ARCHWAY Randomized Phase 3 Trial of the Port Delivery System With Ranibizumab for Neovascular Age-related Macular Degeneration

The purpose of this study was to determine the efficacy and safety of a first-in-class investigational long-term antivascular endothelial growth factor (VEGF) treatment approach with the port delivery system with ranibizumab (PDS) compared to the standard-of-care treatment of monthly intravitreal ranibizumab for patients with neovascular wet macular degeneration (nAMD). The PDS requires surgical implantation of a refillable reservoir that continuously releases ranibizumab into the vitreous cavity.

The authors perform a multi-center, randomized, open-label phase 3 noninferiority (NI) and equivalence trial of 418 patients with a diagnosis of nAMD from September 2018 to June 2019. Patients were diagnosed within 9 months of screening and were previously treated with good anatomic and visual response with at least 3 intravitreal injections of antivascular endothelial growth factor therapy (anti-VEGF). Patients on anticoagulant or antiplatelet therapy other than aspirin or nonsteroidal anti-inflammatory drugs were excluded if the medications could not be safely held before PDS surgery.

Patients were randomized 3:2 to either the PDS with ranibizumab implant surgery and a fixed every 6-month refill-exchange or to intravitreal ranibizumab injections every month. The primary endpoint was change from baseline BVCA score at the average of 9-10 months using ETDRS and masked visual acuity assessor. Additional secondary and exploratory outcomes were performed, including change from baseline central subfield thickness (CST) over time and a previously validated PDS Patient Preference Questionnaire (PPPQ).

Of 418 patients, 248 patients received PDS every 6 months, and 167 received treatment with monthly intravitreal ranibizumab. Over 98% of patients in the PDS every 6-month arm did not require supplemental treatment before the first refill-exchange procedure at the 6-month interval. The adjusted mean change in BCVA from baseline at 9-10 months was +0.2 in the PDS every 6-month arm and +0.5 in the monthly intravitreal ranibizumab arm, respectively. The CST change from baseline was 10.3 micrometers in the PDS every 6-month arm compared to 4.4 micrometers in the monthly intravitreal ranibizumab arm. The PPPQ showed an impressive 93.2% of PDS-treated patients preferred treatment of their nAMD with the PDS every 6 months over intravitreal injections.

Ocular adverse events of special interest (AESIs) were prespecified and unbalanced between the groups. Patients in the PDS 6-month arm had 19% ocular AESI compared to 6% in the monthly intravitreal ranibizumab arm. The most common ocular AESI in the PDS arm was vitreous hemorrhage at 5.2%, followed by conjunctival erosions at 2.4%, conjunctival retractions at 2%, endophthalmitis 1.6%, and retinal detachment 0.8%. Ocular AESI in the PDS 6-month arm occurred most frequently within a month of surgery, and 7.3% of patients required additional procedures related to ocular AESI. The most common ocular AESI in the monthly intravitreal ranibizumab arm was cataract 3.6%, followed by vitreous hemorrhage at 2.4%. There were no differences in the systemic adverse events between the PDS 6-month arm and the monthly intravitreal injection arm.

The take-away from this paper is that this is the first phase 3 trial demonstrating a long-acting anti-VEGF treatment approach with PDS every 6 months was noninferior and had equivalent efficacy to the current standard of care of monthly intravitreal injections of ranibizumab. The PDS is now FDA approved for surgical implantation and refill procedures under the brand name Susvimo.