Arshad Khanani, MD, Sierra Eye Associates/University of Nevada Reno School of Medicine

If faricimab is approved and available, I will initially use it in patients who are already on treatment but cannot have it extended, or if they have persistent fluid despite monthly injections of anti-VEGF agents. And once I see the efficacy that we have seen in clinical trials, I’ll translate faricimab into naïve patients with neovascular AMD [age-related macular degeneration] as well as diabetic macular edema [DME]. Faricimab—based on the durability and efficacy data that we have seen as well as the comparable safety data that’s available—appears to be an agent that can be utilized in the first line in patients with neovascular AMD as well as diabetic macular edema.

In terms of other agents in the pipeline, I think this is an exciting time for physicians as well as patients because we have many ways to target this disease, and now in-clinic agents as well as surgical implants or delivery to help our patients. When you look at injectables, KSI-301 is a large antibody biopolymer conjugate that has an anti-VEGF molecule attached to a large biopolymer. It has shown great durability in the phase 2b trial in patients, naïve patients with wet AMD, RVO [retinal vein occlusion], and DME. Those pivotal trials in neovascular AMD, the DAZZLE study as well as GLEAM and GLIMMER in DME as well as BEACON in RVO, are ongoing, again to see how durable KSI-301 is compared with aflibercept. Another molecule that is in phase 3 trial is conbercept. It is approved in China for wet age-related macular degeneration. It has a very similar design to aflibercept, but it has some differences with additional domains which may translate into better durability, but we don’t know that data yet. The PANDA-1 and PANDA-2 studies are ongoing, and we expect to see the data soon. There are other agents in the pipeline; OPT-302, that’s an add-on agent that blocks VEGF-C and -D. This is a second injection on top of anti-VEGF injections in phase 2, which was a large program, that showed that patients treated with the dual injection action gained more vision than patients who just receive an anti-VEGF agent. That program is going to start phase 3 programs soon. Looking at gene therapies, intravitreal gene therapy with ADVM-022 has shown great durability. The majority of the patients treated in the OPTIC trial received 1 injection and did not need supplemental treatment. As gene therapy is a new space, there are some patients with inflammation, especially in the high doses, and we are learning what’s causing it. But the good news is patients were managed with topical drops. There’s surgical gene therapy approaches with Regenxbio’s RGX-314 that has shown excellent safety profile as well as longer-term durability, but this is done in the operating room. There have been some patients with pigmentary changes, and we’re still learning about what that means. That program also now is in suprachoroidal, in-clinic approach. We don’t have any data from the AAVIATE and ALTITUDE studies, but we should later this year. Then with the port delivery system, we had very positive phase 3 trial data from the Archway trial last year showing most of the patients in the phase 2 LADDER study go about 16 months before their refill of the port, which is placed in the OR. In Archway, they had mandatory 6-month refills, but patients had noninferior vision or equivalent vision compared to monthly gold standard injections. It’s a surgical procedure, so there’s been some conjunctival erosions, retractions, and a high rate of endophthalmitis compared to injection. We’re still learning about it. Overall, when I look at the pipeline, I think the good news is that 3 or 5 years down the road, our patients with retinal vascular diseases will have excellent options to maintain their visual acuity long-term, which is a challenge currently. I think many of these approaches should be approved, so we can decrease the treatment burden for our patients with retinal vascular diseases.

Whenever a new agent is approved, we still need to collect real-world data to see if the efficacy and the safety of the agent is similar to what was seen in the trial. Recent experience with brolucizumab has been an eye-opener for all of us where safety has really been paramount. We saw cases, rare events, but we saw cases of retinal vasculitis and retinal artery occlusion that were not really picked up in the clinical trial. I think any agent that’s new, of course there’s reservation to utilize it to make sure that we are not harming our patients. But the good news is that FDA approval is a rigorous process, and once the FDA approves a drug, I am pretty confident using it, but of course while paying attention to the data. Because you may have 2000 or 4000 patients across multiple indications in these clinical trials, but once you have 10,000, 20,000, 30,000 or 50,000 patients treated in the real world, you can really see the signals of safety that were not there in the clinical trial. I am open to trying any new approved agent quickly, but I’m very careful in evaluating the safety as well as efficacy in my personal practice compared to clinical trial. If it pans out to be the same or better, then of course that agent will be used a lot more in our practices compared to if there are new signals of safety, then of course people will not utilize the agent. The bottom line is we have good agents that work, so it’s a much higher bar for any new treatment that comes in. The treatment has to be the same or better in terms of efficacy, but it has to be comparable in terms of safety.

I think these are exciting times for physicians who treat retinal diseases as well as for patients. With impending approval hopefully for faricimab soon, we’ll have an option that can decrease treatment burden in our patients. I’m still looking for long-term, 2-year and 3-year and longer, data to see if we can actually maintain vision in our patients with neovascular AMD by decreasing fibrosis and other vision-threatening, long-term events. As far as the pipeline, I’m also very excited about gene therapy and sustained delivery with port delivery systems, and we’ll learn more about these approaches as time goes on. Overall, these are good times to be involved with all the clinical trials to advance care for our patients with retinal vascular diseases. I want to thank you for your attention.

Videos

Dr Arshad Khanani highlights various strategies currently under investigation for the treatment of age-related macular degeneration and explains the impact long-term data and real-world evidence has on his treatment decisions. 

Newer Therapies for AMD and Supporting Data 

Looking at patients with diabetic macular edema, the BOULEVARD study, which was a phase 2 study, showed the efficacy of faricimab compared to ranibizumab. The YOSEMITE and RHINE trials are phase 3 global trials that were designed to look at the safety and efficacy of faricimab compared to aflibercept. The comparator here was aflibercept because it’s a better drying agent in patients with diabetic macular edema. In the YOSEMITE and RHINE studies, patients were either treated with 6 loading doses of faricimab and then treated every 8 weeks, or they received 4 loading doses of faricimab and then went into this PTI, or personalized treatment interval, where they got treatment based on their anatomic as well as visual acuity response. As I said, this was compared to patients treated with aflibercept as part of the label, which was 5 floating doses and then every 8-week treatment. In terms of the top line data, the studies met the primary end point of noninferiority of faricimab compared with aflibercept, but I think for patients with diabetic macular edema, we have to look at some other secondary outcomes. Of course, just like patients with neovascular AMD [age-related macular degeneration], these patients have a high treatment burden, they don’t like to come into clinic, they have commercial insurances, they have to take a day off from work, and it’s a working population, so the treatment burden is really high. But the good news is that looking at the durability of faricimab in the PTI arm, over 70% of patients were on at least q12 week dosing interval at week 52, and half of the patients in the study in the PTI arm went into q16 weeks. So again, you’re significantly reducing the treatment burden for patients with diabetic macular edema by increasing the interval between treatment by using a bispecific antibody that blocks VEGF-A as well as ANG-2. But the other thing which was impressive in this trial is the anatomic improvements in these patients. 

When you look at patients that were treated with faricimab, there were more patients who had an absence of intraretinal fluid compared with aflibercept at week 56. There was a higher proportion of patients who were able to get to normal or near normal OCT [optical coherence tomography] compared were aflibercept. I think this is exciting that you can control the disease well by using a bispecific antibody, and there’s a better drying effect that you saw on CST [central subfield thickness] improvement in this trial. The bottom line is faricimab is better in durability compared with aflibercept, better in drying effect compared with aflibercept, and of course safety is again crucial for a new molecule. And the good news is that the safety of faricimab was comparable to aflibercept. We have seen that in the phase 2 trials as well as the neovascular AMD trials, which is good news for patients.

Considerations for treating patients with diabetes who have wet age-related macular degeneration with faricimab to reduce treatment burden based on results of recent clinical trials. 

Faricimab Data for Diabetic Patients With AMD 

In terms of the data we have on faricimab and neovascular AMD [age-related macular degeneration], we have 2 large phase 2 trials—especially AVENUE, a very large trial—which showed efficacy of faricimab given monthly or every other month where patients had good visual acuity gains. The safety was very comparable to ranibizumab. Then the SIERRA [-AMD] trial, where I was the lead author on that paper, we looked at patients receiving faricimab every 16 weeks and every 12 weeks. We know that patients with current treatment—let’s say ranibizumab, based on the EXCITE trial and other trials—they cannot sustain vision with quarterly dosing. When we designed STAIRWAY, we were looking at whether we can sustain visual acuity gains with every 12-week or every 16-week dosing compared to monthly ranibizumab. The STAIRWAY trial really showed the durability, where every 16-week and every 12-week dosing with faricimab was comparable, in terms of visual acuity as well as anatomy, to ranibizumab. That’s why we used that to design the phase 3 pivotal TENAYA and LUCERNE trials. The key thing about the trial design is that the patients receive faricimab. They receive 4 loading doses, and the reason that was done is that, based on prior data, we saw that patients continue to gain vision with faricimab with 4 loading doses. They receive 4 loading doses followed by disease activity at week 20 and week 24. Let’s say the patient gets treated, they’re in the faricimab group, these are all naïve patients that are in this trial. If they had disease activity at week 20, they were moved to the every 8-week treatment because they’re high-need patients. If they had disease activity at week 24, then they were put into the every 12-week treatment arm. But if they had no disease activity at week 24, they continued on and got into the every 16-week arm. One thing to keep in mind, there are no rescues in this trial. Patients, once they are in a swim lane, they stayed in the swim lane throughout the study. The other thing to keep in mind is the fact that the comparator here is different than in STAIRWAY. The comparator here actually is aflibercept, and the reason for that was, as I said, aflibercept is a better drying agent and the most utilized agent. Aflibercept was used for the label where patients receive 3-monthly dosing followed by every 2-month dosing based on the label. When I look at the data, this was a noninferiority trial design. Another thing to keep in mind—when you have good visual-acuity patients, like there were in TENAYA and LUCERNE, and it’s a noninferiority trial design that we are looking at—is whether patients have durability with faricimab, where faricimab patients are getting treated every 8 to up to 16 weeks. Can they do similar or better than aflibercept? Mean visual acuity was about 60 letters in TENAYA at baseline and about 58 to 59 in LUCERNE. I am mentioning that because we are used to seeing 9 to 11 letter gains in ANCHOR and MARINA and VIEW 1 and VIEW 2, but those patients were close to 50 to 55. The visual acuity gains that we’re getting here in TENAYA and LUCERNE are actually 5 to 7 letters, and that’s because patients are starting at better visual acuity. 

What was noticed was that these studies met the primary end point of noninferiority, where the patient is treated with faricimab up to 16 weeks, were comparable to patients treated with aflibercept. Then the other thing to look at is obviously the CST [central subfield thickness] or the drying effect of faricimab compared with aflibercept. It appears to me that there is a trend where patients treated with faricimab actually appear to have dry retina and less fluctuations compared with aflibercept. Again, the majority of these patients are not treated q8 weeks. In terms of durability, 45% of patients in LUCERNE and TENAYA went q16 weeks. That’s every 4 months of treatment. I think that is significant in terms of decreasing the treatment burden, and if you look at patients going 12 weeks or longer, almost 80% of patients went 12 weeks or longer in TENAYA and LUCERNE while maintaining their visual acuity, similar to aflibercept, while maintaining their CST, which were similar to aflibercept, and again, patients treated with aflibercept were treated every 8 weeks. Of course, it’s a newer agent. We have large clinical trial data from the phase 2 program, but safety is crucial. The good news is the safety was comparable in faricimab. Compared with aflibercept there were no cases of retinal vasculitis or retinal artery occlusion in this trial, which is really reassuring that we have an agent that is more durable compared with aflibercept but also has comparable safety.

An overview of key clinical trials that have explored the potential of faricimab as a treatment option for patients with wet age-related macular degeneration. 

Faricimab Data in Wet AMD 

 Looking at treatments in the pipeline, the most advanced program currently is faricimab, and luckily, we’ve been involved with faricimab since the early days when we participated in the initial trial. The faricimab program is really done well in terms of collecting and showing data. We recently had a readout of the phase 3 trials in both DME [diabetic macular edema] and neovascular AMD [age-related macular degeneration]. But before we talk about that, let’s talk about what faricimab is. Faricimab is a bispecific antibody. It’s the first bispecific antibody that is being utilized in ophthalmology to treat retinal diseases. It’s an intravitreal injection just like other injections we do. What it does is it blocks VEGF-A. It has two arms, since it’s a bispecific, and VEGF-A has been known to control disease. That’s what we do with ranibizumab, aflibercept, bevacizumab, and brolucizumab. It blocks VEGF-A, but another thing it does is block ANG2 [angiopoietin-2]. There has been a lot of preclinical work, as well as early clinical work, showing the benefit of blocking ANG2. ANG2 is a soluble ligand that gets up-regulated in retinal vascular diseases. 

If you look at patients with neovascular AMD, at patients with diabetic retinopathy, at patients with retinal vein occlusion, we have data showing that levels of ANG2 are elevated. In normal quiescent vessels, levels of ANG2 are low, but the levels of ANG1 are activated, the type II receptor is phosphorylated and active, and the vasculatures are stable. There is no leakage, there is no inflammation. The parasites are not lost. When ANG2 goes up, it leads to leakage, it leads to breakdown of the trijunction, it leads to parasite loss leading to inflammation, and fibrosis, based on the preclinical work. It’s exciting that we now have a single injection—basically 1 molecule with 2 targets—to address retinal vascular diseases.

The rationale for studying faricimab, a bispecific antibody that targets 2 distinct pathways, as a treatment option for patients with wet age-related macular degeneration. 

Arshad Khanani, MD, Sierra Eye Associates/University of Nevada Reno School of Medicine

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