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Priya Vakharia Geographic Atrophy Current and Future
Priya Vakharia Geographic Atrophy Current and Future
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REVIEW
CURRENT
OPINION Geographic atrophy: current and future therapeutic
agents and practical considerations for
retinal specialists
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Purpose of review
Geographic atrophy (GA) from age-related macular degeneration (AMD) remains a leading cause of vision
loss. The purpose of this review is to summarize currently available intravitreal therapeutics, and discuss
pipeline therapeutics that are currently in clinical trials.
Recent findings
The FDA approval of pegcetacoplan and avacincaptad pegol, both approved in 2023, represent the first
therapeutics to treat GA. These are delivered via intravitreal injections, and have been shown to slow
progression of GA. Both drugs have a risk of new onset neovascular age-related macular degeneration
(nAMD). Initial indications seem to be that pegcetacoplan therapy has higher risks of inflammation,
vasculitis, and nonarteritic ischemic optic neuropathy (NAION) as compared to avacincaptad pegol, but
more real-world data will help to clarify this further. Pipeline therapeutics that we discuss include intravitreal
gene therapy, oral anticomplement therapy, and intravitreal injections of a novel glycoprotein.
Summary
Both pegcetacoplan and avacincaptad pegol are FDA approved to treat GA. The decision to treat patients
is still complex and nuanced, but the approval of two treatments for GA is a tremendous advance in our
field. Future therapeutics may further refine our ability to treat patients more effectively and safely.
Keywords
avacincaptad pegol, dry age-related macular degeneration, geographic atrophy, pegcetacoplan, pipeline
therapeutics
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Treatment of GA with avacincaptad pegol showed a and fundus autofluorescence (FAF) (Figs. 1 and 2)
reduced GA lesion growth rate of 14% with monthly
[9]. The average rate of GA progression ranges from
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FIGURE 1. Fundus autofluorescence (a) shows hypoautofluorescence corresponding to areas of geographic atrophy, with
perilesional hyperautofluorescence suggestive of areas of dysfunctional RPE. The corresponding atrophy can be seen on near
infrared imaging (b) as areas of hyporeflectivity. This patient has foveal-threatening GA. GA, geographic atrophy; RPE, retinal
pigment epithelium.
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Geographic atrophy: current and future therapeutic agents and practical considerations for retinal specialists Vakharia and Eichenbaum
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FIGURE 2. Spectral-domain OCT imaging of a patient with foveal-threatening GA. Near-infrared imaging (a) shows foveal-
threatening GA. The scan is segmented at the location of the green line, with corresponding cross-sectional B-scan (b) showing
full thickness central GA with choroidal hypertransmission (white arrow). GA, geographic atrophy; OCT, optical coherence
tomography.
every other month (EOM) intravitreal dosing via also known as Izervay (Iveric Bio/Astellas, Cranbury,
intravitreal injection, and has shown reductions NJ), is an anticomplement injection targeting C5,
in the rate of GA lesion growth at 2 years of 19% further downstream on the complement cascade
&&
in the monthly arm and 16% in the EOM arm in than C3 [18 ]. It is approved for monthly dosing
DERBY, or 22% in the monthly arm and 18% in the in concordance with the effects seen at that dosing
&&
EOM arm in OAKS [14 ]. The GALE extension study rate at the 1-year primary endpoint. There is a
showed even higher numbers at 3 years, with potential label update to every-other-month dosing
reduced GA lesion growth of 35% in the monthly possible based on the 2 year results, since patients
arm and 24% in the EOM arm compared to pro- were re-randomized to monthly or EOM dosing at
jected sham. There were increased treatment effects the end of year 1, and the results maintained with
noted with cumulative dosing (13% monthly/14% both dosing strategies through year 2. In the
EOM from months 0 to 6 compared to 39% monthly/ GATHER2 trial at year 2, patients had a 14% reduc-
32% EOM arm from months 24–30) [15,16]. Even tion in the mean rate of GA growth with monthly
higher numbers were noted in the nonsubfoveal injections and 19% with EOM injections [19,20].
lesion group, with 45% in the monthly arm Similar to pegcetacoplan, the treatment effect seems
and 33% in the EOM arm from months 24 to 30 to increase with continued use, with the treatment
[15,16]. effect (mean rate of GA growth from baseline) more
Treatment with pegcetacoplan is not without than doubling over 2 years as compared to the treat-
risks. As with all intravitreal injections, there is a risk ment effect over 1 year [19,20].
of endophthalmitis. Intraocular inflammation was Treatment with avacincaptad pegol has risks
reported at a rate of 2–4%, ischemic optic neuro- similar to pegcetacoplan, including a risk of
pathy at a rate of 0.2–1.7%, and new-onset neo- endophthalmitis as with all intravitreal injections
vascular AMD at a rate of 7–12% (as compared to 3% and a risk of neovascular AMD at a rate of 11.6%
&&
new-onset nAMD in the sham arms) [14 ]. There compared to 9% sham. There was only one reported
have also been postmarketing reports of occlusive case of nonserious intraocular inflammation in the
and nonocclusive retinal vasculitis, at a rate of about GATHER2 trial [19,20], so the risk of inflammation
1 in 10 000 injections, all seen after the first injec- with avancicaptad pegol may be less than with
&&
tion of pegcetacoplan [17 ]. pegcetacoplan. There is less real-world data to date
On August 4, 2023, the second therapy for the with avancicaptad pegol since it has not been com-
treatment of GA was approved. Avacincaptad pegol, mercially available for as long.
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The first potential therapeutic is danicopan, an are currently being enrolled as of Spring 2024 into
oral complement factor D inhibitor, sponsored by part 2 of this phase 2 study, which is a double-masked,
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Alexion Pharmaceuticals (Boston, MA) [21]. Danico- randomized, multicenter study looking at high dose
pan is approved in Japan for paroxysmal nocturnal every-other-month AVD-104, monthly low dose
hemoglobinuria [22]. This is a phase 2, double- AVD-104, and active comparator (monthly avacin-
masked, placebo-controlled, dose range finding captad pegol). The primary endpoint is the difference
study of danicopan (ALXN2040) in patients with in the rate of growth of the GA area as measured by
GA secondary to AMD. Enrollment is complete, with FAF [24,25]. While this remains an intravitreal ther-
around 365 participants enrolled. The primary out- apy, it is possible that the ability of this particle
come measure being studied is change from baseline to modulate the inflammatory activity of immune
to week 52 in the square root of the total GA lesion cells could serve an unmet need to in retina, and
area in the study eye, as measured by FAF. Patients this mechanism of action may perform differently
enrolled have nonfoveal GA without any history of than pure complement activity modulation with
wet macular degeneration in their study eye. Patients pegcetacoplan or avacnicaptad pegol.
in this study receive either Danicopan 100 mg b.i.d.,
200 mg b.i.d., 400 mg b.i.d., or placebo. At 52 weeks, if
the optimal dose is determined, patients will be PRACTICAL CONSIDERATIONS IN
switched to the optimal dose for the remainder of REGARDS TO TREATMENT
the study through week 104 [21]. An oral therapeutic The decision to treat a patient is complex and
would be welcome in the vitreoretinal community as nuanced. Current FDA-approved therapies such as
a way to treat this disease without the heavy treat- pegcetacoplan and avacincaptad pegol only slow
ment burden that come with intravitreal injections. progression of disease, but do not stop progression
The second potential therapeutic that we would and do not reverse any prior changes. Furthermore,
like to highlight is intravitreal gene therapy JNJ- at 2 years, both drugs failed to show any visual acuity
81201887, sponsored by Janssen pharmaceuticals or function benefit in prespecified endpoints in
(Beerse, Belgium) [23]. This trial is recruiting as patients who were treated with anticomplement
of Spring 2024, and is a phase 2b, randomized, therapies compared to sham, although there are
double-masked, multicenter, dose-ranging, sham- posthoc analyses for both drugs suggesting some
controlled clinical trial to evaluate intravitreal visual benefit, either based on microperimetry
JNJ-81201887 (AAVCAGsCD59) compared to sham [26] or numbers of letters lost [20]. As with all
for treating GA secondary to AMD. Patients eligible clinical trials, therapies that are currently in devel-
to enroll in this trial are nonfoveal involving GA opment could succeed or could fail, and only time
patients, with the goal of around 300 patients to be will tell if any of these potential therapeutic options
included in the study. The investigational product, have functional benefits from our patients.
JNJ81201887, is a gene therapy that codes for an That being said, without any treatment, the
anti-CD59 protein. CD59 is the final component of natural history of the disease is that patients with
the complement cascade, and inhibiting CD59 GA will progress relentlessly and experience visual
activity may reduce the formation of membrane loss. These patients often remain optimistic and
attack complex and subsequent cell death. Patients hopeful that current and future therapeutics will
are randomized to receive either JNJ81201887 low help their visual acuity.
dose, high dose, or sham. The primary endpoint is Currently, the ideal patient to treat is likely one
change from baseline in square root of GA lesions that has not yet experienced vision loss from foveal
area in the study eye at month 18, measured by FAF GA, who is motivated and wishes to do everything
[23]. Gene therapy remains promising in the GA possible to avoid GA progression. However, even
landscape due to the ability to deliver a therapeutic foveal-involved GA patients with some preserved
agent with a single treatment. visual function can have treatment, and it is reason-
The third therapeutic that we would like to touch able to have a discussion regarding treatment
on is a novel glycoprotein delivered via intravitreal options with all patients who have GA, focusing
injection [24,25]. The SIGLEC trial is a multiple dose on certain key points.
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Geographic atrophy: current and future therapeutic agents and practical considerations for retinal specialists Vakharia and Eichenbaum
6. Lindblad AS, Lloyd PC, Clemons TE, et al., Age-Related Eye Disease Study
First, patients need to understand that these Research Group. Change in area of geographic atrophy in the Age-Related
drugs are not stopping progression or reversing pro- Eye Disease Study: AREDS report number 26. Arch Ophthalmol 2009;
127:1168–1174.
gression, but are slowing progression. Second, the 7. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular
risks of therapies need to be stressed, specifically the degeneration and disease burden projection for 2020 and 2040: a systematic
review and meta-analysis. Lancet Glob Health 2014; 2:e106–e116.
risks of endophthalmitis, wet AMD, inflammation, 8. Sacconi R, Corbelli E, Querques L, et al. A review of current and future
vasculitis, and NAION as discussed previously. management of geographic atrophy. Ophthalmol Ther 2017; 6:69–77.
9. Holz FG, Sadda SR, Staurenghi G, et al. Imaging protocols in clinical studies in
Third, it is important to stress the importance of
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