Evaluation of Ranibizumab Port Delivery System Refill Regimens in Neovascular Age-Related Macular Degeneration: A Phase IIIb Randomized Study

The primary objective of this study is to evaluate the **efficacy** of **ranibizumab** 100 mg/mL delivered via the port delivery system (PDS) every 36 weeks (Q36W) compared with every 24 weeks (Q24W) in patients with **neovascular age-related macular degeneration** (nAMD). This evaluation is based on the change from baseline in best-corrected visual acuity (BCVA) score, averaged over Weeks 68 and 72. The clinical relevance of this objective lies in determining the optimal dosing interval for maintaining visual acuity in nAMD patients, potentially reducing the treatment burden associated with more frequent dosing.

Secondary objectives include assessing the efficacy of ranibizumab delivered via PDS Q36W versus Q24W based on various visual acuity metrics over time, patient preference for PDS versus intravitreal treatment (IVT), and changes in center point thickness (CPT). Additionally, the study aims to evaluate the safety and tolerability of ranibizumab delivered via PDS, including device and procedure-related safety. The pharmacokinetic profile of ranibizumab delivered via PDS Q36W compared with Q24W will also be assessed, along with the formation of anti-drug antibodies (ADAs) to ranibizumab delivered via PDS. These secondary objectives are crucial for understanding the broader implications of PDS use in terms of patient outcomes, safety, and immunogenicity.

The clinical trial involves a total of **259 participants** diagnosed with **neovascular age-related macular degeneration (nAMD)**. The study population includes both male and female subjects, with an age range categorized under code "4", indicating a specific age group as per the trial's classification system. Participants were selected based on specific ocular inclusion criteria, such as an initial diagnosis of nAMD within nine months prior to the screening visit and previous treatment with at least three anti-vascular endothelial growth factor (VEGF) intravitreal injections. The trial population is characterized by a history of visual acuity data and a best-corrected visual acuity (BCVA) of 34 letters or better, using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The study also includes individuals with any subtype of nAMD lesions involving the macula. Both genders are represented, and the trial includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed in the provided data.

The clinical trial is designed to evaluate the **efficacy**, safety, and pharmacokinetics of a 36-week refill regimen for the Port Delivery System with **ranibizumab** in patients with neovascular age-related macular degeneration (nAMD). This is a Phase IIIb, global, multicenter, randomized, visual assessor-masked study. The trial will compare the outcomes of ranibizumab delivered every 36 weeks (Q36W) versus every 24 weeks (Q24W), focusing on changes in best-corrected visual acuity (BCVA) scores averaged over Weeks 68 and 72. The study is expected to conclude by December 31, 2026, with recruitment having commenced on March 21, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific ocular criteria, such as a diagnosis of nAMD within the last nine months and previous treatment with anti-VEGF injections. Follow-up visits will occur at regular intervals to monitor BCVA scores, assess treatment satisfaction, and evaluate any adverse events. The end-of-study visit will finalize data collection and assess the overall outcomes of the treatment regimen.

The expected length of participant involvement is up to 72 weeks, with conditions for early termination including the occurrence of severe adverse events or withdrawal of consent. The trial will utilize a combination product that includes a device, specifically the ranibizumab/Port Delivery System, which is administered via implantation. The primary endpoint is the change in BCVA score from baseline, while secondary endpoints include the proportion of patients achieving specific BCVA scores, treatment satisfaction, and the incidence of adverse events. The study aims to provide comprehensive data on the long-term management of nAMD using the Port Delivery System with ranibizumab.

The clinical trial involves the use of **ranibizumab**, an active substance classified as a protein of other origin. The experimental medication, identified as RO4893594, is provided in the form of a **solution for injection**. This product is administered via **implantation** using a combination product that includes a device, specifically the ranibizumab/Port Delivery System. The maximum daily dose is 2 mg, with a total maximum dose of 6 mg over a treatment period of 72 weeks. The administration schedule is set at every 36 weeks (Q36W) or every 24 weeks (Q24W), depending on the study arm. The product is not a pediatric formulation and is not classified as an orphan drug.

Another treatment used in the study is Lucentis, a 10 mg/mL solution for injection in a pre-filled syringe, also containing **ranibizumab**. This product is similarly administered via **implantation** using the ranibizumab/Port Delivery System. The dosing regimen mirrors that of RO4893594, with a maximum daily dose of 2 mg and a total maximum dose of 6 mg over 72 weeks. Lucentis is provided by Novartis Europharm Limited and is not a pediatric formulation or an orphan drug.

Both treatments are part of a Phase IIIb, global, multicenter, randomized, visual assessor-masked study aimed at evaluating the efficacy, safety, and pharmacokinetics of a 36-week refill regimen for the Port Delivery System with **ranibizumab** in patients with neovascular age-related macular degeneration. Participant compliance is monitored through scheduled visits and assessments to ensure adherence to the dosing schedule and to evaluate the change from baseline in best-corrected visual acuity (BCVA) score averaged over Weeks 68 and 72.

The efficacy of the clinical trial will be assessed by evaluating the change from baseline in **best-corrected visual acuity (BCVA)** score, which will be averaged over Weeks 68 and 72. This primary endpoint will be measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, starting at a distance of 4 meters. Secondary endpoints include the change from baseline in BCVA score over time, the proportion of patients achieving a BCVA score of 69 letters or better, and the proportion of patients with a BCVA score of 38 letters or worse, both averaged over Weeks 68 and 72 and over time. Additionally, patient preferences for the delivery method of **ranibizumab** via the Port Delivery System (PDS) compared to intravitreal treatment will be assessed using the PDS Patient Preference Questionnaire (PPPQ) at Weeks 24, 40, and 72.

Further secondary endpoints involve the mean overall treatment satisfaction at Week 40, as measured by the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) total score, and the proportion of patients who lose less than 10, less than 5, or gain 0 or more letters in BCVA score from baseline, both averaged over Weeks 68 and 72 and over time. Changes from baseline in central point thickness (CPT) and central subfield thickness (CST) up to and including Week 72 will also be evaluated. The incidence and severity of ocular and systemic adverse events, as well as adverse device effects, will be compared between the Q36W and Q24W arms. Observed serum concentrations of **ranibizumab** at specified timepoints and the incidence of treatment-emergent anti-drug antibodies (ADAs) to **ranibizumab** during the study will be monitored.