Geographic atrophy treatment options ignite debate on concerns, expectations
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The FDA approval of Izervay has provided a second welcomed treatment option for geographic atrophy, with good efficacy and a favorable safety profile.
“It’s great news for our field as well as patients suffering from geographic atrophy,” Healio | OSN Retina/Vitreous Board Member Arshad M. Khanani, MD, MA, FASRS, said. “Geographic atrophy is a progressive, devastating disease that causes decline in vision and a loss of autonomy for numerous patients over time. It’s disheartening to witness some of my patients who had perfect vision a decade ago now facing legal blindness due to geographic atrophy.”
Source: Sabrina Merrill
Approval of Izervay (avacincaptad pegol, Iveric Bio) was based on the results of the GATHER1 and GATHER2 trials showing reduction in the mean rate of geographic atrophy (GA) growth at 1 year by 35% and 18%, respectively. Post hoc analysis of the pooled data from the two studies signaled a 56% reduction in the rate of vision loss, quantified as 15 or more EDRS letters, as compared with sham.
“In both GATHER1 and GATHER2 studies, we have seen an early response to treatment with continuous separation of the curves between treated and sham groups over time. This gives us confidence that treatment with Izervay will benefit our patients in the long term. In the clinical trials, Izervay was well tolerated, but we need to generate real-world data for Izervay to confirm its safety in a large number of patients,” Khanani said.
Potentially safer, waiting for more data
Avacincaptad pegol is a synthetic pegylated RNA aptamer designed to inhibit complement C5.
“It is thought that inhibiting C5, which is more distal in the complement pathway, may be a better option because it preserves the anti-inflammatory effects of C3,” Jaclyn L. Kovach, MD, said.
The reports of rare inflammatory adverse events following the administration of Syfovre (pegcetacoplan injection, Apellis Pharmaceuticals) in the real world created concern in the retina community and sparked discussion on whether Izervay may be a potentially safer alternative.
“We will only know this when both of these drugs have been used in the real world for a considerable amount of time. And of course, these drugs would need to be compared head to head in clinical trials to know for sure,” Kovach said.
“The Izervay clinical trial results are promising, without safety reports at 1 year. However, Syfovre did not have these severe cases of retinal vasculitis in the clinical trials either,” Lejla Vajzovic, MD, said.
Patients should continue to be monitored, and real-world evidence needs to be collected before drawing conclusions.
“I am excited about the safety and efficacy results of Izervay in GATHER1 and GATHER2 at year 1, I’ll be even more excited to see those at year 2, and I’ll definitely be happy to use it in post-approval. But I think with any new drug, we need to be cautious, inform our patients and monitor them carefully,” she said.
Syfovre adverse events
So far, there are 10 confirmed events of retinal vasculitis with Syfovre, seven occlusive and three nonocclusive, according to the latest report by Apellis, out of more than 100,000 vials distributed since launch and 24,000 clinical trial injections. All reported events were observed between 8 and 18 days after the first injection.
Apellis is working closely with the American Society of Retina Specialists and ASRS Research and Safety in Therapeutics Committee to monitor these patients, review potential other cases and keep the ophthalmology community updated. Structural defects in the 19-gauge filter needle previously provided in certain injection kits were identified by the company as potentially correlated with these adverse events. New kits with an 18-gauge filter needle were distributed, and Apellis recommended that physicians discontinue use of the previous kits.
“All of our kits were replaced with the new kits that have the recommended needle,” Vajzovic said.
Different attitudes
Safety concerns have challenged the initial optimism among retina specialists, but attitudes are diverse. Kovach treated several patients with Syfovre but temporarily paused using the medication after she heard of the adverse events.
“As the weeks go by and there are no additional cases, I will resume administering this drug to patients, switching to the 18-gauge needle,” she said.
Vajzovic has stopped using the drug in new patients but continues to use it in those who already received a few injections, monitoring them closely.
“The clear understanding from the report was that this is something that has happened after first and second injection. So, for those who have had prior injections, I feel more comfortable continuing to treat them. But definitely I am examining these patients routinely to make sure that we are not missing any signs of inflammation,” she said.
Khanani stopped using Syfovre after the safety events of occlusive retinal vasculitis were reported by ASRS and has made a switch to Izervay, which he considers superior in terms of safety based on the clinical trial data. Khanani said that it is important to generate real-world efficacy and safety data for any new drug that comes to the market.
“If you look at Syfovre prescribing information, there is a 4% rate of intraocular inflammation in the monthly treated group and 2% in the every other month group. There is also a risk of ischemic optic neuropathy reported in 1.7% of patients treated monthly and 0.2% of patients treated every other month. If you look at the prescribing information for Izervay, there is no mention of intraocular inflammation or ischemic optic neuropathy,” he said. “Even though clinical trial data from the GATHER program gives us confidence that Izervay is safe in a clinical trial setting, we still need real-world data to establish the safety of Izervay in a large number of patients treated outside the clinical trial setting. We are launching a study to look at real-world efficacy and safety of both Syfovre and Izervay.”
Nathan C. Steinle, MD, still feels confident using Syfovre. No case of retinal vasculitis was seen following the 24,000 injections performed in trials, and the event rate for severe inflammatory reactions in the real world has been rare. The event rate of retinal vasculitis so far has been approximately 0.01%, one out of 10,000 injections.
“The rate of patients actually losing vision with these events is even more rare than the one in 10,000,” he said.
Of the 10 confirmed cases, six had partial or full recovery, three had severe visual impairment unlikely to recover, and one outcome is still pending.
“Rare things happen rarely. We will learn more over time, but I am still certainly comfortable using the drug and continue to use it on a daily basis,” Steinle said.
Divergent points of view
Steinle said that, at this point in time, pegcetacoplan can rely on more trial data, as well as real-world data, as compared with avacincaptad pegol.
GATHER1 and GATHER2 were about one-third the size of OAKS and DERBY, with a total of 292 patients vs. 839 patients receiving the active treatment. GATHER1 and GATHER2 only included patients with non-foveal involvement, while most patients in the OAKS and DERBY trials had foveal-involving lesions. In addition, Izervay has data only up to 12 months, while 30-month data are available for Syfovre. The GALE 3-year extension trial is currently ongoing with the patients who have completed the OAKS and DERBY trials (83%), all of them receiving the active treatment monthly or every other month.
“The 30-month data release at the ASRS meeting showed exactly what we had hoped for, that this drug continues to work, and it continues to work at an increasing rate over time, even better at month 24 to 30 than it did in the previous checkpoints,” Steinle said.
Increased efficacy over time was shown for both extrafoveal and subfoveal lesions, with an impressive 45% reduction in GA progression for extrafoveal lesions in the 24- to 30-month time period. No cases of endophthalmitis and no change to the safety profile were reported in the first 6 months of GALE.
Khanani expressed a different point of view, pointing out that the outcomes in the GATHER program were more consistent as compared with the OAKS and DERBY trials.
“Izervay is the first molecule in a geographic atrophy clinical trial program that met the primary prespecified endpoint at month 12 in two phase 3 trials, ultimately leading to its approval based on 1 year of data. In contrast, Syfovre met the primary endpoint in the OAKS trial but not in the DERBY trial, and its approval was granted after the analysis of 24-month data,” he said.
He restated the difference in the intraocular inflammation event rate, showing that C5 could be a better and safer target.
“Blocking the complement downstream may be beneficial to keep the upstream benefits of the complement system. This is just a hypothesis, and the precise cause of Syfovre-related events remains unknown. However, I don’t attribute it to the needle itself as we regularly employ 19-gauge needles for all other medications in our clinic, and these events persist with Syfovre even after discontinuing the use of 19-gauge needles,” Khanani said.
One additional advantage of Izervay, in his opinion, is that it is easier to draw and inject because it is less viscous than Syfovre.
“Both of these injections are administered in a volume of 100 µL, but Syfovre is notably viscous, requiring longer time to draw into the syringe, whereas drawing Izervay is comparable to the process with the anti-VEGF drugs we commonly use in our clinical practice. Having prefilled syringes available for both of these medications would be highly advantageous,” he said.
Challenges ahead
Patients receiving treatment for GA should be made aware of potential complications and educated to seek help as soon as possible if they notice any pain, decrease in vision or redness in their eye that could be signs of inflammation, according to Kovach.
“Treating inflammation as early as possible will certainly improve the chances of a favorable prognosis,” she said.
They should also be made aware of the frequency and long duration of treatment, which may last for the rest of their life. However, patients who previously had no hope and were expected to go blind are eager to embrace this opportunity.
“Lots of them are very excited to have for the first time ever treatment options. We are also thrilled, as a community, no question about it, although it is definitely a challenge on multiple levels,” Vajzovic said.
The burden of monthly injections, from both the patient and clinician perspective, has already been experienced in wet age-related macular degeneration, as well as diabetic macular edema and diabetic retinopathy.
“And this is a very prominent disease involving millions of patients, not just in the U.S. but internationally,” she said.
“We will need to streamline our clinical workflow to be able to treat all of these patients, and we will need additional resources. Different practices will benefit from different strategies. We will have to get creative from a clinical operations perspective,” Kovach said.
Injection-only clinics with nursing staff administering the treatment could potentially be a solution but not for the entire course of treatment. Because both pegcetacoplan and avacincaptad pegol showed a higher rate of conversion to neovascular AMD compared with sham, regular monitoring will be needed, according to Steinle.
“You might have one or two appointments per year in injection-only clinics, but OCT imaging will be needed the rest of the time,” he said.
“Almost all insurances cover these approved drugs, as geographic atrophy progresses in all patients leading to vision loss overtime,” Khanani said.
“It’s worth noting that while the cost of treating geographic atrophy to the health care system is substantial, it’s crucial to recognize that maintaining vision can lead to substantial savings in indirect expenses related to falls and disability,” he said.
Treating both GA and wet AMD
Because GA and wet AMD can occur simultaneously in the same eye, simultaneous treatment for both conditions may be required. In addition, both pharmacotherapies for GA were associated with increased rates of wet AMD, 12% with monthly Syfovre at 2 years and 7% with monthly Izervay at 1 year or Syfovre every other month at 2 years.
While the presence of wet AMD in either eye was one of the exclusion criteria for the avacincaptad pegol phase 3 trials, the pegcetacoplan trials admitted patients with wet AMD in the fellow eye.
“In addition, if the treated eye converted to wet AMD, patients were kept in the trial and were treated for both conditions on the same day, anti-VEGF first and pegcetacoplan at least 30 minutes later, provided that IOP was 21 mm Hg or lower,” Steinle said.
In everyday practice, it may be difficult to replicate this schedule from a patient flow and patient volume standpoint but also from a payment standpoint because insurance does not cover both drugs in one eye on the same day.
“We have been staggering injections instead. The patient will receive anti-VEGF 1 month and come back for pegcetacoplan the following month,” Steinle said.
For patients who have wet AMD in one eye and GA in the other eye, the injections are performed on the same day in his clinic.
“We have found that it is easy for patients to accept that concept. When they are already coming in for the wet AMD injections, they are happy to have the fellow eye treated on the same day,” he said.
Kovach is also treating the two conditions on separate days.
“I have been doing two separate visits, which adds to our clinic burden. That emphasizes the need for better workflow streamlining strategies,” she said.
“That is a definite challenge,” Vajzovic said. “We have a large number of patients who are doing really well with their wet AMD treatment but eventually develop geographic atrophy and start losing vision. We all are excited to offer those patients additional treatment options, but this comes with additional treatment burden.”
She attempted to treat these patients on the same day with both injections but switched to separate appointments because of insurance coverage.
“A monthly injection is burdensome, two injections on a monthly basis are even more burdensome, and we need to figure out better and more creative strategies,” she said.
“If we can be assured that both drugs are eligible for reimbursement when administered on the same day, it would have advantages for clinical capacity and reduce the burden on patients. This would potentially allow us to administer both drugs in a single session,” Khanani said.
Future developments
With the available medications, GA treatment is likely to remain a fixed-dosing regimen because there is no way of determining from visit to visit how the eye is responding to the treatment. Longer-lasting therapeutic options are the next goal.
“It would be advantageous if we could incorporate approved drugs into a sustained-delivery platform, such as an implant with a multi-month duration,” Khanani said. “And when we consider gene therapy, the prospect of a single treatment enabling the eye to continuously produce the required protein would carry significant clinical importance.”
“I think that complement inhibition will continue to be the future, whether it be through gene therapy, a reservoir implant or some type of change of the molecule itself that has a longer half-life in the eye,” Steinle said.
What is available now is a first big step, which will lead to more research and a better understanding of GA. Advances in therapeutic solutions will follow, Vajzovic said.
“The most exciting front is gene therapy, to have an ocular biofactory of a protein that permanently inhibits specific components of the complement pathway. It might be a one-and-done approach for these patients,” she said.
Currently, the eyes that are eligible for treatment are those in which GA is encroaching on the fovea. By slowing down progression, therapy helps to preserve central vision. Earlier or later stages of the disease are not an indication.
“What we all want is a treatment that targets earlier disease, intermediate dry AMD, to try to halt the disease or slow the progression, so that patients don’t experience vision loss,” Kovach said. “And prevention, of course. There are many drugs currently in the clinical trial pipeline. Hopefully they will offer significant steps forward in our efforts to combat this potentially debilitating disease.”
- References:
- Apellis announces preliminary U.S. net revenues of approximately $74 million for Syfovre (pegcetacoplan injection) in the third quarter of 2023. https://investors.apellis.com/news-releases/news-release-details/apellis-announces-preliminary-us-net-revenues-approximately-74. Published Oct. 5, 2023. Accessed Oct. 9, 2023.
- Apellis provides update on review of rare safety events with Syfovre (pegcetacoplan injection) for geographic atrophy. https://investors.apellis.com/news-releases/news-release-details/apellis-provides-update-review-rare-safety-events-syfovrer. Published July 29, 2023. Accessed Oct. 10, 2023.
- Apellis provides updates on injection kits and rare safety events with Syfovre (pegcetacoplan injection). https://investors.apellis.com/news-releases/news-release-details/apellis-provides-updates-injection-kits-and-rare-safety-events. Published Aug. 22, 2023. Accessed Oct. 10, 2023.
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- For more information:
- Arshad M. Khanani, MD, MA, FASRS, of Sierra Eye Associates in Reno, Nevada, can be reached at arshad.khanani@gmail.com.
- Jaclyn L. Kovach, MD, of Bascom Palmer Eye Institute in Naples, Florida, can be reached at jkovach@med.miami.edu.
- Nathan C. Steinle, MD, of California Retina Consultants, can be reached at nathancsteinle@gmail.com.
- Lejla Vajzovic, MD, of Duke University School of Medicine, can be reached at lejla.vajzovic@gmail.com.
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