Efficacy Evaluation of Intravenous Prasinezumab (RO7046015) in Early Idiopathic Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled Phase II Study

The primary objective of this study is to evaluate the **efficacy** of RO7046015 (prasinezumab) compared to placebo at Week 52 in participants with early Parkinson's disease (PD), specifically those in Hoehn and Yahr (H&Y) Stages I-II who are either untreated or treated with monoamine oxidase-B (MAO-B) inhibitors since baseline. This is measured by the change from baseline on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score, which is the sum of Parts I, II, and III. The clinical relevance of this objective lies in its potential to demonstrate the therapeutic benefit of RO7046015 in slowing the progression of early idiopathic Parkinson's disease, thereby improving patient outcomes.

Secondary objectives include: - Evaluating the effects of RO7046015 versus placebo at Week 52 on various clinical and imaging parameters, including MDS-UPDRS sub-scores, dopamine transporter imaging with DaT-SPECT, Montreal Cognition Assessment (MoCA) total score, Clinical Global Impression of Improvement (CGI-I), Patient Global Impression of Change (PGIC), Schwab and England Activity of Daily Living (SE-ADL) score, time to worsening in motor or non-motor symptoms, and time to start of dopaminergic PD treatment. - Assessing the safety and tolerability of RO7046015 for up to 104 weeks plus a 12-week treatment-free follow-up, and up to Part 3 Week 260 plus a 12-week treatment-free follow-up, with or without concomitant dopaminergic treatment. - Evaluating the immunogenicity of RO7046015. - Describing the pharmacokinetics of RO7046015 using population PK modeling.

The clinical trial involves a total of **214 participants** diagnosed with **Early Idiopathic Parkinson's disease (PD)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a diagnosis of PD for two years or less and a Hoehn and Yahr Stage I or II classification. The trial includes individuals who are either untreated or have been on a stable dose of monoamine oxidase-B (MAO-B) inhibitors, such as rasagiline or selegiline, for at least 90 days prior to baseline. The general health status of participants is such that their clinical condition does not necessitate dopaminergic PD medication, nor is it expected to require such treatment within 52 weeks from baseline. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **prasinezumab** in participants with early **Parkinson's disease**. The trial spans a duration of 52 weeks, with an extension phase allowing all participants to receive treatment for an additional six years. The primary objective is to assess the change from baseline in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score at Week 52. Secondary endpoints include changes in various sub-scores of the MDS-UPDRS, dopamine transporter imaging, cognitive assessments, and the incidence of adverse events.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility, which includes a brain DaT-SPECT scan consistent with Parkinson's disease. The inclusion criteria require participants to have a diagnosis of idiopathic Parkinson's disease for two years or less, be in Hoehn and Yahr Stage I or II, and not require dopaminergic treatment within 52 weeks from baseline. If participants are on a stable dose of MAO-B inhibitors, they must have maintained this regimen for at least 90 days prior to baseline.

Following the screening, participants will be randomized to receive either the investigational product or placebo via **intravenous infusion**. Regular follow-up visits will be scheduled to monitor efficacy and safety, including assessments of motor and non-motor symptoms, cognitive function, and global impressions of change. The end-of-study visit will occur at the conclusion of the 52-week period, with the option to continue in the extension phase.

The expected length of participant involvement is approximately one year, with conditions for early termination including the need for dopaminergic treatment or the occurrence of significant adverse events. The trial aims to provide comprehensive data on the efficacy and safety of prasinezumab in early Parkinson's disease, contributing to the understanding of its potential therapeutic benefits.

The clinical trial involves the administration of **prasinezumab**, an investigational medication, under the product name RO7046015. Prasinezumab is a **humanized IgG1, kappa anti-alpha-synuclein antibody** and is formulated as a **solution for infusion**. The pharmaceutical form is specifically designed for **intravenous infusion**. The maximum daily dose of prasinezumab is 4500 mg, with a total maximum dose of 214.5 mg over a treatment period of 364 days. The administration schedule is determined by the study protocol, ensuring that the dosing aligns with the trial's objectives and safety parameters. The investigational product is not a pediatric formulation and is not classified as an orphan drug.

In addition to the experimental treatment, the study includes a **placebo** as a comparator to evaluate the efficacy of prasinezumab. The placebo is administered in a manner identical to the investigational drug, ensuring blinding and maintaining the integrity of the study design. Participants may also continue treatment with monoamine oxidase-B (MAO-B) inhibitors if they were receiving such therapy at baseline. Compliance with the dosing regimen is monitored throughout the study to ensure adherence and to accurately assess the treatment's impact on early **Parkinson's disease**. The trial is conducted in a double-blind manner, with neither participants nor investigators aware of the treatment assignments, to minimize bias and enhance the reliability of the results.

The efficacy of the investigational product **prasinezumab** will be assessed in a randomized, double-blind, placebo-controlled, 52-week Phase II clinical trial involving participants with early Parkinson's disease. The primary endpoint for evaluating efficacy is the change in the total score of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), which is the sum of Parts I, II, and III, from baseline to Week 52. This scale is a validated tool used to measure the severity and progression of Parkinson's disease symptoms.

Secondary endpoints include several additional measures: changes from baseline in MDS-UPDRS Part IA, Part IB, Part I total, Part II total, Part III total, and Part III subscores; changes in dopamine transporter imaging with single photon emission computed tomography (DaT-SPECT) in the ipsilateral putamen; changes in the Montreal Cognitive Assessment (MoCA) total score; changes in Clinical Global Impression (CGI-I) and Patient Global Impression of Change (PGIC); changes in Schwab and England Activities of Daily Living (SE-ADL); time to worsening in motor or non-motor symptoms as measured by MDS-UPDRS; time to the start of dopaminergic Parkinson's disease treatment; incidence and severity of adverse events and serious adverse events; incidence of anti-drug antibodies; and population and individual primary pharmacokinetic parameter estimations.