VEGF inhibitors that may treat AMD: port delivery system
Karl Csaky, MD, PhD: We’re going to change course a bit. Nancy, we want to make sure we leave room for some of the other exciting agents we interview. One of them, probably the most important, is the port delivery system [PDS]. Can you tell us about how you used the port delivery system in testing, your overall thinking at this point on the results and how you are trying to conceptualize where we’re going with the port delivery system?
Nancy M. Holekamp, ââMD: It’s a paradigm shift. It is a surgical procedure that implants a drug delivery system in a patient’s eye. This drug delivery system is a reservoir of anti-VEGF; currently it is ranibizumab. Because it’s a port delivery system, through this port you can do a renewal exchange and put in a new drug every 6 months. It is wet tested [age-related] macular degeneration [AMD], diabetic macular edema, and Jennifer’s last point, in patients with nonproliferative, moderately severe or severe diabetic retinopathy. It’s exciting, and I participated in the clinical trials. When I ask patients to participate in the clinical trial, they are happy that they don’t have injections into their eyes. In fact, patients in AMD trials received an average of about 5 injections of anti-VEGF. Then they would get this port delivery system. Then they were asked what they preferred, the port delivery system or injections, and 93% of people preferred the port delivery system. He has great appeal to patients.
It is important to note that the clinical trial for AMD has ended. This was a phase 3 registration trial, and it showed that this port delivery system, which is implanted during surgery and recharged every 6 months until approximately weeks 36 to 40, was not inferior to monthly ranibizumab. We started this program by talking about monthly injections which are good for patients with wet macular degeneration. It’s exciting new technology, and certainly a paradigm shift. Surgery is part of everyone’s skill as retinal surgeons, as physicians. It has great appeal to patients, and it appears to be effective. I’ll let Carl or someone else talk about the safety profile because clinical trials always tell us a lot about safety as well.
Karl Csaky, MD, PhD: Carl, you taught us a lot about the PDS system. Let’s look inside your brain one more time. Tell us about sustainability as the key parameter we are looking for. We are talking about faricimab which may have been given to a group of patients at 16 weeks. When you think of PDS in the real world, Nancy just alluded to the security aspects, but share with us your thoughts on PDS in your practice, in the real world. How do you see its integration, at least with the data we have on neovascular AMD?
Carl Regillo, MD, FACS: I am a huge fan of PDS. As Nancy mentioned, it has successfully passed all 3 phases of clinical trials. The Archway Phase 3 trial met the primary endpoint of being both non-inferior and visually equivalent – controlling vision and controlling disease through the primary endpoint. We have about 20 months of follow-up for efficacy and safety. The efficiency is superlative. We have disease control as effective as standard monthly ranibizumab, standard dose injections.
Keep in mind that this is a one-time trip to the operating room [operating room], with relatively short local anesthesia. It is an outpatient operation, then the device is filled in the office with a special needle. It’s a one-off trip to the operating room, unless there’s a complication, and we’ll get to that. In general, as Nancy mentioned, any vitreoretinal surgeon can learn to put this in place. It’s a unique surgical procedure, a unique device, but it’s an extremely powerful platform. This is true sustained delivery. Although the Phase 3 program required the device to be refilled every 6 months and its performance was excellent, 98% of patients were able to go through the first 6 months without the need for additional injections. This initial implantation and filling of the device lasted adequately for 6 months in the vast majority of patients. Really powerful. But even better, at that same high concentration of ranibizumab used in the device in phase 3, but in the phase 2 study, which showed a median durability of almost 16 months. This meant that patients, after 3 or 4 injections on average during the induction phase, introduced into the maintenance phase, could achieve more than a year of durability. When we talk about the risk-benefit ratio, we have to consider how powerful it is to deliver a drug for a very long time to the majority of our patients, beyond the 6 months that were mandated in the phase 3 trial.
Let’s talk about the risk. It is a device. It’s surgery, so it’s not going to look as clean, especially early in the first few months or the first year of follow-up compared to safe intravitreal injections. We know it is safe. The rate of endophthalmitis per injection is 1 in 3000; however, a cumulative rate of endophthalmitis from anti-VEGF treatment in wet AMD over 4 or 5 years and 30 or 40 injections could approach 1%. Another aspect of the prospect of comparing apples to apples is the long term safety of having a device in the eye and filling it so often compared to many injections over many years. When you look at the difference in adverse events between the device and the injection arm, most of the adverse events have occurred within that first 40 weeks, then you start to see some adverse events getting worse at a higher rate. or faster, not quite as much in the monthly arm.
Let me provide you with the safety profile of the main device-related adverse events after 20 months of follow-up in Archway, the Phase 3 study. Vitreal bleeding was a big problem, but it is manageable. It turned out to be 6% in the device arm versus 3.6% in the monthly injection arm, and none of these were severe enough to require further intervention. Its good; it is harmless but a nuisance. Retinal detachment was weak, only one or two cases in the device arm and none in the injection arm. A retinal detachment rate of less than 1%.
Endophthalmitis is where there is a little difference. It is higher in the device arm, 1.6% over 20 months compared to 0.6% in the injection arm. There’s an imbalance there, no doubt, and most of those cases of endophthalmitis were associated with some conjunctival problem on the device. Part of it is inevitable. Erosion of the conjunctiva on a scleral-based appliance will occur. We see it with our glaucoma devices in our glaucoma patients. This is a discreet device, and I think we can reduce the rates of conjunctiva problems, which were around 4.5%. However, 4.5% is not negligible. This requires returning to the operating room to repair the conjunctiva, to avoid other problems such as endophthalmitis.
Another potentially serious complication requiring a return to the operating room: dislocation of the device. Some of them occur in conjunction with the refill exchange procedure. Throughout the clinical trial program, we learned a lot about how to alleviate these problems, like bleeding and conjunctiva problems. Now we have learned how to potentially alleviate dislocations with strict surgical control and technique. With proper surgical technique and training, once this device hits the market, there is a good chance that it will first be approved by the FDA for wet AMD; we’re in the process of getting FDA approval. It’s something that will be in our hands within months or a year of FDA approval – many surgeons will embrace it and offer it. This doesn’t necessarily mean that many of our patients will want the device, but it is a great option for patients who need frequent injections and are motivated to achieve the best possible long-term vision results.
This transcript has been edited for clarity.