A Randomized, Double-blind, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous TAK-341 in Subjects With Multiple System Atrophy

General 1. The subject (or, when applicable, the subject’s legally acceptable representative) signs an informed consent form indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. 2. The subject is an outpatient of either sex, at least 40 years old, at the time of consent. 3. Subjects must, in the opinion of the investigator, be able to participate in all scheduled evaluations, likely to be compliant, and likely to complete all required tests, including neuroimaging brain scans and lumbar punctures. 4. The subject has a body mass index (BMI) ≥18 and ≤35 kg/m2 at screening. Diagnostic 5. The subject has a diagnosis of possible or probable MSA using the modified Gilman et al, 2008 diagnostic criteria (Gilman et al. 2008) (Appendix F). 6. The subject’s onset of first MSA symptoms (including parkinsonism, cerebellar symptoms, orthostatic or urinary symptoms) occurred ≤4 years before screening, as assessed by the investigator. 7. The subject’s anticipated life expectancy is ≥3 years, per investigator judgment. 8. The subject has an UMSARS Part I score of ≤21 (excluding Item #11, sexual function), and additionally has: a) Severity score ≤2 on the swallowing item (#2). b) Severity score ≤2 on the ambulation item (#7). c) Severity score ≤2 on the falling item (#8). 9. The subject has an UMSARS Part IV disability score ≤3. 10. Subject has a MoCA ≥18. Additionally, subject has sufficiently intact cognition to complete study assessments and follow study instructions, per investigator's judgment. 11. A male subject who is nonsterilized and sexually active with a female partner of childbearing potential is eligible to participate if he agrees to use a barrier method of contraception study and for 90 days plus 5 half-lives (total of 190 days) after the last dose. 12. Female subjects are eligible to participate if (a) they are not pregnant or nursing and (b) they are of nonchildbearing potential or agree to use highly effective contraception from the signing of informed consent throughout the study and for 30 days plus 5 half-lives (total of 130 days) after the last dose of study drug.

Medical History 1. The subject has serious or unstable clinically significant illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic or autoimmune (eg, multiple sclerosis), hematologic, or other major disease, which, in the judgment of the investigator, is poorly controlled or otherwise likely to deteriorate, compromises the subject’s safety or ability to complete the study, or compromises the interpretation of the study results. 2. The subject has other medical problems (neurological, visual, orthopedic, psychiatric) that, in the opinion of the investigator, may significantly interfere with completion of the study or interpretation of study endpoints. 3. The subject has a disorder that is likely to interfere with drug disposition and elimination. 4. In the opinion of the investigator, the subject has a diagnosis of depression or other psychiatric disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), AND this disorder is poorly controlled AND of sufficient severity to interfere with completion of the study or interpretation of the endpoints. 5. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within the past year before screening. Subjects who have positive answers on Item 4 or 5 on the C-SSRS (based on the past year) before randomization are excluded. 6. The subject has a history of alcohol or substance use disorder (except tobacco use disorder), as defined by the DSM-5, within 1 year before screening or between screening and randomization, or, in the opinion of the investigator, the subject’s current or past use of substances may interfere with performance on the assessments. 7. The subject has a positive finding on an alcohol or illicit drug screen. A positive result for cannabis or prescription medications does not require exclusion. 8. The subject has undergone surgery for the treatment of MSA (eg, pallidotomy, deep brain stimulation, fetal tissue transplantation). 9. The subject has a history of epilepsy or seizures, except self-limited febrile childhood seizures. 10. The subject has any contraindication to lumbar puncture including but not limited to thrombocytopenia or other coagulation disorders (including subjects who are receiving anticoagulants and cannot safely stop them), the presence of cutaneous or soft-tissue infection overlying or adjacent to the site of lumbar puncture, previous spinal surgery that could complicate access to the subarachnoid space, or conditions associated with raised intracranial pressure such as a closed head injury within 3 months or benign intracranial hypertension, or any spinal abnormality or other aspects (eg, tattoos in the midline lumbar area) or other clinical findings (papilledema seen with ophthalmoscopy) that may complicate or contraindicate lumbar puncture, as judged by the investigator. Subjects who are using low-dose aspirin, low molecular weight heparin, coumadin, or other anticoagulants may still participate if use of these medications can be safely suspended before lumbar puncture, per investigator judgment and local medical practices. Diagnostic Assessments 11. Any clinically significant abnormality as determined by investigator at screening or between screening and randomization in physical examination findings, vital signs, ECGs, or clinical laboratory test results that may compromise the subject’s safety or ability to complete the study or compromise the interpretation of the study results. 12. Presence of any of the following contraindications to MRI: claustrophobia that would contraindicate brain MRI or the presence of a pacemaker; cardiac defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; recently placed (within 1 year) coronary or carotid stent; ear implant; CSF shunt; other implanted medical device (eg, insulin pump); or metal fragments or foreign objects in the eyes, skin, or body. 13. Ophthalmic abnormalities. The following are considered exclusionary: a) Ophthalmic abnormalities and conditions that, in the judgment of the investigator and/or ophthalmologist, would affect subject safety and/or impair the ability to perform a quality ophthalmological evaluation. b) Congenital or acquired ophthalmic conditions (primary or secondary) that are considered poorly controlled within the last 12 months before screening, with or without treatment, or otherwise expected to lead to significant deterioration in visual acuity in the next 12 months after randomization. c) Any ocular opacities that may prevent quality fundus assessment. d) Neovascular or exudative (wet) form of age-related macular degeneration. 14. The subject has any of the following at the screening visit: estimated glomerular filtration rate (determined with the Chronic Kidney Disease Epidemiology Collaboration equation) < 50 mL/min; QT interval with Fridericia correction method > 450 ms for male subjects and > 470 ms for female subjects; a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 1.5 × the upper limit of normal (ULN). 15. Clinically significant vital sign abnormalities at screening, defined as (a) systolic blood pressure ≥160 mm Hg, (b) diastolic blood pressure ≥90 mm Hg (blood pressure assessed with the subject at rest in the seated position; may be repeated up to 3 times), or (c) pulse rate < 45 or > 100 beats per minute (subject at rest in the seated position). 16. The subject has a positive hepatitis B surface antigen test result, known or suspected active hepatitis C infection, or known history of HIV infection. Note: Subjects with positive hepatitis C virus (HCV) serology results may be enrolled if results from a quantitative polymerase chain reaction for HCV RNA is negative, to exclude active hepatitis C infection, and if the investigator agrees that the subject can safely participate in the study. 17. The subject has a brain MRI that shows clinically significant evidence of malignant, ischemic, demyelinating, structural, or degenerative brain disease (other than MSA) that may confound diagnosis or subject safety during the study, or the subject has findings that compromise the safety of lumbar puncture per investigator judgment. 18. The subject has a current blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory tests of coagulation. Other 19. The subject has poor venous access such that IV drug delivery or PK/safety blood sampling would be difficult. 20. The subject has participated in another study investigating active or passive immunization against αSYN for PD or MSA, or has had immunoglobulin G therapy, within 6 months before screening. 21. The subject’s participation in a previous study of a disease-modifying therapy (with proven receipt of active treatment) will compromise the interpretability of the data from the present study, per consultation with medical monitor or designee. For example, subjects who participated in a study of gene therapy and antisense oligonucleotides (or other disease-modifying treatment) and received active treatment would be excluded. 22. The subject has received any investigational compound that, in the opinion of the investigator or sponsor, may not have completely washed out before the screening visit or may affect the safety or efficacy evaluations. 23. The subject has a positive pregnancy test result at screening. 24. The subject is an immediate family member, is a study site employee, or is in a dependent relationship (eg, as a spouse, parent, child, or sibling) with a study site employee who is involved in the conduct of this study. 25. The subject has donated 400 mL or more of his or her blood volume within 90 days before the start of the screening visit.