A Proof of Concept, Phase IIa, Open Label Study to Evaluate the Safety and Efficacy of Afamelanotide in Patients with Early Parkinson's Disease

The primary objective of this Phase IIa, open-label study is to evaluate the **safety** of afamelanotide in participants with early Parkinson's Disease (PD). Assessing the safety profile of afamelanotide is clinically relevant as it determines the potential risks associated with its use in this patient population, which is crucial for further development and therapeutic application.

Secondary objectives include:

• Evaluating the changes in **α-synuclein** levels in blood in patients with early PD after treatment with afamelanotide.
• Assessing the changes in **inflammation** in patients with early PD following treatment with afamelanotide.
• Investigating the changes in **neuromelanin** in participants with early PD after treatment with afamelanotide.
• Evaluating the changes in **cognition** in participants with early PD following treatment with afamelanotide.
• Assessing the clinical improvement in participants with early Parkinson’s Disease following treatment with afamelanotide.

These secondary objectives aim to provide insights into the potential therapeutic effects of afamelanotide on various biomarkers and clinical outcomes in early PD, which could inform future treatment strategies.

The clinical trial focuses on evaluating the safety of afamelanotide in participants with early **Parkinson's Disease**. The study population includes both male and female subjects, aged between 40 and 85 years. Participants are required to have been diagnosed with Parkinson's Disease less than three years prior to the first screening visit and should not yet require dopaminergic medication nor be expected to within three months of enrollment. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is a **Phase IIa** open-label study designed to evaluate the safety and efficacy of **afamelanotide** in patients with early **Parkinson's Disease**. The trial will involve the administration of afamelanotide as a **solution for injection** via **subcutaneous injection**. The study is set to commence recruitment on May 1, 2024, and is expected to conclude by January 1, 2025. Participants will be involved in the study for a maximum treatment period of 8 weeks, with a maximum daily dose of 0.08 mg/kg and a total dose not exceeding 0.88 mg/kg.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Parkinson's Disease within the last three years and an age range of 40 to 85 years. Participants must not require dopaminergic medication at the time of enrollment or expect to need it within three months. Following the screening, participants will undergo regular follow-up visits to monitor safety and efficacy outcomes, including the assessment of treatment-emergent adverse events and changes in biomarkers such as **α-synuclein** levels, inflammation markers, and neuromelanin. Cognitive and clinical improvements will also be evaluated from baseline to Day 56±2.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the need for dopaminergic medication. The trial is not categorized as low intervention, and the data collected will be used to support future marketing authorization efforts for afamelanotide.

The clinical trial involves the administration of the experimental medication **afamelanotide**, marketed under the name **PRENUMBRA**. This medication is provided in the form of a **solution for injection**. The active substance, afamelanotide, is a protein-based compound classified as a hormone analogue. The pharmaceutical form is specifically designed for **subcutaneous injection**. The dosing regimen for afamelanotide is set at a maximum daily dose of 0.08 mg/kg, with a total maximum dose of 0.88 mg/kg over the course of the treatment period. The treatment duration is limited to a maximum of 8 weeks. The medication is not formulated for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety and efficacy of afamelanotide in patients with early Parkinson's disease. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of CLINUVEL PHARMACEUTICALS LTD, with the medication being authorized for use in this specific clinical context.

The efficacy of afamelanotide in patients with early Parkinson's Disease will be assessed through a series of secondary endpoints. These include changes in **α-synuclein** levels in plasma, inflammation biomarkers in plasma, neuromelanin in MRI series, cognition, and clinical improvement. Measurements will be taken from baseline to Day 56±2. The assessment of these parameters will involve laboratory tests for biomarker levels and imaging techniques for neuromelanin evaluation. Cognitive and clinical improvements will be evaluated using appropriate validated scales. Data collection and analysis will be conducted at specified timepoints to ensure consistency and reliability in the assessment of treatment efficacy.