Article

The Retinal Drug-Delivery Pipeline

An expert roundtable discusses what’s on the way for retina therapy.

New Pathways in Retinal Drug Delivery

Recent advances in treatment for neovascular AMD, retinal vein occlusion, and retinal vascular diseases such as DME have had tremendous impact on patients’ quality of life. There are now 3 approved anti-VEGF drugs, but treatment regimens are not ideal for physicians or patients. Many retina specialists have very busy waiting rooms, despite often implementing a treat-and-extend protocol. Recent reports also suggest that although treat-and-extend maintains vision at least for the first year, vision can decline over time. Real-world data also show that vision gains achieved early with anti-VEGF are lost over time. There are new treatments coming down the pipeline, including the Port Delivery System (PDS; Genentech), sustained-delivery compounds, and gene therapies. In this roundtable discussion, Allen Ho, MD, leads a conversation about pipeline therapies related to retinal drug delivery.

Dr. Ho: We have assembled a very experienced group of clinicians and clinical researchers to address this topic. Dr. Dugel, where do you think patients would appreciate a reduction in burden of treatment, and which particular new strategies might be most likely to achieve that?

Dr. Dugel: It is often underestimated how extraordinarily variable retinal diseases are: some patients require intensive treatment, and some don’t. Also, the burden of treatment is surveillance, not the actual injection. The challenge now is in identifying those patients who require the appropriate treatment intensity and personalizing their care as early as possible. In the near future, we may be able to identify patients by biomarkers or genetic testing who may require more or less intense treatment. And for those patients requiring more intense treatment, I think we will have treatments ranging from long-acting agents, such as GB-102 (Graybug Vision), KSI-301 (Kodiak Sciences), to PDS. I am very convinced that gene therapy will be in our portfolio in the near future. We desperately need to figure out how to identify patients who require different levels of treatment and which of these technologies will fit in the appropriate intensity of treatment.

Dr. Ho: Dr. Avery, I have heard you talk about a similar concept about heterogeneity of the requirement for treatment, for example, in neovascular AMD patients who were treated in the HARBOR trial.1 But still many patients still require frequent injections. Let’s discuss PDS and gene therapy, for which you’ve performed many surgical procedures. If you had both of them available to you and they were both hypothetically durable for 6 months on average, would you offer one over the other? How would you make the treatment choice for your patient?

Dr. Avery: I think they are similar in that, hopefully, they will greatly reduce treatment burden for our patients. However, they’re very different in what we might expect for duration of effect. It is possible that gene therapy may last for years, or even indefinitely, whereas we know that the PDS is likely to run out over time.2 The HARBOR trial you mentioned is a great example of that variability in an individual patient’s need for treatment; in that trial, there was a complete spread from patients needing just 1 or 2 injections over 2 years, to some needing an injection every month. Depending on the patient, you may need to be refilling the PDS more frequently than 6 months. In a gene therapy patient, you may still need to supplement the gene product with additional intravitreal injections, but this would likely only be necessary in the very severe patients and would still likely reduce the treatment burden in this very difficult group. On the other hand, the average patient will probably have a dramatic reduction in treatment burden with either treatment.

One hypothetical concern I have about gene therapy is that there is an advantage to being able to stop therapy if we ever see a complication of chronic anti-VEGF therapy, such as increased risk of geographic atrophy, or if gene therapy causes a complication. It’s hard to turn off the gene once inserted. After many years of intermittent injections, we have not proven increased geographic atrophy with more intensive injections, but there are still some concerns about this possibility, and continuous anti-VEGF therapy remains a potential concern. On the other hand, patients love the idea of having a gene therapy injection and never having to have another treatment. Also, gene therapy does not require a piece of hardware in the eye, which could over years cause conjunctival erosion and endophthalmitis. These are advantages to the potential one-time treatment with gene therapy. I think that we need more time and more experience with both therapies. But our patients are very excited about the potential of more durable treatments.

Dr. Ho: Dr. Wykoff, let’s assume we have in our armamentarium a 1-month, a 2-month, and a 3-month drug. If one of the newer drugs, KSI-301 for example, was a 4-month drug, at what time point would you consider using that drug repetitively? Or would you consider using a surgical procedure that might last even longer, for example, 6 months? Is there, in your mind, a pivot point on a high-demand patient?

Dr. Wykoff: I agree with the use of an individualized approach. I think for most patients with wet AMD, for the foreseeable future, we will continue initiating therapy with bolus anti-VEGF injections; they work really well. Repeated injections over many years have proven to be remarkably safe, with some patients needing few injections while maintaining stability with long intervals between retreatments. Where I think new devices and gene therapies will first be deployed when commercially available is in patients who require more frequent injections to keep their exudative disease process under control.

I’d like to add 2 points about long-term VEGF suppression. First, recent work spearheaded by Usha Chakravarthy, MD, has brought the importance of long-term fluid control back into the spotlight. Secondary analyses of the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)3 and Alternative Treatments to Inhibit VEGF in Age-related Choroidal Neovascularization (IVAN)4 data sets and then repeated with the HAWK and HARRIER data sets5 have indicated that fluctuations in CST are probably what is most damaging to visual outcomes over time. The data suggest the need for consistent VEGF blockade to minimize fluid fluctuations. Second, there is a theoretical concern that chronic VEGF suppression intraocularly may lead to atrophy. To the contrary, if we consider the animal models of gene therapy where an anti-VEGF protein is expressed inside healthy eyes of nonhuman primates, those eyes have tolerated chronic VEGF suppression exceptionally well for many years without signs of retinal or optic nerve atrophy.

Ultimately, the goal is to find the right treatment for the right patient that is going to minimize exudative disease activity over time. If we have a drug that’s more durable than our current standard of care, I think the field will transition patients who currently need chronic, repeated injections to that newer modality. Among patients requiring aggressive therapy with our most durable agent, those are the patients who I would first consider switching to gene therapy or a port.

Dr. Ho: Dr. Kaiser, do you think there are any particular compounds or early clinical trials using other mechanisms besides anti-VEGF suppression that will likely raise the bar on improving mean visual acuity over time?

Dr. Kaiser: Yes, I hope so. If we look at all the anti-VEGF clinical studies, we have no drug that’s any better than any other. Efficacy is essentially the same when they are delivered on a fixed schedule. In the future, we will see differentiation with durability and maybe even drying capabilities. In the short term, brolucizumab (Beovu; Novartis) and abicipar (Allergan/Molecular Partners)6 appear to be more durable than current medications. In the future, KSI-301 and the PDS appear promising for even longer durability with 1 injection. Gene therapy with either Regenxbio’s or Adverum’s approaches may be even longer. But we’re starting to see some evidence that if we combine anti-VEGF with other pathways, we may get better visual outcomes. Nothing’s been proven conclusively, because all we have are phase 2 studies, but the first to show that we can get significantly better outcomes over anti-VEGF monotherapy and maybe longer durability was faricimab (Genentech/Roche)7 with their combined Ang2 and VEGF inhibitor. There is also a Tie2 activator and VEGF inhibitor from Asclepix Therapeutics (ATX107), which is just entering clinical studies and has promise. In preclinical models, the drug appears to last up to a year with 1 injection, so it would be very exciting if this could be replicated in clinical studies.

The Australian company Opthea is using a different technique. We know that with VEGF blockade, we’re blocking mainly VEGF-A activating VEGF receptor 2, which is the most pathologic. When we do this, it upregulates the other VEGF isoforms, in particular VEGF-C, which still activates VEGF receptor 2. OPT-302 blocks VEGF-C and -D using a VEGF Trap molecule. Opthea has shown in a phase 2 study significant improvements in vision when OPT-302 is combined with an anti-VEGF over anti-VEGF monotherapy (NCT03345082). This drug alone would not be efficacious; it has to be combined with another VEGF-A inhibitor. Thus, we’re starting to see new drugs that may have better efficacy, which is encouraging because not only do we want to move the bar up in terms of durability, but also we want to move the bar up in terms of efficacy.

Dr. Ho: Great. Does anyone else want to mention any efforts that they think are promising?

Dr. Dugel: I think there are 2 things we should emphasize. One is the pharmacokinetic profile of VEGF inhibition. What we’re doing right now is inhibiting VEGF in a pulsatile fashion. There are some signals that suppressing VEGF on a constant basis as opposed to on a pulsatile basis might improve efficacy. Dr. Wykoff alluded to that: there are studies that have been done by Usha Chakravarthy and her group. There are studies that we have done with the HAWK and HARRIER results, and those results have been remarkably consistent. If you can reduce fluid fluctuation over time, visual acuity may actually improve and the efficacy may be better. Intuitively this makes sense, because you’re reducing the amount of trauma to the photoreceptor cells. When you look at the PDS study, for instance, in the highest dose, there was a signal toward better efficacy with constant suppression. So we may be actually able to get better efficacy by changing our VEGF suppression profile in and of itself. And that may also pertain to companies such as Kodiak and Graybug, as well as in gene therapy.

The second thing that I would mention is that, as we all know, the greatest reason for loss of vision over time in patients with neovascular macular degeneration is atrophy and fibrosis. I would love to see all the exciting complement inhibitors for dry macular degeneration and geographic atrophy, like APL-2 from Apellis Pharmaceuticals and Zimura from Iveric bio, studied for neovascular macular generation over a period of time, to see if a combination would improve our long-term outcomes.

Dr. Ho: One of the ways to change the pharmacokinetics — and hopefully improve efficacy and maybe reduce the atrophy associated with chronic treatment — is to change the dynamic by bringing the patient to the operating room for a PDS device or gene therapy, assuming that it’s safe and efficacious over time. The Regenxbio gene therapy product is a surgical procedure in the operating room. Dr. Avery, you’re involved with these gene therapy trials. Could you speak to that?

Dr. Avery: Sure. Adverum Biotechnologies presented their first human data at the Retina Society meeting in 2019.8 It was proof of concept because the treatment produced enough aflibercept-type molecule in the eye to treat the fluid in those 6 patients for whom they showed OCT scans, and this is with an intravitreal injection, so it can be done in the office. We previously thought that subretinal delivery would be more effective, because the internal limiting membrane acts as a barrier to intravitreal virus vectors in some cases. However, it is possible this intravitreal injection is transfecting the peripheral retina or even the iris ciliary epithelium. Whatever is being transfected, it’s making enough aflibercept to treat these patients. That’s very exciting because it would not require a trip to the operating room.

Regenxbio is exploring suprachoroidal delivery, the same needle that was used in the Clearside Biomedical studies of triamcinolone but to administer a virus vector, and that procedure could be done in the office. Peter Campochiaro, MD, and others have shown in monkeys a very good uptake and transduction of the Regenxbio viral vector in that mechanism using suprachoroidal delivery.9,10 Those are 2 exciting options that may make it unnecessary to go to the operating room.

Dr. Ho: Pulling gene therapy out of the operating room with an intravitreal injection or a suprachoroidal injection would be very exciting, assuming long-term safety and efficacy. Dr. Wykoff, you have been involved in the Clearside Biomedical trials with suprachoroidal injection. Is it fair to say that a suprachoroidal injection is certainly not the same as an intravitreal injection from a patient’s standpoint or from the retina specialist standpoint? Would you comment a little bit on the differences?

Dr. Wykoff: While the technique for injection of a medication into the suprachoroidal space is distinct from an intravitreal injection with a shallower learning curve, it is certainly an approach that can be readily performed in the retina clinic. We’ve become used to intravitreal injections, during which there is no resistance when injecting the pharmaceutical agent. Suprachoroidal delivery is very different; instead of injecting into a real space like the vitreous cavity, we are expanding a potential space. Natively there is no, or very little, space between the choroid and scleral anteriorly, where we do these injections. The needle is short, just long enough to extend through the width of the sclera, but not long enough to enter the vitreous cavity. The technique involves remaining perpendicular to the scleral surface while dimpling the conjunctiva and sclera to ensure placement of the needle tip in the correct location, and then gently depressing the plunger; if any resistance is encountered, do not force it. Instead, continue to maintain gentle pressure and maneuver the tip slightly until the resistance gives and the injection is delivered. If the choroid is separated from the overlying sclera too rapidly, this can cause pain for the patient, so inject slowly, over 5-10 seconds. This feels much slower than a typical intravitreal injection, but take your time. The technique takes a little practice, but Clearside has developed videos and a physical eye model for practice.

Dr. Ho: Dr. Kaiser, do you have any summary comments for us? You’ve got a very good overview of the future landscape, what we need to do, and where our efforts need to go for patients.

Dr. Kaiser: We’ve talked about 2 different approaches. The first approach is to use anti-VEGF drugs that last longer in the form of brolucizumab, abicipar, KSI-301, and others. The second approach is to block another pathway or to block more of the VEGF pathway in the form of anti-Ang2 combination drugs and the combination of anti-VEGF-A and a blocker of VEGF-C and -D. Finally, we discussed the idea of using different devices or different techniques to enable the anti-VEGF to last longer through either a surgical implantation of a PDS that you refill every 6 or more months all the way up to intravitreal, suprachoroidal, or subretinal gene therapy, which, I caution our readers is still really in its infancy but could offer some very exciting outcomes in the future if they do provide sustained anti-VEGF therapy. The field is getting very exciting and we have learned from our experience to design better drugs.

I want to echo the sentiments in particular of Drs. Wykoff and Dugel that, even with these new pathways, we need to be careful of the idea of fluctuation in intraretinal fluid. Like with concussions, where one is bad but multiple are a lot worse, the neurologic tissue of the retina really may not do well with so much fluctuating fluid. Age-related macular degeneration is a lifelong disease. The more we can do to control disease, the better outcomes we will have.

Dr. Ho: Thanks for those comments and to our entire panel for their perspectives. It is clear from this very esteemed, expert clinical triallist group that although we’ve made revolutionary strides for patients with neovascular AMD, there’s no question that we’re very sensitive to patient needs and where we still need to go. The ecosystem of science, industry, and clinical trial centers is very rich and active in trying to reach a higher place for our patients. We need to preserve this delicate balance and emphasize the value of these efforts in preserving vision and quality of life. Great preclinical and clinical science has been highlighted in this roundtable, and time and careful study will determine the roles of these programs in the not-too-distant future. RP

Robert L. Avery, MD, is founder and CEO of California Retina Consultants, Santa Barbara, California. Pravin U. Dugel, MD, is managing partner of Retinal Consultants of Arizona in Phoenix, Arizona, and clinical professor at the USC Roski Eye Institute, University of Southern California Keck School of Medicine in Los Angeles, California. Allen C. Ho, MD, is a professor of ophthalmology at the Thomas Jefferson University School of Medicine and director of retina research at Wills Eye Hospital in Philadelphia, Pennsylvania. Peter K. Kaiser, MD, is the Chaney Family Endowed Chair in Ophthalmology Research and a professor of ophthalmology at the Cole Eye Institute, Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio. Charles C. Wykoff, MD, PhD, is codirector of research at Retina Consultants of Houston and Blanton Eye Institute and a clinical assistant professor of ophthalmology at Weill Cornell Medical College at the Houston Methodist Hospital in Houston, Texas. Related to this article, Dr. Avery reports financial relationships with Adverum Biotechnologies, Allergan, Apellis Pharmaceuticals, Clearside Biomedical, Genentech, Novartis, and Regenxbio. Related to this article, Dr. Dugel reports advisory board membership with, stock ownership of, and consultancy to Graybug Vision and Clearside Biomedical; consultancy to Asclepix Therapeutics, Adverum Biotechnologies, and Kodiak Sciences; and advisory board membership with and consultancy to Genentech, Novartis, Regenxbio, Allergan, and Opthea. Related to this article, Dr. Ho reports financial relationships with Adverum Biotechnologies, Allergan, Asclepix Therapeutics, Genentech, and Regenxbio. Related to this article, Dr. Kaiser reports financial relationships with Allergan, Asclepix Therapeutics, Clearside Biomedical, Novartis, Opthea, and Regenxbio. Related to this article, Dr. Wykoff reports consultancy for and research with Adverum Biotechnologies, Iveric bio, Kodiak Sciences, Genentech/Roche, Novartis, Opthea, Regenxbio, and Clearside Biomedical; and research with Graybug Vision.

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