Recently approved Izervay offers new treatment for patients with geographic atrophy

Arshad M. Khanani, MD, MA, FASRS, talked with Marlisa Miller, editorial intern for Optometry Times®, to discuss the recent FDA approval of avacincaptad pegol intravitreal solution (Izervay) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Avacincaptad pegol intravitreal solution (Izervay) is a new complement C5 inhibitor and is the only approved GA treatment with a statistically significant reduction (p < 0.01) in the rate of GA progression at the 12-month primary endpoint across two phase 3 clinical trials.

Related: Iveric Bio receives FDA approval for avacincaptad pegol intravitreal solution for treatment of geographic atrophy

Video transcript

Editor's note: This transcript has been edited for clarity.

Marlisa Miller, editorial intern:
Hello, everyone. I'm Marlisa Miller with Optometry Times and I'm sitting down with Dr Arshad Khanani to talk about the recent FDA approval of acacincaptad pegol, also known as IZERVAY, used to treat geographic atrophy. Welcome Dr Khanani, it's great to have you here.

Arshad M. Khanani, MD, MA, FASRS:
It's a pleasure to be here.

Miller:
First, can you tell me a little bit about IZERVAY?

Khanani:
Absolutely. So avacincaptad pegol, ACP, or IZERVAY, is a complement C5 inhibitor. We know that patients who have geographic atrophy have hyperactive complement system, which leads to cell death, and progression of geographic atrophy. So IZERVAY blockS C5, which is the downstream target in the complement system. What the trials have shown is that in the GATHER-1 and GATHER-2 trials, which were pivotal Phase 3 trials, IZERVAY was able to slow down the progression of geographic atrophy in patients with GA.

Miller:
Great. Can you tell me a little bit more about the GATHER-1 and GATHER-2 clinical trials?

Khanani:
Absolutely. So GATHER-1 was a Phase 2/3 clinical trial that looked at different doses of IZERVAY and compared [it] to Sham injection. It was a randomized double-masked study. It met the primary endpoint where the slowdown of GA in patients treated with IZERVAY was significant compared to patients who are treated with Sham. We saw an effect that actually was obvious early in the treatment course, and it increased over time. The primary endpoint was at 12 months, and the trial met statistically significant P value. We also just recently published the extension data from 12 to 18 months and we actually saw continuous benefit of patients who are treated with IZERVAY. This was followed by a large global double-masked randomized GATHER-2 study. In that study, patients were treated with 2 milligrams of IZERVAY. That was the dose that was found to be optimal in terms of efficacy and safety in GATHER-1. Here, patients were randomized to either receive IZERVAY, 2 milligrams, or sham injections every month. The primary endpoint was, again, at 12 months looking at reduction in the GA progression or growth rate in the treated arm compared to sham. Again, this trial met the primary endpoint.

So, IZERVAY is the first molecule in our space that actually met statistically significant primary endpoint in both pivotal Phase 3 trials. Of course, you have a new agent [and] you need to make sure that it's safe. The good news is that in GATHER-1 and GATHER-2, there was really no clinically significant inflammation that was seen. There was only 1 case of asymptomatic vitreous cells in GATHER-1 that actually resolved without treatment. We didn't see any retinal vasculitis in the occlusive retinal vasculitis. We did see that because it's a 100 microliters injection, there was a small percent of patients, around 9%, that had a transient increase in intraocular pressure. Looking at onset of neovascular AMD, what we have seen is that in multiple complement inhibitor trials, we have seen [an] increased rate of neovascular wet AMD. In patients who are treated with complement inhibitors, we're still trying to understand why it happens. It could be a response from the body to slow down GA, but we still don't know. We saw [a] 7% rate of neovascular AMD in patients with today's survey, compared to 4% in the sham group survey. [It's} a slight increase, but obviously, we have good treatment options available to treat neovascular AMD. The GATHER-1 and GATHER-2 data set is very powerful in terms of efficacy as well as safety, and that's why it led to the approval of IZERVAY by the FDA.

Miller:
Great. So, is IZERVAY a good fit for all patients with GA? Or, are there a specific set of requirements patients have to meet to be able to have this treatment available to them?

Khanani:
That's an excellent question. So of course, in the clinical trials, the population that was studied was non-foveal-involving GA patients as long as the center point of the fovea was not involved. So there were some inclusion and exclusion criteria, which are pretty standard for GA trials except in this trial, central involvement was not included. Obviously, the reason for that was the fact that we're looking for the benefit for patients who don't have central involvement so that we can show that slowing down GA may end up with functional benefit. So actually in GATHER-1 and GATHER-2, if you look at the vision loss analysis, we saw [a] 56% reduction in catastrophic vision loss, which was persistent, defined as 50 letter or more vision loss of 2 consecutive visits. There was a significant reduction in patients treated with IZERVAY. So yes, the trial population was non-foveal, but the label actually allows us to treat any patient. I think as physicians, when a new treatment comes out it's exciting for patients who have been suffering with this geographic atrophy for a long time. It's a disease that can be very devastating [and] leads to irreversible vision loss. So I think we have to offer the treatment to all patients with GA. I think looking at risk, benefit, and treatment burden, we decided the patients want to proceed with it. At this stage, the label is very, very inclusive for all kinds of GA because we know that if it's going to help patients with non-foveal GA, it's going to help patients with central GA also, it's just that for trials, we picked that patient population of non-foveal-involving.

Miller:
So, although optometrists cannot administer this injection, they are still the first line of defense for patients with geographic atrophy. What are some early signs and symptoms optometrists should look out for with GA?

Khanani:
Well, I think that optometrists will be the physicians that actually help these patients get treatment. Since the efficacy of these drugs is best when you treat early, time matters in terms of slowing down GA because once you involve the center, the damage is done, the tissue is gone, and it's irreversible damage. Optometrists will play a key role in diagnosing these patients, and in referring these patients to the retinal specialists. Our optometry colleagues are excellent at looking at the back of the eye. They have the imaging tools, they have the color photos, the OCT, the infrared, and what they need to do is look for GA. Many of these patients with non-central GA may not have symptoms. They may have 2020 vision, but they may have complaints of not being able to read a line, they're missing spots or other functional deficits. They may need to ask the questions because just the Snellen visual acuity may not be impacted. Optometrist will play a key role, and now we have a safe, effective agent to treat this condition. I think co-managing is very important for the optometry community. Also, many of these patients have long standing relationships with the optometrist and they trust their judgment. So when we commit them to injections frequently, [or] monthly, to slow down this disease, they may go back to the optometrist to say if they should actually commit to this. I think education of our optometry colleagues as well as counseling of the patients by the optometrist will be a key role in actually getting this treatment to as many patients with GA as we can.

Miller:
Great, how do you anticipate this approval of IZERVAY will change the treatment paradigm for patients with GA.

Khanani:
This is a big breakthrough in that sense that this is the second medicine that got approved for geographic atrophy. We have another medicine called SYFOVRE that was approved earlier in the year. But lately, we have heard of some safety events, and that's why the uptake has been limited for many physicians who are using it or not using it, just like myself. Having a new agent that has shown good efficacy and excellent safety profile in the trial is very important for our field. It's super important for patients with geographic atrophy, because I have many patients who receive 1 or 2 doses of SYFOVRE and they didn't want to proceed because of the small risk of irreversible vision loss due to occlusive retinal vasculitis after the American Society of Retina Specialists sent the release out. I think those patients were committed to treatment and having a new treatment is beneficial. Obviously, we have to be super vigilant with any new treatment. We need to make sure we look for any safety signals that can come out in the real world when these treatments go to a large number of patients. But, looking at the safety profile that we have seen in the GATHER-1 and GATHER-2 studies, it appears that IZERVAY is very safe in terms of risk of intraocular inflammation, but [a] large number of patients will be needed to prove that. I think my uptake will be very fast because I've served as an investigator in the GATHER-1 and GATHER-2 studies and I've not seen any adverse events of intraocular inflammation in any of my patients. I actually had patients who are waiting for their fellow eye [be] part of the trial and the open label extension of GATHER-2 be because they were so happy in terms of tolerating the treatment. The bottom line is, I think the uptake will be there. Obviously, there will be some physicians who will be cautious. Physicians who didn't use SYFOVRE and heard about all these events may not want to try a new medicine right away. It usually takes about 3 to 6 months for the community to get comfortable with the safety of a new agent. Then, the uptake even goes higher. But physicians were using SYFOVRE and physicians who were part of the GATHER study, I think they'll be comfortable using IZERVAY as soon as it's available.

Miller:
Do you have anything else you'd like to mention about this approval?

Khanani:
Absolutely. Having a disease like GA, where I had patients who went from 2020 vision in a decade, to legally blind in both eyes, lost their independence, cannot drive, [and] they cannot take care of themselves. It's a devastating disease. As a field, we've been trying really hard to come up with treatments for GA and it's a very high bar to, number 1 meet the primary endpoint in 2 trials. Number 2, have efficacy and safety that can lead to FDA approval. This is actually a very huge moment for all eye care providers, optometrists, ophthalmologists, and retina specialists, because having a treatment that can be efficacious and safe for a disease like GA, will make a difference in our patients lives. I think they will be able to keep their independence longer if we start treating these patients early. The main thing is to have collaboration between all the eye care specialists so that we can give our patients the treatment they need so they can keep their independence longer.

Miller:
Great. Well, thank you so much for taking the time to chat today, Dr. Kahani, and I cannot wait to hear more on IZERVAY.

Khanani:
It's a pleasure to be here. Thank you.