How does the FDA approval of Pegcetacoplan (Syfovre) and Avacincaptad pegol (Izervay) help NZ AMD patients with geographic atrophy?

Leo Sheck

minute read

The US Food and Drug Administration approved the use of pegcetacoplan (Syfovre) for the treatment of geographic atrophy in age-related macular degeneration (AMD) on 17 Feb 2023, followed by approval of avacincaptad pego (Izervay) for the same condition on 4 August 2023. Here, I explore how the approval of these medications affect the treatment of geographic atrophy, a previously untreatable condition, in New Zealand.

A Case of Geographic Atrophy with AMD

A 83 year old European woman presented to my clinic with poor vision in both eyes. She had an established diagnosis of geographic atrophy with age-related macular degeneration. She had never had neovascular (wet) changes and had not required anti-VEGF injections in the past. Her best corrected visual acuity was 6/36 right and 6/60 left, and was pseudophakic in both eyes. Fundoscopy showed bilateral geographic atrophy.

Fundus photograph of the macular region showing bilateral geographic atrophy

OCT images of the maculae showing geographic atrophy

This patient was very keen to preserve her vision and had the financial means to do so. She was aware that there were medications approved by the Food and Drug Administration in the United States for the treatment of geographic atrophy.

What would you advise her?

Pegcetacoplan (Syfovre), Avacincaptad Pegol (Izervay), and Complement Inhibition in AMD Geographic Atrophy

Both Pegcetacoplan and Avacincaptad Pegol act on the complement pathway. Pegcetacoplan inhibits C3 and Avacincaptad Pegol inhibits C5, and both drugs require intravitreal injections for administration. The end result for both of these medications is a reduction in the activation in the complement cascade within the eye.

A schematic diagram on the complement cascade in age-related macular degeneration. Excessive activation of the complement cascade has been shown to worsen age-related macular degeneration. The CFH protein regulates this cascade by removing C3b and accelerates the breakdown of C3 convertase. CFI helps the breakdown of C3b and C4b (not shown) in the presence of CFH.

Pegcetacoplan (Syfovre) - Clinical Data

The pivotal phase 3 trials that led to the FDA approval of Syfovre are the Derby and Oaks trials. OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively (quoted directly from the abstract). Patients were randomised to pegcetacoplan monthly, pegcetacoplan every other month, and sham. Further data has been released in the 36 month extension study.
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The effect of pegcetacoplan on the size of geographic atrophy in the above trials is summarised on this diagram from Apellis below.

Composite data on the effect of pegcetacoplan on GA lesion over time. Source: apellis.com

However, Derby and Oaks were not able to show a visual acuity improvement with pegcetacoplan therapy for geographic atrophy. The risks of macular neovascularisation are 5-7% in the monthly group, 3-5% in the every other month group, and 1-3% in the sham group at month-12, and 11-13% in the monthly group, 6-8% in the every other month group, and 2-4% in the sham group at month-24.

Avacincaptad Pegol (Izervay) - Clinical Data

GATHER2 is the phase 3 pivotal trial leading to the FDA approval of avacincaptad pegol. The 24-month data has yet to be published but the 12-month data was published by Lancet in 2023. 448 eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 μL intravitreal injection or sham for the first 12 months. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. (above quoted directly from the abstract)

The research group concluded that there is significantly slower geographic atrophy growth over 12 months. There is an 18% difference in geographic atrophy area growth between the avacincaptad pegol group and the sham group. The data is summarised in the graph below.

Mean change in geographic atrophy in Gather2, from Khanani et al. 2023

The research team has reported no significant adverse reaction from the medication. Similar to Derby and Oaks, Gather2 was not able to demonstrate a visual acuity benefit with avacincaptad pegol treatment. However, in a post-hoc study combining the results of Gather1 and Gather2, there was a 56% relative reduction in risk of persistent loss of ≥15 BCVA ETDRS letters with avacincaptad pegol at month 12, with a higher proportion of study eyes treated retained the threshold for driving (8.7% of treated patients vs 13.6% of patients in sham group lost their eligibility to drive).

The risk of macular neovascularisation at the 12-month mark is 7% for the avacincaptad pegol vs 4% for the sham group.

Case Selection for Pegcetacoplan and Avacincaptad Pegol Treatment

Geographic atrophy is a slowly progressive disease, and for many patients, their central vision may not be affected within their lifetimes. However, paracentral scotoma from geographic atrophy can cause significant visual symptoms, such as letters jumping around when reading (when letters come in and out of the paracentral scotoma area), and difficulty tracking lines of text when reading a paragraph. Many patients also report poor quality of vision with geographic atrophy despite good acuity.

On the other hand, the treatment burden with either pegcetacoplan and avacincaptad pegol is high, ranging from injection once every two months to once every month indefinitely. The volume of injection is higher than the typical anti-VEGF injections as well (0.1ml with pegcetacoplan and avacincaptad pegol, vs 0.05ml with anti-VEGF), which may translate to a higher risk of intraocular pressure spike and glaucoma. The benefit of these injections is modest with no clear visual acuity benefit in the trials above. Furthermore, there is a risk of triggering a conversion to neovascular AMD, which will require further anti-VEGF therapy and can result in vision loss.

The challenge here is to find those patients who are most likely to benefit from these treatments, rather than a blanket rule of treating all patients with geographic atorphy.

Quantify and Track Progression of Macular Sensitivity and Scotoma with Microperimetry

Visual acuity is an incomplete measurement of the central visual function, as it does not take into account any deficit in the visual field near central fixation. In patients with geographic atrophy, traditional visual field testing strategies (e.g. SITA 24-2 or SITA 10-2) testing without eye-tracking do not give sufficient information to quantify and track progression of macular sensitivity to guide treatment.

Recently, microperimetry testing (MAIA, now discontinued, and Nidek MP-3), combining eye tracking and macular specific testing strategy, is available clinically to assess macular sensitivity. Microperimetry will give useful information on the size and severity of paracentral scotoma, which can be significant despite excellent visual acuity (if fovea is not involved), and track the progression of these scotomas.

MAIA microperimetry testing result of the right eye of the above patient. The nasal geographic atrophy area has absolute loss of sensitivity, and the rest of the macular sensitivity is impaired

At this stage, patients with geographic atrophy will benefit from microperimetry testing to quantify their macular sensitivity, and the potential of treatment can be discussed if:

progression of scotoma over time
absolute scotoma threatening the fovea, especially if associated with loss of foveal sensitivity

There has been some evidence of benefit of pegcetacoplan treatment on macular sensitivity. However, microperimetry testing is not widely available with the only machine available in the University of Auckland Ophthalmology Research Department.

Using OCT Data to Identify GA Patients Likely to Benefit from Pegcetacoplan and Avacincaptad Pegol with Artificial Intelligence (AI)

I have discussed on this blog the use of autofluorescence, OCT, and AI to assess geographic atrophy. The intuition here is that any treatment for geographic atrophy does not actually target the atrophic area where both the retinal pigment epithelium and the ellipsoid layer are lost and non-recoverable, but instead target the junctional area where the retinal pigment epithelium is still present and the ellipsoid layer impaired, but not yet completely lost.

The team led by Prof Schmidt-Erfurth has done exactly the above using AI to analyse the OCT findings in Derby and Oaks. Attenuation of the ellipsoid layer precedes the loss of retinal pigment epithelium (RPE) in geographic atrophy. The AI algorithm in this paper can automatically segment area with RPE loss, and the area of ellipsoid loss with RPE preservation.

Ellipsoid layer attenuation (green) and RPE loss (blue) prior to pegcetoplan treatment (left) and after 24 months of treatment. Image from Schmidt-Erfurth, et al.

What they have found is that pegcetacoplan actually acts on the green area to slow down conversion from ellipsoid loss with RPE preservation to geographic atrophy with RPE loss (blue area), and it also slows down the enlargement of the green area over time. They also found that patients that had the most benefit from pegcetacoplan are those patients whom had the biggest discrepancy between the green and blue area, i.e. a large area of ellipsoid loss with RPE preservation but a small area with RPE loss.

This algorithm has now been packaged to a commercially available software product, RetInsight, which is available via the Heidelberg Spectralis HEYEX2 platform. HEYEX2 will be available in my practice, Retina Specialists, in 2025.

Patient Monitoring while on Pegcetacoplan or Avacincaptad Pegol Treatment

Unlike anti-VEGF injections, there is yet no known biomarker in the macula to indicate treatment effect for GA patients on either pegcetacoplan or avacincaptad pegol, i.e. there is nothing to alert the treating ophthalmologist that the treatment is working or not. Nevertheless, serial OCT imaging (with every treatment) is required to ensure that there is no neovascular transformation.

In the longer term, one could compare the growth rate of the geographic atrophy between the treated and the untreated eye (if only one eye is treated), or the growth rate before and after initiation of treatment, to give an idea on treatment efficacy. Rate of change in microperimetry measurement can be used in a similar way. However, at this stage, there is no easy way to calculate the growth rate of geographic atrophy within the Heidelberg Spectralis OCT platform. I am hoping that the availability of AI integration with HEYEX2 AppWay will offer ophthalmologists specific metrics for tracking geographic atrophy.

Cost of Treatment

Section 29 of the Medicine Act provides access to unapproved medicines that have been imported into New Zealand to medical practitioner. So although these medications are yet to be approved by MedSafe, patients with geographic atrophy who will benefit from treatment can access them via their ophthalmologists.

At the time of writing, pegcetacoplan is available only via Bionical Emas. It is priced at $2190 USD per vial. There is a $1430 USD freight and packaging charge per delivery.

Progress on the Case above

It turned out that this woman has already been seen in Houston, United States, and was started on pegcetacoplan (Syfovre) in the right eye. I have continued with her treatment here in New Zealand with pegcetacoplan every two months. The medication was obtained via the Section 29 pathway as discussed above. Her ongoing monitoring is by both OCT and microperimetry, and so far her vision is stable.

My Recommendations for AMD patients with GA in New Zealand

Both pegcetacoplan and avacincaptad pegol offer our geographic atrophy patients some hope in retarding the progression of their disease. However, the effect of these medications is modest, with a risk of neovascular conversion, and the financial burden is considerable. These medication can be considered in geographic atrophy patients only if the lesion is foveal threatening or the patient is highly symptomatic.

On the other hand, it is worthwhile for all patients with geographic atrophy to be assessed with both high resolution OCT (ideally with RetInsight algorithm) and microperimetry by an ophthalmologist, and followed up yearly to track progression. The availability of these newer agents should be discussed with the patients. I am hopeful that, in the future, some of these medications may become funded, and also newer agents to tackle geographic atrophy that are more effective will become available.

About Dr Leo Sheck

Dr Sheck is a RANZCO-qualified, internationally trained ophthalmologist. He combined his initial training in New Zealand with a two-year advanced fellowship in Moorfield Eye Hospital, London. He also holds a Doctorate in Ocular Genetics from the University of Auckland and a Master of Business Administration from the University of Cambridge. He specialises in medical retina diseases (injection therapy), cataract surgery, ocular genetics, uveitis and electrodiagnostics.