The primary objective of this study is to assess the safety and tolerability of exidavnemab after multiple dosing versus placebo.

This Phase 2a, randomized, double-blind, placebo-controlled, multicenter, multinational, multiple ascending dose (MAD) trial is designed to investigate the safety, tolerability, and pharmacokinetics (PK) of exidavnemab in participants with mild to moderate Parkinson's Disease (PD) on stable symptomatic PD medication and Patients With Multiple System Atrophy.

The trial will evaluate two dose cohorts versus placebo. Participants in each cohort will be randomly allocated in a 2:1 ratio to receive either exidavnemab or placebo. There will be approximately 12 evaluable participants with PD in Cohort 1 and approximately 24 evaluable participants in Cohort 2 (approximately 12 participants in each of Cohorts 2a and 2b), resulting in approximately 36 participants, 24 with PD and 12 with MSA, randomized in total.

Inclusion Criteria for Cohorts 1 and 2a (Parkinson's Disease):

1. Male and female participants 40 to 85 years of age.
2. Body weight more than or equal to 50 kg and less than or equal to 120 kg.
3. Have idiopathic PD (i.e., not induced by drugs or other diseases) as defined by bradykinesia combined with at least 1 of resting tremor and rigidity, as per the Movement Disorder Society Criteria for PD (Postuma, et al. 2015).
4. Classified as Stage 1 to 2.5 on the modified Hoehn and Yahr scale for the staging of PD severity.
5. Participants must have cognition inconsistent with dementia as confirmed by a score of more than or equal to 22 on the MoCA.
6. Stable and optimized symptomatic PD medication, defined as the same list of medications for at least 3 months prior to the Screening Visit with no change in the dose for at least 1 month prior to the Baseline Visit, and no planned changes in dose-regimen during trial participation.
7. Prior (any time; i.e., no time limit) or current DaT-SPECT or DaT-PET consistent with dopamine transporter deficit, as per the Movement Disorder Society Criteria for PD(Postuma, et al. 2015). For participants who have not undergone DaT-SPECT or DaT-PET prior to Screening, or who have previously undergone DaT-SPECT or DaT-PET scan(s) but without results consistent with dopamine transporter deficit, DaT-SPECT or DaT-PET should be performed and read locally as part of the Screening procedures.
8. Positive smell test showing hyposmia, as defined by UPSIT scores of around or below the 15% percentile for their relevant sex and age group. Cut-off scores are provided below for reference (Table 5.1; based on Brumm, et al. 2023) Ability to use a tablet device to measure cognitive function, as per Investigator judgment.

Inclusion Criteria for Cohort 2b (Multiple System Atrophy):

1. Male and female participants 40 to 85 years of age.
2. Body weight more than or equal to 50 kg and less than or equal to 120 kg.
3. Have clinically established or clinically probable MSA (either MSA-P or MSA-C), as per the Movement Disorder Society criteria for the diagnosis of MSA (Wenning, et al. 2022).
4. Classified as Stage 1 to 3 on the modified Hoehn and Yahr scale for the staging of MSA severity.
5. Participants must have cognition inconsistent with dementia as confirmed by a score of more than or equal to 22 on the MoCA.
6. Negative urine or serum pregnancy test at the Screening Visit and Baseline for premenopausal women, and for women who have experienced menopause onset less than 12 months prior to the first planned dose of trial medication.
7. Males and POCBP must agree to practice an effective means of birth control during their participation in the trial and until 3 months after their last dose of the trial medication. See specific guidelines regarding contraceptive methods in Section 14.1.
8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and trial procedures.

Exclusion Criteria for Cohorts 1 and 2a (Parkinson's Disease):

1. Known hypersensitivity to trial medication, the infusion solution, or excipients.
2. More than 5 years of symptomatic treatment for PD.
3. History of neurosurgical intervention for PD including implantation of brain stimulation.
4. Diagnosis of PD dementia or another dementia.
5. Any psychiatric diagnosis or symptoms (e.g., hallucinations, major depression, or delusions) that could interfere with trial procedures.
6. Freezing episodes occurring on a weekly basis or more frequently.
7. Motor fluctuations occurring on a weekly basis or more frequently.
8. Levodopa-induced troublesome dyskinesia of a severity that would significantly interfere with the participant's ability to participate or perform trial procedures as determined by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Subscale IV.

Exclusion Criteria for Cohort 2b (Multiple System Atrophy):

1. Known hypersensitivity to the trial medication, the infusion solution, or excipients.

2. Any psychiatric diagnosis or symptoms (e.g., hallucinations, major depression, or delusions) that could interfere with trial procedures.

3. History of significant cardiovascular disease or arrhythmia within 6 months of Screening.

4. Abnormal ECG that is or may be clinically significant in the Investigator's opinion and after consultation with the Medical Monitor, including left bundle branch block, atrial fibrillation, QTcF more than 450 msec for males and more than 470 msec for females at the Screening Visit or Baseline.

5. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening.

6. Abnormal liver function tests: GGT, TBil, ALP, ALT, and AST higher than the ULN and regarded as potentially clinically significant by the Investigator.

   Note: Gilbert's syndrome is not exclusionary.

7. Poorly controlled diabetes as defined by hemoglobin A1C of more than 8%.

8. Contraindication, condition, or concomitant medication incompatible with lumbar puncture (e.g., lumbar scoliosis, coagulopathy, and infected skin at needle puncture site), 1.5T or 3T MRI (e.g., aneurysm clip, metal fragments [e.g., in-skull and cardiac devices other than those approved as safe for use in MRI scanners], and internal electrical devices such as a cochlear implant, spinal cord stimulator, or cardiac pacemaker/defibrillator).

Participants in each cohort will be randomly allocated in a 2:1 ratio to receive either exidavnemab or placebo.