A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE MASKED, SHAM-CONTROLLED STUDY TO INVESTIGATE THE EFFICACY, SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF RO7200220 ADMINISTERED INTRAVITREALLY IN PATIENTS WITH UVEITIC MACULAR EDEMA

The primary objective of this study is to evaluate the **efficacy** of RO7200220 on functional outcomes compared with sham in patients with **uveitic macular edema**. This is clinically relevant as it aims to determine the therapeutic potential of RO7200220 in improving visual function, which is a critical aspect of managing this condition.

Secondary objectives include:

• Evaluating the efficacy of RO7200220 on best-corrected visual acuity (BCVA) functional outcomes compared with sham at Week 20, which is 8 weeks after the final study drug dose.
• Assessing the efficacy of RO7200220 on mean BCVA-functional outcomes compared with sham.
• Evaluating the efficacy of RO7200220 on mean anatomical outcomes, specifically the change in central subfield thickness (CST), compared with sham.
• Assessing the efficacy of RO7200220 on additional functional, anatomical, and participant-reported outcomes compared with sham.
• Evaluating the safety of RO7200220 compared with sham, and specifically in the study eye compared with the fellow eye.
• Characterizing the pharmacokinetics of RO7200220.
• Characterizing the aqueous humor pharmacodynamics, focusing on interleukin-6 (IL-6).
• Investigating the formation of serum anti-drug antibodies (ADAs) and evaluating their potential effects.

The clinical trial involves a total of **163 participants** diagnosed with **Uveitic Macular Edema**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as a diagnosis of macular edema associated with non-infectious uveitis, confirmed by spectral-domain optical coherence tomography, and a best corrected visual acuity letter score within a specified range. The trial population includes individuals with active or inactive, acute, or chronic non-infectious uveitis of any etiology and anatomical type. The study considers a vulnerable population, indicating that additional ethical considerations are in place. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is a **Phase III**, multicenter, randomized, double-masked, sham-controlled study designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of RO7200220 administered intravitreally in patients with **uveitic macular edema**. The trial aims to assess the functional outcomes of the treatment compared to a sham procedure. The study is expected to last until June 2025, with recruitment having commenced in March 2023. Participants will be involved in the study for a maximum treatment period of 52 weeks, depending on the specific product administered.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of macular edema associated with non-infectious uveitis and specific visual acuity requirements. Following the screening, participants will be randomized to receive either the investigational product, IL6-Mab, or a sham treatment. The investigational product is a **humanised IgG2 monoclonal antibody against interleukin-6**, administered as a solution for injection via intravitreal use.

Study visits will include regular follow-up assessments to monitor the primary endpoint, which is the proportion of participants achieving a ≥15 letter improvement in best-corrected visual acuity (BCVA) from baseline at Week 16. Secondary endpoints will be evaluated at various time points, including Weeks 20 and 52, and will assess changes in BCVA, central subfield thickness, and other visual and safety parameters. The end-of-study visit will conclude the participant's involvement, with comprehensive assessments to evaluate the long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is not classified as low intervention, and the investigational product is not an orphan drug. The study's design ensures rigorous evaluation of the investigational product's efficacy and safety in a controlled environment, contributing valuable data to the understanding of treatment options for uveitic macular edema.

The clinical trial involves the administration of **IL6-Mab**, a **humanised IgG2 monoclonal antibody against interleukin-6**. This experimental medication is provided in the form of a **solution for injection**. The pharmaceutical form is specifically designed for **intravitreal use**, which involves the injection of the solution directly into the eye. The dosage regimen for IL6-Mab is set at a maximum daily dose of 1 mg, with a total maximum dose of 12 mg over the course of the treatment. The treatment period for this medication is up to 52 weeks for one formulation (RO 720-0220/F12-01) and up to 48 weeks for another formulation (RO 720-0220/F13-01). The medication is not a paediatric formulation and is not classified as an orphan drug.

In this study, a sham-controlled approach is employed as the comparator treatment. The sham procedure involves a simulated injection process without the administration of the active medication, serving as a control to evaluate the efficacy and safety of IL6-Mab. This method allows for the assessment of the treatment's impact on functional outcomes in patients with uveitic macular edema. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the pharmacokinetics and pharmacodynamics of the investigational drug.

The efficacy of the investigational product, **RO7200220**, will be assessed in a Phase III, multicenter, randomized, double-masked, sham-controlled study involving patients with uveitic macular edema. The primary endpoint for evaluating efficacy is the proportion of participants achieving a ≥15 letter improvement from baseline in Best Corrected Visual Acuity (BCVA) at Week 16. Secondary endpoints include the proportion of participants with a ≥15 letter improvement from baseline in BCVA at Week 20, change from baseline in BCVA score at Weeks 16, 20, and 52, and change from baseline in central subfield thickness (CST) at Weeks 16, 20, and 52. Additional secondary endpoints involve the proportion of participants with uveitic macular edema resolution from baseline at Weeks 16 and 52, time to rescue treatment, and the number and type of rescue treatments received.

Further assessments will include the proportion of participants with a ≥15 letter improvement from baseline in BCVA at Week 52, the proportion of participants without a ≥15 letter loss from baseline in BCVA at Weeks 16 and 52, and the number of pro re nata (PRN) injections received. The study will also evaluate the time to first PRN injection, change from baseline in the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite score at Weeks 16 and 52, and the incidence and severity of ocular and non-ocular adverse events. Pharmacokinetic and pharmacodynamic parameters will be assessed through the concentration of RO7200220 in aqueous humor (AH) and serum over time, IL-6 suppression in AH, and the incidence and titer of anti-drug antibodies (ADAs) to RO7200220. The relationship between ADA status and efficacy, safety, ocular pharmacokinetics, and pharmacodynamics endpoints will also be explored.