Chirag Jhaveri, MD

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The port delivery system is an ocular delivery system that is surgically inserted via the pars plana area in the superotemporal quadrant of the eye. It provides continuous delivery of ranibizumab to the posterior segment. It has a reservoir chamber where a higher concentration of ranibizumab is held, and there is slow release into the vitreous cavity. It has been approved for use in patients with neovascular AMD [age-related macular degeneration], although other indications, including diabetic macular edema, are also being investigated.

With the approval of Lucentis [ranibizumab] for the indications of neovascular AMD, the treatments for neovascular AMD were revolutionized. However, there still is a significant treatment burden for many of our patients who require frequent, often monthly, injections. The treatment burden for both the patients and the family can be quite high. In addition, although we’re delivering a nice bolus of anti-VEGF treatment, there is a waning of the amount of medication in the vitreous cavity. Therefore, a more sustained, endurable treatment modality was needed. Like most devices, the port delivery system was started in the preclinical stages, where it was developed and then tested in nonhuman subjects. Once its safety was verified, it went on to trials to verify safety in human patients, and then to look at the efficacy.

In the phase 2 LADDER study, the technique that was done in human patients initially showed an increased risk for vitreous hemorrhages. The technique for implantation was modified to include laser cautery of the corneal bed]. After this, the incidence of vitreous hemorrhages dropped precipitously. Prior to the amendment, there were 6 out of 10 cases of vitreous hemorrhage. After the amendment, there were no cases of vitreous hemorrhage out of 48 patients within the first month, which is generally considered the postoperative period. At 2 months, there was 1 patient who did have a vitreous hemorrhage.

Although the procedure is generally well tolerated, since it is surgical procedure, there are some potential complications that surgeons and patients should be aware of. Initially, in the LADDER study, there was a higher rate of vitreous hemorrhages. A modification of the procedure has since reduced those rates tremendously. Any surgery has a risk of infection, and with respect to the implant itself, if the conjunctiva is not closed properly or not covering the implant adequately, there is a possibility of the implant being exposed. Also, if the conjunctiva is very thin, there is a possibility of erosion. Therefore, presurgical evaluation and meticulous care to close the conjunctiva are very important.

When evaluating a patient preoperatively, you want to take note of a few things. Particularly, you want to take note of the conjunctiva to see if it’s very thin, and if there’s good mobility of the conjunctiva, so that you can adequately access the subconjunctival and sub-Tenon space. In addition, you also want to note any areas of potential scleral thinning, so that when you’re making your wound you’re aware, and so you don’t start making your wound too deep. In addition, you may also want to avoid those areas, so that there isn’t a risk of dehiscence or any other potential issues with the wound.

Videos

Expert insight on the history of the port delivery system in neovascular AMD and how it has impacted patient experience and outcomes.

The Development and Safety of Port Delivery System in Retinal Diseases 

 I think the port delivery system [PDS] can have a very significant clinical impact on the treatment of wet AMD [age-related macular degeneration]. We’re all aware of the treatment burden patients have with frequent intravitreal injections. In addition, we know the peaks and troughs of anti-VEGF injections can affect the recurrence of wet AMD. Given that it is a continuous delivery of anti-VEGF therapy, not only can this potentially reduce the treatment burden for patients, there is also a possibility for disease modification with the port delivery system.

The fact that many patients in the LADDER study did not even meet refill criteria, and that 98% of patients in the ARCHWAY trial did not need any additional treatment before the first refill, implies that we may be actually modifying the disease to the point of even potential quiescence for some of these patients.

Now that we have the port delivery system as an approved option, it’s important to consider how it can fit into our treatment plan. I have plenty of patients who require monthly or Q2 monthly [every 2 months] intravitreal injections. I think these are the patients I will first have a discussion with, and talk to them if they’re interested in potentially having a longer-term delivery of intravitreal anti-VEGF. Reducing the treatment burden will be very appealing for many of these patients. Of course, the risk and benefits of surgery need to be weighed carefully for such patients. One of the factors that I consider for PDS is the frequency of injections that the patients have. I also will look at the stability for these patients. If these patients can be stable on a monthly or every 2 months setting, we may still discuss it. However, if they’re having recurrent fluid, I think I’ll be much more likely to discuss the port delivery system. If a patient happens to be very stable with injections only every 3 or 4 months, the port delivery system may not be as appealing for some of these patients, unless they’re against getting transscleral intravitreal injections. With respect to insurance approval, of course many of these questions are yet be answered. However, we certainly hope and anticipate for insurance to cover this procedure. It is yet to be determined if it will be a step-wise approach, but I surely hope these critical patient-care decisions are left up to the physician, with explanation and discussion with the patient, and not mandated policy.

Having performed many of these surgeries already during the clinical trials, I can say that the patients who have received the port delivery system are quite happy. They do notice a stability of their disease. In addition, with the refill procedure, although technically it is very different from an intravitreal injection, and the surgeon has to be very aware of the different techniques, for the patient experience, it’s quite nice. It’s more tolerable because there’s no transscleral penetration of a needle. Patients often report that this was a much more comfortable and easier process to do. In terms of the implantation, it’s also considered to be quite painless. Most patients may have a little bit of itchiness or mild irritation immediately in the first 1 to 2 days of the postoperative period. Otherwise, it is a very well-tolerated procedure, and patients seem to have a very good experience.

With the approval of the port delivery system for neovascular AMD, I think the future for this platform is quite interesting; it has a lot of great potential. Studies are underway for both diabetic macular edema, as well as diabetic retinopathy. In addition, as we develop better compounds that may be more efficacious, such as bispecific molecules, marrying the PDS platform with these new molecules may yield even better results for our patients. I think there are a lot of exciting possibilities for the PDS platform.

As our retina specialty embarks upon a new era for the treatment of wet macular degeneration, I think as colleagues, it’s important that we utilize all the resources available. I highly encourage you to use all of the information, as well as surgical device liaisons, for example, in order to help maximize our patient outcomes.

Closing out his discussion on the port delivery system in retinal diseases, Chirag Jhaveri, MD, considers how this approach has impacted the treatment landscape. 

Clinical Implications of Port Delivery System in Retinal Diseases

As we all start performing more of these surgeries, since it is now approved for the use of neovascular AMD [age-related macular degeneration], it is going to be very important to review videos prior to implantation of the PDS [port delivery system] in our patients. In addition, there are surgical simulators that can give you great hands-on experience. I anticipate many of these simulators to be available at many of our meetings, including ASRS [the American Society of Retina Specialists] and AAO [American Academy of Ophthalmology]. It’s also very important to have a good relationship with your surgical device liaison. These individuals are going to be very helpful in guiding you through your first few surgeries. They will be present as needed in your operating room, and they will definitely be there for your first few cases. I highly recommend utilizing them, as they’re wonderful resources to help guide you through your first few cases.

The surgical device liaisons are individuals who you can get in touch with through the company representatives. They are individuals who are there for your resource, and to help guide you in learning any of the tips, pearls, and steps that you would like to discuss for the PDS implantation.

A detailed description of both the implantation and the refill is going through publication approval. These will also have associated videos. In addition, if you would like more videos, you can also discuss this with your surgical device liaison, and they’re happy to provide additional teaching techniques and videos.

Concise insight on education and training strategies that will optimize use of the port delivery system in retinal diseases.

PDS in Retinal Diseases: Practical Advice on Education and Training 

The LADDER trial was a phase 2 trial that showed overall good safety and efficacy for the port delivery system [PDS] for the treatment of neovascular AMD [age-related macular degeneration]. It looked at varying doses of ranibizumab in the PDS implant. Patients were dosed at 10-mg, 40-mg, and 100-mg concentrations. Interestingly, and this is different than the ARCHWAY study which we’ll talk about shortly, patients were only given a refill of ranibizumab if they met criteria of worsening fluid, vision, or new submacular hemorrhage. The 100-mg concentration, which is what is approved, showed that about 80% of patients were able to go 6 months or longer before needing a refill; the median time for needing the first refill in the 100-mg group was nearly 16 months.

Overall, the port delivery system procedure was very well tolerated. As mentioned before, after the modification of the technique, patients did not have any vitreous hemorrhage within the first month. The refill procedure was also very well tolerated, and was able to be done in an in-office setting.

Coming from very good results from the LADDER trial, ARCHWAY was the phase 3 trial, which was a 2-year study comparing monthly ranibizumab to the PDS implant with 100 mg ranibizumab and refills [every] 6 months. The patients enrolled in this study were patients who had wet AMD, were diagnosed within 9 months of screening, and who were responding to anti-VEGF treatment. The ARCHWAY trial showed that 98% of patients were able to go without any additional treatment in the PDS group. The PORTAL trial is an extension study that will be looking at how patients do beyond 2 years. The safety and tolerability of the procedure were also consistent with the LADDER study, particularly with respect to very low incidence of vitreous hemorrhage, as well as the procedure being very well tolerated.

The patients who were included in the ARCHWAY study were recently diagnosed with neovascular AMD. All the patients had to be diagnosed within 9 months of their screening visit, and they all had to show a good response to anti-VEGF therapy.

The ARCHWAY study so far shows that patients are tolerating the port delivery system very well, even in a long-term manner. We’re also showing that patients have good, consistent visual recovery, as well as good stability of their macular thickness. We also analyzed patients with fluid fluctuations, and showed that patients with the port delivery system have good minimization of fluid fluctuations, similar to having monthly ranibizumab injections. I’m also excited about learning what longer-term data are going to show in the PORTAL study. The PORTAL study is looking at patients well beyond 2 years, as well as multiple refills beyond 2 years.

Chirag Jhaveri, MD, reviews the trial design and results of the LADDER and ARCHWAY studies, which tested the port delivery system in neovascular AMD. 

Author | Chirag Jhaveri, MD

Articles

Clinical Implications of Port Delivery System in Retinal Diseases

PDS in Retinal Diseases: Practical Advice on Education and Training

PDS in Retinal Diseases: Interpreting the LADDER and ARCHWAY Studies

The Development and Safety of Port Delivery System in Retinal Diseases