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A headline year for retina disease drug development concurrently brought about research and discussion into the safety outcomes of these new agents.
Vigilance in therapeutic safety remains crucial in medicine, spanning from drug design and clinical trial outcomes to its continuing importance as a therapy enters real-world clinical application. This year, the significance of safety in medicine was particularly notable in the subspecialty of retina within the field of ophthalmology.
This is mostly in part to the fact that the retina treatment landscape experienced a striking growth in 2023, with new US Food and Drug Administration (FDA)-approved novel therapeutics defining the field’s year. In February 2023, the retina community experienced a watershed moment as pegcetacoplan injection (SYFVORE) from Apellis Pharmaceuticals became the first FDA-approved agent for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
“The first thing I would say is, this is the most important advance in retina care in over a decade,” Charles Wykoff, MD, PhD, the director of clinical research at Retina Consultants of Texas told HCPLive. “We, as retina specialists, to anyone that’s in eye care, deal extensively with patients with macular degeneration. The biggest unmet need in that category has been a treatment for geographic atrophy.”
But, concerning reports of retinal vasculitis related to pegcetacoplan injection would arise soon thereafter, putting a damper on some of this excitement. Retinal vasculitis, defined as a systemic inflammatory disorder characterized by inflammation of the retinal vessels, is a vision-threatening condition.
As early as April, cases of retinal vasculitis were reported in the real-world use of pegcetacoplan injection for GA and these reports continued to arise during the next 3 months. By October, there were 10 confirmed events of retinal vasculitis and 2 suspected events associated with pegcetacoplan injection. These findings sparked a debate on safety that grabbed the retina community’s attention, even as there remain many unknowns.
“I think one of the things that's critically important to us as clinicians who want to help our patients is that with new therapeutics, we are vigilant, and focused not only on efficacy, but on safety as well,” Veeral Sheth, MD, the director of clinical research at University Retina and Macula Associates, told HCPLive. “We’ve seen some cases of inflammation that have been reported with pegcetacoplan injection and I think it’s important to discuss because we're going to have to understand exactly what's happening and the scale at which it's happening.”
Geographic atrophy (GA), an advanced form of dry AMD, is a leading cause of blindness globally, affecting 5 million people worldwide, including ≥1 million people in the United States. Unlike the neovascular form of AMD, which has a robust pipeline of anti-vascular endothelial growth factor (VEGF) therapeutics, patients with GA have previously had no available treatments able to stop the progression of the disease.
Based on pivotal phase 3 data, the initial excitement for the approval of pegcetacoplan injection was substantial as patients with GA would finally have a treatment for the debilitating, progressively blinding disease.
A targeted C3 therapy, pegcetacoplan is designed to provide comprehensive control of the complement cascade, a part of the immune system linked to the onset and progression of various diseases. By inhibiting this pathway, pegcetacoplan may lower the inflammatory damage being done in the retinal pigment epithelial (RPE) cells and photoreceptors in eyes with GA.
Its FDA approval was based on the pivotal phase 3, multicenter, randomized, double-masked, sham-controlled OAKS and DERBY studies across a broad and heterogeneous population of patients with GA secondary to AMD. Across OAKS and DERBY, both every other month and monthly dosing of pegcetacoplan were shown to have meaningful reductions in GA lesion growth with increasing effects over time, with a strong safety profile, among ≥1200 patients with GA.
“These drugs can slow down the progression or the loss of cell death over time,” David Lally, MD, director of the retina research institute at New England Retina Consultants told HCPLive. “That’s important because now for the first time, physicians have tools in our tool belt that we can offer to patients that will have some interaction in the course of disease in that patient.”
By the end of July 2023, Apellis provided an update on 7 total cases of retinal vasculitis among eyes with GA treated with pegcetacoplan injection: 2 each in April and May and 3 in June. Of the 7 reported cases, 4 were reports of occlusive vasculitis.
The company evaluated and reviewed the pegcetacoplan manufacturing process and drug product, as well as the safety data in the phase 3 trials, at the time of first reports in April. They reported no changes in the formulation between clinical trials and commercial supply and found no indication the drug product manufacturing or clinical profile was associated with the risk of retinal vasculitis. Study investigators and independent reviewers of the phase 3 trials also identified zero events of retinal vasculitis in the data.
It seemed the gathering of retina specialists at the American Society of Retina Specialists (ASRS) 41st Annual Meeting became the perfect forum for discussion of these new safety reports. At ASRS 2023, some stressed the familiarity of pegcetacoplan among investigators, given the more than 23,000 intravitreal injections administered across the clinical trial program, including OAKS and DERBY and GALE.
“With any new molecules that come forward, of course, we’re looking for these very rare events,” Nathan Steinle, MD, California Retina Consultants, told HCPLive. “The overall calculated incidence or vasculitis up to this point is in the order of 1 in 10,000 pegcetacoplan injections, making it exceedingly rare.”
At the time, Steinle presented new data from the GALE extension trial at ASRS 2023. According to the data, pegcetacoplan injection reduced nonsubfoveal GA lesion growth by up to 45% between months 24 to 30, compared to the projected sham arm. Given the safety reports announced that weekend, other clinicians expressed caution on administering the pegcetacoplan injections to patients, particularly those with bilateral GA.
“I think it’s important to know that there is a risk and to be aware of retinal vasculitis or occlusive vasculitis when using pegcetacoplan injection,” Dilsher Dhoot, MD, California Retina Consultants, told HCPLive. “I’m cautious, I’m not doing bilateral injections from the start. I believe there are efficacy benefits for this drug, which can help patients, but it requires a frank discussion.”
A few weeks later, in August 2023, Apellis shared an update on injection kits and events of retinal vasculitis associated with pegcetacoplan injection. Their investigations identified internal structural variations in the 19-gauge filter needle in certain injection kits—as a result, the company recommended the use of kits with the 18-gauge filter needle.
However, Apellis was unable to establish a causal relationship between the structural variations in the 19–gauge filter needle and the rare event of retinal vasculitis in real-world treatment. Another confirmed event of retinal vasculitis occurred in June 2023, bringing the total to 8 confirmed events of retinal vasculitis: 5 occlusive events and 3 non-occlusive events.
Apellis indicated that more than 100,000 vials have been distributed for commercial use and clinical trials, while the events of retinal vasculitis remained very rare at an estimated real-world rate of 0.01% per injection.
A landmark moment in retina in August 2023 was the approval of a second complement inhibitor, avacincaptad pegol (IZERVAY), for the treatment of GA secondary to AMD. Avacincaptad pegol targets the complement 5 (C5) pathway, as opposed to the C3 pathway with pegcetacoplan injection. Based on the pivotal GATHER2 trial, avacincaptad pegol showed a mean 17.7% reduction in GA area growth over 12 months, with no events of endophthalmitis, intraocular inflammation, or ischemic optic neuropathy in the study data.
By October 2023, there were 10 confirmed events of retinal vasculitis: 7 occlusive and 3 non-occlusive events. Since the previous update, Apellis identified 1 new confirmed event that occurred in early August and 2 new suspected events from August and September. Among 2 previously suspected cases, the company confirmed 1 event while the other was determined to not be retinal vasculitis.
Among the confirmed vasculitis events, 6 patients recovered full or partial vision, while 3 patients experienced severe vision impairment unlikely to be resolved, and 1 outcome was still pending. Vision in both suspected events was pending at the time of release. All suspected events were independently evaluated and adjudicated by 2 external sources, including 4 retina/uveitis experts and an independent reading center.
“Right now, like with any new treatment, we are still in that phase where we are trying to understand what’s happening, so we know how we are going to use these treatments,” Sheth said. “And how we are going to counsel our patients, and if we do see a case like this, determine what to do.”
At the 127th Annual American Academy of Ophthalmology (AAO) Meeting in San Francisco, updated data from the GALE extension trial continued to show increasing treatment effects over time with pegcetacoplan injection. At year 3, pegcetacoplan injection reduced GA lesion growth with monthly (35%) and every-other-month (24%; both P <.0001) treatment compared with sham.
Reports from GALE also indicated the consistent safety profile of pegcetacoplan injection in year 3, consistent with previously reported data. In the first year of GALE, reports of new-onset wet AMD were 7.1% in the monthly arm and 2.3% in the every-other-month arm. A single event of ischemic optic neuropathy was reported in the monthly arm between months 24 to 30 and a single case of endophthalmitis was reported between months 30 to 36.
Rates of IOI were 0.26% per injection from months 0 to 36, not including 4 cases linked to impurities identified in 2018. Overall, Apellis identified zero events of retinal vasculitis in the pegcetacoplan clinical trial program, following ≥24,000 injections administered to date.
“In the real world, I am using pegcetacoplan and I am a believer in anti-complement therapy. I think it's a conversation to be had with each patient, what the risk-benefit ratio looks like,” Wykoff said. “I think those are the conversations that clinicians are having across the country and some patients are interested in engaging with this therapy, knowing they're not going to see better, but that you're going to slow the progression of the disease.”
However, there remain lingering concerns across the retina community that may not be resolved anytime soon. Physicians, much like their patients, are questioning the therapeutic benefit in relation to the observed safety signals and how to use the therapy in clinical practice.
“It’s the same finding I would say with physicians. Some see it as a move forward for the field and are engaged and think it is a useful add,” Wykoff said. “Other clinicians are most hesitant, largely driven by these many nuanced safety discussions. It’s a field that continues to evolve.”
But, keeping in mind the ongoing transformation in the field, many retina specialists have indicated their desire to put their heads together to evaluate the data, and determine the best path forward, while prioritizing the safety of their patients above all else. As more safety data continues to be collected and analyzed, it is clear that retina specialists are working overtime, together, to help patients retain and restore vision in a safe manner.
“We’re going to learn a lot about efficacy and we’re going to learn a lot about safety,” Sheth said“Clinicians banding together and coming up with these data points is crucial for us to educate each other as a field.”
And if this therapy represents a pathway to a more promising future for individuals with retinal conditions and preserving a portion of their vision for the rest of their lifetime, then retina specialists may offer renewed optimism for a life unhindered by limitations.
“We look at these therapies as an opportunity to afford patients more time with the vision today, than what they would have had without this treatment,” Lally said. “If the patients live long enough, over time, their disease will significantly progress. The treatments don’t stop the inevitable. But, permitting that patient to have more time, more hope, in keeping vision, offers that benefit to the patient.”