A lower anti-VEGF treatment frequency for neovascular age related macular degeneration (nAMD) could prove a significant breakthrough in adherence – one of the leading causes of treatment “failure”.
In search of a more prolonged approach over existing treatments first PBS-listed 15 years ago¹, alternative anti-VEGF agents and drugs are being explored. But still regular anti-VEGF injections – every four months in the best cases – remain the gold standard.
In October 2021, the US approved a new, first-of-its-kind, treatment device for nAMD, namely the Port Delivery System (PDS), delivering a customised formulation of ranibizumab.² The approval was based on the Phase 3 ARCHWAY randomised controlled trial.³ The PDS is a permanent, refillable implant surgically inserted via the pars plana into the vitreous cavity and buried under the conjunctiva. The device is pre-filled with a specific ranibizumab concentration (100 mg/ml) which diffuses slowly and continually into the vitreous gel, maintaining a therapeutic level of anti-VEGF.
The device will need to be refilled at a specific interval in an office or clinicbased refill-exchange procedure. It has a controlled release element at one end, letting ranibizumab diffuse into the vitreous cavity, and an extra-scleral flange encasing a silicone septum at the other end where the refill occurs. This therapy aims to replace regular injections, with refills occurring up to twice per year.
The two-year, Phase 3 ARCHWAY study compared the PDS to monthly ranibizumab injections in recently diagnosed nAMD (previously treated with intravitreal anti-VEGF therapy for up to nine months). It demonstrated a PDS filled every 24 weeks had non-inferior visual outcomes to monthly ranibizumab over one year. It showed 98% of the PDS group didn’t need additional treatment, and was well tolerated. The PDS’ main issue is it’s a new device implanted with a new surgical technique. It’s associated with an increased risk of potential complications (similar to the first IOL implantation or glaucoma tube surgery). Possible complications for PDS include vitreous haemorrhage, conjunctival erosion or retraction, endophthalmitis, rhegmatogenous retinal detachment, and septum dislodgement. It’s comforting to know these rates appear to be trending down due to a combination of improving techniques and experience.
Based on these encouraging results, a new study, Velodrome (a Phase 3b, global, multicentre, randomised, visual-assessor-masked study), is assessing the efficacy, safety, and pharmacokinetics of the PDS with ranibizumab 100 mg/mL delivered every 36 weeks compared with 24 weeks. It aims to recruit over 440 nAMD patients worldwide. The first patient in Australia (and first outside the US) was under the care of A/Prof Adrian Fung in Sydney, and the implant procedure was performed in July 2021. Many new trial sites are now recruiting across Australia. More recently, the first patient was enrolled on trial by A/ Prof Fred Chen in WA.
In July 2022, the first patient underwent the procedure at our site, the Queensland Eye Institute. All sites are carefully selected to ensure they have the necessary clinical expertise, personnel, and equipment support. A strict inclusion and exclusion criteria is followed for participants to ensure patient safety. The surgeons are specially trained via online seminars and courses to ensure they’re familiar with the device and implantation procedure. Surgical steps are meticulously explained – with regards to the importance of tissue (conjunctiva and tenon) handling – to reduce the risk of postoperative implant exposure, haemostasis to minimise vitreous haemorrhage risk, and precise measurement of the sclerotomy to ensure a snug fit for the device.
Surgeons used model eyes to practise the technique prior to the implantation date. There is a Global Surgical Device Liaison from the trial company on site to supervise and to maximise outcomes. Our patient was enrolled after four injection doses and a failure to extend the injection interval. He underwent the implantation procedure uneventfully in July. He responded favourably and provided the nAMD remains under control, the refill-exchange will take place in 2023. Patients recruited across Australia is approaching 30, but due to the recently reported complication of septum dislodgement, there is a pause to this trial and all PDS implantation.
Due to its complication rate, PDS isn’t suitable for all needing intravitreal injections for nAMD, but will add to the treatment armamentarium for a certain patient subgroup, for example, those needing short injection intervals. The PDS is perhaps the first new treatment providing a paradigm shift in nAMD management. On the horizon, there are other potential treatments, including molecules with dual actions or gene therapy.4 The future of the nAMD management is exciting and forever changing.
ABOUT THE AUTHOR:
Name: A/Prof Anthony Kwan
Qualifications: MBCHB, MD (London), FRCOphth (UK), FRANZCO
Organisations: Queensland Eye Institute, Mater Hospital Brisbane, and the University of Queensland
Position: Director of Vitreoretinal Service (QEI), Senior Staff Specialist and consultant vitreoretinal surgeon
Location: Brisbane
Years in profession: 30, clinical practice and research
References
- https://www.pbs.gov.au/pbs/news/2007/06/listing-of-lucentis
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Susvimo BLA 761197, approval letter, Oct 22, 2021. Retrieved Jan 28, 2022 from https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761197Orig1s000_ltr.pdf
- Holekamp, N. M., Campochiaro, P. A., Chang, M. A., Miller, D., Pieramici, D., Adamis, A. P., Brittain, C., Evans, E., Kaufman, D., Maass, K. F., Patel, S., Ranade, S., Singh, N., Barteselli, G., & Regillo, C. Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology, 129 (3), 295-307 (2022).
- Jiménez-Gómez Y, Alba-Molina D, Blanco-Blanco M, Pérez-Fajardo L, Reyes-Ortega F, Ortega-Llamas L, Villalba-González M, Fernández-Choquet de Isla I, Pugliese F, Stoikow I, González-Andrades M. Novel Treatments for Age-Related Macular Degeneration: A Review of Clinical Advances in Sustained Drug Delivery Systems. Pharmaceutics, 14(7):1473 (2022).
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