A Phase IIa, Open Label Study to Evaluate the Safety 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 patients with early **Parkinson's Disease** (PD) following treatment. 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, inflammation, cognition, and **neuromelanin** in patients with early PD after treatment with afamelanotide. Additionally, the study aims to assess clinical improvement in these patients. These secondary objectives are important for understanding the broader impact of afamelanotide on disease pathology and patient outcomes, potentially guiding future therapeutic strategies for Parkinson's Disease.

The clinical trial involves participants diagnosed with **Parkinson's Disease** within the last three years, who are not yet requiring dopaminergic medication and are not expected to need it within three months of enrollment. The study population includes both male and female subjects, aged between 40 and 85 years. Participants are selected based on their diagnosis and current treatment status, ensuring they meet the specified inclusion criteria. The trial does not focus on a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **Phase IIa, open-label study** to evaluate the safety of **afamelanotide** in patients with early **Parkinson's Disease**. The trial aims to assess the safety profile of afamelanotide following its administration. The study will involve participants aged 40 to 85 years who have been diagnosed with Parkinson's Disease within the last three years and are not yet requiring dopaminergic medication. The trial will not employ a randomized or double-blind design, as it is open-label, meaning both the researchers and participants will be aware of the treatment being administered.

The trial is expected to last approximately eight months, with participant involvement spanning from the initial screening visit to the end-of-study visit. The sequence of study visits includes an inclusion (screening) visit, where eligibility criteria are confirmed, followed by baseline assessments on Day 1. Subsequent follow-up visits will occur periodically, with the primary endpoint being the assessment of treatment-emergent adverse events, including clinically significant changes in laboratory results. Secondary endpoints include changes in **α-synuclein** levels, inflammation biomarkers, cognition, and clinical improvement from baseline to Day 56±2. The end-of-study visit will conclude the participant's involvement, assessing overall safety and any long-term effects of the treatment.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. Such conditions may include the development of significant adverse events or the need for dopaminergic medication. The study will utilize **PRENUMBRA**, a solution for injection, administered via subcutaneous injection, with a maximum daily dose of 0.08 mg/kg and a total dose not exceeding 0.88 mg/kg over the treatment period. The trial is set to commence recruitment on September 1, 2023, with an estimated end date of April 1, 2024.

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** and is manufactured by CLINUVEL PHARMACEUTICALS LTD. Afamelanotide is a hormone analogue with a protein origin classified as "Protein - Other." The medication is administered via **subcutaneous injection**. The dosing regimen specifies a maximum daily dose of 0.08 mg/kg and a maximum total dose of 0.88 mg/kg over a treatment period not exceeding 8 weeks. The trial aims to evaluate the safety of afamelanotide in patients with early Parkinson's disease.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of afamelanotide. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the safety profile of afamelanotide, and no pediatric formulation is involved in this study.

Efficacy in the clinical trial evaluating the safety of **afamelanotide** in patients with early Parkinson's Disease will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the assessment of treatment-emergent adverse events, including clinically significant changes in laboratory results. Secondary endpoints include several parameters measured from baseline (Day 1) to Day 56±2. These parameters are changes in α-synuclein levels in plasma, changes in inflammation biomarkers in plasma, changes in cognition, changes in neuromelanin (NM) in MRI series, and changes in clinical improvement. The collection and analysis of these efficacy parameters will be conducted at specified timepoints, ensuring a comprehensive evaluation of the treatment's impact over the course of the study.