Introduction and Objectives
Significant progress has been made in the treatment and management of neovascular AMD. That fact is indisputable. The array of anti-VEGF agents available for use in the clinic today provide patients with a good chance of achieving anatomic control of their eye disease, which, in most cases, corresponds with an opportunity to improve or maintain functional vision. Factors such as the timing of initiating intervention relative to disease onset, whether patients will adhere to the treatment schedule, and the frequency of injections are the main drivers in determining the success of treatment over the long-term.
However, the treatment of neovascular AMD in real-world settings remains challenging:
- Durability of currently available anti-VEGF agents is about 2 months on average with a range of about 4 to 12 weeks in the maintenance phase of therapy;
- Current anti-VEGF therapeutics must be injected in the office frequently to be most effective, which exacts a burden on patients, their families, and on the provider;
- Some patients may be undertreated, even with monthly or bimonthly dosing; and
- Response to anti-VEGF therapy is variable, and VEGF targeting alone may be incomplete or suboptimal for some patients.
The good news for our patients is that new therapeutics and delivery systems are in development, some offering novel mechanisms of action or aiming for new targets in the complex AMD pathophysiologic pathway, offer significant promise to alleviate treatment burden via increased durability. While the usual caveats apply about pipeline products, the fact that we are questioning how to make our treatment paradigm even better speaks volumes about how far we have come in the anti-VEGF era.
In the following, an esteemed panel of experts on the subject of neovascular AMD take stock of the current landscape of treatments and take a peek down the pipeline at some of the promising agents and molecules on the near and far development horizon. Their wealth of experience in the clinic and in research settings results in a robust and honest assessment of whether new therapeutics will help address treatment challenges and unmet need. In sum, the takeaway is that the future is bright, indeed, for patients with neovascular AMD.
— Carl D. Regillo, MD
Durability of Current Agents
Carl D. Regillo, MD: What are your impressions of the durability of currently available anti-VEGF agents?
Caroline R. Baumal, MD: The majority of my nAMD patients experience reduction of fluid and stabilization or improvement with any of the available anti-VEGF agents. There may be some subtle differences in anti-VEGF durability from the available phase 3 study data, but this may partly be related to the study design. The HARBOR study confirmed the heterogeneity of patient response to anti-VEGF therapy.1 In real-world clinical practice, it often comes down to how we use these agents, as well as patients’ tolerance for therapy.
Dr. Regillo: There is some variability in response to current therapies, but the range in durability is similar. In the ATLAS Trial, which was a prospective study out of Wills Eye Hospital looking at the exudative-free interval after 2 years of treatment with aflibercept (Eylea, Regeneron) using a treat-and-extend protocol, about 25% of patients required retreatment every 4 to 6 weeks, with the remainder extended to 8 weeks or more. At the far end, 38% were able to be extended and maintained successfully every 12 weeks or more, with 13% to 14 weeks, and only 6% to 16 weeks. Overall, patients received a mean 8 injections in year 1 and 6.5 in year 2, and the median exudative-free interval was 9 weeks at the end of 2 years of treatment.2 Charlie Wykoff and colleagues have also published data on treat-and-extend using ranibizumab (Lucentis, Genentech) that is comparable. In this study, called the Trex-AMD trial, at the end of 2 years, about 40% or so of patients were on 4- to 6-week intervals, just over one-third were extended to 12 weeks, and the mean maximal extension was 8.5 weeks.3 Patients received 10 and 8 injections in years 1 and 2, respectively. There is also the prospective LUCAS trial with bevacizumab (Avastin, Genentech) and ranibizumab, which showed that 47% of patients were extended to 8 or more week treatment intervals and 33% extended to 12 weeks.4 Taken together, the data show that the mean durability of current anti-VEGF treatments is about 2 or so months. Based on the Hawk and Harrier 1-year results, that may be a little longer with brolucizumab, but we will have to see how that plays out in real-world practice.5
Usha Chakravarthy, MD, PhD, CBE: These data are consistent in the first 2 years. Beyond 2 years, there is very little data about whether patients stay on the same interval that was established in the early part of treatment. There are some data out of Australia that seem to suggest that the interval might change around 4 to 5 years after treatment initiation.6
Dr. Baumal: Therapeutic decisions, particularly when related to retreatment, need to be individualized. However, many factors that do not necessarily show up in clinical trials affect patients in the real world, including a variety of reasons why a patient might become lost to follow-up. For example, where I practice in Boston, some older patients miss appointments due to unpredictable weather in the winter months. Some of those patients can extend an extra week or 2, but to be realistic, I often have my patients return for follow-up on the earlier side as I anticipate weather-related issues. That is good for my patients, but those kinds of real-world issues pose challenges in finding the correct retreatment interval. On top of that, there is a whole discussion about anti-VEGF agent choice, which may in some cases be driven by insurance coverage and availability. I typically give three monthly loading doses, and if there is no sign of improvement after three injections or suboptimal improvement after six injections, I will consider performing additional imaging and switching to a different agent. There is a new agent available, brolucizumab (Beovu, Novartis), and my clinical experience so far is similar to the findings from in HAWK and HARRIER: OCT is drier, with some prolonged durability.5 However, until there is more information about this rare side effect of occlusive vasculitis, I reserve the use of brolucizumab for select patients.
Dr. Regillo: There are no studies out there that point to any significant, clinically meaningful differences in terms of efficacy, safety, or even durability with the currently available anti-VEGF drugs to treat AMD. Response to therapy is somewhat variable between patients, but the differences in drug responses for a given patient are small. This is not entirely surprising given that all of them work the same way by binding VEGF-A.
Rishi P. Singh, MD: As clinicians review data from clinical trials, it is important to scrutinize how the retreatment intervals are determined and whether the criteria align with their clinical practice. Some studies introduce wide intervals for central subfield thickness (CST) or VA for retreatment, but we typically would not tolerate 1 line of vision loss or 75 µm of fluid, for example, before retreating.
Dr. Regillo: A lot of study designs allow some degree of exudation persistence or recurrence. That could give you 2, maybe even 4 more weeks of apparent, additional durability depending on the specific study exudation threshold triggering retreatment or interval adjustment.
Dr. Chakravarthy: Are there any baseline characteristics, maybe angiographic characteristics or lesion types, that will predict which patients can have extended anti-VEGF intervals?
Dr. Baumal: A interesting study utilizing machine learning on HARBOR data found that early response to anti-VEGF therapy as well as the subretinal fluid volume on OCT may be predictive of anti-VEGF injection requirements.7 Type 1 choroidal neovascularization (CNV) and smaller lesions may be able to be treated with longer intervals.8 On the other hand, in my experience, very large lesions with extensive subretinal hyperreflctivity and exudation may be more difficult to extend the interval.
Dr. Regillo: Unfortunately, baseline ocular characteristics are not predictive of the intensity or frequency of treatment required for optimal exudative control. It really is a trial-and-error process for each and every one of our patients that typically takes a year or so to determine.
Dr. Singh: There is a remarkable contrast that emerges from assessing outcomes from the major treatment trials to date: treatment exacts a significant burden on patients, and by extension, their families; however, higher burden of treatment is associated with more favorable outcomes:
- Across MARINA,9 ANCHOR,10 HARBOR,1 CATT,11 and View 1 and 2,12 there was a mean improvement of 8.4 letters of vision in the first year, but mean number of injections delivered was 10.2 [unpublished data]—even though some of these trials followed prn formats with OCT-driven retreatment;
- In SEVEN-UP,13 a retrospective analysis of patients who completed MARINA/ANCHOR and then HORIZON, the protocol was investigator-based treatment, which resulted in patients getting a mean 6.8 anti-VEGF injections during years 4 to 7 but losing about 8.6 letters from baseline; and
- A subset of SEVEN-UP patients with higher injection burden in years 4 through 7 gained 4 letters of vision from baseline, suggesting that vision outcomes deteriorate with suboptimal dosing frequency.
In a study in our institution, we found a linear correlation between mean 5-year change in BCVA and mean number of injections over the same time period.14 Taken together, these data tell us that, in real-world practice, regardless of which anti-VEGF drug is used, as long as we use them frequently, we can get good visual outcomes. Now, whether the dosing is maintainable or not is another story. I think that is a patient and provider-level discussion, but certainly, we can see linear correlations with good vision and frequent dosing. We cannot let our foot off the gas if we want to maintain vision over time in these patients.
Dr. Regillo: The data from current studies looking at visual outcomes compared to baseline from years 2 and beyond are consistent in showing that fewer than 6 treatments per year is associated with loss of vision gains over time. That suggests some degree of undertreatment. For example, in CATT the mean number of treatments per year in years 3 to 5 was around four-and-a-half and patients lost about 11 letters of acuity over that follow-up time frame.15 Certainly, there are other factors that contribute to vision loss in AMD over time such as atrophy, but the data across all the studies, whether it is treat-and-extend or prn, show a letter-gained-per-injection relationship. If we want to have 8 to 10 letters gained in the first year on average for our patients with AMD, we need a mean of around 8 to 10 injections. Conversely, if we are averaging less than every other month in year 2 and beyond with our current therapeutics, then we are probably not going to maintain the initial vision gains over time, and that is probably mostly due to recurrent exudation and associated growth of choroidal neovascularization.
Dr. Chakravarthy: I am glad to hear you qualify the statement by saying that there are other reasons for functional loss, because features like progressive atrophy and fibrosis also contribute. We can see this in a publication from the IVAN group last year, where we had unprecedented follow-up right out to 7 years.16 There was a subset of patients who received nearly seven to eight injections a year all the way through, and some of them continued to lose function. There was a subset of patients who received very few injections and maintained function. So, the fact that under-treatment does lead to vision losses to a certain extent is absolutely right, but it is not entirely the whole story, and it should not stop us from seeking better treatments that will better preserve outer retinal function.
Pipeline and Novel Agents
Faricimab
Dr. Regillo: There are a number of molecules in early- and late-stage development that offer extended duration of action via various mechanisms. The hope is that some of these will make their way to the clinic and demonstrate truly longer duration of action and maybe other potential benefits, such as better anatomic or visual outcomes over time.
Faricimab (Roche) is a bispecific monoclonal antibody with two antigen binding sites, one to VEGF-A and one to angiopoietin two (Ang2).17 The rationale for targeting Ang2 comes from preclinical work showing its expression is upregulated in vascularized regions of choroidal neovascularization (CNV)18 and hypoxia19; it increases potency of VEGF in inducing permeability20; and that it has a dual function in promoting angiogenesis and mediating inflammation.21 It is currently being investigated in the phase 3 TENAYA and LUCERNE clinical trial program, with some results recently reported (Figure 1).22 The topline result is that the study met its primary endpoint, with faricimab demonstrating noninferiority to aflibercept in BCVA change from baseline averaged over weeks 40, 44, and 48. Patients gained about 6 or 7 letters out to weeks 40 to 48 for both faricimab and aflibercept, the control treatment, with faricimab dosed less frequently (Figure 2). Are there any surprises so far?
Figure 1. Randomization schema for TENAYA and LUCERNE.
Figure 2. Mean BCVA change in TENAYA and LUCERNE.
Dr. Baumal: On initial inspection, the mean BCVA letter gains in these studies are less than in the phase 3 pivotal studies for ranibizumab and aflibercept. However the upper limit of BCVA included in TENAYA and LUCERNE studies started at 20/32, and the mean BCVA was about 20/63. Because the majority of eyes had fairly good starting vision, robust vision changes are unlikely. That said, the important things to note are that baseline criteria were well balanced between the arms, and the aflibercept arm had similar gains.
Dr. Chakravarthy: It would be interesting to look at the data by baseline starting acuity to see the ranges of response.
Dr. Singh: The anatomic response in this study looks very promising (Figure 3). There is comparable exudative control in both studies compared to aflibercept, yet the dosing is less frequent. With these treatment intervals, you might expect some amplitude changes and variability of CST, which may be a negative prognosticator, but that has not been the case so far, which is reassuring.
Figure 3. CST change on OCT in TENAYA and LUCERNE.
Dr. Regillo: Does the fact that the study used different treatment intervals for aflibercept and faricimab complicate or preclude a determination about any durability differences?
Dr. Baumal: It does not seem productive to test a new medication in a manner that would not have potential to demonstrate benefit. This trial is appropriately pushing the envelope, which is what patients need in the real world, so I think it is acceptable that faricimab was not used at exactly the same interval as the aflibercept control arm. I want to see it used differently. And one can still comment on durability because 45% of faricimab treated eyes could be maintained at Q16 weeks. I would like to look closely at the baseline and posttreatment vision and OCT features of faricimab treated patients to see if factors can be identified to predict long-term durability. These features may have the potential to be applied to clinical practice.
Dr. Regillo: In both TENAYA and LUCERNE, about 80% of patients were treated at either 12- or 16-week intervals, and about 20% of patients were treated at 8-week intervals. To me, this suggests that faricimab is more durable even if we factor in that some degree of exudation was allowed in the process of determining the treatment interval. Overall, this is still looking very promising for enhanced durability compared to what we have in the clinic at this time.
The safety analysis is equally as important to discuss. In the trials, both aflibercept and faricimab were well tolerated and adverse events were balanced across arms and across studies. With higher rates of inflammation seen in the brolucizumab phase 3 trials, there is a heightened awareness for possible inflammatory issues, and that is something specifically we should be taking a close look at for any new treatments in development. In TENAYA, 5 of 133 patients (1.5%) and 2 of 336 patients (0.6%) in the faricimab and aflibercept arms, respectively, experienced any intraocular inflammation through week 48, excluding endophthalmitis. In LUCERNE, these were 8 of 331 (2.4%) and 6 of 326 (1.8%) in the faricimab and aflibercept arms, respectively. A small imbalance in both trials. Is this a reason for concern?
Dr. Baumal: There is not a large imbalance in rates of inflammation between groups, and the rates are not altogether surprising. However, it would be important to understand the mechanism of inflammation and have more details on the following: Did the inflammation responded to topical steroid treatment? Did the patients continue in the study and did the inflammation recur after another injection? What was the severity of inflammation and what was the final visual outcome in these eyes?
More generally, there are three important things to note about reports of inflammation in clinical trials. First, it would be helpful to have a standardized approach to evaluate eyes with inflammation as new therapies are developed to encompass new mechanisms. Second, ophthalmology studies are not powered to find rare adverse events occurring at a rate of under 1%. With brolucizumab, the HAWK and HARRIER studies were not powered to detect the rare occurrences of occlusive retinal vasculitis. Third, the occurrence of intraocular inflammation is not necessarily unique to that molecule. During the history of development of ranibizumab and aflibercept, there were reports of inflammation. There was also inflammation noted in the studies with abicipar (Allergan), and reports of inflammation have been noted with some of the gene therapies. Perhaps inflammation is something we should specifically follow for all new drugs.
Dr. Singh: It might be too early to make any decisions based on reports of inflammation in these studies. I think recent experience might be raising our concern, and that is a good thing, but these numbers are very small and actually slightly duplicative. In these trials, if a patient has two of these outcomes, they might get counted twice. The numbers right now are not concerning, but they do not tell the whole story. We should wait until we see the 2-year outcomes.
Dr. Chakravarthy: The absence of any signal in terms of the intraocular inflammation is reassuring. It does not look anything like the kind of signal that showed up with brolucizumab. Having said that, you really do need to have it introduced into the wider real world when you might end up treating patients who have had past uveitis and different types of patients that you would not enroll into clinical trials. If the drug gets regulatory approval, it is likely to catch on because the durability data seem quite impressive in terms of 16-week extension. That will certainly make a huge difference on the burden, to the patient and the provider. I would like to see some more data on the morphological outcomes, how much atrophy and fibrosis there are in the 2-year data. I would also like to know the proportions of patients who exhibit these characteristics, because I think that is going to give us a better idea about whether the introduction of faricimab is going to make a difference functionally.
Dr. Singh: One thing that could potentially be important for some of our patients is that faricimab offers a different mechanism of action. My hunch is that this could have a role for patients receiving very frequent treatment, but whether a patient’s insurance covers the drug could determine if we get a chance to use it. Will we have to use step therapy or demonstrate failure of gold standard anti-VEGF before switching? There are a lot of unknowns, but this is still an intriguing molecule to follow in its continued development.
Conbercept
Dr. Regillo: Another drug in phase 3 trials is Conbercept (Chengdu Kanghong Pharmaceutical group). It is similar to aflibercept in that it blocks VEGF-A along with placental growth factor.23 It has been approved in China for a number of years and is being studied in the phase 3 Panda trial with aflibercept as the control treatment (Figure 4). While we wait for data to be reported, are there any expectations that this drug will offer more durability?
Figure 4. Randomization schema for the phase 3 Panda studies.
Dr. Singh: I would say not necessarily. This study design replicates a lot of what we already do, which is to say they are aiming for 12- to 14-week intervals of retreatment. I do not see a true treat-and-extend paradigm in this study design. Conbercept was given Q12 versus Q8 with capped prn at Q16, but are we going to see much difference? The answer is probably not.
Dr. Regillo: Mechanistically you cannot really expect too much of a difference, but time will tell. Panda is fully enrolled and results should be available this year.
KSI-301
Dr. Regillo: Another molecule that is generating a lot of attention is KSI-301 (Kodiak Sciences), which features a unique molecular design. It is an anti-VEGF-A antibody that is covalently bound to a biopolymer conjugate to form what the company is calling its antibody biopolymer conjugate, or ABC platform.24 There is some suggestion it could offer enhanced ocular durability with extended intraocular half-life and improved bioavailability compared with currently available anti-VEGF agents. In a phase 1b study, 80% of patients achieved a 6-month treatment free interval at least once during follow-up after the loading phase of three monthly injections. It is now in a pivotal study called the DAZZLE trial for wet AMD. In the study, patients will receive retreatment every 12, 16, or 20 weeks depending on prespecified disease activity assessments.
Dr. Baumal: Rather than making the molecule smaller as with brolucizumab, the KSI-301 antibody biopolymer conjugate is larger in an effort to increase its durability and efficacy. One thing to pay attention to is the disease activity assessment retreatment criteria, which is broadly defined. Whether that is in line with one’s individual clinical decision-making is something to be considered. But I think that the KS-301 study design is really pushing the envelope and appears promising.
Dr. Regillo: It is worth repeating that durability is defined in different ways, depending on the threshold of exudation that is deemed tolerable. Disease activity in this trial was a five or more letter decrease and OCT central subfield thickness (CST) of 50+ µm increase at week 20 or 24 compared to week 12; or, a 75 µm increase on OCT CST at week 20 or 24 compared to week 12. The question we should be asking is, would I be doing anything different with my patients in my own clinic?
Dr. Chakravarthy: Another question we may want to ask is, because this is now a larger molecule, is there potential for additional epitopes and are there more opportunities for sensitization to the drug?
Dr. Regillo: In preclinical studies, the larger size molecule with the biopolymer effectively doubles the half-life compared to an antibody or fusion protein alone. So far in human studies, across three disease states, KSI-301 has demonstrated good tolerance with very low rates of intraocular inflammation, but we will certainly have a better feel for all this with the larger scale pivotal studies.
PDS
Dr. Regillo: Another very interesting development in the pipeline is the Port Delivery System (PDS), which is really a device-drug combination being tested for the treatment of neovascular AMD and now also diabetic retinopathy and macular edema. The scleral-based intravitreal implant is an 8-mm long silicone reservoir that is inserted surgically through a 3.5 mm incision. It holds about 20 mL of a high concentration version of ranibizumab and the drug diffuses passively out of the device into the vitreous cavity down a concentration gradient. The refill of the device is performed in the clinic setting using a specialized 34-gauge exchange needle. Let’s get your impressions of the surgery?
Dr. Singh: I have only used it in wet lab, but I think this should be within the skill set of any vitreoretinal surgeon as long as he or she pays attention to some important steps. For instance, photocoagulation of the uvea to minimize bleeding. As well, the incision size has to be large enough to insert the sizable implant, but you have to be careful not to make it too big and risk it not sitting securely without sutures. There is some need for precision, but the steps can be learned fairly quickly.
Dr. Regillo: It does require a high degree of precision with certain steps of the surgical technique, and the refill in the office also requires accuracy in terms of proper entry into the port. It is definitely more time consuming and more challenging than an intravitreal anti-VEGF injection. In my experience, however, it is well tolerated by patients.
Dr. Singh: I am actually quite enamored by the technology. The ability to exchange 100% of the reservoir is impressive.
Dr. Regillo: It is an elegant system, to say the least, and the data on how it performs to control exudation are impressive. The phase 2 LADDER study was conducted with the primary endpoint being the median time to first refill of the device. PDS was compared to monthly ranibizumab injections, and only patients diagnosed with neovascular AMD within the prior 9 months who had responded to two or more doses of anti-VEGF treatment were enrolled. With this study design, you would not expect significant BCVA gains because patients were previously treated with vision improvement before enrollment, and that was the case. In LADDER, vision was well maintained, 80% of patients in the highest dose group (ranibizumab 100 mg/mL) went 6 months or more without refill, and the median time to first refill was 15.8 months. That high dose was then used in the phase 3 ARCHWAY study, which sought to establish if PDS 100 mg/mL refilled Q24 weeks was noninferior and equivalent to gold standard intravitreal ranibizumab 0.5 mg at Q4 weeks. It is a planned 2-year study, with a primary endpoint of change in BCVA from baseline averaged over weeks 36 and 40. The study was successful in meeting its primary endpoint with PDS both noninferior and equivalent to monthly ranibizumab in BCVA. In the intravitreal ranibizumab arm, BCVA was 75.5 ETDRS letters (Snellen 20/32) at baseline and 76.0 ETDRS letters (Snellen 20/32) averaged at weeks 36/40, and in the PDS arm, BCVA was 74.4 ETDRS letters (Snellen 20/32) and 74.6 ETDRS letters (Snellen 20/32) at the same time points. On OCT, center point thickness was 177.4 µm versus 180.0 µm (+2.6 µm) in the ranibizumab arm at baseline and week 36, respectively; and it was 176.9 µm versus 182.3 µm (+5. µm) in the PDS arm at baseline and week 36, respectively.25,26 What is really encouraging is that we saw these results continue essentially unchanged out to 72 weeks, which would encompass three refill exchanges per protocol (Figures 5 and 6).27
Figure 5. Mean central point thickness at 72 weeks in the Archway Trial.
Figure 6. BCVA outcomes at 72 weeks in the Archway Trial.
My takeaway is that these data demonstrate excellent exudative control. Additionally, separate analyses have found minimal fluctuation of OCT values28 and that PDS delivers anti-VEGF levels that are above the trough of monthly injections at every time point, suggesting continuous delivery of effective anti-VEGF drug levels over time.29 Another thing we should note is that in the PDS arm, 1.6% of patients in the first 24 weeks, and 5.4% of patients between weeks 28 and 48, required supplemental intravitreal ranibizumab. So, the need for rescue therapy using the study’s criteria was very infrequent.
As with all new drugs and devices, we must closely examine the safety profile. The rates of cataract, infection, and conjunctival issues, some which required surgical repair, were higher in the PDS versus intravitreal ranibizumab arm, as expected. What was encouraging with the most recent, longer follow-up data analysis is that the rates of important adverse events with PDS like endophthalmitis and device exposure decreased after week 40 (Figure 7). The one adverse event of note that come up later on in the course of follow-up is the small potential for implant dislocation, most cases of which were associated with the refill-exchange procedure. These cases were investigated, and it was found that the initial surgical incision size was generally larger than the protocol specified. Surgical procedure guidelines have been modified for the current PDS studies, which should help to minimize the dislocation risk going forward.
Figure 7. Summary of safety outcomes in the Archway Trial.
Figure 8. BCVA outcomes in a phase 2b study evaluating OPT-302.
Tyrosine Kinase Inhibitors (TKIs)
Dr. Regillo: There are several tyrosine kinase inhibitors (TKI) being studied for the treatment of neovasculuar AMD. They are a class of small molecules being packaged in various sustained release platforms for intravitreal (or suprachoroidal) delivery, but data are limited thus far with the programs only in phase 1 or 2 clinical trials. The promise here is that they may offer 6 month or greater treatment intervals, and that would be significant for our patients if there is a comparable level of efficacy and safety to our current anti-VEGF biologics.
GB-102 (Graybug) is one such product. It is a sustained release formulation of sunitinib, which is a TKI approved as an oral agent for solid tumors. It blocks all three VEGF receptors, and thus offers pan-VEGF blockade. GB-102 is delivered via dissolvable PLGA microparticles. The drug depot that forms after it is injected into the vitreous slowly releases sunitinib as it biodegrades with the intended purpose of every 6-month dosing in neovascular AMD. The phase 1/2a Adagio study, which studied version 1.0 of the platform technology, demonstrated extended durability as maintenance therapy after prior anti-VEGF therapy, but 28% of participants exhibited particle migration to the anterior chamber. The phase 2b Altissimo study used a different version (version 2.0) that was designed to reduce particle dispersion. The study, similar to Adagio, was in the setting of maintenance therapy with 1- or 2-mg formulations injected every 6 months compared to aflibercept Q8W. Some data were announced in a press release in early March.31 Overall, the 1-mg dose performed better than the 2-mg dose: median time to first supported treatment was 5 months and 48% were rescue-free through 6 months, and only 10% experienced migration of particles. Although CST in the GB-102 1 mg group was consistent with the aflibercept arm, the mean change from BCVA for the 20 patients completing the study was 9 letters lower across all time points. Do you have any questions upon hearing these data?
Dr. Baumal: It would be important to understand the circumstances around the lower BCVA in the GB-102 arm. Did the molecule migrate to the anterior chamber and affect the lens or was it because disease was not controlled? If there is a lack of disease control, we look at that outcome a little differently. Even though we often use OCT as our endpoint, vision is what keeps patients driving and reading. The visual outcome is important for getting buy-in.
Dr. Regillo: At this point we do not know if a TKI is going to be on par with currently available anti-VEGF agents. There are some other TKIs that are worth mentioning:
- CLS-AX (axitinib injectable suspension; Clearside Bio) is a TKI suspension for suprachoroidal injection; it is being studied in the phase 1/2a OASIS Trial.32
- OTX-TKI (axitinib hydrogel fiber intravitreal implant, Ocular Therapeutix) is a sustained release TKI delivered via a biodegradable polymer implant for intravitreal injection. A phase 1 study was recently completed.33
- EYP-1901 (vorolanib intravitreal implant; EyePoint) is a pan VEGF TKI also in a biodegradable implant for intravitreal injection. The active agent, vorolanib, was tested as an oral agent (X-82) for nAMD in phase 1 and 2 studies,34 and the phase 1 DAVIO Trial is currently enrolling (NCT04747197).
We hope to have some more data in 1 or 2 years to help us understand if this is a promising class of therapeutics.
Dr. Chakravarthy: As you pointed out earlier, for every 10 molecules that are tested in phase 1 and phase 2, we are lucky to have even one make it through to a phase 3 study program.
Gene Therapy
Dr. Regillo: Gene therapy to manage neovascular AMD is a very exciting area of research.
- RGX-314 (REGENXBIO) is an AAV8 viral vector product that is delivered subretinally (via vitrectomy) to produce a VEGF-A antibody fragment protein.
- ADVM-022 (Adverum Biotechnologies) is an AAV.7m8 viral vector product that is delivered intravitreally to produce an anti-VEGF-A fusion protein.
Looking at the data from the phase 1/2 studies of these programs thus far, there is a strong positive correlation between dose and reduction in requirement for anti-VEGF injections. The usual caveats are applicable about early stage development, but both programs look very promising and are entering pivotal studies. In addition, RGX-314 is also starting trials with a suprachoroidal delivery approach. Your thoughts about the prospect of a single treatment to effectively manage neovascular AMD?
Dr. Baumal: I am excited for the potential of gene therapy, especially with respect to durability. However, longer term safety data are needed. As well, it will be interesting to see what the longer-term and larger studies tell us about any differences in the route of administration. Not all patients will qualify for subretinal delivery.
Dr. Regillo: Gene therapy is not titratable, at least as far as we know at this point. Is that a concern?
Dr. Singh: I think so. Some of the available data on systemic bioavailability of gene therapy products are= potentially concerning, as well. We will have to learn more about whether the viral vector becomes available to the system and whether there are any potential implications.
Dr. Regillo: As mentioned before, in the process of evaluating any new molecule or drug, we need to know the details about the safety profile, particularly with regards to inflammation and any direct retinal adverse effects. The proposed subretinal approach is a surgical procedure and retinal tear and detachment are potential complications. If the suprachoroidal approach works, then that is an office-based approach, which has obvious advantages.
Dr. Chakravarthy: The suprachoroidal approach would seem to be preferable. I am slightly less concerned about the long-term effects in AMD, particularly if you are going to use it in someone who is older than 80 years. I think that the benefits might well outweigh any kind of disadvantages that might emerge from gene therapy. In a younger person, it is a little bit more concerning.
Concluding Remarks
Dr. Regillo: Anti-VEGF therapy has been a major advance in the treatment of neovascular AMD. Based on pivotal trial results, we know that when administered frequently, we can often maintain vision gains over at least a few years in most of our patients. We also know that vision outcomes are better when the disease is caught early. That said, the treatment burden and treatment adherence associated with anti-VEGF therapy to maintain the initial vision gains is a significant issue in the real-world setting. Simply put, the durability of our current anti-VEGF agents is relatively limited, and there is a large unmet need for treatments that have longer duration of action. The good news is that there are a number of therapeutic approaches in development that look very promising in reducing treatment burden, which should translate into better visual outcomes for our patients.
Dr. Chakravarthy: The greatest unmet need is still around the durability of our current treatment agents, but also the fact that we do not have treatments that stop this disease process. If any of the molecules in the pipeline demonstrate an ability to stop or even reverse the disease process, we will enter an entirely different paradigm of treatment. Even better, if we see proof that any of these drugs, or ones we have not heard about yet, actually protect the morphology of the outer retina, it will significantly impact long-term eye health of patients with neovascular AMD.
Dr. Baumal: Two decades ago, there were limited treatment options of laser and photodynamic therapy for select eyes with neovascular AMD. Many patients did not benefit from therapy and were seen once or twice a year. Now there is effective, vision saving anti-VEGF therapy, but it requires patients to return monthly or every other month and this produces a heavy treatment burden on the patients and their caregivers. There is also considerable heterogeneity in patient anti-VEGF treatment response. It seems that our field is on the precipice of having newer agents, drug delivery devices, and home OCT monitoring. These innovations will allow us to do even more for our patients. I am looking forward to the future developments and to the clinical data that will better inform our treatment decisions.
Dr. Singh: We have made incredible strides in the 15 years since anti-VEGF therapy came to the clinic, and I think that the amount of knowledge that we have is going to grow exponentially in the next 15 years. The potential for agents with new mechanisms of action to enter the clinic is very promising. In the past, the unmet need was to slow or stop progression, and now we are dealing more so with the nuanced impact of treatment, including patient heterogeneity, disease progression, and the limited durability of currently available agents. And so, I really look forward to the next 15 years to see how this all pans out.
Dr. Regillo: The next 3 to 5 years is going to be very exciting with a lot of positive developments expected. We are moving into the next generation of anti-VEGF agents along with drugs with novel mechanisms of action and new ways to deliver therapies, all of which hold the promise of better disease control. Couple that with home OCT as a potential way to monitor and precisely determine when a patient needs to be treated, and our patients’ outcomes are highly likely to improve significantly.
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