RU2848183C1 - Treatment of parkinson's disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to a method for maintaining or slowing the decline of motor function in a subject suffering from Parkinson's disease or having a risk of developing Parkinson's disease, comprising administering to the subject a regimen of Prasinezumab, wherein the maintenance includes reducing the progression of Parkinson's disease, as shown by the prolongation of the time to progression, which is at least 5 points according to the International Movement Disorder Society – Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part III, and the sinking retardation includes at least one of the following: (a) slowing down the decline of the patient's motor function score according to MDS-UPDRS, Part III, (b) delaying the deterioration of one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, pronation-supination wrist movements, forefoot tapping, mobility of the legs, getting up from a chair, gait, freezing when walking, postural stability, posture, hand tremor, rest tremor amplitude, rest tremor constancy or Hoehn and Yahr stage; (c) improving bradykinesia; where the regimen of Prasinezumab includes 1000–5000 mg of intravenous administration of Prasinezumab at intervals of 3–5 weeks, also relates to a method for maintaining or increasing cerebral blood flow in a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to a subject a regimen of Prasinezumab, also relates to a method for improving cognitive function in a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to a subject a regimen of Prasinezumab, also relates to a method for treating a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a regimen of Prasinezumab, where the treatment includes (a) reducing the progression of Parkinson's disease, as shown by the extension of the time to progression, which is at least 5 point progression according to the International Movement Disorder Society – Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part III, or (b) delaying the decline in motor function, including at least one of the following: i. slower decline in the patient's motor function score according to MDS-UPDRS, Part III; ii. delaying the deterioration of one or more of the following: speech, facial expression, rigidity, finger tapping, wrist movements, pronation-supination wrist movements, forefoot tapping, leg mobility, standing up from a chair, gait, walking stiffness, postural stability, posture, hand tremor, rest tremor amplitude, rest tremor constancy or Hyun and Yahr stage; iii. improved bradykinesia.

EFFECT: group of inventions provides maintaining or delaying the decline in motor function or increasing cerebral blood flow in a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, improves the cognitive function in a subject suffering from Parkinson's disease or having a risk of developing Parkinson's disease, provides treatment of a subject suffering from Parkinson's disease or having a risk of developing Parkinson's disease.

39 cl, 22 dwg, 4 tbl, 5 ex

Description

Cross-reference to related applications

[001] This application claims priority to U.S. Provisional Application No. 63/076,913, filed September 10, 2020, U.S. Provisional Application No. 63/076,915, filed September 10, 2020, U.S. Provisional Application No. 63/076,916, filed September 10, 2020, and U.S. Provisional Application No. 63/158,191, filed March 8, 2021, the disclosures of each of which are incorporated by reference in their entireties.

List of sequences

[002] The machine-readable form of the Sequence Listing is filed with this application in electronic form and is incorporated herein by reference in its entirety. The Sequence Listing is contained in an ASCII text file created on September 9, 2021, having the file name “20-1293-WO_Sequence-Listing_ST25.txt” and a size of 15 KB.

Prerequisites for the creation of the invention

[003] Parkinson's disease (PD) is a slow-onset, chronic, progressive neurodegenerative disorder that affects an estimated 7 to 10 million people worldwide. In the United States, 725,000 people are reported to have the disease, with more than 50,000 new cases occurring annually. Although 5 to 10 percent of patients are diagnosed before age 50, PD is generally considered a disease that affects older adults, affecting one in every 100 people over age 60, and is more common in men than women.

[004] Alpha-synuclein is a protein that is commonly associated with synapses and is thought to play a role in neural plasticity, learning, and memory. Alpha-synuclein can aggregate to form insoluble fibrils under pathological conditions and is a major component of the pathology that characterizes several neurodegenerative disorders, including Parkinson's disease. Soluble alpha-synuclein oligomers can be neurotoxic. The accumulation of alpha-synuclein with similar morphological and neurological changes in species and animal models as diverse as humans, mice, and flies suggests that this molecule contributes to the development of Parkinson's disease. Antibodies directed against alpha-synuclein may reduce alpha-synuclein deposits and Parkinson's disease symptoms.

[005] Current treatments for PD control the early motor symptoms of the disease primarily through the use of dopamine replacement therapy and dopamine receptor agonists. Treatment with levodopa and other dopaminergic drugs temporarily eliminates motor symptoms. However, this does not reverse, slow, or stop the pathological processes associated with the disease. As the disease progresses, these drugs become less effective in controlling symptoms.

[006] Patients taking these medications frequently develop side effects such as motor complications (e.g., response fluctuations, extinction phenomena, and drug-induced dyskinesias), as well as nausea, daytime sleepiness, sleep attacks, orthostatic hypotension, or impulse control disorders. Symptomatic treatments for non-motor symptoms of PD (e.g., sleep disturbances, anxiety, and depression) are also available. However, to date, no approved treatments have been demonstrated to protect neurons or modify the course of the disease. There is an urgent need for new therapies that target the underlying cause of Parkinson's disease and, unlike symptomatic therapies, slow its relentless progression.

The essence of the invention

[007] In one aspect, the invention provides a method for maintaining or slowing the decline in motor function in a subject having Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen, wherein maintaining comprises reducing the progression of Parkinson's disease, as shown by prolonging the time to progression, comprising a progression of at least 5 points on the MDS-UPDRS Part III scale, and slowing the decline comprises at least one of the following:

(a) slowing the decline in the patient's motor function score according to the MDS-UPDRS Part III scale,

(b) slowing of deterioration in one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination movements, toe tapping, leg mobility, chair rising, gait, freezing of gait, postural stability, posture, hand tremor, resting tremor amplitude, resting tremor persistence, or Hoehn and Yahr stage; or

(c) improvement of bradykinesia;

where the Prasinezumab regimen includes 1000-5000 mg of Prasinezumab at intervals of 3-5 weeks.

[008] improvement of at least 18%, 24%, 25%, 33%, 35%, or 45% compared with placebo after one year of treatment.

[009] In another aspect, the invention provides a method of maintaining or increasing cerebral blood flow in a subject having Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen comprising 1000-5000 mg Prasinezumab at intervals of 3-5 weeks.

[0010] In some techniques, cerebral blood flow is maintained or increased in the putamen.

[0011] In some techniques, cerebral blood flow is maintained or increased in the pallidum.

[0012] In some methods, cerebral blood flow is maintained or increased in the premotor area.

[0013] In some methods, blood flow is assessed by changes in MRI with labeled arterial spins (MRI-ASL).

[0014] In yet another aspect, the invention provides a method for improving cognitive function in a subject having Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen comprising 1000-5000 mg of Prasinezumab at intervals of 3-5 weeks.

[0015] In some methods, the subject does not have a cognitive impairment.

[0016] In some methods, the improvement in cognitive function is measured using the Montreal Cognitive Assessment (MoCA), and wherein the improvement is at least 0.2 on the MoCa score.

[0017] In another aspect, the invention provides a method for maintaining or slowing the decline in motor function in a subject having Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen, wherein maintaining comprises reducing the progression of Parkinson's disease, as shown by prolonging the time to progression, comprising a progression of at least 5 points on the MDS-UPDRS Part III scale, and slowing the decline comprises at least one of the following:

(a) slowing the decline in the patient's motor function score according to the MDS-UPDRS Part III scale,

(b) slowing of deterioration in one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination movements, toe tapping, leg mobility, chair rising, gait, freezing of gait, postural stability, posture, hand tremor, resting tremor amplitude, resting tremor persistence, or Hoehn and Yahr stage; or

(c) improvement of bradykinesia;

where the Prasinezumab regimen includes 1000-5000 mg of Prasinezumab at intervals of 3-5 weeks.

[0018] In some methods, the subject has been diagnosed with a mild subtype of parkinsonism with predominantly motor symptoms, a diffuse malignant subtype, or an intermediate subtype, and in some methods, the subject has been diagnosed with a diffuse malignant subtype of Parkinson's disease.

[0019] In some methods, slowing the decline in a patient's motor function score includes an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76%, or 109% compared to placebo after one year of treatment.

[0020] In some routes, Prasinezumab is administered intravenously.

[0021] In some methods, the method further comprises administering to the subject an MAO-B inhibitor.

[0022] In some methods, the subject is a previously untreated subject, a subject diagnosed with PD within the last two years, or a subject previously treated with an MAO-B inhibitor.

[0023] In some methods, the subject has a body weight greater than 65 kg and receives a dose of 4500 mg of Prasinezumab every 4 weeks.

[0024] In some methods, the subject has a body weight less than 65 kg and receives a dose of 3500 mg of Prasinezumab every 4 weeks.

[0025] In some methods, the subject is administered a dose of 1500 mg of the antibody once every 4 weeks.

[0026] In some methods, the subject receives Prasinezumab every 4 weeks for at least 52 weeks.

[0027] In some methods, the subject is a man.

[0028] In another aspect, the invention provides a method of treating a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a regimen of Prasinezumab, wherein the treatment comprises

(a) a reduction in the progression of Parkinson's disease, as demonstrated by a prolongation of time to progression, representing at least a 5-point progression on the MDS-UPDRS Part III scale, or

(b) slowing the decline in motor function, including at least one of the following:

(i) slowing the decline in the patient's MDS-UPDRS Part III motor function score;

(ii) slowing of deterioration in one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination movements, toe tapping, leg mobility, chair rising, gait, freezing of gait, postural stability, posture, hand tremor, resting tremor amplitude, resting tremor persistence, or Hoehn and Yahr stage;

(iii) improvement of bradykinesia,

where the Prasinezumab regimen includes 1000-5000 mg of Prasinezumab at intervals of 3-5 weeks.

[0029] In some methods, the subject is diagnosed with a mild, predominantly motor subtype, a diffuse malignant subtype, or an intermediate subtype of Parkinsonism, and in some methods, the subject is diagnosed with a diffuse malignant subtype of Parkinson's disease.

[0030] In some methods, slowing the decline in a patient's motor function score includes an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76%, or 109% compared to placebo after one year of treatment.

[0031] In some routes, Prasinezumab is administered intravenously.

[0032] In some methods, the method further comprises administering to the subject an MAO-B inhibitor.

[0033] In some methods, the subject is a previously untreated subject, a subject diagnosed with PD within the last two years, or a subject previously treated with an MAO-B inhibitor.

[0034] In some methods, the subject has a body weight greater than 65 kg and receives a dose of 4500 mg of Prasinezumab every 4 weeks.

[0035] In some methods, the subject has a body weight less than 65 kg and receives a dose of 3500 mg of Prasinezumab every 4 weeks.

[0036] In some methods, the subject is administered a dose of 1500 mg of the antibody once every 4 weeks.

[0037] In some methods, the subject receives Prasinezumab every 4 weeks for at least 52 weeks.

[0038] In some methods, the subject is a man.

Brief description of the drawings

[0039] Fig. 1 shows the change in MDS-UPDRS total score (Parts I, II, and III) from baseline to week 52. Patients who started PD symptomatic treatment cooperated until the last visit before starting PD symptomatic treatment. The results show that the change from baseline in MDS-UPDRS total score (Parts I, II, and III) at week 52 was not achieved in each treatment group compared to the placebo group (pooled dose levels: -14.0%, -1.30, 80% CI=(-3.18, 0.58); low dose level: -21.5%, -2.02, 80% CI=(-4.21, 0.18); and high dose level: -6.6%, -0.62, 80% CI=(-2.82, 1.58)). Bars represent 80% CI. MDS-UPDRS (Movement Disorder Society Unified Parkinson's Disease Rating Scale).

[0040] Fig. 2 shows the improvement in MoCA score from baseline to week 52. MoCA (Montreal Cognitive Assessment) is a 30-point scale, and a higher score indicates better cognitive functioning. On average, patients receiving prasinezumab had a cognitive score within the normal range at baseline. Patients receiving prasinezumab showed an improvement in MoCA score.

[0041] Figure 3 shows the CGI-I confirming the reduced risk of worsening in patients at 52 weeks. Clear signals favoring prasinezumab were demonstrated at both dose levels, as assessed by the Clinical Global Impression of Improvement (CGI-I) scale.

[0042] Figure 4 shows the PGI-C confirming a reduced risk of worsening in patients at 52 weeks. Clear signals favoring prasinezumab were demonstrated at both dose levels, as assessed by the Patient Global Impression of Change (PGI-C) scale.

[0043] Fig. 5 shows an MRI-ASL (arterial spin labeled MRI) analysis showing changes in cerebral blood flow. Red color indicates higher blood flow, and blue color indicates lower blood flow. In patients receiving placebo, blood flow decreased compared to baseline at 52 weeks (see arrows). In patients receiving prasnezumab, blood flow increased compared to baseline at 52 weeks (see arrows). Images are from a subset of all individuals receiving prasnezumab (low/high dose), and the images are composite images obtained by overlaying images obtained from patients to create an average image.

[0044] Figs. 6A, 6B, and 6C show that patients on prasinezumab had improvements in blood flow in the putamen, pallidum, and premotor area, respectively, compared to baseline after 52 weeks. Improved cerebral blood flow in the putamen indicates potential synaptic protection.

[0045] Fig. 7A shows the change in MDS-UPDRS Part III total score from baseline to week 52 based on the site assessment confirming a reduction in motor decline (pooled dose levels: -25.0%, -1.44, 80% CI=(-2.83, -0.06); low dose level: -33.8%, -1.88, 80% CI=(-3.49, -0.27); and high dose level: -18.2%, -1.02, 80% CI=(-2.64, 0.61)). *Patients who started PD symptomatic treatment cooperated until the last visit before starting PD symptomatic treatment. Bars represent 80% CI.

[0046] Fig. 7B shows the change in MDS-UPDRS Part III total score from baseline to week 52 based on central assessment confirming a reduction in motor decline (pooled dose levels: -35.0%, -1.88, 80% CI= (-3.31, -0.45); low dose level: -45.4%, -2.44, 80% CI= (-4.09, -0.78); and high dose level: -24.7%, -1.33, 80% CI= (-2.99, 0.34)). Prasinezumab reduced motor decline by 35% compared to placebo after one year of treatment according to central assessment on MDS-UPDRS Part III. *Patients who initiated symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI.

[0047] Fig. 8 shows a reduction in time to motor impairment with a delay in progression to clinically significant impairment. Prasinezumab prolonged the time to clinically significant worsening in motor impairment progression in patients receiving prasinezumab compared to placebo over 52 weeks, as measured by the site-assessed time to at least a 5-point progression on the MDS-UPDRS Part III (pooled dose levels: HR=0.82, 80% CI=0.64-0.99; low dose level: HR=0.77, 80% CI=0.63-0.96; and high dose level: HR=0.87, CI=0.70-1.07). *Wald/test confidence interval. Pooled dose analysis is a post hoc analysis. CI = confidence interval; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale.

[0048] Figure 9 shows a reduction in bradykinesia progression from baseline to week 52, confirming a clinical reduction in bradykinesia progression. Efficacy was observed as a change from baseline in bradykinesia in patients receiving prasinezumab compared to placebo at week 52 based on site assessment (pooled dose levels: -27.0%, -0.75, 80% CI=(-1.62, 0.11); low dose level: -38.3%, -1.07, 80% CI=(-2.07, -0.07); and high dose level: -15.7%, -0.44, 80% CI=(-1.45, 0.56)). Pooled dose analysis is a post hoc analysis. CI is a confidence interval; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale.

[0049] Fig. 10 shows that MAO-B inhibitor treatment and the diffuse malignant subphenotype had more rapid disease progression as assessed by MDS-UPDRS Part III. Patients who started symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, sex, DaT-SPECT binding coefficient in the putamen (contralateral to the most clinically affected side), baseline MDS-UPDRS, corresponding endpoint. Pooled dose analysis is a pre-specified exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg. CI = confidence interval; DaT-SPECT - dopamine transporter imaging by single-photon emission computed tomography; MAO-B - monoamine oxidase B; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale; MMRM - mixed-effects model for repeated measures; PD - Parkinson's disease.

[0050] Figures 11A, 11B, and 11C show that the slowing of clinical deterioration with prasinezumab was most pronounced in subjects with more rapid disease progression. Patients who initiated symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, sex, DaT-SPECT binding coefficient in the putamen (contralateral to the most clinically affected side), baseline MDS-UPDRS, corresponding endpoint. Pooled dose analysis is a pre-specified exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg. CI = confidence interval; DaT-SPECT - dopamine transporter imaging by single-photon emission computed tomography; MAO-B - monoamine oxidase B; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale; MMRM - mixed-effects model for repeated measures; PD - Parkinson's disease.

[0051] Figs. 12A, 12B and 12C show that a greater effect is observed in prasinezumab-treated subjects with more rapid disease progression, as confirmed by central assessment.

[0052] Figures 13A, 13B, and 13C show that the slowing of clinical deterioration with prasinezumab was most pronounced in subjects with more rapid motor progression as assessed by digital scores. Patients who initiated symptomatic treatment for PD were cooperative until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, sex, DaT-SPECT putamen binding coefficient (contralateral to the most clinically affected side), baseline MDS-UPDRS, and the corresponding endpoint. Pooled dose analysis represents the study's pre-specified exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg. CI - confidence interval; DaT-SPECT - dopamine transporter imaging by single-photon emission computed tomography; MAO-B - monoamine oxidase B; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale; MMRM - mixed-effects model for repeated measures; PD - Parkinson's disease.

Description

[0053] The invention is directed to the use of Prasinezumab and other similar humanized antibodies against alpha-synuclein for the treatment, prevention and/or amelioration (e.g., reducing the progression of the disease) of Parkinson's disease, including early stage Parkinson's disease.

[0054] In one aspect of the invention, Prasinezumab is used to improve, maintain, or reduce the decline in motor function in subjects with Parkinson's disease. In one aspect of the invention, one measure of motor function is the Movement Disorder Society Universal Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, a clinical assessment of motor function. In another aspect of the invention, the MDS-UPDRS Part III assessment is an assessment performed at a study center. In another aspect of the invention, the MDS-UPDRS Part III assessment is a central assessment. Motor symptoms associated with Parkinson's disease include slowness of movement (bradykinesia), tremor, changes in speech, facial expression, rigidity, and gait. In one aspect of the invention, Prasinezumab is used to delay clinically significant worsening of the progression of movement disorders as assessed by the MDS-UPDRS Part III assessment.

[0055] In another aspect of the invention, prasinezumab is used to maintain or improve cerebral blood flow as assessed by changes in MRI with labeled arterial spins (MRI-ASL). In one aspect of the invention, prasinezumab is used to demonstrate improvement in cerebral blood flow in brain regions including the premotor region, pallidum, and putamen, a brain region associated with dopaminergic loss and the presence of alpha-synuclein pathology in Parkinson's disease, suggesting an effect on the underlying biology associated with disease progression.

[0056] In another aspect of the invention, Prasinezumab is used to maintain or improve cognitive function in patients. In one aspect of the invention, the patient has normal cognitive function. The Montreal Cognitive Assessment (MoCA) can be used as a screening tool for patients with complaints of mild cognitive impairment, and they typically have a Mini-Mental State Examination (MMSE) score within the normal range.

[0057] In another aspect of the invention, Prasinezumab is used to improve, maintain, or reduce the decline in motor function in subjects with Parkinson's disease. In one aspect of the invention, one measure of motor function is the Movement Disorder Society Universal Parkinson's Disease Rating Scale (MDS-UPDRS), Part III, Clinical Assessment of Motor Function. In another aspect of the invention, the MDS-UPDRS, Part III assessment is an assessment performed at a study center. In another aspect of the invention, the MDS-UPDRS, Part III assessment is a central assessment. Motor symptoms associated with Parkinson's disease include slowness of movement (bradykinesia), tremor, changes in speech, facial expression, rigidity, and gait. In one aspect of the invention, prasinezumab is used to delay clinically significant worsening of the progression of movement disorders as assessed by the MDS-UPDRS, Part III.

[0058] Before turning to further aspects of the invention, a number of terms are defined below. When used, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0059] Alpha-synuclein is a highly conserved protein that is abundant in neurons, particularly at presynaptic terminals, and is thought to misfold and aggregate to form protein structures that are closely associated with the pathology of Parkinson's disease. Aggregated alpha-synuclein proteins form brain lesions that are hallmarks of neurodegenerative synucleinopathies. Furthermore, misfolding and aggregation can often be accompanied by β-amyloid deposition in some neurodegenerative diseases, and alpha-synuclein and tau aggregates coexist in some neurodegenerative diseases, including Parkinson's disease.

[0060] Naturally occurring wild-type human alpha-synuclein is a 140 amino acid peptide with the following amino acid sequence (GenBank accession number: P37840):

[0061] The protein has three recognizable domains: a repeating N-terminal domain spanning amino acids 1-61; a NAC (non-amyloid component) domain beginning at approximately amino acids 60-95; and a C-terminal acidic domain beginning at approximately amino acids 98 to 140. Unless the context otherwise requires, reference to alpha-synuclein or fragments thereof includes the above-mentioned natural wild-type human amino acid sequences and their human allelic variants, particularly those associated with Parkinson's disease.

[0062] Unless the context otherwise requires, the term "about" includes minor variations, such as values within the standard error of measurement (e.g., SEM) of the stated value. A designation of a range of values includes all integers within the range, or defining the range, and all subranges defined by integers within the range. In the context of this application, statistical significance means p≤0.05. Unless the context otherwise requires, the term "about" encompasses values within the standard deviation of the mean of the stated value or +/- 5% of the stated value, whichever is greater.

[0063] Compositions or methods "comprising" or "including" one or more listed elements may include other elements not specifically listed. For example, a composition that "comprises" or "includes" a polypeptide sequence may comprise the sequence alone or in combination with other sequences or ingredients.

[0064] A subject has an increased risk of a disease if the subject has at least one known risk factor (e.g., age, genetic, biochemical, family history, and situational exposure) that makes subjects with that risk factor have a statistically significantly higher risk of developing the disease than individuals without the risk factor.

[0065] The terms "subject" or "patient" include humans and other mammals that receive either prophylactic or therapeutic treatment, including subjects that have not previously received treatment. In the context of the present application, the terms "subject" or "patient" refer to any individual subject for which treatment is required, including other mammalian subjects such as humans, cattle, dogs, guinea pigs, rabbits, etc. Also intended to be included as a subject are any subjects participating in clinical trials that do not exhibit any clinical signs of disease, or subjects participating in epidemiological studies, or subjects used as controls. In some aspects of the disclosure, the patient is a male patient, and in some aspects of the disclosure, the patient is a female patient.

[0066] The term "disease" refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, disease, abnormality, pathology, ailment, condition, or syndrome in which physiological functions are impaired, regardless of the etiology.

[0067] The term "symptom" refers to a subjective sign of a disease, such as a change in gait, perceived by the subject. "Sign" or "signal" refers to objective signs of a disease observed by the clinician or treating physician.

[0068] As used herein, the terms "treat" and "treatment" refer to alleviating or improving one or more symptoms, signs, signals, or effects associated with a disease, preventing, inhibiting, or delaying the onset of one or more symptoms or consequences of a disease, reducing the severity or frequency of one or more symptoms or consequences of a disease, and/or increasing or tending to achieve desired results as described herein. A treatment regimen refers to a combination of parameters characterizing the administration of an antibody of the present invention, including any or all doses, frequency of administration, route of administration, and total duration of administration.

[0069] The terms "prophylaxis," "prevent," or "prevention" as used herein refer to contacting (e.g., administering) the compositions of the present invention to a subject prior to the onset of a disease, with or without pre-existing alpha-synuclein pathology (primary and secondary prevention), thereby delaying the onset of clinical symptoms and/or alleviating disease symptoms after the onset of the disease, compared to when the subject was not contacted with the peptide or immunotherapeutic compositions, and do not refer to completely suppressing the onset of the disease. In some cases, prevention may occur for a limited time following administration of the peptide or immunotherapeutic compositions of the present invention. In other cases, prevention may occur throughout the duration of treatment involving administration of the peptide or immunotherapeutic compositions of the present invention.

[0070] The terms "reduction," "reduce," or "reducing," as used herein, refer to reducing or suppressing an increase in a value or score of a symptom, sign, signal, or effect associated with Parkinson's disease. In other embodiments, the terms "reduction," "reduce," or "reducing," as used herein, refer to reducing or suppressing an increase in the amount of alpha-synuclein present in a subject or in a subject's tissue, which includes reducing or suppressing an increase (e.g., reducing the rate of increase) in the amount of alpha-synuclein present, accumulated, aggregated, or deposited in a subject or in a subject's tissue. In some embodiments, reducing or suppressing an increase (e.g., reducing the rate of increase) in the amount of alpha-synuclein present, accumulated, aggregated, or deposited in a subject refers to the amount of alpha-synuclein present, accumulated, aggregated, or deposited in the central nervous system (CNS) of the subject. In some embodiments, reducing or suppressing an increase (e.g., decreasing the rate of increase) of the amount of alpha-synuclein present, accumulated, aggregated, or deposited in a subject refers to the amount of alpha-synuclein present, accumulated, aggregated, or deposited in the periphery (e.g., in the peripheral circulation) of the subject. In some embodiments, reducing or suppressing an increase (e.g., decreasing the rate of increase) of the amount of alpha-synuclein present, accumulated, aggregated, or deposited in a subject refers to the amount of alpha-synuclein present, accumulated, aggregated, or deposited in the brain of the subject. In some embodiments, the reduced alpha-synuclein is a pathological form(s) of alpha-synuclein (e.g., fibular alpha-synuclein inclusions, oligomeric or fibrillar alpha-synuclein conglomerates, and protofibrillar intermediates of alpha-synuclein oligomers). In some other embodiments, pathological indicators of a neurodegenerative disease and/or synucleinopathy are reduced.

[0071] As used in the context of this application, the terms "site evaluation," "site evaluator," "site monitoring," and the like refer to in-person evaluations of the subject performed by sponsor staff or representatives at the sites where the clinical trial is being conducted.

[0072] In the context of this application, the terms "centralized assessment," "centrally assessed," "centralized monitoring," etc., refer to remote assessment conducted by sponsor personnel or representatives (e.g., clinical trial specialists, data processing and analysis specialists, or statisticians) at a location other than the centers where the clinical trial is being conducted.

[0073] As used herein, the term "subgroup analysis," etc., refers to repeating the analysis of a study after dividing the study population into subgroups that represent a variable or variables (e.g., a mixed population with early Parkinson's disease may be divided into subgroups that include (1) a mild movement-predominant subtype, (2) a diffuse malignant subtype, or (3) an intermediate subtype, depending on standardized assessment of orthostatic hypotension, mild cognitive impairment, rapid eye movement (RBD) sleep behavior disorder, depression, anxiety, and Unified Parkinson Disease Rating Scale Part II and Part III scores at baseline). The purpose of a subgroup analysis is typically to assess whether the association of two variables differs depending on a third variable, such as Parkinson's disease subtype.

[0074] Prasinezumab (PRX002/RG7935/RO7046015/NEOD002) is a humanized immunoglobulin G1 (IgG1) class monoclonal antibody (mAb) derived from the murine parent antibody 9E4 (produced by the hybridoma assigned ATCC accession number PTA-8221) and directed against an epitope at the C-terminus of human α-synuclein (amino acids 118-126). In biochemical and biophysical experiments, prasinezumab binds to both soluble and insoluble forms of human α-synuclein, and with greater relative affinity/avidity to aggregated compared to monomeric forms of α-synuclein. In cell culture, prasinezumab effectively blocks the intercellular transmission of α-synuclein. Prasinezumab comprises the heavy chain variable region of SEQ ID NO: 1 and the light chain variable region of SEQ ID NO: 4. Prasinezumab comprises the heavy chain (SEQ ID NO: 10, with or without the C-terminal lysine) and the light chain (SEQ ID NO: 9). Other exemplary humanized forms of the murine 9E4 antibody include three exemplary humanized mature light chain variable regions (SEQ ID NOs: 2, 3) and three exemplary humanized mature heavy chain variable regions (SEQ ID NOs: 5, 6, 7). The exemplary mature light and heavy chain variable regions may be paired in any combination. See WO 2019/064053, which is incorporated herein by reference in its entirety. As demonstrated herein, Prasinezumab is the first potentially disease-modifying anti-alpha-synuclein antibody to demonstrate evidence of efficacy across multiple clinical endpoints in patients with early-stage Parkinson's disease.

[0075] Turning now to various aspects of the disclosure, the Montreal Cognitive Assessment (MoCA) is a screening tool for patients with complaints of mild cognitive impairment and who typically have a Mini-Mental State Examination (MMSE) score within the normal range. The MoCA is a 30-point scale, and a higher score indicates better cognitive functioning. Generally, a score of at least 26 on the MoCA scale indicates the absence of cognitive impairment.

[0076] Cerebral blood flow, as assessed by changes in MRI with labeled arterial spins (MRI-ASL), can be used to demonstrate improvement in cerebral blood flow. According to one aspect of the invention, a treatment regimen with Prasinezumab can reduce the decline in, maintain, or improve cerebral blood flow in a patient. In one aspect of the invention, blood flow is improved in the premotor cortex, pallidum, and/or putamen, a brain region associated with the loss of dopaminergic terminals and the presence of alpha-synuclein pathology in Parkinson's disease, suggesting an effect on the underlying biology associated with disease progression.

[0077] According to one aspect of the invention, a treatment regimen using prasinezumab can reduce the decline in, maintain, or improve cognitive function in patients, including patients whose cognitive function is within the normal range. In one aspect of the invention, cognitive function is assessed using the MoCA scale. For example, Prasinezumab can improve cognitive function measured by the MoCA scale by 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9 or 30; or by at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, at least 3.9, at least 4, at least 4.1, at least 4.2, at least 4.3, at least 4.4, at least 4.5, at least 4.6, at least 4.7, at least 4.8, at least 4.9, at least 5, at least 5.1, at least 5.2, at least 5.3, at least 5.4, at least 5.5, at least 5.6, at least 5.7, at least 5.8, at least 5.9, at least 6, at least 6.1, at least 6.2, at least 6.3, at least 6.4, at least 6.5, at least 6.6, at least 6.7, at least 6.8, at least 6.9, at least 7, at least 7.1, at least 7.2, at least 7.3, at least 7.4, at least 7.5, at least 7.6, at least 7.7, at least 7.8, at least 7.9, at least 8, at least 8.1, at least 8.2, at least 8.3, at least 8.4, at least 8.5, at least 8.6, at least 8.7, at least 8.8, at least 8.9, at least 9, at least 9.1, at least 9.2, at least 9.3, at least 9.4, at least 9.5, at least 9.6, at least 9.7, at least 9.8, at least 9.9, at least 10, at least 10.1, at least 10.2, at least 10.3, at least 10.4, at least 10.5, at least 10.6, at least 10.7, at least 10.8, at least 10.9, at least 11, at least 11.1, at least 11.2, at least 11.3, at least 11.4, at least 11.5, at least 11.6, at least 11.7, at least 11.8, at least 11.9, at least 12, at least 12.1, by at least 12.2, at least 12.3, at least 12.4, at least 12.5, at least 12.6, at least 12.7, at least 12.8, at least 12.9, at least 13, at least 13.1, at least 13.2, at least 13.3, at least 13.4, at least 13.5, at least 13.6, at least 13.7, at least 13.8, at least 13.9, at least 14, at least 14.1, at least 14.2, at least 14.3, at least 14.4, at least 14.5, at least 14.6, at least 14.7, at least 14.8, at least 14.9, at least 15, at least 15.1, at least 15.2, at least 15.3, at least 15.4, at least 15.5, at least 15.6, at least 15.7, at least 15.8, at least 15.9, at least 16, at least 16.1, at least 16.2, at least 16.3, at least 16.4, at least 16.5, at least 16.6, at least 16.7, at least 16.8, at least 16.9, at least 17, at least 17.1, at least 17.2, at least 17.3, at least 17.4, at least 17.5, at least 17.6, at least 17.7, at least 17.8, at least 17.9, at least 18, at least 18.1, at least 18.2, at least 18.3, at least 18.4, at least 18.5, at least 18.6, at least 18.7, at least 18.8, at least 18.9, at least 19, at least 19.1, at least 19.2, at least 19.3, at least 19.4, at least 19.5, at least 19.6, at least 19.7, at least 19.8, at least 19.9, at least 20, at least 20.1, at least 20.2, at least 20.3, at least 20.4, at least 20.5, at least 20.6, at least 20.7, at least 20.8, at least 20.9, at least 21, at least 21.1, at least 21.2, at least 21.3, at least 21.4, at least 21.5, at least 21.6, at least 21.7, at least 21.8, at least 21.9, at least 22, at least 22.1, at least 22.2, at least 22.3, at least 22.4, at least 22.5, at least 22.6, at least 22.7, at least 22.8, at least 22.9, at least 23, at least 23.1, at least 23.2, at least 23.3, at least 23.4, at least 23.5, at least 23.6, at least 23.7, at least 23.8, at least 23.9, at least 24, at least 24.1, at least 24.2, at least 24.3, at least 24.4, at least 24.5, at least 24.6, at least 24.7, at least 24.8, at least 24.9, at least 25, at least 25.1, at least 25.2, at least 25.3, at least 25.4, at least 25.5, at least 25.6, at least 25.7, at least 25.8, at least 25.9, at least 26, at least 26.1, at least 26.2, at least 26.3, at least 26.4, at least 26.5, at least 26.6, at least 26.7, at least 26.8, at least 26.9, at least 27, at least 27.1, at least 27.2, at least 27.3, at least 27.4, at least 27.5, at least 27.6, at least 27.7, at least 27.8, at least 27.9, at least 28, at least 28.1, at least 28.2, at least 28.3, at least 28.4, at least 28.5, at least 28.6, at least 28.7, at least 28.8, by at least 28.9, at least 29, at least 29.1, at least 29.2, at least 29.3, at least 29.4, at least 29.5, at least 29.6, at least 29.7, at least 29.8, or at least 29.9.

[0078] In another example, Prasinezumab may improve cognitive function, as measured by the MoCA scale, by 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50%, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90%, 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.60%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 10.10%, 10.20%, 10.30%, 10.40%, 10.50%, 10.60%, 10.70%, 10.80%, 10.90%, 11.00%, 11.10%, 11.20%, 11.30%, 11.40%, 11.50%, 11.60%, 11.70%, 11.80%, 11.90%, 12.00%, 12.10%, 12.20%, 12.30%, 12.40%, 12.50%, 12.60%, 12.70%, 12.80%, 12.90%, 13.00%, 13.10%, 13.20%, 13.30%, 13.40%, 13.50%, 13.60%, 13.70%, 13.80%, 13.90%, 14.00%, 14.10%, 14.20%, 14.30%, 14.40%, 14.50%, 14.60%, 14.70%, 14.80%, 14.90%, 15.00%, 15.10%, 15.20%, 15.30%, 15.40%, 15.50%, 15.60%, 15.70%, 15.80%, 15.90%, 16.00%, 16.10%, 16.20%, 16.30%, 16.40%, 16.50%, 16.60%, 16.70%, 16.80%, 16.90%, 17.00%, 17.10%, 17.20%, 17.30%, 17.40%, 17.50%, 17.60%, 17.70%, 17.80%, 17.90%, 18.00%, 18.10%, 18.20%, 18.30%, 18.40%, 18.50%, 18.60%, 18.70%, 18.80%, 18.90%, 19.00%, 19.10%, 19.20%, 19.30%, 19.40%, 19.50%, 19.60%, 19.70%, 19.80%, 19.90%, 20.00%, 20.10%, 20.20%, 20.30%, 20.40%, 20.50%, 20.60%, 20.70%, 20.80%, 20.90%, 21.00%, 21.10%, 21.20%, 21.30%, 21.40%, 21.50%, 21.60%, 21.70%, 21.80%, 21.90%, 22.00%, 22.10%, 22.20%, 22.30%, 22.40%, 22.50%, 22.60%, 22.70%, 22.80%, 22.90%, 23.00%, 23.10%, 23.20%, 23.30%, 23.40%, 23.50%, 23.60%, 23.70%, 23.80%, 23.90%, 24.00%, 24.10%, 24.20%, 24.30%, 24.40%, 24.50%, 24.60%, 24.70%, 24.80%, 24.90%, 25.00%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%; or by at least 0.10%, at least 0.20%, at least 0.30%, at least 0.40%, at least 0.50%, at least 0.60%, at least 0.70%, at least 0.80%, at least 0.90%, at least 1.00%, at least 1.10%, at least 1.20%, at least 1.30%, at least 1.40%, at least 1.50%, at least 1.60%, at least 1.70%, at least 1.80%, at least 1.90%, at least 2.00%, at least 2.10%, at least 2.20%, at least 2.30%, at least 2.40%, by at least 2.50%, at least 2.60%, at least 2.70%, at least 2.80%, at least 2.90%, at least 3.00%, at least 3.10%, at least 3.20%, at least 3.30%, at least 3.40%, at least 3.50%, at least 3.60%, at least 3.70%, at least 3.80%, at least 3.90%, at least 4.00%, at least 4.10%, at least 4.20%, at least 4.30%, at least 4.40%, at least 4.50%, at least 4.60%, at least 4.70%, at least 4.80%, at least 4.90%, at least 5.00%, at least 5.10%, at least 5.20%, at least 5.30%, at least 5.40%, at least 5.50%, at least 5.60%, at least 5.70%, at least 5.80%, at least 5.90%, at least 6.00%, at least 6.10%, at least 6.20%, at least 6.30%, at least 6.40%, at least 6.50%, at least 6.60%, at least 6.70%, at least 6.80%, at least 6.90%, at least 7.00%, at least 7.10%, at least 7.20%, at least 7.30%, at least 7.40%, at least 7.50%, at least 7.60%, at least 7.70%, at least 7.80%, at least 7.90%, at least 8.00%, at least 8.10%, at least 8.20%, at least 8.30%, at least 8.40%, at least 8.50%, at least 8.60%, at least 8.70%, at least 8.80%, at least 8.90%, at least 9.00%, at least 9.10%, at least 9.20%, at least 9.30%, at least 9.40%, at least 9.50%, at least 9.60%, at least 9.70%, at least 9.80%, at least 9.90%, at least 10.00%, at least 10.10%, at least 10.20%, at least 10.30%, at least 10.40%, at least 10.50%, at least 10.60%, at least 10.70%, at least 10.80%, at least 10.90%, at least 11.00%, at least 11.10%, at least 11.20%, at least 11.30%, at least 11.40%, at least 11.50%, at least 11.60%, at least 11.70%, at least 11.80%, at least 11.90%, at least 12.00%, at least 12.10%, at least 12.20%, at least 12.30%, at least 12.40%, at least 12.50%, at least 12.60%, at least 12.70%, at least 12.80%, at least 12.90%, at least 13.00%, at least 13.10%, at least 13.20%, at least 13.30%, at least 13.40%, at least 13.50%, at least 13.60%, at least 13.70%, at least 13.80%, at least 13.90%, at least 14.00%, at least 14.10%, at least 14.20%, at least 14.30%, at least 14.40%, at least 14.50%, at least 14.60%, at least 14.70%, at least 14.80%, at least 14.90%, at least 15.00%, at least 15.10%, at least 15.20%, at least 15.30%, at least 15.40%, at least 15.50%, at least 15.60%, at least 15.70%, at least 15.80%, at least 15.90%, at least 16.00%, at least 16.10%, at least 16.20%, at least 16.30%, at least 16.40%, at least 16.50%, at least 16.60%, at least 16.70%, at least 16.80%, at least 16.90%, at least 17.00%, at least 17.10%, at least 17.20%, at least 17.30%, at least 17.40%, at least 17.50%, at least 17.60%, at least 17.70%, at least 17.80%, at least 17.90%, at least 18.00%, at least 18.10%, at least 18.20%, at least 18.30%, at least 18.40%, at least 18.50%, at least 18.60%, at least 18.70%, at least 18.80%, at least 18.90%, at least 19.00%, at least 19.10%, at least 19.20%, at least 19.30%, at least 19.40%, at least 19.50%, at least 19.60%, at least 19.70%, at least 19.80%, at least 19.90%, at least 20.00%, at least 20.10%, at least 20.20%, at least 20.30%, at least 20.40%, at least 20.50%, at least 20.60%, at least 20.70%, at least 20.80%, at least 20.90%, at least 21.00%, at least 21.10%, at least 21.20%, at least 21.30%, at least 21.40%, at least 21.50%, at least 21.60%, at least 21.70%, at least 21.80%, at least 21.90%, at least 22.00%, at least 22.10%, at least 22.20%, at least 22.30%, at least 22.40%, at least 22.50%, at least 22.60%, at least 22.70%, at least 22.80%, at least 22.90%, at least 23.00%, at least 23.10%, at least 23.20%, at least 23.30%, at least 23.40%, at least 23.50%, at least 23.60%, at least 23.70%, at least 23.80%, at least 23.90%, at least 24.00%, at least 24.10%, at least 24.20%, at least 24.30%, at least 24.40%, at least 24.50%, at least 24.60%, at least 24.70%, at least 24.80%, at least 24.90%, at least 25.00%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, by at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0079] Without being bound by a specific theory, neutralization of toxic synuclein by prasinezumab and reduction of gliosis may result in synaptic protection and improved neuronal activity, which improves cognitive function. Furthermore, neurodegeneration of the locus coeruleus (LC)-norepinephrine network is slowed by prasinezumab treatment; the LC innervates the neurovascular system, and protection from toxic synuclein may improve cognitive function. Furthermore, protection of motor function by prasinezumab administration may reduce the need for patients to recruit cortical areas to compensate, freeing up cortical capacity to support cognitive function.

[0080] In various aspects of the invention, the Prasinezumab dosing regimen comprises about 1000-5000 mg of Prasinezumab administered at 3-5 week intervals. In particular aspects, the Prasinezumab dosing regimen comprises about 1000, 2000, 3000, 4000, or 5000 mg of Prasinezumab administered at 3, 4, or 5 week intervals, or as further described herein.

[0081] The Clinical Global Impression-Score (CGI-S) is a measure of disease severity rated on a 7-point scale, with the CGI-S using a response range from 1 (normal, not at all ill) to 7 (among the most ill). The Clinical Global Impression-Score (CGI-I) is a clinician's assessment of disease severity and progression, while the Patient Global Impression-Change (PGI-C) is designed to measure change in health status from the patient's perspective. Both CGI-I/PGI-C scores range from 1 (much improved) to 7 (much worse). Progressors on the CGI-I and PGI-C are classified as patients with scores of 5-7 (i.e., rated as "minimally worse," "much worse," or "much worse").

[0082] Without being bound by a specific theory, neutralization of toxic synuclein using Prasinezumab and reduction of gliosis may lead to synaptic protection and improved neuronal activity, which increases cerebral blood flow. Furthermore, neurodegeneration of the locus coeruleus (LC)-norepinephrine network is slowed by Prasinezumab treatment; LC innervates the neurovascular system, and protection from toxic synuclein may improve cerebrovascular regulation.

[0083] In one aspect of the invention, a method for improving blood flow comprises administering a Prasinezumab regimen according to the invention. In various aspects of the invention, the Prasinezumab administration regimen comprises about 1000-5000 mg of Prasinezumab at 3-5 week intervals. In particular aspects, the Prasinezumab administration regimen comprises about 1000, 2000, 3000, 4000, or 5000 mg of Prasinezumab administered at 3, 4, or 5 week intervals, or as further described herein.

[0084] In another aspect of the invention, the MDS-UPDRS Part III is a clinical motor function assessment that evaluates motor symptoms associated with Parkinson's disease. In one aspect, Prasinezumab can be used to reduce the decline in motor function in a subject having Parkinson's disease or at risk of developing Parkinson's disease, comprising administering a Prasinezumab regimen to the subject. For example, Prasinezumab may reduce the decline in motor function as measured by the MDS-UPDRS Part III by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%; or by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least or 100%.

[0085] In another example, Prasinezumab can reduce the decline in motor function by 35% compared to placebo after one year of treatment, according to the centrally assessed MDS-UPDRS Part III scale, and by 25% compared to placebo after one year of treatment, according to the MDS-UPDRS Part III scale assessed at the study center. In addition, Prasinezumab can be used to alleviate bradykinesia, one of the main symptoms of Parkinson's disease, which is assessed as a component of the MDS-UPDRS Part III clinical assessment of motor function.

[0086] In one aspect, Prasinezumab can be used to maintain motor function or delay a clinically significant worsening of the progression of motor disorders in a subject having Parkinson's disease or at risk of developing Parkinson's disease, wherein the method comprises administering a Prasinezumab regimen to the subject. The method can reduce the progression of Parkinson's disease, such as delay a clinically significant worsening of the progression of motor disorders. A reduction in disease progression can be demonstrated, for example, by prolonging the time to progression by at least 5 points on the MDS-UPDRS Part III.

[0087] In various aspects of the invention, the Prasinezumab administration regimen comprises 1000-5000 mg of Prasinezumab administered at 3-5 week intervals. In particular aspects, the Prasinezumab administration regimen comprises about 1000, 2000, 3000, 4000, or 5000 mg of Prasinezumab administered at 3, 4, or 5 week intervals, or as further described herein.

[0088] In another aspect of the invention, the method may improve the patient's MDS-UPDRS Part III motor function score and/or improve one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, pronation-supination hand movements, toe tapping, leg mobility, chair rise, gait, freezing of gait, postural stability, posture, body bradykinesia, hand tremor, resting tremor amplitude, resting tremor persistence, or Hoehn and Yahr stage. Furthermore, the method of the invention may improve bradykinesia, such as by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% compared to placebo after one year of treatment. Motor function can also be measured, for example, based on positive signals related to motor function, determined by a digital motor score, which includes a total score consisting of an assessment of signs of bradykinesia (80%) and signs of resting tremor (20%).

[0089] In another aspect of the invention, the MDS-UPDRS Part III is a clinical motor function assessment that evaluates motor symptoms associated with Parkinson's disease. In one aspect, Prasinezumab can be used to reduce the decline in motor function in a subject having Parkinson's disease or at risk of developing Parkinson's disease, comprising administering a Prasinezumab regimen to the subject. For example, Prasinezumab may reduce the decline in motor function as measured by the MDS-UPDRS Part III by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139% or 140%; or by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139% or at least 140%.

[0090] In another example, Prasinezumab can reduce the decline in motor function by 35% compared to placebo after one year of treatment, according to the centrally assessed MDS-UPDRS Part III scale, and by 25% compared to placebo after one year of treatment, according to the assessment of the MDS-UPDRS Part III scale performed at the study center. In addition, Prasinezumab can be used to alleviate bradykinesia, one of the main symptoms of Parkinson's disease, which is assessed as a component of the clinical assessment of motor function of MDS-UPDRS Part III.

[0091] In one aspect, Prasinezumab can be used to maintain motor function or delay a clinically significant worsening of the progression of motor disorders in a subject with Parkinson's disease or at risk of developing Parkinson's disease by administering a Prasinezumab regimen to the subject. The method can reduce the progression of Parkinson's disease, such as delay a clinically significant worsening of the progression of motor disorders. A reduction in disease progression can be demonstrated, for example, by prolonging the time to progression by at least 5 points on the MDS-UPDRS Part III.

[0092] In various aspects of the invention, the Prasinezumab administration regimen comprises 1000-5000 mg of Prasinezumab administered at 3-5 week intervals. In particular aspects, the Prasinezumab administration regimen comprises about 1000, 2000, 3000, 4000, or 5000 mg of Prasinezumab administered at 3, 4, or 5 week intervals.

[0093] In another aspect of the invention, the method may improve the patient's MDS-UPDRS Part III motor function score and/or improve one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination movements, toe tapping, leg mobility, chair rise, gait, freezing of gait, postural stability, posture, body bradykinesia, hand tremor, resting tremor amplitude, resting tremor persistence, or Hoehn and Yahr stage. Furthermore, the method of the invention may improve bradykinesia, such as by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% compared to placebo after one year of treatment. Motor function can also be measured, for example, based on positive signals related to motor function, determined by a digital motor score, which includes a total score consisting of an assessment of signs of bradykinesia (80%) and signs of resting tremor (20%).

[0094] Compositions

[0095] Compositions (also known as pharmaceutical compositions) of the invention include an antibody, such as Prasinezumab, a similar humanized antibody 9E4 or an antigen-binding fragment thereof, a buffer, and one or more excipients. The compositions can be prepared for storage in liquid form or in lyophilized form. When stored in lyophilized form, the compositions can be reconstituted with a liquid (e.g., sterile water) to the concentrations and properties described herein. When it is said that a lyophilized composition can be reconstituted by adding water to obtain a composition with the desired concentrations of components and pH, this means that the lyophilized composition can be reconstituted in this manner simply by adding water (i.e., without adding additional amounts of components or adding an acid or base to change the pH). The concentrations and properties of a pre-lyophilized liquid composition can also be as described below if the lyophilized composition is reconstituted to the same volume as the composition before lyophilization. If the volume differs, the concentrations of the compositions should be adjusted proportionally. For example, if the reconstituted volume is half the pre-lyophilization volume, the concentrations of the components in the lyophilized composition should be half those in the reconstituted composition.

[0096] Pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and are prepared in accordance with GMP requirements. The pharmaceutical compositions can be presented as a unit dosage form (i.e., a single-dose dosage). The pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, diluents, excipients, or auxiliary substances. The dosage form depends on the selected route of administration. For injection, prasinezumab can be formulated as aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, saline, or acetate buffer (to reduce discomfort at the injection site). The solution can contain substances used to formulate compositions, such as suspending, stabilizing, and/or dispersing agents. Alternatively, Prasinezumab may be lyophilized for reconstitution with a suitable vehicle, such as sterile, pyrogen-free water, prior to administration.

[0097] Pharmaceutically acceptable carrier compositions may also include additives, including, but not limited to, water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, acacia, casein, agar, polyethylene glycol, diglycerol, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, and surfactants acceptable as pharmaceutical additives.

[0098] The compositions (also known as pharmaceutical compositions) of the invention include an antibody (e.g., Prazinezumab or another chimeric, veneered, or humanized variant of murine 9E4), a buffer, one or more sugars and/or polyols, and a surfactant, and have a pH in the range of about 5 to about 7.5. The compositions can be prepared for storage in liquid form or in lyophilized form. When stored in lyophilized form, the compositions can be reconstituted with a liquid (e.g., sterile water) to the concentrations and properties described herein. When it is said that a lyophilized composition can be reconstituted by adding water to obtain a composition with the desired concentrations of components and pH, this means that the lyophilized composition can be reconstituted in this manner simply by adding water (i.e., without adding additional amounts of components or adding an acid or base to change the pH). The concentrations and properties of a pre-lyophilized liquid composition may also be as described below if the lyophilized composition is reconstituted to the same volume as the composition before lyophilization. If the volume differs, the concentrations of the compositions should be adjusted proportionally. For example, if the reconstituted volume is half the pre-lyophilization volume, the concentrations of the components in the lyophilized composition should be half those in the reconstituted composition.

[0099] Some compositions include a filler, which may be the same as or different from the sugar/polyol component. Typically, the compositions are sterile, for example, this is achieved by sterile filtration using a 0.2 μm or 0.22 μm filter. Some compositions have a bioburden of ≤ about 3 CFU/30 mL. Some compositions contain ≤ about 0.1 EU/mg bacterial endotoxins. The compositions of the present invention are also typically stable due to low to undetectable levels of fragmentation and/or aggregation, as further defined below, upon freezing and thawing. Other compositions are stable after reconstitution of a lyophilized cake for at least three months at 40 degrees Celsius. In some compositions, less than about 10% of the antibodies are present in the composition as an aggregate. In some compositions, less than or about 5% of the antibodies are present in the composition as an aggregate.

[00100] In some compositions, the antibody concentration is in the range of about 5 mg/mL to about 100 mg/mL. In some compositions, the antibody concentration is in the range of about 5 mg/mL to about 50 mg/mL. In some compositions, the antibody concentration is in the range of about 25 mg/mL to about 50 mg/mL. For example, the antibody may be present at a concentration of about 35-45 mg/mL or about 40 mg/mL. The antibody may be in a sterile liquid dosage form from about 50 mg/vial to about 500 mg/vial or more. The antibody may be present in a lyophilized dosage form from about 40 mg/vial to about 500 mg/vial. For example, the antibody may be in a sterile liquid or lyophilized dosage form of about 250-350 mg/vial or about 200 mg/vial.

[00101] The antibody in the composition may be any of the antibodies described above, including any of the chimeric, veneered, or humanized variants of the 9E4 antibody described above.

[00102] The disclosed compositions use buffers to achieve a suitable pH for the antibody, such as, for example, histidine, succinate, and citrate buffers. Some compositions have a pH in the range of about 5.5 to about 7, such as pH 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. Some compositions have a pH from about 5.5 to about 6.5. Some compositions have a pH of about 6.0, and other compositions have a pH of about 6.5. In some compositions, the citrate buffer or succinate buffer is present at a concentration in the range of about 10 mM to about 30 mM, such as about 15-25 mM or about 20 mM. Some citrate buffers contain sodium citrate dehydrate and citric acid monohydrate in a concentration range of about 15 mM to about 20 mM and about 2 mM to about 6 mM, respectively.

[00103] Suitable sugars and/or polyols for the compositions include trehalose, sucrose, mannitol, or a combination thereof. The sugars/polyols serve as bulking agents, lyoprotectants, and/or tonicity adjusting agents. For example, some compositions include trehalose present at a concentration in the range of about 220 mM to about 260 mM, sucrose present at a concentration in the range of about 220 mM to about 260 mM, or a mixture of sucrose present at a concentration in the range of about 20 mM to about 40 mM and mannitol present at a concentration in the range of about 200 mM to about 220 mM. Some compositions include trehalose present at a concentration of about 230 mM or 240 mM. Other compositions include sucrose present at a concentration of about 230 mM or 240 mM. Other compositions include a mixture of sucrose at a concentration of about 50 mM and mannitol at a concentration of about 200 mM. Another composition includes a mixture of sucrose at a concentration of about 28 mM and mannitol at a concentration of about 212 mM. Some such compositions are characterized by an osmolality in the range of about 250-400, 300-400, or 300-350 mOsm/kg, for example, 335 mOsm/kg.

[00104] The compositions may contain a surfactant to reduce antibody aggregation and absorption onto surfaces. Suitable surfactants include polysorbate 20 (PS20) present at a concentration in the range of about 0.005% to about 0.05% by weight. PS20 protects against a significant increase in aggregation or turbidity that would otherwise occur in 9E4 antibody compositions. Polysorbate 20 may be present at a concentration in the range of about 0.01% to about 0.05%. For example, the concentration may be 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, or 0.05%. Alternatively, in some compositions, polysorbate 20 is present at a concentration in the range of about 0.05 g/L, 0.1 g/L, 0.15 g/L, 0.2 g/L, 0.25 g/L, 0.3 g/L, 0.35 g/L, 0.4 g/L, 0.45 g/L, or 0.5 g/L. Some compositions include polysorbate 20 at a concentration of 0.2 g/L (i.e., 0.163 mmol/L).

[00105] An exemplary composition (liquid, pre-lyophilized, or reconstituted from lyophilization) has a pH in the range of about 5.5 to about 7 and includes: (a) Prasinezumab or a chimeric, veneered, or humanized version of the 9E4 antibody, or a fragment thereof that specifically competes with 9E4 for binding to an antigen, at a concentration in the range of about 10 mg/mL to about 50 mg/mL; (b) a citrate buffer or a succinate buffer present at a concentration in the range of about 10 mM to about 30 mM; (c) one or more sugars and polyols ("sugar/polyol") selected from trehalose present in a concentration in the range of about 220 mM to about 260 mM, sucrose present in a concentration in the range of about 220 mM to about 260 mM, and a mixture of sucrose present in a concentration in the range of about 20 mM to about 40 mM, and mannitol present in a concentration in the range of about 200 mM to about 220 mM; and (d) polysorbate 20 present in a concentration in the range of about 0.005% to about 0.05% by weight. For example, the composition may include: (a) an antibody comprising a light chain having an amino acid sequence presented as SEQ ID NO: 1, 2, 3, or 9, and a heavy chain comprising an amino acid sequence presented as SEQ ID NO: 4, 5, 6, or 10, with or without a C-terminal lysine, and which is present at a concentration of about 40 mg/mL; (b) citrate buffer at a concentration of about 20 mM; (c) trehalose at a concentration of about 230 mM; (d) polysorbate 20 at a concentration of about 0.02%; and a pH of about 6.0.

[00106] Some lyophilized compositions include: (a) a humanized version of the 9E4 antibody (e.g., Prasinezumab) or an antigen-binding fragment thereof; (b) citrate; (c) trehalose; and polysorbate 20. The lyophilized composition may include about 200 mg of antibody. Some lyophilized compositions may be reconstituted with sterile water. Some lyophilized compositions include 100-300 or 150-250 mg, or 15-35 or 20-25 mg sodium citrate dehydrate, 1.65-2.75 or 2-2.3 mg citric acid monohydrate, 360-500 or 400-470 mg trehalose dehydrate, and 0.5-1.5 mg or 0.75-1.25 mg polysorbate 20. An exemplary lyophilized composition includes 200 mg of antibody 9E4 (e.g., humanized antibody 9E4), 25 mg sodium citrate dehydrate, 2.15 mg citric acid monohydrate, 435 mg trehalose dehydrate, and 1 mg polysorbate 20. Another exemplary lyophilized composition includes 200 mg of antibody 9E4 (e.g., humanized antibody 9E4), 25 mg sodium citrate dehydrate, 3.15 mg citric acid monohydrate, 435 mg trehalose dehydrate, and 1 mg polysorbate 20. Such compositions can be reconstituted to a volume of about 5 mL. Other lyophilized compositions include the same components in the same proportions as any of the compositions described in this subsection, but in different amounts (e.g., 400 mg antibody, 50 mg sodium citrate, 4.3 mg citric acid monohydrate, 870 mg trehalose dehydrate, and 2 mg polysorbate 20).

[00107] Lyophilized compositions can be reconstituted to an antibody concentration of about 30-50 or 35-45 mg/mL, such as about 40 mg/mL; (b) with citrate buffer present at a concentration of about 10-30 or 15-25 mM, preferably about 20 mM; (c) with trehalose present at a concentration of about 160-330 or 200-260 mM, such as about 230 mM; (d) with polysorbate 20 present at a concentration of about 0.1-0.3 or 0.15-0.25 g/L, such as about 0.2 g/L; and (e) a pH of about 5.5-6.5, such as about 6.0.

[00108] Liquid or reconstituted lyophilized compositions may be substantially isotonic, which implies an osmolality of about 250-350 mOsm/kg water. The osmolality of some compositions is about 335 mOsm/kg. The osmolality of some compositions is 270-300 mOsm/kg. Liquid or reconstituted lyophilized compositions may also be hypertonic (>350 mOsm/kg water) or hypotonic (<250 mOsm/kg water).

[00109] Any of the described compositions can be prepared without pharmaceutical excipients, carriers, etc., other than those described above as components of the composition. Such a composition can be described as consisting of the listed components or consisting essentially of the listed components if minor amounts of other components are present that do not affect the properties of the composition. The compositions can be prepared in accordance with good manufacturing practices (GMP) approved or receiving approval by the FDA for the preparation of drugs for administration to humans.

[00110] Diagnostic criteria for Parkinson's disease

[00111] The methods of the present invention are typically used with subjects who have been diagnosed with Parkinson's disease by a qualified practitioner or who are at increased risk for developing it compared to the general population, as evidenced by genetic or biochemical markers, family history, or prodromal symptoms of the disease. Such subjects include anyone who has previously been prescribed treatment or prevention for Parkinson's disease. Diagnosis of a synucleinopathy of the Parkinson's disease type can be based on art-recognized criteria for possible or probable Parkinson's disease, such as the DSM-V or DSM IV-TR criteria, the Lewy Body Dementia Association, the Parkinson's Disease Society, and the like. However, the diagnosis can also be based on the presence of any signs or symptoms of Parkinson's disease that allow the treating physician to conclude that the subject likely has Parkinson's disease. Examples of diagnostic criteria for possible or probable PD are provided below.

• Group A: resting tremor, bradykinesia, rigidity and asymmetric onset.

• Group B features: suggest an alternative diagnosis.

• Marked postural instability within the first 3 years after symptom onset.

• Phenomenon of freezing in the first 3 years.

• Hallucinations not associated with medication during the first 3 years.

• Dementia preceding motor symptoms within the first year.

• Supranuclear gaze palsy (other than limited upward gaze) or slow vertical saccadic eye movement.

• Severe symptomatic autonomic dysfunction not related to medication.

[00112] Documentation of a condition known to cause parkinsonism and likely associated with the subject's symptoms (e.g., focal brain lesions in relevant locations or use of antipsychotics within the past 6 months).

[00113] Criteria for a possible diagnosis of Parkinson's disease include the following: at least 2 of the 4 Cluster A features are present; at least 1 of these is tremor or bradykinesia, and either no Cluster B features are present, or symptoms have been present for less than 3 years and none of the Cluster B features are present today; and either a significant and sustained response to levodopa or a dopamine agonist has been documented, or the subject has not tried appropriate treatment with levodopa or a dopamine agonist.

[00114] Criteria for a probable diagnosis of Parkinson's disease include the following: at least 3 or 4 of the group A features are present and none of the group B features are present, and a significant and sustained response to levodopa or a dopamine agonist has been documented.

[00115] The methods of the present invention can also be used for subjects at risk of developing Parkinson's disease. A subject at risk of developing Parkinson's disease may have one or more risk factors for developing Parkinson's disease. Risk factors for Parkinson's disease may include: age (Parkinson's disease typically begins in middle or old age, and the risk increases with age), genetics/heredity (i.e., having a close relative with Parkinson's disease increases the risk of developing PD), gender (men are more likely to develop Parkinson's disease than women), head injury (trauma to the head, neck, or upper cervical spine may increase a person's risk of developing Parkinson's disease), and exposure to toxins (e.g., chronic exposure to herbicides and pesticides may increase the risk of PD to some extent).

[00116] More recently, Parkinson's disease has been divided into three subtypes: mild movement-predominant (MM), diffuse malignant (DM), and intermediate. These subtypes are based on the symptoms experienced, particularly motor symptoms, cognitive impairment, rapid eye movement (REM) sleep disorder, and dysautonomia (a disorder of the autonomic nervous system, which controls involuntary processes in the body such as heart rate and sweating).

[00117] Treatment regimens

[00118] A therapeutically effective amount is a dose that, when administered for an effective period of time, achieves the desired clinical effect. Administration regimens may be adjusted to ensure an optimal therapeutic response. For example, multiple divided doses may be administered at set intervals (e.g., once daily, once weekly, once monthly), or the dose may be proportionally reduced depending on the complexity of the therapeutic situation.

[00119] For therapeutic purposes, the antibody is administered to a subject diagnosed with PD in a regimen (dose, frequency, and route of administration) known or suspected to be effective in improving or at least slowing down further worsening of at least one sign or symptom of the disease. For prophylactic purposes, the antibody is administered to a subject at increased risk of synucleinopathy, but not yet having sufficient symptoms to be diagnosed with the disease, in a regimen known or suspected to be effective in inhibiting or delaying the onset of at least one sign or symptom of the disease.

[00120] An exemplary dosage range for antibodies is from 1000 to 5000 mg of the alpha-synuclein antibody administered intravenously at 3-5 week intervals, such as every 4 weeks. In some embodiments, an exemplary dosage range for antibodies is from 3000 to 5000 mg of the alpha-synuclein antibody administered intravenously at 3-5 week intervals, such as every 4 weeks. In some subjects, the dosage is 3500-4500 mg every 3-5 weeks, such as every 4 weeks. Subjects may receive the same or different dosages (e.g., depending on the subject's body weight). In some methods, the subject receives one of two fixed dosages. For example, subjects with a body weight less than 65 kg may receive 3500 mg, and subjects with a body weight greater than or equal to 65 kg may receive 4500 mg. In some methods, the dose range for at least some subjects is 45-75 mg/kg, such as 50-70 mg/kg, 45 mg/kg, 60 mg/kg, or 65 mg/kg. Doses are typically administered multiple times at intervals of 3-5 weeks, such as every 28 days, every four weeks, or every calendar month. Subjects may receive at least 6, 9, 12, or 18 doses at such intervals or may receive doses for as long as symptoms of the condition persist or for the remainder of the subject's life. In some regimens, an initial loading dose of 2000 mg is administered, followed by doses in a range greater than or equal to 2000 mg but less than the intended target dose until the intended target dose is reached. For example, a subject may receive an initial loading dose of 2000 mg, followed by dose increases to 3500 mg or 4500 mg. Dose escalation may be a single subsequent incremental dose or a gradual increase of several doses until the target dose or a dose within the target range is reached. For example, a subject may receive an initial dose of 2000 mg followed by doses of 3500 mg. Alternatively, a subject may receive an initial dose of 2000 mg followed by one or more subsequent doses greater than or equal to 2000 mg but less than 3500 mg, followed by subsequent doses of 3500 mg. Similarly, a subject may receive an initial dose of 2000 mg followed by doses of 4500 mg. Alternatively, a subject may receive an initial dose of 2000 mg followed by subsequent doses greater than or equal to 2000 mg but less than 4500 mg, followed by subsequent doses of 4500 mg. In some regimens, the subject receives a dose of 3,000-5,000 mg of the antibody intravenously every four weeks for at least 52 weeks. In multiple-dose regimens with a dose within a specified range, such as 3,500-5,000 mg, the subject may receive the same or different doses within the specified range with each administration. In some regimens, the subject receives the same dose within a specified range with each administration.

[00121] In another exemplary administration regimen, a dose of 1300-1700 mg of antibody is administered to a subject intravenously at intervals of 3-5 weeks. An exemplary dose is 1500 mg. Subjects may receive one fixed dose or two or more different doses within this range, based on, for example, the subject's body weight. Some subjects receiving a dose within this range receive 18-25 mg/kg of antibody, such as 20 mg/kg. As with other methods, the intervals may be 3-5 weeks, such as administration every 4 weeks or every calendar month. Subjects may receive at least 6, at least 9, at least 12, or at least 18 doses, or may receive doses at such intervals for as long as symptoms persist or for the remainder of the subject's life.

[00122] Any of the treatment regimens may be accompanied by monitoring the subject receiving the treatment to track changes in motor and/or cognitive impairment. Preferably, such monitoring includes at least one assessment before and after the start of treatment. Preferably, the monitoring indicates a reduction in motor and/or cognitive impairment, which is a response to treatment, compared to the state before the start of treatment, or at least indicates a decrease in the rate of deterioration compared to the previous rate of deterioration in the subject or the rate of deterioration in control patients not receiving any immunotherapy. The subjects may also be monitored for changes in autonomic dysfunction, gastrointestinal dysfunction, visual hallucinations, or one or more psychological symptoms, among other signs or symptoms.

[00123] Administration of the regimens of the present invention may be performed concurrently with administration of another agent effective for the treatment or prevention of the disease being treated. The other agent may be another immunotherapeutic agent described herein or another agent for the treatment of Parkinson's disease, including levodopa, benzaseride, carbidopa, dopamine agonists, non-ergot dopamine agonists, catechol-O-methyl ("COMT") inhibitors such as, for example, entacopone or tolcopon, monoamine oxidase ("MAO") inhibitors including MAO-b inhibitors such as, for example, rasagaline or selegiline, amantadine, or anticholinergic agents, which may be used in combination with the regimens of the present invention. Some such other agents reduce one or more symptoms of the disease without affecting the causal factors.

Examples

[00124] Example 1. Phase II clinical trials of Prasinezumab

[00125] A Phase II trial was conducted for the alpha-synuclein antibody, Prasinezumab, in subjects with Parkinson's disease (PASADENA, Clinical Trial No. NCT03100149). The trial has two treatment arms and one control arm. Subjects were randomized to arms in a 1:1:1 ratio, with N=316. The initial phase of the study was a 52-week, double-blind treatment. During the initial phase of the study, subjects did not receive other treatments for Parkinson's disease (including symptomatic treatment). Subjects in one treatment arm received a fixed dose of 1500 mg of the antibody (low dose) intravenously every four weeks. Subjects in the other treatment group received 3,500 mg or 4,500 mg of the antibody (high dose) intravenously every four weeks based on body weight, with subjects weighing less than 65 kg receiving the low dose and those weighing 65 kg or more receiving the high dose. Subjects in the second group received a loading dose of 2,000 mg and optionally additional escalating doses of 2,000 mg or more to reach a target dose of 3,500 mg or 4,500 mg. Dosage continued for one year (52 weeks). The trial then had an extension period during which subjects initially assigned to the placebo group received one of the two treatment regimens from the initial phase, while subjects in the treatment groups in the initial phase continued to receive the same treatment as before. During the extension phase of the study, subjects could receive systemic treatment with levodopa and the antibody being studied, but did not receive other treatments for Parkinson's disease.

Table 1
Baseline characteristics of patients in the Phase II study Placebo
(n=105)* Low dose
(n=105)* High dose
(n=106)* All patients Age (years)
Mean (SD) 59.9 (8.7) 60.3 (8.8) 59.4 (9.8) 59.9 (9.1) Floor
Male N (%)
Female N (%) 71 (67.6)
34 (32.4) 71 (67.6)
34 (32.4) 71 (67.0)
35 (33.0) 213 (67.4) Body weight (kg)
Mean (SD) 75.74 (14.48) 78.02 (13.66) 76.17 (13.03) Duration of the disease
Mean (SD) 9.9 (6.8) 10.2 (6.3) 10.1 (6.5) 10.1 (6.5) MAO-Bi Yes
No 38 (36.2) 38 (36.2) 39 (36.8) 115 (36.4) 67 (63.8) 67 (63.8) 67 (63.2) 201 (63.6) Subphenotypes Diffuse malignant 15 (14.3) 21 (20.0) 23 (21.7) 59 (18.7) Mild, predominantly motor disturbances 39 (37.1) 28 (26.7) 39 (36.8) 106 (33.5) Intermediate 51 (48.6) 56 (53.3) 44 (41.5) 151 (47.8) MDS-UPDRS total
Mean (SD) 32.01 (12.98) 31.49 (13.32) 30.75 (12.10) 31.41 (12.78) MDS-UPDRS, Part III,
Mean (SD) 21.54
(9.11) 21.90
(9.14) 20.97 (8.81) 21.47 (9.00) MDS-UPDRS, Part II
Mean (SD) 5.55 (4.0 9) 4.94 (3.99) 5.50 (4.07) 5.33 (4.04) MDS-UPDRS, Part I
Mean (SD) 4.91 (3.71) 4.64 (4.16) 4.27 (3.57) 4.61 (3.83) H&Y stage I (%)
II (%) 20 (19.0) 29 (27.6) 29 (27.4) 78 (24.7) 85 (81.0) 76 (72.4) 77 (72.6) 238 (75.3) MoCA overall score
Mean (SD) 27.83
(2.0 1) 27.97
(1.94) 27.81 (2.15) SCOPA-AUT
Mean (SD) 7.68 (5.36) 7.95 (5.83) 8.52 (5.93) PDSS-2
Mean (SD) 9.41 (6.41) 8.57 (6.21) 8.49 (5.94) The nature of REM sleep
Positive (≥5)
Negative (<5) 24 (22.9%)
81 (77.1%) 34 (32.4%)
71 (67.6%) 27 (25.7%)
78 (74.3%) SE-ADL category
Independent.
Not independent. 104
(99.0%)
1 (1.0%) 104
(100%)
0 106 (100%)
0 CGI-S
Average (SD) 3.0 5 (0.63) 3.0 5 (0.63) 3.0 6 (0.64) PDQ-39
Mean (SD) 10.0 8
(7.0 6) 9.59 (7.54) 9.36 (6.82) DaT-SPECT imaging
Mean (SD) 1.0 6 (0.30) 1.0 4 (0.33) 1.0 8 (0.34) Patients with evaluable data at week 52 ^† 76 (72.4) 75 (73.5) 73 (70.9) 224 (70.9) *n represents the number of participants contributing to the summary statistics. Percentages are based on n.
Visits are time-limited. Non-evaluable data are considered to include initiation of symptomatic treatment for PD in a patient, an increase in MAO-Bi (if the patient was taking MAO-Bi at the start of the study), or study withdrawal.
H&Y - Hen and Yar; MAO-Bi - monoamine oxidase B inhibitor; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale; PD - Parkinson's disease; SD - standard deviation

[00126] Prasinezumab was found to be generally safe and well tolerated, with most adverse events reported as mild or moderate and similar for placebo and both treatment groups. The majority of reported adverse events (AEs) (92%) were mild (grade 1-2). One grade 4 AE was reported, which was considered unrelated to study drug. There were no grade 5 AEs (see Table 2).

Table 2
Safety data overview Placebo
(n=105) Low dose
(n=105) High dose
(n=106) All patients
(n=316) Total number of AE* 411 428 549 1388 Total number of fatal AEs (grade 5)* 0 0 0 0 Total number of patients with at least one (%): AE 87 (82.9) 98 (93.3) 97 (91.5) 282 (89.2) SAE 5 (4.8) 7 (6.7) 8 (7.5) 20 (6.3) AE grades 3-4 8 (7.6) 4 (3.8) 8 (7.5) 20 (6.3) AEs leading to treatment discontinuation or temporary cessation of treatment 1 (0.9) 2 (1.9) 5 (4.7) 8 (2.5) All degrees of IRR 17 (16.2) 20 (19.0) 36 (33.9) 73 (23.1) IRR grade 1-2 17 (16.2) 20 (19.0) 35 (33) 72 (22.8) IRR grade 3 0 0 1 (0.9) 1 (0.3) *Most AEs were grade 1-2. Only one grade 4 AE (suicide attempt) was reported and was considered unrelated to study treatment (high-dose group). The most common (>1.0%) grade 3-4 AEs were: radius fracture – in two patients (1.9%) in the placebo group (but in none of the patients in the prasinezumab-treated groups) and anxiety – in two patients (1.9%) in the high-dose group (none in the low-dose or placebo groups).
Percentages are based on the N in the column headings. Only treatment-related AEs are displayed if the response to the Study Drug Adjustment Report Form question was "drug discontinued."
When calculating frequency for a preferred term, multiple instances of the same AE in a subject are counted only once.
When calculating the frequency of the "total number of events" rows, multiple instances of the same AE in a subject are counted separately.
AE - adverse event; IRR - infusion-related reaction; SAE - serious AE

[00127] Objectives:

[00128] The primary objective was to evaluate the efficacy of prasinezumab compared with placebo at week 52 in participants with early PD (H&Y stages I and II) who were untreated or receiving MAO-B inhibitors from baseline, as measured by change from baseline in the MDS UPDRS total score (sum of Parts I, II, and III).

[00129] Secondary objectives are to evaluate the effects of prasinezumab compared with placebo at week 52 in participants with early PD (H&Y stages I and II) who were untreated or treated with MAO-B inhibitors at baseline, based on the following:

• MDS UPDRS;

• Visualization of dopamine transporters by single-photon emission computed tomography (DaT-SPECT) in the ipsilateral (to the clinically dominant side) putamen;

• Total score on the Montreal Cognitive Assessment (MoCA);

• Clinical Global Impression of Improvement (CGI-I);

• Patient Global Impression of Change (PGI-C);

• Assessment of activities of daily living according to the Schwab and England scale (SE-ADL);

• Time to worsening of motor or non-motor symptoms; and/or

• Time to initiation of dopaminergic PD therapy (levodopa or dopamine agonists).

[00130] Example 2 Patients with Parkinson's disease treated with Prasinezumab show improvement in cognitive function

[00131] The study did not meet the primary endpoint of change in MDS-UPDRS total score (Figure 1; -21.5% Low dose: -2.02 80% CI -4.21, -0.18; -6.6% High dose: -0.62 80% CI -2.82, -1.58). However, an unexpected efficacy signal was observed for change from baseline in cognitive function. Clear signals favoring prasinezumab were demonstrated at both dose levels as determined by the Montreal Cognitive Assessment (MoCA), a screening assessment of cognitive function. On average, patients receiving prasinezumab had cognitive function scores within the normal range at baseline, and patients receiving prasinezumab showed improvement in their MoCA scores (the MoCA is a 30-point scale, with a higher score indicating better cognitive function). Figure 2, for example, shows that the improvement was at least 0.2 on the MoCA score scale.

[00132] ANCOVA analysis showed that the difference in adjusted mean absolute change from baseline in MoCA total score at week 52 was 0.22 (80% CI: -0.09, 0.54) in the low dose group and 0.44 (80% CI: 0.13, 0.75) in the high dose group compared to the placebo group (see Table 3 below).

Table 3
Change in MoCA score Absolute change from baseline Placebo
(N=105) Prasinezumab
Low dose
(N=105) Prasinezumab
High dose
(N=105) n 104 100 103 Adjusted mean (SE) 0.07 (0.177) 0.30 (0.181) 0.51 (0.178) 80% CI for adjusted mean (-0.16, 0.30) (0.06, 0.53) (0.28, 0.74) Adjusted mean difference (SE) 0.22 (0.245) 0.44 (0.243) 80% CI for the difference in adjusted means (-0.09, 0.54) (0.13, 0.75)

[00133] Further analyses based on the CGI-I and PGI-C confirmed the reduced risk of worsening. Consistent signals favoring prasinezumab were also demonstrated at both dose levels for the Clinical Global Impression of Improvement (CGI-I) and the Patient Global Impression of Change (PGI-C), two measures of global impression of change. Based on both the CGI-I and PGI-C, which assess physician and patient change in health status, respectively, patients receiving prasinezumab demonstrated a reduced risk of worsening. (Figure 3 and Figure 4).

[00134] Example 3: Parkinson's Disease Patients Treated with Prasinezumab Show Improved Brain Blood Flow

[00135] The study did not meet the primary endpoint of change in MDS-UPDRS total score (Fig. 1; -21.5% Low dose: -2.02 80% CI -4.21, -0.18; -6.6% High dose: -0.62 80% CI -2.82, -1.58). However, an unexpected efficacy signal was observed regarding the change in cerebral blood flow from baseline to week 52. In an analysis of cerebral blood flow assessed by changes in MRI-labeled arterial spins (MRI-ASL), in a subset of patients, patients receiving prasinezumab showed improved cerebral blood flow in the putamen, a brain region associated with dopaminergic loss and the presence of alpha-synuclein pathology in Parkinson's disease, suggesting an effect on the underlying biology associated with the disease (Figure 5).

[00136] Assessment of specific brain regions showed improved blood flow in the putamen, pallidum, and premotor region (Figures 6A, 6B, and 6C).

[00137] Example 4. Patients with Parkinson's disease treated with Prasinezumab show improvement in motor function

[00138] The study did not meet the primary endpoint of change in MDS-UPDRS total score (Figure 1; -21.5% Low dose: -2.02 80% CI -4.21, -0.18; -6.6% High dose: -0.62 80% CI -2.82, -1.58). However, an unexpected efficacy signal was observed in terms of change from baseline in MDS-UPDRS Part III score in patients receiving prasinezumab compared to placebo at 52 weeks. Patients receiving prasinezumab demonstrated less decline in motor function compared to the placebo group at one year and a delay in the time to clinically significant worsening of movement disorder progression in patients with early Parkinson's disease.

[00139] When assessed by the MDS-UPDRS Part III, patients exhibited less decline in motor function across study centers (Figure 7A; pooled dose levels: -25.0%, -1.44, 80% CI=(-2.83, -0.06); low dose level: -33.8%, -1.88, 80% CI=(-3.49, -0.27); and high dose level: -18.2%, -1.02, 80% CI=(-2.64, 0.61)).

[00140] Prasinezumab also reduced the decline in motor function by 35% compared to placebo after one year of treatment, as measured by the centralized MDS-UPDRS Part III Clinical Assessment of Motor Function (Fig. 7B; pooled dose levels: -35.0%, -1.88, 80% CI= (-3.31, -0.45); low dose level: -45.4%, -2.44, 80% CI= (-4.09, -0.78); and high dose level: -24.7%, -1.33, 80% CI= (-2.99, 0.34)).

[00141] Furthermore, treatment with prasinezumab resulted in reduced disease progression in patients receiving prasinezumab, as demonstrated by the delay in time to clinically significant worsening in movement disorder progression, as measured by the site-based assessment of time to at least a 5-point progression on the MDS-UPDRS Part III, compared to placebo at one year, with a hazard ratio of 0.82 (Figure 8).

[00142] Efficacy signals were observed in the change from baseline in bradykinesia in patients receiving prasinezumab compared to placebo at week 52 at the study center assessment (pooled dose levels: -27.0%, -0.75, 80% CI=(-1.62, 0.11); low dose level: -38.3%, -1.07, 80% CI=(-2.07, -0.07); and high dose level: -15.7%, -0.44, 80% CI=(-1.45, 0.56)) (Figure 9). Bradykinesia is a core symptom of Parkinson's disease and is assessed as a component of the MDS-UPDRS Part III motor function clinical assessment.

[00143] Example 5. Patients with Parkinson's disease treated with Prasinezumab show improvement in motor function

[00144] The study did not meet the primary endpoint of change in MDS-UPDRS total score (Figure 1; -21.5% Low dose: -2.02 80% CI -4.21, -0.18; -6.6% High dose: -0.62 80% CI -2.82, -1.58; and Table 4). However, an unexpected efficacy signal was observed for the change from baseline in MDS-UPDRS Part III score in patients receiving prasinezumab compared with placebo at 52 weeks. Patients receiving prasinezumab demonstrated less decline in motor function compared with placebo at one year and a delay in time to clinically significant worsening of movement disorder progression in patients with early Parkinson's disease.

Table 4 Placebo
(n=105) 1500 mg
(n=105) 4500 mg
(n=106) Total number of AE 411 428 549 Total number of fatal AEs (grade 5)* 0 0 0 Total number of patients with at least one (%) AE 87 (82.9) 98 (93.3) 97 (91.5) SAE 5 (4.8) 7 (6.7) 8 (7.5) AE grades 3-5 8 (7.6) 4 (3.8) 8 (7.5) AEs leading to treatment discontinuation or temporary cessation of treatment 1 (1.0) 2 (1.9) 5 (4.7) All degrees of IRR 17 (16.2) 20 (19.0) 36 (33.9) IRR grade 1-2 17 (16.2) 20 (19.0) 35 (33.0) IRR grade 3 0 0 1 (0.9) *Most AEs were grade 1-2. Only one grade 4 AE (suicide attempt) was reported and was considered unrelated to study treatment (high-dose group). The most common (>1.0%) grade 3-4 AEs were: radius fracture, reported in two patients (1.9%) in the placebo group (but in none of the patients in the prasinezumab-treated groups), and anxiety, reported in two patients (1.9%) in the 4500 mg dose group (none in the 1500 mg dose group or the placebo group).
Percentages are based on the N in the column headings. Only treatment-emergent AEs are displayed if the response to the Study Drug Adjustment Report Form question was "drug discontinued." When calculating the frequency by preferred term, multiple occurrences of the same AE in a subject are counted only once. When calculating the frequency of the "total number of events" rows, multiple occurrences of the same AE in a subject are counted separately.
4500 mg for ≥65 kg; 3500 mg for <65 kg.
AE - adverse event; CI - confidence interval; DaT-SPECT - dopamine transporter imaging by single-photon emission computed tomography; IRR - infusion reaction; MAO-B - monoamine oxidase B; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale; MMRM - mixed-effects model for multiple measures; PD - Parkinson's disease. SAE - serious AE

[00145] When assessed by the MDS-UPDRS Part III, patients demonstrated reduced motor decline across study centers (Figure 7A; pooled dose levels: -25.0%, -1.44, 80% CI=(-2.83, -0.06); low dose level: -33.8%, -1.88, 80% CI=(-3.49, -0.27); and high dose level: -18.2%, -1.02, 80% CI=(-2.64, 0.61)).

[00146] Prasinezumab also reduced motor decline by 35% compared to placebo after one year of treatment, as measured by the centrally assessed MDS-UPDRS Part III Clinical Assessment of Motor Function (Fig. 7B; pooled dose levels: -35.0%, -1.88, 80% CI= (-3.31, -0.45); low dose level: -45.4%, -2.44, 80% CI= (-4.09, -0.78); and high dose level: -24.7%, -1.33, 80% CI= (-2.99, 0.34)).

[00147] Furthermore, treatment with prasinezumab resulted in reduced disease progression in patients receiving prasinezumab, as demonstrated by the delay in time to clinically significant worsening in movement disorder progression, as measured by the site-based assessment of time to at least a 5-point progression on the MDS-UPDRS Part III, compared to placebo at one year, with a hazard ratio of 0.82 (Figure 8).

[00148] Efficacy signals were observed in the change from baseline in bradykinesia in patients receiving prasinezumab compared to placebo at week 52 at the study center assessment (pooled dose levels: -27.0%, -0.75, 80% CI=(-1.62, 0.11); low dose level: -38.3%, -1.07, 80% CI=(-2.07, -0.07); and high dose level: -15.7%, -0.44, 80% CI=(-1.45, 0.56)) (Figure 9). Bradykinesia is a core symptom of Parkinson's disease and is assessed as a component of the MDS-UPDRS Part III motor function clinical assessment.

[00149] To differentiate the effects of prasinezumab treatment on different subphenotypes in the overall population, subgroup analyses were performed in the overall population. For example, subjects requiring symptomatic therapy such as MAO-B inhibitors and subjects with the diffuse malignant subphenotype. It was observed that while the progression of movement disorders in Parkinson's disease in the untreated early-stage population was generally slow (approximately 5 points per year on the MDS-UPDRS Part III; Fig. 10, upper panel), the progression of movement disorders in more aggressive subtypes of Parkinson's disease in the overall population was significantly more rapid. The subgroup of patients receiving MAO-B inhibitors experienced a change of ~7 points per year; Fig. 10, middle panel), and the diffuse malignant subphenotype demonstrated a change of ~10 points per year; Fig. 10, lower panel).

[00150] Referring to Fig. 10, patients who started symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, sex, DaT-SPECT binding coefficient in the putamen (contralateral to the most clinically affected side), baseline MDS-UPDRS, corresponding endpoint. Pooled dose analysis is a pre-specified study exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg. CI - confidence interval; DaT-SPECT - dopamine transporter imaging by single photon emission computed tomography; MAO-B - monoamine oxidase B; MDS-UPDRS - Movement Disorder Society Unified Parkinson's Disease Rating Scale; and MMRM - mixed-effects model for multiple measures.

[00151] Again, when assessed by MDS-UPDRS Part III across study centers, patients in the pooled overall population demonstrated a 25% reduction in motor function decline compared to placebo after one year of treatment, as determined by study center. The effects of the low doses were stronger, with a 33.8% reduction in function decline, while the higher dose showed an 18.2% reduction in decline (see Fig. 11A; pooled dose levels: -25.0%, -1.44, 80% CI=(-2.83, -0.06); low dose level: -33.8%, -1.88, 80% CI=(-3.49, -0.27); and high dose level: -18.2%, -1.02, 80% CI=(-2.64, 0.61)).

[00152] In the MAO-B inhibitor treatment subgroup, a 39% reduction in motor function decline was observed compared to placebo after one year of treatment, as assessed by the study center. The effects of the low doses were stronger, with a 71.1% reduction in function decline; while the higher dose showed a 4% reduction in function decline after one year (see Fig. 11B; pooled dose levels: -39.0%, -2.66, 80% CI=(-4.87, -0.45); low dose level: -71.1%, -4.85, 80% CI=(-7.33, -2.37); high dose level: -4.0%, -0.28, 80% CI=(-2.82, 2.25)).

[00153] In the diffuse malignant subtype subgroup, a 63.9% reduction in motor function decline was observed compared to placebo after one year of treatment, as assessed by the study center. The low-dose and high-dose regimens performed similarly, demonstrating a 68.3% reduction in function decline at the low dose and a 63.2% reduction at the high dose after one year (see Fig. 11C: pooled dose levels: -63.9%, -7.86, 80% CI=(-12.9, -2.82); low dose level: -68.3%, -8.4, 80% CI=(-14.2, -2.59); high dose level: -63.2%, -7.77, 80% CI=(-13.4, -2.14)).

[00154] Referring to Figs. 11A-11C, patients who started symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, gender, DaT-SPECT binding coefficient in the putamen (contralateral to the most clinically affected side), baseline MDS-UPDRS, corresponding endpoint. Pooled dose analysis is a pre-specified exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg.

[00155] When assessed by central monitoring or assessment according to MDS-UPDRS Part III, patients in the pooled overall population demonstrated a 35% reduction in motor function decline compared to placebo after one year of treatment, as assessed centrally. The effects of low doses were stronger, with a 45.4% reduction in function decline, while the higher dose demonstrated a 24.7% reduction in decline (see Fig. 12A; pooled dose levels: -35.0%, -1.88, 80% CI= (-3.31, -0.45); low dose level: -45.4%, -2.44, 80% CI= (-4.09, -0.78); and high dose level: -24.7%, -1.33, 80% CI= (-2.99, 0.34)).

[00156] In the MAO-B inhibitor treatment subgroup, a 52.1% reduction in motor function decline was observed compared to placebo after one year of treatment, according to the central assessment. The effects of the low doses were stronger, with a 74.1% reduction in function decline; while the higher dose showed a 17.3% reduction in function decline after one year (see Fig. 12B; pooled dose levels: -52.1%, -3.16, 80% CI=(-5.50, -0.82); low dose level: -74.1%, -4.49, 80% CI=(-7.08, -1.90); high dose level: -17.3%, -1.05, 80% CI=(-3.97, 1.87)).

[00157] In the diffuse malignant subtype, a 76.1% reduction in motor function decline was observed compared to placebo after one year of treatment, according to the central assessment. The effects of the low doses were stronger, with a 108.7% reduction in function decline; while the high dose demonstrated a 70.5% reduction in function decline after one year (see Fig. 12C; pooled dose levels: -76.1%, -9.24, 80% CI=(-15.4, -3.07); low dose level: -108.7%, -13.2, 80% CI=(-21.2, -5.17); high dose level: -70.5%, -8.56, 80% CI=(-16.0, -1.10)).

[00158] Referring to Figs. 12A-12C, patients who started symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, gender, DaT-SPECT binding coefficient in the putamen (contralateral to the most clinically affected side), baseline MDS-UPDRS, corresponding endpoint. Pooled dose analysis is a pre-specified exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg.

[00159] Patients also completed daily smartphone-based motor tests using input surfaces (e.g., screen) and internal sensors to assess bradykinesia, tremor/bradykinesia, tremor only, rigidity and postural instability, and cognitive function. Results were combined to create the “PASADENA Digital Motor Score.” Frequent testing allowed modeling of the slopes of the motor impairment progression curves to reflect primarily bradykinesia scores. This mixed model demonstrated a slowing of motor impairment progression, as measured by the PASADENA Digital Motor Score, in both the low- and high-dose groups (compared to placebo).

[00160] In the pooled overall population, a 25.0% reduction in the decline in PASADENA Digital Motor Score was observed compared to placebo after one year of treatment. The effects of the low doses were stronger, with a 30.3% reduction in decline; while the higher dose showed a 21.5% reduction in decline after one year (see Fig. 13A; pooled dose levels: -25.0%, -0.030, 80% CI=(-0.050, -0.010); low dose level: -30.3%, -0.040, 80% CI=(-0.063, -0.017); high dose level: -21.5%, -0.029, 80% CI=(-0.052, -0.006)).

[00161] In the MAO-B inhibitor treatment subgroup, a 26.0% reduction in PASADENA digital motor score decline was observed compared to placebo after one year of treatment. The effects of the low doses were stronger, with a 31.0% reduction in score decline with a reduction in functional decline; whereas the higher dose showed a 20.9% reduction in decline after one year (see Fig. 13B; pooled dose levels: -26.0%, -0.032, 80% CI=(-0.062, -0.003); low dose level: -31.0%, -0.039, 80% CI=(-0.072, -0.049); high dose level: -20.9%, -0.026, 80% CI=(-0.060, 0.008)).

[00162] In the diffuse malignant subtype, a 35.7% reduction in PASADENA digital motor score decline was observed compared to placebo after one year of treatment. The effects of the low dose were less potent, with a 25.2% reduction in score decline; whereas the high dose demonstrated a 46.2% reduction in decline after one year (see Fig. 13C; pooled dose levels: -35.7%, -0.055, 80% CI=(-0.105, -0.005); low dose level: -25.2%, -0.039, 80% CI=(-0.094, 0.017); high dose level: -46.2%, -0.071, 80% CI=(-0.126, -0.017)).

[00163] Referring to Figs. 13A-13C, patients who started symptomatic treatment for PD cooperated until the last visit before starting symptomatic treatment for PD. Bars represent 80% CI. Estimates are based on MMRM with the following covariates: MAO-B inhibitor at baseline (yes/no), treatment, week, age <60 vs ≥60, gender, DaT-SPECT binding coefficient in the putamen (contralateral to the most clinically affected side), baseline MDS-UPDRS, corresponding endpoint. Pooled dose analysis is a pre-specified exploratory analysis. 4500 mg for ≥65 kg; 3500 mg for <65 kg.

SEQUENCES

[00164] SEQ ID NO:1 is the variable region of Hu9E4VLv3.

DIQMTQSPSSLSASVGDRVTITCKSIQTLLYSSNQKNYLAWFQQKPGKAPKLLIYWASIRKSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSYPLTFGGGTKLEIK

[00165] SEQ ID NO:2 is the variable region of Hu9E4VLv1.

DIQMTQSPSSLSASVGDRVTITCKSIQTLLYSSNQKNYLAWFQQKPGKAPKLLIYWASIRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSYPLTFGGGTKLEIK

[00166] SEQ ID NO:3 is the variable region of Hu9E4VLv2 (no backmutations).

DIQMTQSPSSLSASVGDRVTITCKSIQTLLYSSNQKNYLAWYQQKPGKAPKLLIYWASIRKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSYPLTFGGGTKLEIK

[00167] SEQ ID NO:4 is the variable region of Hu9E4VHv3.

EVQLVESGGGLVQPGGSLRLSCAASGTFFSNYGMSWVRQAPGKGLEWVASISSGGGGSTYYPDNVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARGGAGIDYWGQGTLVTVSS

[00168] SEQ ID NO:5 is the variable region of Hu9E4VHv1.

EVQLVESGGGLVQPGGSLRLSCAASGTFFSNYGMSWVRQAPGKGLEWVASISSGGGGSTYYPDNVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCSRGGAGIDYWGQGTLVTVSS

[00169] SEQ ID NO:6 is the variable region of Hu9E4VHv2.

EVQLVESGGGLVQPGGSLRLSCAASGTFFSNYGMSWVRQAPGKGLEWVASISSGGGSTYYPDNVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCSRGGAGIDYWGQGTLVTVSS

[00170] SEQ ID NO:7 is the variable region of Hu9E4VHv4 (no backmutations).

EVQLVESGGGLVQPGGSLRLSCAASGTFFSNYGMSWVRQAPGKGLEWVASISSGGGSTYYPDNVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGGAGIDYWGQGTLVTVSS

[00171] SEQ ID NO:8 is the amino acid sequence of naturally occurring wild-type human alpha-synuclein.

MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA

[00172] SEQ ID NO:9 is the amino acid sequence of the light chain of Prasinezumab

DIQMTQSPSSSLSASVGDRVTITCKSIQTLLYSSNQKNYLAWFQQKPGKAPKLLIYWASIR 60

KSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYYSYPLTFGGGTKLEIKRTVAAPS 120

VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS 180

LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 220

[00173] SEQ ID NO:10 is the amino acid sequence of the heavy chain of Prasinezumab

EVQLVESGGGLVQPGGSLRLSCAASGTFFSNYGMSWVRQAPGKGLEWVASISSGGGSTYY 60

PDNVKGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCARGGAGIDYWGQGTLVTVSSASTK 120

GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS 180

LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF 240

LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR 300

VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN 360

QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN 420

VFSCSVMHEALHNHYTQKSLSLSPGK 446

--->

SEQUENCE LIST

<110> PROTHENA BIOSCIENCES LIMITED

F. HOFFMANN-LA ROCHE AG

<120> TREATMENT OF PARKINSON'S DISEASE

<130> 20-1293-WO

<150> US 63/076,913

<151> 2020-09-10

<150> US 63/076,915

<151> 2020-09-10

<150> US 63/076,916

<151> 2020-09-10

<150> US 63/158,191

<151> 2021-03-08

<160> 10

<170> PatentIn version 3.5

<210> 1

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region Hu9E4VLv3

<400> 1

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 2

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region Hu9E4VLv1

<400> 2

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 3

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region of Hu9E4VLv2 (without back mutations)

<400> 3

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 4

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region Hu9E4VHv3

<400> 4

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 5

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region of Hu9E4VHv1

<400> 5

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 6

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region Hu9E4VHv2

<400> 6

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 7

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<223> Variable region of Hu9E4VHv4 (without back mutations)

<400> 7

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 8

<211> 140

<212> Protein

<213> Homo sapiens

<400> 8

Met Asp Val Phe Met Lys Gly Leu Ser Lys Ala Lys Glu Gly Val Val

1 5 10 15

Ala Ala Ala Glu Lys Thr Lys Gln Gly Val Ala Glu Ala Ala Gly Lys

20 25 30

Thr Lys Glu Gly Val Leu Tyr Val Gly Ser Lys Thr Lys Glu Gly Val

35 40 45

Val His Gly Val Ala Thr Val Ala Glu Lys Thr Lys Glu Gln Val Thr

50 55 60

Asn Val Gly Gly Ala Val Val Thr Gly Val Thr Ala Val Ala Gln Lys

65 70 75 80

Thr Val Glu Gly Ala Gly Ser Ile Ala Ala Ala Thr Gly Phe Val Lys

85 90 95

Lys Asp Gln Leu Gly Lys Asn Glu Glu Gly Ala Pro Gln Glu Gly Ile

100 105 110

Leu Glu Asp Met Pro Val Asp Pro Asp Asn Glu Ala Tyr Glu Met Pro

115 120 125

Ser Glu Glu Gly Tyr Gln Asp Tyr Glu Pro Glu Ala

130 135 140

<210> 9

<211> 220

<212> Protein

<213> Artificial sequence

<220>

<223> Prasinezumab light chain

<400> 9

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser

20 25 30

Ser Asn Gln Lys Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys

35 40 45

Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val

50 55 60

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

<210> 10

<211> 446

<212> Protein

<213> Artificial sequence

<220>

<223> Prasinezumab heavy chain

<400> 10

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<---

Claims (49)

1. A method for maintaining or slowing the decline in motor function in a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen, wherein maintaining comprises reducing the progression of Parkinson's disease as indicated by prolonging the time to progression, which is at least a 5-point progression on the Movement Disorder Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS), Part III, and slowing the decline comprises at least one of the following: (a) slowing the decline in the patient's motor function score according to the MDS-UPDRS Part III scale, (b) slowing the deterioration of one or more of the following: speech, facial expression, rigidity, finger tapping, wrist movements, pronation-supination wrist movements, toe tapping, leg mobility, rising from a chair, gait, freezing while walking, postural stability, posture, hand tremor, resting tremor amplitude, constancy of resting tremor or Hoehn and Yahr stage; (c) improvement of bradykinesia; where the Prasinezumab regimen comprises 1000-5000 mg of Prasinezumab administered intravenously at intervals of 3-5 weeks. 2. The method of claim 1, wherein the slowing down of the decline in the patient's motor function score comprises an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76%, or 109% compared to placebo after one year of treatment. 3. The method of claim 1, wherein the slowing down of the decline in the patient's motor function score comprises an improvement of at least 18%, 24%, 25%, 33%, 35%, or 45% compared to placebo after one year of treatment. 4. The method according to claim 1, wherein the subject is diagnosed with a mild subtype with predominantly motor symptoms, a diffuse malignant subtype, or an intermediate subtype of Parkinsonism. 5. The method according to claim 1, wherein the subject is diagnosed with a diffuse malignant subtype of parkinsonism. 6. The method of any one of claims 1-5, further comprising administering to the subject a monoamine oxidase inhibitor (“MAO”). 7. The method of claim 6, wherein the MAO inhibitor is an MAO-B inhibitor. 8. The method of claim 1, wherein the regimen comprises 1500 mg of Prasinezumab every four weeks. 9. The method of claim 8, wherein maintaining the decline in motor function includes slowing the progression of Parkinson's disease, as evidenced by a slowdown in the time to progression of at least 5 points on the MDS-UPDRS Part III scale. 10. The method of claim 8, wherein slowing the decline in motor function comprises slowing the decline in the patient's MDS-UPDRS Part III motor function score. 11. A method for maintaining or increasing cerebral blood flow in a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen comprising intravenous administration of 1000-5000 mg of Prasinezumab at intervals of 3-5 weeks. 12. The method of claim 11, wherein cerebral blood flow is maintained or increased in the putamen. 13. The method of claim 11, wherein cerebral blood flow is maintained or increased in the pallidum. 14. The method of claim 11, wherein cerebral blood flow is maintained or increased in the premotor area. 15. The method according to any one of paragraphs 11-14, wherein the blood flow is assessed by changes in MRI with labeled arterial spins (MRI-ASL). 16. The method according to any one of claims 11-15, wherein the regimen comprises 1500 mg Prasinezumab. 17. A method for improving cognitive function in a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a Prasinezumab regimen comprising intravenous administration of 1000-5000 mg of Prasinezumab at intervals of 3-5 weeks. 18. The method according to claim 17, wherein the subject does not have a cognitive impairment. 19. The method of claim 17, wherein the improvement in cognitive function is measured using the Montreal Cognitive Assessment (MoCA), and wherein the improvement is at least 0.2 on the MoCA score. 20. The method of any one of claims 17-19, further comprising administering to the subject an MAO-B inhibitor. 21. The method of any one of claims 17-20, wherein the subject is a previously untreated subject, a subject diagnosed with Parkinson's disease (PD) within the last two years, or a subject previously treated with an MAO-B inhibitor. 22. The method according to any one of paragraphs 1-7 and 11-21, wherein the subject has a body weight greater than 65 kg and receives a dose of 4500 mg of Prasinezumab once every 4 weeks. 23. The method according to any one of paragraphs 1-7 and 11-21, wherein the subject has a body weight less than 65 kg and receives a dose of 3500 mg Prasinezumab once every 4 weeks. 24. The method according to any one of paragraphs 1-7 and 11-21, wherein the subject is administered a dose of 1500 mg Prasinezumab once every 4 weeks. 25. The method of any one of claims 1-23, wherein the subject receives Prasinezumab once every 4 weeks for at least 52 weeks. 26. The method according to any one of paragraphs 1-23, wherein the subject is a man. 27. A method of treating a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease, comprising administering to the subject a regimen of Prasinezumab, wherein the treatment comprises (a) a reduction in the progression of Parkinson's disease, as demonstrated by a prolongation of time to progression, representing at least a 5-point progression on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part III, or (b) slowing down the decline in motor function, including at least one of the following: i. slowing down the decline in the patient's motor function score according to the MDS-UPDRS Part III scale; ii. slowing of deterioration in one or more of the following: speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination movements, toe tapping, leg mobility, chair rising, gait, freezing of gait, postural stability, posture, hand tremor, resting tremor amplitude, resting tremor persistence, or Hoehn and Yahr stage; iii. improvement of bradykinesia, and where the Prasinezumab regimen includes intravenous administration of 1000-5000 mg Prasinezumab at intervals of 3-5 weeks. 28. The method according to claim 27, wherein the subject is diagnosed with a mild subtype with predominantly motor symptoms, a diffuse malignant subtype, or an intermediate subtype of Parkinsonism. 29. The method according to claim 28, wherein the subject is diagnosed with a diffuse malignant subtype of parkinsonism. 30. The method of any one of claims 27-29, wherein the slowing down of the decline in the patient's motor function score comprises an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76% or 109% compared to placebo after one year of treatment. 31. The method of any one of paragraphs 27-30, further comprising administering to the subject a monoamine oxidase inhibitor (“MAO”). 32. The method of claim 31, wherein the MAO inhibitor is an MAO-B inhibitor. 33. The method of any one of claims 27-32, wherein the subject is a previously treatment-naive subject, a subject diagnosed with Parkinson's disease (PD) within the last two years, or a subject previously treated with an MAO-B inhibitor. 34. The method according to any one of claims 27-32, wherein the subject has a body weight greater than 65 kg and receives a dose of 4500 mg of Prasinezumab once every 4 weeks. 35. The method according to any one of claims 27-32, wherein the subject has a body weight less than 65 kg and receives a dose of 3500 mg of Prasinezumab once every 4 weeks. 36. The method according to any one of claims 27-32, wherein the subject is administered a dose of 1500 mg Prasinezumab once every 4 weeks. 37. The method of any one of claims 26-36, wherein the subject receives Prasinezumab once every 4 weeks for at least 52 weeks. 38. The method according to any of paragraphs 27-32, wherein the subject is a man. 39. The method according to any one of claims 1-38, wherein the subject has an early stage of Parkinson's disease.