

6. The method of Claim 5 wherein, the inversion haplotype is located within the p arm regions of the first and second chromosomes or parts thereof.

7. The method of Claim 5 or 6 wherein, the inversion haplotype includes an inversion of the entire 8p23.1 region.

8. The method of Claim 6 or 7 wherein, the inversion further includes the flanking regions at the inversion boundaries.

9. The method of any of Claims 5 to 8 wherein, the at least a part of the first and I or second chromosome of pair 8 which are analysed comprise at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% of the full chromosome.

10. The method of any of Claims 5 to 9 wherein, the therapeutic agent prevents, reduces or alleviates one or more symptoms of Parkinson’s disease.

11. The method of any of Claims 5 to 10 wherein, the therapeutic agent improves the symptoms associated with PD according to a symptomatic or diagnostic test and / or scale.

12. The method of any of Claims 5 to 10 wherein, the therapeutic agent prevents, reduces or alleviates Parkinson’s disease progression.

13. A method of conducting a clinical trial in subjects diagnosed with Parkinson’s disease or exhibiting one or more symptoms of PD comprising:a) obtaining genetic data from the cohort of subjects comprising, for each subject in the cohort, at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,b) analysing the first and second chromosomes or parts thereof to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,c) stratifying each subject in the cohort into one of three subgroups, namely N / N, N / l or l / l, andd) administering the subject a study drug.

14. The method of Claim 15 wherein the inversion haplotype is located within the p arm regions of the first and second chromosomes or parts thereof.

15. The method of Claim 13 or 14 wherein, the inversion haplotype includes an inversion of the entire 8p23.1 region.

16. The method of Claim 14 or 15 wherein, the inversion further includes the flanking regions at the inversion boundaries.

17. The method of any of Claims 13 to 16 wherein, the at least a part of the first and / or second chromosome of pair 8 which are analysed comprise at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% of the full chromosome.

18. A method of analysing the results of an ongoing or completed clinical trial in which the achievement of an effect indicative of efficacy of a study drug in a cohort of subjects diagnosed with PD or exhibiting one or more symptoms of PD has been assessed comprising:a) obtaining genetic data from the cohort of subjects enrolled in the clinical trial comprising, for each subject in the cohort, at least a part of a first chromosome from the chromosome 8 pair and at least part of a second chromosome from the chromosome 8 pair,b) analysing the first and second chromosomes or parts thereof, to identify inversion haplotypes and scoring each of the first and second chromosomes as N if no inversion haplotype is present or I if an inversion haplotype is present,c) stratifying each subject into one of three subgroups, namely N / N, N / l or l / l, and d) identifying whether each subject achieved the effect indicative of efficacy in PD.

19. The method of Claim 18 wherein, the effect indicative of efficacy of a study drug is a primary and / or secondary outcome of the clinical trial.

20. The method of Claim 18 or 19, further comprising ceasing administering the study drug to subjects in a subgroup showing neutral or negative responses to the study drug if the clinical trial is ongoing.

21. The method of any of Claims 18 to 20, wherein stratification may utilise genetic data provided by each subject prior to, during or following the clinical trial.

22. The method of any of Claim 18 to 21, wherein the inversion haplotype includes an inversion of the entire 8p23.1 region.

23. The method of Claim 22, wherein the inversion further includes the flanking regions at the inversion boundaries.

24. The method of any of Claims 18 to 23 wherein, the at least a part of the first and I or second chromosome of pair 8 which are analysed comprise at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% of the full chromosome.

25. The method of any one of Claims 1 to 24, wherein the method is computer-implemented.

Images