Fighting for Sight: Geographic Atrophy Drug Development Meets Its Future

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After decades of unmet needs in the progressive form of vision loss, the complement inhibitor drug class is nearing the market for affected patients.

The long and winding road in drug development may span generations and lead down many avenues before a promised treatment is available to the public. By regulatory standards, the timeline may often be accelerated, but for the patients, the debilitating effects can be far-reaching.

For patients with geographic atrophy (GA), fulfilling an unmet need is slowly becoming a reality with the advent of treatments for the advanced form of dry age-related macular degeneration (AMD). This past year was host to landmark trials and important conversations, as new agents that have the ability to slow the progression of the GA growth neared closer to regulatory approval.

Experts in ophthalmology have hosted discussions on 2 new agents: avacincaptad pegol (Zimura) and pegcetacoplan. Each agent works to slow the growth of GA, but neither are currently approved by the US Food and Drug Administration (FDA).

“Clearly, everyone's focus is around geographic atrophy and everyone's hitting it from multiple different angles,” said Rishi Singh, MD, President, Martin Health, Cleveland Clinic Florida. “Some are providing subretinal delivery, some are providing it as intravitreal delivery, some are even considering a suprachoroidal approach to this. They’re just all focused on this and I think this is the year for really geographic atrophy hopefully being arrested or reduced through some of these therapies over time.”

New data on both agents were shared at conferences including the 2022 American Society for Retina Specialists (ASRS) Meeting in New York City and the American Academy of Ophthalmology (AAO) 2022 Meeting in Chicago, with interviews from investigators and clinicians dictating the significance and the awe of these new findings.

“I think probably the most meaningful to me is just the incredible amount of research looking at therapies for geographic atrophy,” Charles C. Wykoff, MD, PhD, Director of Clinical Research, Retina Consultants of Texas, said in an interview at AAO 2022. “There’s nothing approved in this space. There are 2 drugs now that have positive phase 3 data and so hopeful that we might have a commercially available agent over the coming months.”

For years, the lack of available agents for GA treatment has led to a significant burden of disease progression among older Americans with AMD, the most common cause of vision loss in the country. Much like the pivotal introduction of anti-vascular endothelial growth factor (VEGF) agents nearly 2 decades ago, the hope is that these agents will be game changers for patients and become more efficacious over time.

Avacincaptad Pegol

The complement inhibitor drug class may be a step closer to achieving this concept, with avacincaptad pegol being exemplary of its potential. The novel investigational complement C5 inhibitor is the first and only therapy to be granted Breakthrough Therapy designation for this indication. The designation from the FDA was based on 12-month pre-specified primary endpoint data in the GATHER clinical trial program, with 2 datasets supporting its use.

The FDA required the mean rate of growth (slope) in GA area from baseline to month 12, with the GATHER1 trial reported a significant treatment difference of 35% and the GATHER2 trial reporting 18%, compared to sham using observed data. Based on these results, the company’s statement highlighted the potential of the agent to safely and effectively preserve central vision in patients with GA.

The Director of Clinical Research at Sierra Eye Associates, Arshad Khanani, MD, presented the efficacy data at AAO 2022. Khanani reiterated that a treatment for GA is the biggest unmet need. Patients in his clinic that he has been following for a long time began with small lesions far from the center and over time, have grown and now have central involvement. These patients who once were functional and had perfect vision are now legally blind in both eyes.

“I think it’s a breakthrough in terms of having any treatment for this devastating disease that progresses in 100% of the patients 100% of the time and takes their independence away,” he told HCPLive. “What we have learned from the trial is to initiate treatment early so we can slow down this disease and so patients can have more functional vision for a longer time or they’re able to drive and read and take care of themselves.”

David Lally, MD, ophthalmologist and investigator with New England Retina Consultants, reiterated the critical findings of the GATHER trials and described that shift for both physicians and patients impacted by the reach of the disease.

“This is the first time that we’ve ever had 2 pivotal studies of which both show statistical significance in the effect of the therapy at reducing lesion sizes,” he told HCPLive. “We’re excited and thrilled to have hopefully the first tool in the belt to impact this disease.”

He additionally defined the progression of GA wherein lesions enlarge and progression central vision loss occurs over time. Common variants of GA development were found in the complement system in genome-wide association studies, he noted. The agent blocks and binds C5 and in doing so, prevents propagation of the central pathway, hopefully reducing cell death and preserving renal tissue over time.


The other agent of note may be closer to the finish line as 2022 nears its end. Intravitreal pegcetacoplan for the treatment of GA was initially granted Priority Review designation, with a Prescription Drug User Fee Act (PDUFA) of November 26, 2022.

The investigational, targeted C3 therapy was designed to regulate excessive activation of the complement cascade which can lead to the onset and the progression of many serious diseases.

By mid-November, the FDA accepted an unsolicited major amendment from Apellis and updated the PDUFA goal date to February, 26 2023, with no plans to hold an advisory committee meeting to discuss the application.

In part, the delay was due to the positive findings in efficacy of the 24-month phase 3 DERBY and OAKS trials, which the company believed would provide the best product profile at launch and minimal impact to launch timing. A pre-specified analysis of GA growth over 24 months showed monthly and every-other-month pegcetacoplan showed a clinically meaningful reduction in GA lesion growth from baseline, compared to sham.

DERBY reported a 19% monthly reduction (P = .0004) and 16% every-other-month (P = .0030) reduction and OAKS reported a 22% monthly reduction (P <.0001) and 18% every-other-month reduction (P = .0002).

“When you look at the treatment benefit of this medication, I think it’s real, I think it’s clinically meaningful,” Wykoff said. “But, it’s not in the percentage that we like, right? We’d love to be talking about a 90% reduction, we’d love to be talking about reversing GA growth and bringing vision back. That’s not what this medicine does, this medicine meaningfully decreases the rate of growth.”

He noted that the story may be more complicated that it seems, particularly when explaining to patients the goals of the therapy. Wykoff said the key point to communicate is that it is probably going to be a lifelong therapy for most and it is crucial to understand that before patients begin to get the maximum benefit.

“You're looking at a paradigm shift here where there's going to be consistent dosing,” he said. “With the anti-VEGF injections that we're so used to using, we've learned to individualize the therapy based on anatomic outcomes. It looks like with this medication, if and when it's available, there'll be more consistent dosing long term every month or every other month, not an insignificant treatment paradigm for patients. But one that I think these patients are many of them are going to welcome in a space where there's nothing currently available.”

As for whether these treatment advances like pegcetacoplan will define the year when looking back, David Boyer, MD, Senior Partner, Retina Vitreous Associates Medical Group, is unsure whether this will be remembered as a “wowee” moment. But, he adds, it is just getting started and may ultimately be a step in the right direction to restore vision for these patients.

“Hopefully we’ll end up treating earlier and potentially reducing overall formation to geographic atrophy and further visual loss,” he said. “I think it’s not a wowee moment, it’s a step. A wowee moment is when a patient comes in and they’re not seeing and suddenly they’re seeing or a patient comes in and thanks me for doing the treatment, like when we first got anti-VEGF agents. But, I think it's going to be a step in the right direction.”