Evaluation of Intravenous Prasinezumab Efficacy and Safety in Early Parkinson's Disease: A Phase IIb Randomized, Double-Blind, Placebo-Controlled Multicenter Study

The primary objective of this study is to evaluate the **efficacy** of prasinezumab compared with placebo based on the time to a confirmed motor progression event in participants with early Parkinson's disease. This is clinically relevant as it aims to determine the potential of prasinezumab to slow the progression of motor symptoms, which are a significant aspect of Parkinson's disease and impact patients' quality of life.

Secondary objectives include:

• Evaluating the efficacy of prasinezumab compared with placebo on the basis of time-to-worsening of the patient's motor function as reported by the patient in the presence of a confirmed motor progression event, time to meaningful worsening in the overall disease as reported by the patient and clinician, change from baseline in motor function, change from baseline in **bradykinesia** and rigidity, and time to onset of motor complications.
• Evaluating the safety of prasinezumab compared with placebo.
• Characterizing the prasinezumab pharmacokinetic (PK) profile.
• Evaluating the immune response to prasinezumab.

The clinical trial involves a total of **188 participants** diagnosed with **Early Parkinson's disease**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a diagnosis of idiopathic Parkinson's disease according to Movement Disorder Society criteria, with symptoms such as bradykinesia and either resting tremor or rigidity. All participants are on stable doses of symptomatic Parkinson's disease medication for at least three months prior to the baseline. The trial includes individuals diagnosed with Parkinson's disease for a period ranging from a minimum of three months to a maximum of three years at the time of screening. Participants are required to have a Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part IV score of 0 at screening and prior to randomization, and must be at Hoehn and Yahr Stage I or II in the OFF medication state at screening and prior to randomization. Additionally, dopamine transporter imaging with single photon emission computed tomography (DaT-SPECT) must indicate a dopamine transporter deficit, as assessed by a central reader. The trial population includes a vulnerable population, reflecting the nature of the disease under investigation.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of intravenous **prasinezumab** in participants with early **Parkinson's disease**. The trial is conducted over an estimated duration from August 2021 to November 2026. Participants will be randomly assigned to receive either prasinezumab or a placebo, administered as a solution for infusion. The primary objective is to assess the time to a confirmed motor progression event, while secondary endpoints include various measures of motor function, adverse events, and changes in vital signs and laboratory assessments.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of idiopathic Parkinson's disease and stable symptomatic medication use. Following randomization, participants will attend regular follow-up visits to monitor efficacy and safety outcomes, including assessments using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and other clinical evaluations. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all study parameters.

Participant involvement is expected to last up to 275 days, with conditions for early termination including significant adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and data collection to support the evaluation of prasinezumab's potential benefits and risks in the target population. The study's methodology and procedures are structured to maintain scientific integrity and participant safety throughout the trial duration.

The clinical trial involves the administration of **prasinezumab**, an investigational medication, to evaluate its efficacy and safety in participants with early Parkinson's disease. Prasinezumab is provided in the form of a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose of prasinezumab is 1500 mg, with a total maximum dose of 103,125 mg over a treatment period of 275 days. The active substance, prasinezumab, is a humanized IgG1, kappa anti-alpha-synuclein antibody, originating from protein sources. The pharmaceutical product is identified by the sponsor product codes RO 704-6015/F01-01 and RO 704-6015/F02-02, and is manufactured by F. Hoffmann-La Roche Ltd.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is referred to as RO7046015 Placebo and is intended to match the experimental treatment in appearance and administration method, although it contains no active substance. The placebo is utilized to ensure the validity of the study by providing a control group for comparison against the effects of prasinezumab.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The study aims to assess the time to confirmed motor progression events as a primary measure of efficacy, with safety evaluations conducted concurrently to monitor any adverse effects associated with the treatment.

The efficacy of **prasinezumab** in the treatment of early Parkinson's disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to a confirmed motor progression event. This will be evaluated to determine the effectiveness of prasinezumab compared to placebo in delaying motor progression in participants.

Secondary endpoints include a variety of measures to further assess the impact of prasinezumab on motor function and overall disease progression. These include:

• Time-to-worsening of the patient's motor function as reported in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II, in conjunction with a confirmed motor progression event.
• Time to meaningful worsening in Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change (CGI-C) on the Overall Disease Subscale.
• Change in motor function from baseline to Week 76, as measured by the MDS-UPDRS Part III score.
• Change in bradykinesia and rigidity from baseline to Week 76, as measured by the MDS-UPDRS Part III bradykinesia and rigidity subscore.
• Time to onset of motor complications assessed through MDS-UPDRS Part IV.

Additional assessments will include the nature, incidence, seriousness, and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). The study will also monitor the incidence of adverse events of special interest, treatment discontinuation due to adverse events, and infusion-related reactions (IRRs).

Changes from baseline in vital signs, electrocardiogram (ECG) assessments, and laboratory measurements will be recorded, along with the incidence of abnormalities in these parameters. The study will also evaluate changes in suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS), serum concentration of prasinezumab at specified timepoints, and the prevalence and incidence of anti-drug antibodies (ADAs) against prasinezumab.