Anti-vascular endothelial growth factor (anti-VEGF) antibodies have been the pillar of therapy for patients with neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME) for nearly two decades. Unfortunately, anti-VEGF therapy requires frequent, repeated intravitreal injections that pose significant burdens for patients, their caregivers, and the healthcare system. Additionally, anti-VEGF therapy is completely ineffective for patient with atrophic age-related macular degeneration. Angiopoietin (Ang) pathways have recently shown the potential to provide a new treatment target that can reduce inflammation in neovascular AMD and DME. Likewise, the cleavage of complement protein C5 is being targeted for treatment options in geographic atrophy. In this session, we will focus on current and emerging therapies for AMD and DME.
Lecturer: Dr. Arghavan Almony, Carolina Eye Associates, North Carolina, USA
DR ALMONY: Hello. Thank you so much for attending the talk today.
I want to state that we’re gonna be talking a lot about the therapeutic pipeline. And we’re gonna focus today on age-related macular degeneration.
So I’ve tried to make the presentation as comprehensive as possible.
But that means that sometimes we can’t get into the level of detail that maybe some of us would like.
In addition, because our attendees today are spanning the spectrum from trainees and mechanical students to seasoned retina specialists, some of this may seem a little primary.
But I wanted to provide information that would be relevant to some of our newer or… Our trainees as well.
These are my disclosures.
And I’d like to begin with an audience question.
So which medications do you use for the treatment of neovascular age-related macular degeneration?
And I’m gonna ask you to select all that apply.
We’ll give you a few minutes or seconds here to answer the question.
Okay. So we can see that biosimilars is about 7%.
And bevacizumab, ranibizumab, and aflibercept are all over 50%, with bevacizumab being the highest.
We do have some users of brolucizumab and faricimab.
Next question: What is your preferred treatment for neovascular or wet/age-related macular degeneration?
So please select one for this one.
If you had just one option, what would you select?
Because we have a global audience here, I think it’s important to understand before we get started what is currently being used, and what the needs are, going forward.
So go ahead and put in your selection. Okay. So we have bevacizumab and aflibercept at 33 and 36%. And then ranibizumab at 24%.
All right. Next question. We’re gonna focus now on diabetic macular edema for a few minutes.
So which treatment do you use for diabetic macular edema?
And again, I’m gonna ask you to select all that apply.
Because there’s a lot of options for the treatment of diabetic macular edema.
We had to break this down into two questions. So you’ll see that the injectables are in question one. And then the other options are in question two.
But go ahead and select all that apply in terms of what treatments you use currently for diabetic macular edema.
All right. Closing up the poll here.
Okay. So for diabetic macular edema, we see a much higher percentage of bevacizumab, followed by aflibercept, and then ranibizumab. Biosimilars are still coming in at 7%.
And then for other options for treatment, we do see that the dexamethasone intraocular implant is used at a fairly high level, followed by intraocular steroid injections and sub-Tenon’s steroid injections.
Focal and grid laser are also used quite a bit in this group of attendees. Okay. Very good.
And now we’re gonna look at: What is your preferred treatment for diabetic macular edema?
So in this section, just pick one.
If you had to only pick one option for the treatment of diabetic macular edema.
What would you choose?
Okay. So we’ll go ahead and close that.
And here we see bevacizumab at the top of the list, followed closely by aflibercept.
And then here we see that dexamethasone intraocular implants — significantly higher than focal or grid laser, followed by intraocular steroid injections.
Okay. Very good.
So we’re gonna begin the discussion with a brief overview of age-related macular degeneration and diabetic macular edema.
And before I begin, I just do want to say that I understand that this is a little bit biased. In terms of availability.
I know that what we’re gonna talk about today — the treatment options are not available worldwide. But I think it’s important that we understand everything that is available.
Because these are things that we are going to have access to at some point.
So we know that macular degeneration is the leading cause of severe and irreversible visual loss, worldwide.
And about 8.7% of the global population is affected by macular degeneration.
The disease has a profound effect on the quality of life of affected individuals. And not just the individuals, but their loved ones.
It represents a major socio-economic challenge for societies, due to the exponential increase in life expectancy, as well as environmental risks.
This is a graphic showing macular degeneration worldwide, and you can see that these numbers are quite incredible.
We see it everywhere. And it is affecting every part of the globe.
Risk factors for macular degeneration include cigarette smoking, which is the biggest modifiable risk factor.
Because we know that cigarette smoking can actually triple the risk of progression to wet or neovascular macular degeneration.
Caucasians are at the highest risk, but certain subsets of macular degeneration are found in Asian populations.
Obesity, atherosclerosis, and genetic factors also play a significant role.
We know that macular degeneration is a disease spectrum. So in the past, we would think about macular degeneration as bimodal. Dry or wet.
But as we understand more about macular degeneration, we know that in early macular degeneration, it’s characterized by multiple small drusen and RPE abnormalities.
That can progress to intermediate macular degeneration, where we can see large drusen.
And further retinal pigment epithelium changes. In late macular degeneration, we have geographic atrophy, or neovascular or wet AMD.
Geographic atrophy is characterized by the progressive loss of photoreceptors, the RPE, and the underlying choriocapillaris, and we know that neovascular or wet AMD is characterized by the formation of choroidal neovascularization.
So let’s just look at non-neovascular AMD for a second. This is also called dry or inactive AMD. And we know that the prevalence of AMD increases with age.
In the Beaver Dam Eye Study, for example, Caucasians were found to have only a 4% prevalence of AMD by age 54.
However, that number increased to 46% by age 75.
A small subset, approximately 10% to 15% of those with dry macular degeneration, may convert to wet or neovascular macular degeneration.
And we know that geographic atrophy is the advanced form of non-neovascular or non-exudative AMD.
So the pathophysiology of GA or geographic atrophy is multifactorial. And it involves a combination of environmental and genetic risk factors.
Numerous mechanisms have been implicated, including oxidative damage, chronic inflammation, excessive accumulation of lipofuscin, and malfunctioning of the complement system.
The pathway of AMD disease progression begins with medium drusen in early macular degeneration.
Followed by large drusen, shown here in intermediate macular degeneration.
We then see retinal pigment epithelium migration and drusenoid pigment epithelial detachments.
Finally, we can see chorioretinal atrophy, which is seen in geographic or late stage dry macular degeneration.
Geographic atrophy is the progressive loss of retinal photoreceptors.
RPE and the underlying choriocapillaris, leading to irreversible loss of visual function. In the photo in the top left, we see a normal eye, with fundus autofluorescence. Below that, optical coherence tomography, and below that, color fundus photography.
On the upper right, we see a patient with geographic atrophy on fundus autofluorescence. Below that, we can see the irregularities in the retinal pigment epithelium layer.
And then below that, on the color fundus photography.
Geographic atrophy, as you can see, is defined by the presence of sharply demarcated lesions of the outer retina.
And sometimes we look at macular degeneration and think about… You know, when we see patients, we’ll say…
You know, dry macular degeneration is not that bad. It is… You’re lucky to have it, because it’s not the wet or active type of macular degeneration.
But you can see the geographic atrophy and scotomas significantly affect a patient’s day-to-day life. In the left panel, you can see how difficult it can be to read with those areas of missing vision.
In the center area, this correlates to the fundus autofluorescence. And in the right, we see a patient who may be driving with geographic atrophy.
They can see, and they may test well, on visual acuity, but it’s certainly not good vision without distractions to be able to drive.
So here… The top is a baseline for three separate patients with geographic atrophy. And in the bottom panel, we see the follow-up.
Now, often when we think about geographic atrophy, we may think about progression in five years, ten years.
But in fact, here, you can see that the progression is quite visible in just under two years. So in the top and bottom panel, you can see how much there’s been progression on the left in 23 months, in the middle over 22 months, and on the right, in just 16 months.
This is why sometimes we will see a patient who has excellent vision. They have dry macular degeneration. They come back a year later, and their vision is significantly now affected by the geographic atrophy.
So now we’re gonna look at wet or active macular degeneration.
This is also called exudative macular degeneration. Because it’s associated with leakage of blood and fluid into and beneath the retina.
Central visual acuity loss leading to severe visual impairment and blindness occurs in this disease, about 90% of severe vision loss, where the patient’s vision is 20/200 or worse, is actually due to neovascular macular degeneration.
And 20/200 or worse is considered legally blind.
So it’s significant. This shows neovascular macular degeneration pathophysiology. We know that it’s complex.
But it includes cell senescence of the retinal pigment epithelium, oxidative stress, lipid metabolism, inflammation, and neovascularization.
In the top right image, we see a healthy retina. In the bottom right, we see what happens in neovascular macular degeneration. We see that the blood vasculature from the choroid extending into the retina, leading to fluid accumulation, and vascular leakage.
So again, when we’re looking at neovascular macular degeneration, we start with medium drusen in early macular degeneration, followed by large drusen in intermediate macular degeneration.
This is followed by retinal pigment epithelium changes.
Followed by a choroidal neovascular membrane. Here we see subretinal fluid.
And then finally, a fibrovascular choroidal neovascular membrane or subretinal fibrosis.
Late macular degeneration can be classified as either wet or neovascular macular degeneration. Which is classified by the choroidal neovascular membrane. Or geographic atrophy, characterized by atrophic lesions.
And we see that overall the prevalence of neovascular AMD and geographic atrophy are similar.
And we know that 90% of diagnosed cases of macular degeneration are dry or inactive.
So now let’s switch gears to diabetic macular edema for a few minutes. This is the worldwide involvement of diabetes.
You know, in 1980, only about 100 million people had diabetes. But in the next 25 years, that number is going to rise to 700 million.
Diabetes is a rapidly growing epidemic, and individuals are at risk for serious macrovascular and microvascular complications, including heart disease and stroke, hypertension, kidney disease, lower limb amputations, peripheral nerve disease, hearing loss, periodontal disease, erectile dysfunction, depression, complications of pregnancy, and of course eye disease.
We know that diabetic macular edema affects about 21 million people worldwide.
And we know that half of patients with diabetic retinopathy will develop diabetic macular edema at some point.
More advanced diabetic retinopathy is a significant risk factor for sustained blindness. And we know that Indigenous populations and minorities are disproportionately impacted.
So risk factors for diabetic macular edema include duration of diabetes, elevated hemoglobin A1C levels, we know that a 1% increase in hemoglobin A1C can lead to a 30% to 50% increased risk of diabetic macular edema, hypertension, hyperlipidemia, renal disease, obesity, and of course, smoking.
So the pathophysiology of DME includes retinal microvascular damage, compromising the blood-retinal barrier, which leads to leakage of plasma constituents into surrounding retinal tissue, leading to macular edema.
There’s macrovascular factors and microvascular factors.
So let’s talk about current treatments for AMD and DME.
For dry macular degeneration, we know that there’s currently no treatment. Prevention is recommended. Such as self-monitoring, nutrition, AREDS2 vitamins. Smoking cessation. And regular eye exams.
We also talk about supportive care and low vision aids. In wet macular degeneration, anti-VEGF injections are the gold standard.
But macular degeneration is a heterogeneous disease, and therefore requires an individualized approach.
We know that 10% to 20% of patients require injections every four weeks. And 10% to 20% of patients require injections every 10 to 12 weeks.
Everyone else falls somewhere in between those two.
For diabetic macular edema, we have multiple treatment options. Anti-VEGF injections, laser photocoagulation. We also have corticosteroid options. And then finally pars plana vitrectomy in specific instances.
So these are treatment recommendations for AMD and DME, by the AAO, the ASRS, and EURETINA. We can see that for AMD, prompt treatment and anti-VEGF are the standard of care.
For DME, sometimes clinical observation in mild cases with good visual acuity, followed again by anti-VEGF and laser photocoagulation. Anti-VEGF treatments for wet AMD that are intravitreal include ranibizumab, aflibercept, brolucizumab, and bevacizumab.
This chart simply shows the dosing regimens and the cost, as well as the target molecules.
For diabetic macular edema, ranibizumab, aflibercept, and bevacizumab are intravitreal anti-VEGF options.
And again, you can see the cost per dose below.
So what are some challenges in intravitreal anti-VEGF treatments? Knowing that they’re the go-to treatments for both neovascular AMD and diabetic macular edema?
Well, we know that when we talk about unmet needs, we’re talking about the burden of disease. Because there is a significant economic investment. There is unresolved medical-legal debates about the use of off-label substances. And there are overwhelming problems in large population management.
The burden of disease has turned into a burden of care. We know that anti-VEGFs are effective in reducing macular edema, reducing neovascularization, and ultimately improving or stabilizing sight.
Unfortunately, frequent intravitreal injections are a burden for patients and their caregivers. Fear and anxiety about injections in some patients is overcome by the prospect of sight preservation.
Appointments for monitoring and injections are regular events that patients plan their lives around. Collectively, anti-VEGF therapy creates financial strain for both patients and caregivers.
Whereas AMD patients are usually retired and on a fixed income, they rely on caregivers who take time away from their jobs to transport them to clinic visits.
In DME patients, these are usually people who are working full-time jobs. So they’re having to take time away from their jobs in order to receive treatment.
A study was done on 75 patients with neovascular AMD, and it was found that the mean time per visit, including preparation, travel, waiting, treatment, and recovery time from the injections, was almost 12 hours per patient.
2/3 of 456 respondents in a recent 2020 survey from the Macular Society indicated that they rely on family or friends to take them to and from their regular eye clinic appointments.
And they indicated an average time commitment of between 1 and 3 hours each time. So these are significant for patients and their caregivers.
We also know that real world experiences have been different when compared with clinical trials. Real world patients with neovascular AMD have been found to receive fewer injections, experience worse visual outcomes, we know that older patients are more likely to be undertreated, patients with poor baseline visual acuity are more likely to be undertreated,
and when it comes to DME, we know they undergo less frequent monitoring in general, receive fewer injections, and receive worse visual outcomes compared with clinical trials.
This shows the real world experience in macular degeneration, compared with the clinical trials. So if you look at the chart on the right, the FDA labeling data for anti-VEGF monotherapy indicates that patients should receive a mean number of 8 to 12 injections per year in neovascular AMD.
When we look at real world data, we find that patients are receiving between 6 and 7 injections. And this directly impacts the visual acuity. So the change in best corrected visual acuity from baseline for patients in clinical trials receiving 8 to 12 injections per year equates to 6 to 11 letters gained.
Whereas in real world data, where patients are receiving significantly fewer injections, it’s half to one letter gained. And this is also true in diabetic macular edema.
Where patients, rather than the 8 to 12 injections per year, are receiving 6 injections per year. And that correlates with the visual acuity that they ultimately have.
So what about loss to follow-up? Those risk factors include age, health literacy, low income, lost insurance coverage, high insurance deductibles, which — the patient may have insurance. They just can’t afford the deductible.
The distance from clinic, and if a patient has unilateral injections. And this is often because if they’re seeing well with one eye, they may not realize how important it is to follow up with their treatment regimen.
For macular degeneration, we know that quality of life declines with disease severity. And this leads to a risk of falls and injury, and increased risk of depression.
So let’s go to another audience question here. What is the greatest unmet needs regarding wet or neovascular AMD? And I’m gonna ask you to select one.
Go ahead and take a few seconds here.
Okay. Go ahead and finalize your choice.
So we find that the need for longer lasting therapies is definitely at the top of the list.
We also want new drug pathways, beyond anti-VEGF, and non-invasive therapies, because nobody likes to receive intravitreal injections.
Since 1999, the American Society of Retina Specialists has been doing a preferences and trends survey, and this has provided a yearly snapshot of its nearly 3,000 members’ preferences on a wide variety of medical, surgical, and socio-economic topics.
So they were asked last year this very question. And you can see that it fits right in with the answers that we are looking at from our audience today.
The need for longer lasting therapies, followed by the need for new drug pathways, especially for dry macular degeneration, and then non-invasive therapies.
So now let’s move to new therapies in the retina pipeline.
This has been a very hot topic, looking at dual targeted therapy. We know that there are many underlying similarities in the pathophysiology of DME and AMD.
And the key pathophysiological process appears to be breakdown of the blood-retinal barrier.
So the question is: Can we combine two medications for better outcomes?
And increased productivity.
Faricimab is the latest in this dual mechanism availability. So we know that VEGF-A is secreted by RPE cells. And it has a critical role in regulating angiogenesis and vascular permeability.
VEGF maintains the integrity of endothelial cells, and is recognized as a neuroprotectant. It’s also highly regulated by hypoxia.
In neovascular AMD, VEGF expression mediates choroidal neovascularization, leading to leakage, hemorrhage, and subretinal fibrosis. In DME, expression of VEGF promotes retinal vascular permeability, leading to protein and fluid accumulation.
The role of angiopoietin-2 or Ang-2 has been highly researched in recent years, and we know that this is a focus of development for next generation therapeutics for retinovascular disorders.
It is involved in vascular development and maintenance, homeostasis, inflammation…
And what we have found is that VEGF-A and Ang-2 actually work in conjunction, to regulate vascular stability and inflammation.
These play an important role in DME, neovascular AMD, and retinal vein occlusion. And faricimab has an area that binds to Ang-2 to reduce inflammation and vascular leakage. It also has an area which binds to VEGF-A, inhibiting vascular leakage and neovascularization.
This inactivated region is engineered to reduce systemic exposure and inflammatory potential.
Faricimab is the first bispecific immunoglobulin-based antibody designed for the eye. It was FDA approved in the United States in October of 2021.
And it can bind to Ang-2 and VEGF-A at the same time. Through a novel mechanism of action, it’s designed to stabilize blood vessels and reduce inflammation and leakage more than either pathway alone.
There are clinical trials which have looked at faricimab in both neovascular AMD and DME. So the TENAYA and LUCERNE trials looked at about 1300 patients, and found non-inferior vision gains, compared with aflibercept at week 48.
But the difference was that more than 50% of faricimab patients were treated every 16 weeks, rather than every 8 weeks.
And more than 75% of faricimab patients were treated every 12 weeks, rather than 8 weeks.
It is generally well tolerated, with no new safety signals. And what’s really important here is that faricimab is the first new class of medications with an effective drug for wet AMD in over 15 years.
So this was the study design. And you can see in the wet AMD study of TENAYA and LUCERNE the visual acuity change was very similar for both Vabysmo and aflibercept.
Again, the mean CST change on OCT was also very similar. But this is comparing Vabysmo every 8 to 16 weeks, versus aflibercept every 8 weeks.
And this is a direct answer to the need for longer lasting therapies.
So patients with wet AMD at year one showed that 78% had every 12 week dosing or every 16 week dosing.
Now, similar trial was done for diabetic macular edema, and this was called the YOSEMITE and RHINE trials. And it was a similar trial. Again, we saw non-inferior vision gains when compared with aflibercept.
More than 50% of faricimab patients were treated every 16 weeks versus every 8 weeks.
And this was the first investigational drug to achieve this level of durability. Which is very exciting for our patients.
Here’s the study design.
And again, we see that with visual acuity, and with CST change, it was very similar.
So dosing of Vabysmo for neovascular AMD is starting at four monthly loading doses. And this is followed by Q4 to Q16 dosing. Q16 weekly dosing, I’m sorry, depending on what we see in the patient’s OCT and visual acuity.
For diabetic macular edema, there’s two options. Physicians can begin with four monthly loading doses or six monthly loading doses. And this is followed by increment extension or reduction, or intervals of every 8 week dosing.
OPT-302 is something that is not yet available. However, it’s a novel inhibitor of VEGF-C and VEGF-D, or VEGF Trap. It’s administered in combination with anti-VEGF-A therapy. So again, a combination drug. And clinical trials have been promising…
The ShORe trial looked at wet AMD. And in this study, the OPT-302 was administered in combination with ranibizumab. Compared with ranibizumab monotherapy.
So this was the design.
And again, the way that the design — the study was designed.
And then the COAST trial also looked at neovascular AMD. However… It looks at OPT-302, given in combination with aflibercept.
Versus aflibercept monotherapy. And the question is: When given in combination, can we go out longer between treatments?
The newest option in the US are biosimilars for wet AMD and diabetic macular edema. I know that in other parts of the world, biosimilars have been available for about 7, 8 years now. But it’s new in the US.
And we know that biosimilars are highly similar, but not identical to the originator biologic, which is an FDA approved product.
We know that biosimilars are not generic drug. And in the US alone, it’s estimated that between 2020 and 2024 the health care system could save an estimated $100 billion by using biosimilars as compared to the originator biologics.
I think these estimates are interesting, and something that we certainly want to follow.
But in other specialties, such as oncology and rheumatology, these high estimates of cost savings have actually not panned out.
There has been some savings. But less than 10%.
The question of biosimilar adoption in the US community is actually likely not going to be the clinician’s choice, because payers may mandate the use as a cost saving measure. And they’re already starting to do that.
So the regulatory pathway for biologics versus biosimilars is slightly different. And these are not just ophthalmic, but overall biosimilars in the biosimilar landscape that have been launched since 2015.
This number is increasing. There are now a total of 30 FDA approved biosimilars, and they represent 10 distinct reference products.
So in oncology and rheumatology, biosimilars were adopted because they are lower cost agents. Priced 10% to 35% lower than their reference biologics. And sometimes up to 40%.
They have some familiarity with biosimilars. And what they found in these subspecialties is that physicians are likely to prescribe a biosimilar if they provide cost savings to the patients.
Or if the insurance company mandates its use. These are biosimilars in the ophthalmology space.
The first ranibizumab biosimilar entered the market in the US this year. And the first aflibercept biosimilar is expected to enter the market in 2024.
So this is one of the ranibizumab biosimilars. You can see its tag line: Created to be similar, with distinct value.
It’s considered to be interchangeable for all indications of Lucentis.
And in terms of efficacy, we see that the study out to 48 weeks showed very similar visual acuity compared with Lucentis.
This is another ranibizumab biosimilar that has become available this year. And again, we see that the baseline to changes in BCVA were similar between the biosimilar and Lucentis and changes in CST.
Lytenava is not available. But it’s a very interesting medication. Because it is an ophthalmic bevacizumab formulation. As you know, bevacizumab is currently used off-label in the United States.
And it is not FDA approved. But we have 15 years of data and experience to go along with that.
It is developed as an innovator therapy, not a biosimilar. And it is seeking indications for wet AMD, diabetic macular edema, and branch retinal vein occlusions.
There are studies that have been done in wet AMD, RVO, and DME. And the trials don’t have the same number of patients participating.
But the trials have shown positive tendencies. The interesting thing about Lytenava is that it will likely fall somewhere between where compounded Avastin pricing is and where biosimilars and biologics are.
It will be interesting to see what happens — at least in the United States — if Lytenava becomes FDA approved, and whether bevacizumab will be used, if it is an option.
So let’s turn now to geographic atrophy. We know that vision loss in geographic atrophy is more than just the visual acuity.
And we talked about how there is significant lesion growth in less time than we previously thought.
These are some OCT and histologic correlations.
What we have come to learn is that macular degeneration, geographic atrophy, and choroidal neovascularization are not mutually exclusive.
So these can happen all at the same time. In the same eye.
And so there are some changes in terms of how we refer to macular degeneration.
There are some exciting things coming down the pipeline for geographic atrophy. We know that the complement pathway is very complex.
And we know that geographic atrophy includes genetic, as well as histopathological and in vitro differences.
So we have found the presence of MAC, indicating activated complement in eyes with drusen. And in vitro studies have found that C5a can prime RPE cells for inflammasome activation, leading to cell death.
These are molecules under investigation for the treatment of geographic atrophy. So a lot of research going on in this.
And this is one of the medications coming down the pipeline for geographic atrophy.
So it all looks at the complement pathway.
And the two that we know may be coming to market soon — both impact the complement pathway, but in different locations.
So this is one trial, GATHER, that was done for the molecule.
They took sham versus 2 milligrams versus 4 milligrams.
And what they found is that there was actually 27% less geographic atrophy progression when this molecule was used, compared with sham.
In both the 2 milligram and the 4 milligram.
This is over 18 months. There are adverse effects. But most of these adverse effects involve the same adverse effects as found in intravitreal injections.
The interesting thing that came out of this study was that there was a conversion rate for choroidal neovascularization which was higher than the sham.
So you can see that the 2 milligram dosing had 6 versus 8 in the 4 milligram dosing, and 3 in the sham dosing.
And so we do know that there is a higher risk of choroidal neovascularization conversion in these patients.
And the dose, the higher dose impacts that as well. So GATHER2 is also gathering information.
This is another molecule, which affects the complement pathway.
And tries to reduce progression of geographic atrophy.
The OAKS and DERBY studies were done, and again, showed reduced progression of geographic atrophy in patients who received the molecule.
Again, adverse effects were found to be very similar to those in intravitreal injections.
And again, we saw that with this molecule, there was also choroidal neovascular membrane development.
The Susvimo ranibizumab port delivery system is very interesting, because while it uses ranibizumab, which is a drug that we’ve had for many years, it is a new platform.
So this is a refillable intraocular implant. Customized formulation of ranibizumab. It’s implanted surgically at the pars plana.
And refill exchange procedures are performed in the office approximately every 6 months.
This is what the platform looks like. And this is what it looks like in the eye.
So we see that the Susvimo implant has very similar efficacy in visual acuity, compared with ranibizumab.
Given every four weeks. And this is exciting, because if patients can go out six months, versus four weeks, for treatment, I think most of my patients would be delighted.
What is very exciting about this is that 98% of patients in the trial did not receive supplemental treatment.
And the port delivery system, again, the ASRS asked about it. Who would you consider it for?
And most people said that they would be considered for patients that required more than 8 injections per year. Which makes sense. You know, if a patient does not require these injections frequently, then perhaps it’s reasonable to have them come to the office, so that they don’t have to undergo a surgical procedure.
But for patients who are having to come in every four weeks, for these injections, doing a simple surgical procedure, and reducing those visits to every six months, I think, would be incredible.
So endophthalmitis levels were higher for the Susvimo implant, compared with intravitreal injections. And things like retinal detachment, implant dislocation, and vitreous hemorrhage were found.
The biggest concern is conjunctival erosion or retraction. Which can allow endophthalmitis or dislocation of the implant.
In October of this year, Genentech did a voluntary recall of Susvimo. So it’s not currently available in the United States to be used. They are working with the FDA. And there were concerns for septum dislodgement. You can see here what that looks like.
And if it’s dislodged, then there’s concerns about whether the medication is being released the way that we think it should be.
So wrapping up here, key takeaways: We know that macular degeneration and diabetic macular edema are heterogeneous diseases.
Patients require individualized approaches to treatment. And we know that we have a lot to learn.
But the retina pipeline offers hope for treatment and reduced burden for our patients.
I’m gonna open up now to… Questions.
And… I know we’ve had some questions submitted.
So if you’ll give me just a moment here, so one participant asked: Is Avastin an FDA approved drug?
Avastin is not an FDA approved drug. We use it because we have over 15 years of experience and data and clinical trials, telling us that we can use it.
Because it’s not FDA approved, does it make clinicians uncomfortable? Yes, definitely.
But in surveys, retina specialists and ophthalmologists have cited that the significant cost difference between bevacizumab or Avastin and the biologic drugs makes it reasonable to use it despite that discomfort.
It’s also required by some payers, either as a step therapy, or indefinitely.
So somebody asked: What is the aim of giving medications once macular degeneration has occurred?
We know that there are no treatments currently for dry or non-exudative macular degeneration. Although we talked about some of the complement inhibition drugs that are going to come down the pipeline.
But once macular degeneration has occurred, meaning, I assume, that it has become wet or neovascular, our goal is to preserve progression.
Our goal is to preserve loss of sight. And possibly even improve vision. We know that patients can actually gain letters of vision with anti-VEGF, and now faricimab treatments.
So that is the aim. To prevent progression. And hopefully to increase vision.
And a follow-up question. Someone else asked: Based on the answer to whether it is approved, bevacizumab — why doesn’t it just get FDA approved?
Well, because there is a lot of cost and manpower involved in getting something FDA approved. So somebody has to actually put in the money and the time to get that approved, and the incentive likely is not there.
Another attendee asked if there’s any anti-VEGF eye drops currently researched. There are some being researched.
But there have been none so far that have been found to penetrate to the level necessary to manage the macular degeneration.
The question… Another question is whether there’s generic ranibizumab or aflibercept. Currently there is no generic of any of the biologics.
Bevacizumab is considered a generic by some. But it’s off-label. And it has never been FDA approved for use in the eye.
There are biosimilars, two biosimilars, that have become available in the US for ranibizumab. This year, there are other biosimilars worldwide available.
But no generics for ranibizumab or aflibercept.
Somebody asked: What are some special OCT findings where you would not choose bevacizumab for macular degeneration treatment?
And would go to another drug? For example, I’ve heard that serous pigment epithelial detachment responds better to aflibercept.
You know… There are some small case reports and studies that have talked about this. But there are no large trials showing us whether one medication works better than another.
In the case of diabetic macular edema, in specific instances, with specific visual acuity findings, they have found that aflibercept may work better.
But these are not overall or worldwide adoption of these standards.
Another attendee asks: Any concerns in patients and cardiovascular accidents with port delivered anti-VEGF?
You know, I think that’s a great question. I think we all know that patients receiving anti-VEGFs may be at a slightly increased risk of cardiovascular, cerebrovascular accidents.
We also know that these patients, because of the systemic findings and because of the age, are also at increased risk for these.
So I think it’s an individual question that physicians have to discuss with their patients.
Again, macular degeneration, diabetic macular edema, these are heterogeneous diseases, and they involve individual approach.
Our time is coming to an end.
I want to thank everyone for attending. We had a lot of attendees. And we had a lot of questions.
So I’m sorry we were not able to get to all of the questions.
But I hope that we can continue this discussion in the future, because I know there’s a lot of interest. Thank you again.