The port delivery system with ranibizumab: understanding nuances for clinical use in the real world

KEYWORDS:

• PDS
• real world
• nAMD
• anti-VEGF

1. Port delivery system

The port delivery system with ranibizumab (PDS/Susvimo, Roche/Genentech Inc., San Francisco, CA) is a sustained release drug delivery device for continuous anti-vascular endothelial growth factor (VEGF) therapy aiming to tackle the outstanding need of curtailing treatment burden by lowering the number of injections in various diseases such as neovascular age-related macular degeneration (n-AMD), diabetic macular edema (DME), and diabetic retinopathy (DR) [1]. PDS has completed 3 phases of clinical trials (Phase 1, Phase 2 LADDER, and Phase 3 ARCHWAY) [2,3]. and has been granted the United States Food and Drug Administration (US FDA) approval for management of n-AMD [4]. This is an index manuscript to review the unique aspects of the device and its use.

1.1. Switching to other anti-VEGF agents

PDS is filled with 20 μL of a new, more concentrated formulation of ranibizumab (100 mg/ml). As per the phase 3 ARCHWAY data, 6 monthly refill provided sufficient concentration to maintain best-corrected visual acuity (BCVA) and control disease activity in 98.4% of the patients comparable to the monthly injection of ranibizumab (10 mg/ml) [3]. In real-world clinical practice, visual results have been sub-optimal to the phase 3 studies due to various practical problems such as missed or delayed visits due to health or transportation issues and variable use of available anti-VEGF agents. Switching anti-VEGF agents in the course of therapy is also not uncommon in clinical practice, and that is sometimes due to perceived suboptimal response. With the PDS implanted in a given patient and supplemental or alternative anti-VEGF treatment potentially needed, does the dose need to be adjusted? Furthermore, where is the ideal place to deliver the anti-VEGF supplemental injection? The answers to these questions can be answered in part based on the design of the ARCHWAY study. With learning’s from the phase 3 study, supplemental ranibizumab injections delivered through the pars plana away from the superotemporal quadrant where the implant is located is well tolerated. What is not known is whether or not the use of another anti-VEGF by intravitreal injection in the eyes with the implant is safe. Most clinicians would speculate that it is likely to be so but that has yet to be determined.

1.2. Need of prior response to anti-VEGF agents

In the Phase 2 LADDER and Phase 3 ARCHWAY trials, the protocols required patients to show a positive response to anti-VEGF to be eligible to participate. Hence, except for the phase 1 study, PDS has not been tested in treatment-naïve wet AMD. Clinicians would want to know if the same practice needs to be followed in the real world, at least in the beginning to have a favorable risk-benefit ratio. It would be ideal if the risk-benefit ratio is established for treatment-naïve patients before routine adoption in this fashion after commercialization. An investigator-sponsored study or smaller phase 3b study may help to answer this question.

1.3. Vitrectomized eyes

None of the PDS trials recruited patients with previously vitrectomized eyes. Hence, it might take some real-world experience or additional studies to know the precise behavior of the implant in terms of its release rate in such eyes [5]. However, as the implant follows first-order kinetics, it probably shouldn’t significantly alter its efficacy. First-order elimination kinetics depends on the concentration of the drug and a constant fraction of the drug from the implant is eliminated per unit time. In in-vitro studies, after the initial implant insertion, ~73% of 100 mg/mL ranibizumab was released from the implant over a period of 6 months and the level could not be quantified after ~450 days. The average active release rate (SD) at 6 months was 3.95 µg/day (0.17) at the initial fill, 3.99 µg/day at the first fill (0.13), 3.85 (0.15) at second fill, and 4.00 (0.17) at the third fill demonstrating reproducibility from implant to implant and between multiple refill-exchanges of the same implant. Increasing ranibizumab concentration from 10 to 100 mg/mL augmented the drug release rate from ~2 to ~17 µg/day. With one injection (100-µL) during a refill-exchange procedure, ~98% of the primary implant contents get substituted with the fresh drug. Due to the continuously decreasing ranibizumab concentration inside the implant, in vitro studies have revealed a gradual decline in the release rates from about 17 µg per day to 4 µg per day. This variance in the release rates ensures maintenance of the drug concentration within therapeutic levels in the vitreous. The studies further highlighted that, following the primary fill, half of the drug gets released in 3 months and 70% over 6 months. After refill, the release rates were seen to be similar to the initial fill. This is important to assure that the concentration of the drug in the vitreous is sustained within therapeutic levels across 24-week treatment cycles.

1.4. Vitreoretinal surgeon’s or a medical retina specialist’s tool

PDS is the first anti-VEGF drug that needs a surgical procedure for implantation. Hence, it will need a vitreoretinal surgeon for initial implantation. However, refills in the office should be able to be performed by either a medical or surgical retina specialist. In phase 3 trials (ARCHWAY) prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm which included, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events occurred within 1 month of implantation [6]. Vitreous hemorrhage was a predominant adverse event during phase 1 and early phase 2 (LADDER) trials. It reduced significantly after optimizing the surgical technique in phase 2 and phase 3 trials (ARCHWAY). However, the implant insertion surgery involves a number of surgical steps in order to minimize postoperative complications including hemorrhage, conjunctival issues, and implant dislocation. The above-mentioned adverse events happened when the investigators were vitreoretinal surgeons. It may not be easy for medical retina specialists in the initial phase of its usage. It will also depend on how the company plans to train its users. During the trial, Genentech’s development team scouted out the best possible ways to train study investigators on the PDS implant and refill procedures to achieve patient safety and reduce the risk of surgically related problems to the outcome of the trial. As a result, in the spring of 2018, Genentech and VRmagic launched two completely new, state-of-the-art virtual reality simulator platforms to train investigators for the PDS clinical trial. Its users were able to practice implant insertion as well as the refill exchange procedure as a supplement to traditional teaching tools such as wet-lab and video instruction methods [7].

To summarize, PDS represents a potential major step forward for sustained drug delivery of anti-VEGF therapy. Every new clinical therapy or procedure leads to unique questions in terms of utilization. It is not possible to have answers for all questions from clinical trials as the trials have their own set of limitations given the various study designs. Over time with both additional study follow-up and experience in practice, clinicians will gain additional insight on some of the important questions that will come up in the real-world with PDS use.

1.5. Expert opinion

US FDA approval of PDS could be an initiator for long-term sustained drug delivery of anti-VEGF. A safe and sustained release of anti-VEGF for the long term (12 months to start with) could be the early goal for the management of retinal diseases that require frequent anti-VEGF injections. It would add value and would be widely accepted if sustained release devices are biodegradable. Exciting research is ongoing in this direction such as OTX-TKI (axitinib intravitreal implant) by Ocular Therapeutix Inc is in the early stages of the clinical trial. Another excellent proprietary cell-based drug delivery system which is under clinical trials with encouraging data is the renexus (NT-501, Neurotech Pharmaceuticals) where human-derived retinal pigment epithelial cells are encapsulated in a semipermeable hollow fiber membrane. In addition, nanoparticles, gene therapy, and microneedles are many other such platforms with promising initial results. Although it is exciting to witness the progress of sustained-release drug delivery efforts, it is equally exciting to see the development of molecules such as brolucizumab (Beovu, Novartis, USA) and faricimab (Vabysmo, Genentech, USA) that provides efficacy up to 12–16 weeks. The probable challenge that these therapies are facing is the risk of immunogenicity due to a probable very high concentration of molecules packed in a small volume. Brolucizumab faced setback due to immunogenic reactions at the retinal vascular levels such as vasculitis and vascular occlusion. Faricimab is yet to receive larger real-world data. However, faricimab had a different mechanism than brolucizumab with a lesser number of molecules compared to brolucizumab. Overall it is a very exciting time for advanced pharmacotherapy-based research and development for the management of retinal diseases and we hope to get an ideal long-term anti-VEGF pharmacotherapy soon.

Author contributions

A Sharma: conception, analysis, drafting, integrity check, final approval. N Parachuri, N Kumar, BD Kuppermann, F Bandello, CD Regillo: drafting, analysis, integrity check.

Declaration of interest

A Sharma has acted as a consultant for Novartis, Allergan, Bayer and Intas. BD Kuppermann has performed clinical research for Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GlaxoSmithKline, Ionis, jCyte, Novartis, Regeneron and ThromboGenics, has acted as a consultant for Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana and Theravance Biopharma and receives an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute at the University of California, Irvine. F Bandello has acted as a consultant for Allergan, Bayer, Boehringer- Ingelheim, FidiaSooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics and Zeiss. CD Regillo has acted as a consultant for Allergan, Chengdu Kanghong, Genentech/Roche, Novartis, Kodiak, Notal, Merck, Shire-Takeda, Adverum, Graybug, and Eyepoint and receives research support from Allergan, Chengdu Kanghong, Genentech/Roche, Novartis, Kodiak, Iveric, and Adverum. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.