A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Intravenous Prasinezumab in Participants with Early-Stage Parkinson’s Disease

This study evaluates prasinezumab, a humanized monoclonal antibody targeting alpha-synuclein, in participants with early-stage Parkinson's disease. The primary objective is to assess the efficacy of prasinezumab compared with placebo. This evaluation is clinically relevant as it targets disease modification in the early stages of Parkinson's disease, when therapeutic intervention may have the greatest potential to alter disease progression.

The secondary objectives include:

• Evaluating the efficacy of prasinezumab compared with placebo regarding change in motor function from baseline at Week 104, as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III off medication score, time to worsening of participants' motor function as reported by the participant in the presence of a confirmed motor progression event, time to meaningful worsening in Clinician Global Impression of Change (CGI-C) Overall Disease Subscale, and time to increase in levodopa equivalent daily dose (LEDD).

• Evaluating the safety of prasinezumab compared with placebo in participants on stable symptomatic monotherapy with levodopa, irrespective of their increase in LEDD during the study and study treatment discontinuation.

• Further characterizing the pharmacokinetics of prasinezumab.

• Further evaluating the immunogenicity of prasinezumab.

• Evaluating long-term safety and tolerability of prasinezumab in participants with early-stage Parkinson's disease who have completed the double-blind treatment period of the study in an open-label extension phase.

This clinical trial enrolled a total of **605 participants** diagnosed with **early-stage Parkinson's disease**. The study population included both **male and female subjects** comprising **adults and elderly individuals**. Participants were selected based on a diagnosis of **idiopathic Parkinson's disease** according to **Movement Disorder Society criteria**, presenting with **bradykinesia** plus at least one other cardinal sign such as **resting tremor** or **rigidity**, with no other known or suspected cause of **parkinsonism**. Enrolled subjects had been receiving Parkinson's disease medication for a minimum of three months prior to baseline. The trial population was further characterized by an **MDS-UPDRS Part IV score** of 0 at screening and a **Hoehn and Yahr Stage** 1 or 2 classification when off medication. The study included a **vulnerable population**. All participants were required to agree to adhere to contraception requirements as specified in the protocol.

This is a Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial designed to evaluate the efficacy and safety of intravenous prasinezumab in participants with early-stage Parkinson's disease. The study employs a randomized controlled design in which participants are assigned to receive either the investigational medicinal product or placebo. Prasinezumab is an immunoglobulin class G1 (IgG1) humanized monoclonal antibody administered as a solution for infusion via intravenous infusion. The trial is expected to commence recruitment in December 2025 and continue until an estimated completion date in July 2031, representing a total trial duration of approximately six years.

The primary objective of the trial is to evaluate the efficacy of prasinezumab compared with placebo in participants with early-stage Parkinson's disease. The primary endpoint is the time to a confirmed motor progression event based on the MDS-UPDRS Part III score from the randomization date. Secondary endpoints include change in motor function from baseline at Week 104 as measured by the MDS-UPDRS Part III off medication score, time to worsening of participants' motor function as reported by the participant in the presence of a confirmed motor progression event, time to meaningful worsening in CGI-C Overall Disease Subscale, and time to increase in LEDD. Additional secondary endpoints focus on safety parameters including the nature, incidence, seriousness, and severity of adverse events according to NCI CTCAE v5.0, incidence of adverse events of special interest, treatment discontinuation due to adverse events, and the nature, incidence, seriousness, severity, and timing of infusion-related reactions (IRRs). Further safety assessments include monitoring of vital signs, ECG assessments, laboratory abnormalities encompassing hematology, clinical chemistry, coagulation, and urinalysis parameters, and evaluation of suicidal ideation or behavior using the Columbia Suicide Severity Rating Scale (C-SSRS). Pharmacokinetic parameters and serum concentrations of prasinezumab at specified timepoints, as well as the prevalence of anti-drug antibodies (ADAs) at baseline and incidence during the study, are also assessed as secondary endpoints.

Eligible participants must have a diagnosis of idiopathic Parkinson's disease based on Movement Disorder Society (MDS) criteria with bradykinesia plus one of the other cardinal signs of Parkinson's disease, specifically resting tremor or rigidity, without any other known or suspected cause of parkinsonism. Participants must have received Parkinson's disease medication for at least three months prior to baseline and must have an MDS-UPDRS Part IV score of zero at screening and prior to randomization. Additionally, participants must demonstrate Hoehn and Yahr (H&Y) Stage 1 or 2 off medication at screening and prior to randomization. Agreement to adhere to contraception requirements is also mandatory for participation. The screening visit serves to assess eligibility criteria and baseline characteristics of potential participants. Follow-up visits occur at specified intervals throughout the treatment period to monitor efficacy and safety outcomes, including motor function assessments, laboratory evaluations, and adverse event monitoring. The end-of-study visit is conducted to perform final assessments and ensure participant safety upon trial completion.

Participant involvement in the study extends for the duration of the treatment period and follow-up assessments, with an expected treatment period as defined by the protocol. Conditions that may lead to early termination from the study include the occurrence of adverse events necessitating treatment discontinuation, participant withdrawal of consent, protocol violations, or investigator discretion based on safety concerns. The trial methodology incorporates rigorous safety monitoring and systematic collection of efficacy data to support the evaluation of prasinezumab as a potential therapeutic intervention for early-stage Parkinson's disease.

The experimental treatment under investigation is **prasinezumab** (RO7046015, also known as RG7935 or PRX002), an **immunoglobulin class G1 (IgG1) humanized monoclonal antibody** targeting **alpha-synuclein**. The active substance is of protein origin. Prasinezumab is supplied as a **solution for infusion** and is administered via **intravenous infusion**. The sponsor product code for this investigational medicinal product is RO 704-6015/F04-01, and it is manufactured by F. Hoffmann-La Roche Ltd. This product is not a paediatric formulation and is being evaluated for its efficacy and safety in participants with **early-stage Parkinson's disease**.

The comparator treatment consists of **placebo** matching prasinezumab. The placebo is administered to maintain the double-blind design of the study, ensuring that neither participants nor investigators are aware of treatment allocation. This allows for an unbiased comparison of the efficacy and safety profile of prasinezumab against a control intervention in the target population.

Efficacy will be assessed through the evaluation of motor progression and functional outcomes in participants with early-stage **Parkinson's disease**. The primary endpoint is the time to a confirmed motor progression event on **MDS-UPDRS Part III score** from the randomization date. Secondary efficacy endpoints include the change in motor function from baseline at Week 104, as measured by the **MDS-UPDRS Part III** off medication score. Additional secondary endpoints evaluate the time to worsening of participants' motor function as reported by the participant in the presence of a confirmed motor progression event, time to meaningful worsening in **CGI-C Overall Disease Subscale**, and time to increase in **LEDD**. These parameters will be collected and analyzed at specified timepoints throughout the study to determine the efficacy of intravenous **prasinezumab** compared with placebo.