Author: Dennis Marcus (United States)
Co-authors: Giulio Barteselli, Derrick Kaufman, Anne Fung, Shamika Gune, Sneha Makadia, Alicia Menezes
The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed for continuous intravitreal ranibizumab release through a surgically implanted, refillable ocular implant. The Archway trial evaluated the safety and efficacy of the PDS for the treatment of neovascular age-related macular degeneration (nAMD). Here, we present results from the Archway September 2020 data cut and report key surgical pearls from the optimization and standardization of the PDS implant insertion procedure.
Archway (NCT03677934) was a phase 3, randomized, active treatment–controlled trial for the treatment of nAMD, conducted at 77 study locations in the United States.
Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/mL with fixed 24-week (W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4W (monthly ranibizumab). Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. All patients had received a diagnosis of nAMD within 9 months of screening and were responsive to anti−vascular endothelial growth factor (VEGF) treatment, with ≥ 3 intravitreal anti-VEGF injections within the previous 6 months. The trial evaluated noninferiority (NI) and equivalence of the PDS Q24W versus monthly ranibizumab on the primary endpoint of best-corrected visual acuity (BCVA) change from baseline averaged over W36/40 (NI margin, –4.5 letters; equivalence margin, ±4.5 letters). The September 2020 data cut extended results through ≥ 48W of follow-up, covering 2 complete refill-exchange intervals for PDS patients. The implant insertion procedure has 7 major steps: peritomy, implant preparation, scleral dissection, pars plana laser ablation, pars plana incision, implant insertion, and conjunctival and Tenon’s capsule closure. Experiences during implant insertion procedures in PDS clinical trials have informed the evolution of PDS surgical methodologies, with the goal of optimizing surgical outcomes.
Change in adjusted mean BCVA score from baseline averaged over W44/48 was 0.0 (PDS Q24W) versus +0.2 (monthly ranibizumab). PDS Q24W was noninferior to monthly ranibizumab at W44/48, with a difference (95% CI) of –0.2 (–1.8, +1.3) letters between arms (equivalence not tested). 98.4% (242/246) and 94.6% (228/241) of PDS Q24W patients assessed for supplemental treatment need did not receive supplemental ranibizumab during the first or second refill-exchange intervals, respectively. The mean total treatment number (initial fill, refill-exchanges, and supplemental injections) through September 2020 was 3.9 (PDS Q24W) versus 19.5 (monthly ranibizumab). PDS implant insertion and refill-exchange procedures were generally well tolerated and the ocular safety profile was generally unchanged from the primary analysis. Systemic safety findings were comparable across arms. Edge-to-edge pars plana laser ablation while maintaining a final incision size of 3.5 mm ensures a secure implant fit and postoperative hemostasis. Delicate/precise handling and dissection of the conjunctiva and Tenon’s capsule during peritomy and closure is critical to preserve tissue integrity over the implant. Capturing both the conjunctiva and Tenon’s capsule is key when anchoring to the anterior limbus with scleral bites. Meticulous hemostasis ensures optimal visualization and minimizes vitreous hemorrhage risk.
As previously reported, Archway met its primary endpoint, demonstrating that PDS Q24W treatment resulted in noninferior and equivalent vision outcomes compared with monthly ranibizumab when averaged over W36/40. BCVA results for the average of W44/48 were consistent with the primary analysis, with the PDS Q24W noninferior to monthly ranibizumab treatment. Over 90% of patients did not receive supplemental treatment before each refill-exchange procedure. The PDS was generally well tolerated, with a favorable benefit-risk profile. Attention to laser application, hemostasis control, and proper handling of the conjunctiva and Tenon’s capsule during the PDS implant insertion procedure is important to minimize complications. To maximize optimal surgical outcomes, the procedure requires careful attention to elements generally not emphasized in other vitreoretinal procedures. With a view to supporting optimal patient outcomes, the PDS procedures have evolved based on learnings from the trial.
DM: Genentech/Roche (consultant); Allergan, Aiviva, Amgen, Boehringer Inglheim Alcon, Aerpio, Kalvista, Ionis, Mylan, Samsung, Novartis, Opthea, Chenghdu, Clearside, Astellas, Allegro, Alimera, Ophthotech/Iveric, Outlook, Gemini, Genentech, ThromboGenics, Tyrogenex, Graybug, Topcon, Optos, Xplore, Gyroscope, Stealth Spiam, Aerie, Apellis, Roche, Novartis, OHR, Xplore, Regenxbio, Kodiak, Zeiss, and Regeneron Pharmaceuticals (Research Grants). GB, DK, AF, SG, SM, AM, VM, JW: Genentech, Inc. (Employee). MM: F. Hoffman-La Roche Ltd. (Employee).
Please add below extra three co-authors: Co-author 7 first name: Varun Co-author 7 last name: Malhotra Co-author 7 affiliation: Genentech, Inc., South San Francisco, CA, USA Co-author 8 first name: Jeffrey Co-author 8 last name: Willis Co-author 8 affiliation: Genentech, Inc., South San Francisco, CA, USA Co-author 9 first name: Merce Co-author 9 last name: Morral Co-author 9 affiliation: F. Hoffman-La Roche Ltd., Basel, Switzerland