Syfovre in clinical practice: Entering the new era of geographic atrophy management
The approval of Syfovre, the first and so far only treatment for geographic atrophy, is a landmark transition in the retina space, comparable to the introduction of anti-VEGF therapies for wet age-related macular degeneration.
“It is a landmark for patients, who historically had nothing, and it is also very meaningful for the field broadly because of all of the failed trials over the last decade. With the approval of a medication that slows the progression of GA with increasing efficacy over time, this has the potential to galvanize the field, encouraging innovation and the development of additional pharmacotherapies,” Charles C. Wykoff, MD, PhD, told Healio/OSN.
Drug development for FDA approval is a lengthy, arduous process, particularly for geographic atrophy (GA), a disease with unique characteristics and pathologic mechanisms. Defining the primary endpoint at the beginning of the clinical trial program was difficult because GA progresses slowly, making visual acuity unsuitable for this purpose.
“There was a lot of work with the FDA to develop a primary endpoint that is suitable for this disease, and most recently the favored FDA-approvable endpoint is a slope analysis looking at the rate of change of geographic atrophy area over time as assessed by fundus autofluorescence. The trial program involved over 1,500 patients treated for up to 2 years, with the phase 3 trials enrolling 1,258 patients,” Wykoff said.
At 1 year, a statistically significant reduction in lesion growth was reported with monthly and every other month pegcetacoplan in the OAKS trial, while in the DERBY trial, the difference between the pegcetacoplan-treated patients and the sham arm failed to reach statistical significance.
“However, by 18 and 24 months, the efficacy curves separated further in both clinical trials, and ultimately, pegcetacoplan demonstrated a clinically meaningful slowing of disease progression,” Wykoff said.
Syfovre (pegcetacoplan injection, Apellis Pharmaceuticals) is now approved in the United States for patients with GA. It is commercially available, although the reimbursement cycle has not been clarified, and official codes for the medication have not been assigned.
An informed decision
The approval of pegcetacoplan as a treatment for GA is the most important advance in retina care in more than a decade, according to Wykoff. All patients with GA may be interested to know that this treatment exists, have a conversation with their treating physician about the benefits, limitations and potential safety signals, and eventually make an informed choice about whether or not to receive treatment if they are eligible.
“An ideal patient may be one with preserved central vision, where we can hopefully meaningfully slow the disease progression and preserve foveal function. However, patients with foveal involvement can also benefit from this medication. Many patients with foveal involvement have adapted remarkably well and still have functional vision. Preserving retinal tissue in these eyes can also be meaningful,” he said.
Patients should be made aware of the limitations of this treatment. Combining the OAKS and DERBY populations, the overall reduction of GA lesion growth ranges between 17% and 21% at 2 years with every other month and monthly dosing, a clinically meaningful but modest effect, Wykoff said.
“Some patients might decide that the benefits are not large enough to outweigh the burden of repeated injections indefinitely and associated risks,” he said. “This is not a cure. To obtain the benefit of treatment, patients will need to be treated long term. It is worth the time to discuss this commitment with patients before initiation of therapy.”
However, the trial data suggest that the treatment benefits increase over time.
“If patients understand this important observation of increasing efficacy over time, I think there will be significant interest in receiving the treatment to slow disease progression and ultimately preserve visual function,” Wykoff said.
Monitor closely for safety signals
In the phase 3 trials, monthly and every other month administration had similar efficacy outcomes, with a slight advantage in favor of the more frequent dosing regimen. However, from a safety perspective, a higher rate of wet AMD development was observed in the eyes that received monthly dosing. The difference was 12% vs. 7%, with 3% in the sham population.
“This is also something patients should be aware of and something to consider in their decision-making process. If they want maximum efficacy, monthly may be appropriate. If there is concern about any of the safety signals, then every other month treatment can be used with the knowledge of similar efficacy towards reduction of GA growth,” Wykoff said.
The trials showed that eyes that develop wet AMD can be successfully treated with anti-VEGF injection and pegcetacoplan on the same day. But the key clinical practice recommendation is to make sure that OCT examination is performed in patients who receive pegcetacoplan regularly.
“Look through the entire volume scan to make sure that potential conversion to wet AMD is diagnosed early, so that treatment can be initiated before the neovascular process causes significant retinal damage and vision loss,” Wykoff said.
Another potential adverse event is intraocular inflammation, as specified in the FDA-approved patient package insert. If it is observed, it should be promptly treated, and after resolution of the inflammation, treatment with pegcetacoplan can be reinitiated. In addition, ischemic optic neuropathy was observed in 1.7% of patients in the monthly arm compared with 0.2% in the every other month arm and no patients in the sham arm.
“This is an important observation from the phase 3 trial program that appears to be dose dependent. More data is needed to understand this safety signal and the clinical implications. There has been a preliminary evaluation of these images by neuro-ophthalmologists, and all of the patients who developed ischemic optic neuropathy have been reported to have had a disc at risk. At this time, this data may encourage every other month dosing. In addition, it is worth evaluating for the presence of a disc at risk in potential patients. It may also be worth trying to minimize substantial intraocular pressure fluctuations with dosing, as pegcetacoplan is given as a 100 µL dose. Looking forward, real-world clinical data will be valuable to further understand this signal and determine if the rate of ischemic optic neuropathy observed in the trials is similar with dosing in routine clinical practice,” Wykoff said.
For more information:
Charles C. Wykoff, MD, PhD, of Retina Consultants of Texas, can be reached at ccwmd@houstonretina.com.
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