Two specialists give their insight into a VEGF inhibitor that could potentially be used as an effective treatment for age-related macular degeneration: port delivery system.
Karl Csaky, MD, PhD: We’re going to switch gears a little. Nancy, we want to make sure we give room for some of the other exciting agents that we’re interrogating. One of them, probably foremost, is the port delivery system [PDS]. Can you talk to us a about how you used the port delivery system in the trials, your overall thinking at this point about the results, and how you’re trying to conceptualize where we’re going with the port delivery system?
Nancy M. Holekamp, MD: It’s a paradigm shift. It’s a surgical procedure that implants a drug delivery system into the eye of a patient. That drug delivery system is a reservoir of anti-VEGF; currently it’s ranibizumab. Because it’s a port delivery system, through that port you can do a refill exchange and put a new drug in every 6 months. It’s being tested in wet [age-related] macular degeneration [AMD], diabetic macular edema, and to Jennifer’s last point, in patients with nonproliferative diabetic retinopathy, moderately severe or severe. It’s exciting, and I’ve been in the clinical trials. When I get patients interested in possibly being in the clinical trial, they’re excited about not having injections in their eye. In fact, patients on the AMD trials had about 5 anti-VEGF injections, on average. Then they would get this port delivery system. Then they would be asked which they liked better, the port delivery system or the injections, and 93% of people liked the port delivery system better. It has great patient appeal.
Importantly, the AMD clinical trial has been completed. This was a phase 3 registration trial, and it showed that this port delivery system, which is implanted at surgery and refilled every 6 months through about weeks 36 to 40, was noninferior to monthly ranibizumab. We began this program by talking about monthly injections being good for patients with wet macular degeneration. It’s exciting new technology, and definitely a paradigm shift. The surgery is within everybody’s skill set as retina surgeons, as physicians. It has great appeal for patients, and it seems to be effective. I’ll let Carl or someone else talk about the safety profile because the clinical trials always tell us so much about safety too.
Karl Csaky, MD, PhD: Carl, you’ve taught us a lot about the PDS system. Let’s peer inside your brain 1 more time. Talk to us about durability as a key parameter we’re looking for. We’re talking about faricimab that’s gone out to maybe a group of patients at 16 weeks. When you think about PDS in the real world—Nancy just alluded to the safety aspects but share with us your thinking about PDS in your practice, in the real world. How do you see it being incorporated, at least with the data we have on neovascular AMD?
Carl Regillo, MD, FACS: I’m very keen on PDS. As Nancy mentioned, it successfully made it through all 3 phases of clinical trials. The Archway phase 3 trial met the primary end point of being both noninferior and equivalent visually—controlling vision and controlling the disease through the primary end point, We have about 20 months of follow-up for both efficacy and safety. Efficacy is superlative. We have disease control that’s as good as monthly gold standard ranibizumab, standard dose injections.
Keep in mind, this is a onetime trip to the OR [operating room], with a relatively short local anesthesia. It’s an outpatient operation, and then the device is refilled in the office with a special needle. It’s a onetime trip to the OR, unless there’s a complication, and we’ll get to that. In general, as Nancy mentioned, any vitreoretinal surgeon can learn how to put this in. It’s a unique surgical procedure, a unique device, but it’s a tremendously powerful platform. It’s true sustained delivery. Although the phase 3 program mandated refilling the device every 6 months, and it performed great, 98% of patients could go the first 6 months without needing any supplemental injections. That initial implantation and filling the device lasted 6 months adequately 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, that showed a median durability of almost 16 months. That meant patients, after 3 or 4 injections on average during the induction phase, introduced in the maintenance phase, could get over a year of durability. When we talk about risk-benefit ratio, we have to consider how powerful it is to deliver drug for a very long time in the majority of our patients, beyond the 6 months that was mandated in the phase 3 trial.
Let’s talk about the risk. It’s a device. It’s a surgery, so it’s not going to look as clean, especially up front in the first few months or the first year of follow-up compared with safe intravitreal injections. We know it’s safe. The per-injection rate of endophthalmitis is 1 in 3000; however, a cumulative endophthalmitis rate of a course of anti-VEGF therapy in wet AMD over 4 or 5 years and 30 or 40 injections could approach 1%. Another aspect to the perspective of comparing apples to apples is long-term safety, of having a device in the eye and then refilling it so often vs many injections over many years. When you look at the difference in the adverse events between the device and the injection arm, most of the adverse events were within that first 40 weeks, and then you start to see some adverse events creeping up at a higher rate or faster, not quite as much in the monthly arm.
Let me give you the safety profile of the key device-related adverse events after 20 months of follow-up in Archway, the phase 3 study. Vitreous hemorrhage was a big problem, but it’s manageable. It came out to be 6% in the device arm vs 3.6% in the monthly injection arm, and none of these was severe enough to require another intervention. That’s good; it’s harmless but a nuisance. Retinal detachment was low, only a case or 2 in the device arm and none in the injection arm. A retinal detachment rate of less than 1%.
Endophthalmitis is where there’s a little difference. It’s higher in the device arm, 1.6% over 20 months vs 0.6% in the injection arm. There’s an imbalance there, no doubt about it, and most of those cases of endophthalmitis were associated with a conjunctival problem over the device. Some of that’s inevitable. Erosion of conjunctival over a scleral-based device is going to happen. We see it with our glaucoma devices in our patients with glaucoma. This is a low-profile device, and I think we can get the rates of conjunctival issues—which came out to about 4.5%—lower. Now, 4.5% is not insignificant. That requires a trip back to the OR to fix the conjunctival, to prevent other problems like endophthalmitis.
One other complication that’s potentially serious and requires a trip back to the OR: the device dislocation. Some of those are occurring in conjunction with the refill exchange procedure. Throughout the clinical trial program, we’ve learned a lot about how to mitigate these problems, like hemorrhage and conjunctival issues. Now we’ve learned how to potentially mitigate dislocations with strict surgical control and technique. With good surgical technique and good training, once this device is commercialized—because there’s a good chance it’s going to be FDA approved for wet AMD first; we’re on the cusp of FDA approval. This is something that’s going to be in our hands within months or within a year upon FDA approval—a lot of surgeons are going to embrace it and offer it. That doesn’t necessarily mean a lot of our patients are going to want the device, but it’s a great option for patients who need injections frequently and are motivated to have the best possible long-term vision outcome.
This transcript has been edited for clarity.