Diana Do, MD

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 Currently, there’s still an unmet need in the treatment of wet age-related macular degeneration [AMD]. Although treat-and-extend regimens or even fixed-dosing regimens have shown to be very efficacious and safe for the treatment of this disease, we understand that in clinical practice, there are many challenges for patients to adhere to any of these regimens. When we looked at retrospective studies to evaluate the number of treatments a patient might have, on average, over a 1-year period, we’ve seen that many patients in clinical practice are undertreated and maybe receive only 5 to 6 injections over a 1-year period. Why is this so? It’s difficult for an older patient to come frequently to the retina specialist’s office, because they often rely on caregivers or family members to bring them to the retina specialist’s office. Therefore, there’s still a significant unmet need to develop novel therapies that can be administered in the clinic, that can provide a more durable clinical effect of VEGF suppression. That’s why we’re excited to see more medicine and biologics in development in phase 3 clinical trials at this time, which are looking to address this unmet need.

 As with virtually any medical condition, you can always aspire to a better treatment [of wet AMD] when that doesn’t reduce the decline of the person for. [Like for treating] Parkinson disease—I was just talking on the phone with someone about that earlier today—vs curing the disease. Of course, there’s an opportunity in wet AMD, whether it’s a gene therapy or something very meaningful, in the sense that it stops the disease in its tracks vs reducing the rate of decline, so there’s always that aspirational unmet need. With regard to the treatments available, they’re good, they’re well tolerated, and they have some very good efficacy or effectiveness as it relates to reducing the loss of visual acuity in wet AMD.

 In the future, novel intravitreal VEGF inhibitors, which are in phase 3 clinical trials, may provide more treatment choices for retina specialists and their patients. We have very efficacious and safe VEGF inhibitors in clinical practice today, but there still remains an unmet need to develop more durable medicines that can provide more VEGF suppression over a longer period of time. I’m excited to see more medicines in development, such as faricimab, which has completed phase 3 clinical trials, or KSI-301, which is in phase 3 clinical trials. In addition, other agents are being evaluated in late-stage development, which will likely provide retina specialists and their patients with even better clinical options in the near future.

 As with any area where there’s significant economic opportunity, there are new products in development for wet AMD. There are device- and biologic-delivery systems that implant something and then the product is released. There will certainly be those kinds of advances. That’s what life sciences companies do, and they do it very well. There could be some incredible change with gene therapy or something that for family impacts the course of disease. That’s an area of science that I’m less familiar with, but it’s certainly a possibility. From our perspective, we’re going to continue to work with our clinical partners toward better outcomes, affordability, and better levels of patient experience, so that’s the triple aim.

Videos

Diana Do, MD, and Steven Peskin, MD, MBA, FACP, discuss unmet needs and future approaches to treatment in wet AMD.

Future of Wet AMD Treatment

 Looking at new therapies, certainly the FDA approval is the most important. Anything that’s approved will most likely find its way to our formulary. Its tier status and other considerations with regard to step edits, step throughs, quantity limits, or prescribing by subspecialists only are different considerations. The availability of the product is largely based on its status within FDA approval. Beyond that, if a product in an area that has established products has any safety signals or safety concerns, then that product may be disadvantaged or have to have a failure of other therapies. If the cost is considerably higher, then we may put in certain guardrails that prefer the less costly product with similar or the same efficacy in front of any new product.

Thinking about formulary, we certainly look at product classes at a minimum every year. If there’s a new product introduced, we’ll look at that product in a thoughtful way to measure comparative effectiveness. The contractual aspects are separate and distinct from what the pharmacy and therapeutics committee [P&T] and the formulary committee does.

In formulary, costs are mentioned, but that’s not the most salient issue. The safety effectiveness and tolerability—any longitudinal data that we can present—are typically the key drivers. Cost might be mentioned if something is 3 times the cost of the existing drugs with seemingly no improvement in effectiveness, and that might certainly get the clinicians on the P&T who are not totally isolated from costs. That’s something that everyone in health care considers broadly speaking.

With regard to challenges with value-based agreements, I don’t see any challenges there as it relates to adherence, persistence, and endurance. We’re looking at our clinicians to achieve the best outcomes, which she or he is certainly looking for. The payment for lower total cost of care per treatment episode is part of the construct for an episode of care—a bundle payment. The challenges always exist concerning whether you’re treating hypertension or diabetes or wet AMD [age-related macular degeneration] with regard to adherence, persistence, and endurance. There’s no particular challenge. We see these patients as being quite motivated because loss of visual acuity is something unlike, say, high blood pressure, because they’re very aware. The patient is very aware. They’re scared, and they don’t want to lose their vision, so they’re highly motivated patients for treatment.

Steven Peskin, MD, MBA, FACP, provides insight into managed care considerations of wet AMD including clinical evidence evaluation, formulary management, and value-based agreements. 

Managed Care Considerations in Wet AMD

 When we’re looking at evidence from wet AMD [age-related macular degeneration], the most important clinical parameter that we use to guide whether an agent is effective is currently the visual acuity. In all these phase 3 clinical trials, the primary end point of these studies is the best-corrected visual acuity obtained over a 1-year period. The FDA accepts that outcome as its main point of determining whether an agent is efficacious. Of course, there are also secondary end points that are evaluated, such as retinal thickness or quality-of-life measures. But the most important end point is visual acuity.

In many of these clinical trials, patient reported outcomes such as quality of life is also important. Quality of life is obviously affected by the patient’s visual acuity. If a patient does not receive an effective therapy for their age-related macular degeneration, then the vision declines and the quality of life also declines. Therefore, quality of life and patient reported outcomes, is almost a surrogate marker for how their vision is doing over time with their therapy.

Over the past decade, there have been many randomized clinical trials that have evaluated the treat-and-extend regimen for wet age-related macular degeneration. The vast majority of these clinical trials have shown that the treat-and-extend regimen is noninferior to fixed monthly or every-2-month dosing of FDA-approved intravitreal VEGF inhibitors. For example, the ALTAIR study, which was conducted overseas, evaluated a treat-and-extend regimen of aflibercept compared with aflibercept given every 2 months on a fixed regimen. In this clinical trial, eyes that were randomized to treat and extend, had noninferior visual acuity outcomes compared with fixed dosing. In addition, there was a slight reduction in the number of treatments given over a 1 to 2-year period. In addition, other clinical trials have evaluated the treat-and-extend regimen for ranibizumab and showed similar results of noninferior visual acuity gains and a slight reduction in intravitreal injections.

For the treatment of wet age-related macular degeneration, many of these intravitreal VEGF inhibitors that are FDA approved are expensive. With proper insurance coverage, there are no significant financial barriers for patients who have adequate coverage. Of course, many patients who don’t have significant medical insurance will be treated by off-label bevacizumab, which is very cost-effective for the treatment of this ocular disease. If there’s more open access to these medicines and adequate coverage, most retina specialists will elect to choose the FDA-approved medicines, which might have slight efficacious benefits and more durability benefits compared with off label bevacizumab.

Diana Do, MD, discusses outcomes of interest for anti-VEGF agents, clinical evidence supporting the treat-and-extend approach, and strategies to overcome financial barriers in wet AMD. 

Clinical Trial Evidence and Outcomes in Wet AMD

 In clinical practice when patients with wet AMD [age-related macular degeneration] present to a retina specialist, we look at the constellation of their findings and then make a recommendation on which intravitreal VEGF inhibitor to start with. If there are no insurance barriers, many retina specialists would prefer to choose an FDA-approved VEGF inhibitor because of the strong efficacy and safety data available with either aflibercept or ranibizumab. Currently, from the phase 3 clinical trials, aflibercept showed that it could be dosed every 2 months compared with monthly dosing of ranibizumab. That provides aflibercept with a slight advantage over ranibizumab for the treatment of wet age-related macular degeneration. In clinical practice, many retina specialists use a treat-and-extend regimen and feel that aflibercept because of its availability and evidence to be dosed every 2 months, it could potentially allow patients to be extended longer than eyes that would be treated with ranibizumab.

In eyes with wet AMD, retina specialists like myself start with intravitreal VEGF inhibitors. In clinical practice, sometimes we choose on-label treatments, such as ranibizumab or aflibercept, at the initiation of therapy. Or if medical insurance dictates, we may start with off-label bevacizumab. If as a clinician I don’t see an optimal response to the medicine that I first chose. If after 3 or 4 injections the patient’s vision has not improved, then I will likely switch to another agent that’s FDA approved. Many clinicians who let’s say start with intravitreal bevacizumab, which is off-label, and don’t see a good response in their patient’s eye, will often switch to aflibercept, which is FDA approved for the treatment of wet age-related macular degeneration. We’ve seen evidence from published case reports that in some eyes the switching of these VEGF inhibitors can provide a beneficial effect.

When retina specialists monitor patients who are undergoing VEGF inhibition therapy for their wet age-related macular degeneration, we look at a couple of parameters. First, we look at visual acuity and how they respond over time to the therapy. In addition, we look at retinal imaging with OCT, which is optical coherence tomography scanning. We use the constellation of the data we get from the clinical exam, the visual acuity, and the OCT imaging to give us an idea if the patient is responding. Usually, after a series of at least 3 injections, most patients will have some sort of response to their VEGF inhibitors. We’ll see an improvement in vision, or a reduction in swelling on the OCT scan. If we don’t see this improvement, then perhaps the patient needs to be switched to another intravitreal VEGF inhibitor. We’ve seen through clinical data that VEGF inhibitors do have differences. And that some VEGF inhibitors may have a more potent or durable effect compared with others.

In wet age-related macular degeneration, bevacizumab which is used off-label, is also a very commonly used medicine for the treatment of this ocular disease. The data for bevacizumab has shown that it’s very efficacious and safe but that it does need to be dosed quite frequently because of its ocular half-life. In many clinical cases, because of insurance issues and step therapy, we have to use bevacizumab as the first-line agent for eyes with wet age-related macular degeneration. If these patients don’t have a good response to bevacizumab after 3 or 4 injections—that is, their vision does not improve significantly, or the retinal edema and swelling does not improve on OCT imaging—then most of these patients will likely be switched to an FDA-approved therapy such as aflibercept or even ranibizumab.

Diana Do, MD, provides insight into anti-VEGF treatment selection for individual patients, evaluation of patient response to therapy, and considerations for switching of agents. 

Treatment Selection in Wet AMD

 At this time, there are 4 available intravitreal VEGF inhibitors for the treatment of wet age-related macular degeneration [AMD]. The first VEGF inhibitor that was approved by the Food and Drug Administration was ranibizumab. This is an antibody to VEGF that is injected into the eye, and pivotal phase 3 clinical trials have shown its efficacy and safety for the treatment of wet age-related macular degeneration.

The second intravitreal VEGF inhibitor that was approved by the Food and Drug Administration was aflibercept. This VEGF inhibitor can be administered every 2 months to patients with wet age-related macular degeneration. The pivotal clinical trials also showed that aflibercept was very efficacious and safe for the treatment of wet age-related macular degeneration. Brolucizumab was most recently approved in 2019 for the treatment of wet age-related macular degeneration. This too is a VEGF inhibitor that is injected into the eye, and also had the potential advantage of being dosed every 3 months in the eyes with active wet AMD. However, most recently we’ve discovered that brolucizumab does have a higher risk of adverse events, such as intraocular inflammation, retinal vasculitis, and retinal artery occlusion, which could lead to irreversible vision loss. Another VEGF inhibitor that is actively used in clinical practice is bevacizumab. This medicine is used off-label but is also very efficacious and safe for the use of treatment in wet AMD. This medicine is usually dosed every month or used in a treat-and-extend regimen, and because it’s used off-label, it’s quite cost-effective compared with the other FDA-approved medicines.

In clinical practice, I’ve had very good success with the use of intravitreal VEGF inhibitors. In particular, when patients have prompt treatment and adhere to a very comprehensive and chronic follow-up regimen, I’ve seen that many patients can have a significant improvement in their visual acuity, and we can maintain this over many years. I use both on-label treatments such as ranibizumab or aflibercept, and I also use off-label bevacizumab for the treatment of this ocular disorder.

 Thinking about the strategies for management of persons with AMD and the choice of therapy, the lowest cost alternative, which has a lot of good clinical data and peer-reviewed literature supporting it, is bevacizumab. That product was brought to market for cancer treatment and is closely associated with 1 of 2 main therapies for wet AMD, Lucentis and Eylea. That’s our approach. We’re working again with a key retina subspecialist on value-based payment models where the retina specialist is, in a sense, given some economic consideration for using the best lowest-cost alternative. If that alternative is 1 of the more expensive branded products, so be it, because the clinical outcomes are of the greatest importance. If a person can be treated with a product that is 10, 20 times lower [in terms of cost] than 1 of the other products and effectively treated, then from a payer perspective, a societal perspective, and our health care professionals’ perspective with value-based payment models, that would be the best alternative.

With regard to bevacizumab as a step-through, it’s not a hard-step edit. It is certainly something from a specialty pharmacy that we will encourage. The program or approach that has proven to be the most effective with our clinical partners is to design a what we call an episode of care. Some folks refer to it as a bundle. That’s been the most effective way to get our retinal subspecialists to think about using bevacizumab as we’ll call it first line, and then for those persons who don’t tolerate or have a good response, then we move into other products, Lucentis and Eylea.

Diana Do, MD, provides an overview of available anti-VEGF agents used in the treatment of wet AMD and Steven Peskin, MD, MBA, FACP, discusses management strategies employed with these agents. 

Management of Anti-VEGF Agents for Wet AMD

 In wet age-related macular degeneration [AMD], there is a theoretical risk of overtreatment. But in clinical practice, we haven’t seen this. Most phase 3 clinical data had patients dosed on fixed regimens. That is, the anti-VEGF medicine was given every month or every 2 months. We have not seen any significant adverse events related to this frequent fixed dosing. Also, in clinical practice, most retina specialists do not employ monthly or bimonthly treatment. The totality of the evidence to date suggests that intravitreal VEGF inhibitors are extremely efficacious and safe. But we have not seen any safety signals related to overdosing, and we know that the No. 1 culprit for vision loss in wet age-related macular degeneration is underdosing in clinical practice.

Delaying treatment for eyes with wet age-related macular degeneration can be very detrimental. We know that undertreatment or no treatment of wet age-related macular degeneration can lead to irreversible scarring and vision loss in the central vision of a patient. Vision loss has an adverse effect on the quality of life a patient and can lead to loss of independence, an inability to read or drive. Therefore, prompt and timely continual treatment of their eye disease is essential to maintaining and improving vision.

I was asked to talk about delaying therapy in wet AMD. In our approach, we’re going to look at requests coming from retinal subspecialists, clinicians who are in the best position to determine whether the person with wet AMD is appropriate for biologics. That will be our true north. We certainly have an authorization process that’s pretty much a standard operating procedure among health plans for biologics. That’s really going to be our approach. It’s the clinician’s decision about what treatment to use at what time. Certainly, site of service is something we look at, and most of these treatments are given in office.

Thinking about the challenges associated with wet AMD, any condition where there’s a level of complexity will always offer challenges. That said, we’re feeling very good about where we are working with our retina subspecialist to develop innovative payment models, which reward better outcomes, affordability, and higher level of patient experience. Hopefully, the fourth part of the aim is health care professional sustainability and reducing some of the abrasion that’s associated with some of the interventions where we can have the clinicians accountable for clinical outcomes, economic outcomes, and patient experience, as well as reduce some of what might be called the hassle factor.

Diana Do, MD, and Steven Peskin, MD, MBA, FACP, discuss overtreatment and undertreatment in wet AMD in addition to the risks associated with delays in therapy. 