Avacincaptad pegol (ACP) is a pegylated RNA aptamer that binds to complement C5. Its brand name is IZERVAY. Developed by Astellas Pharma, it is provided as an intravitreal injection solution. In August 2023, the U.S. FDA approved it as a treatment for geographic atrophy (GA) secondary to age-related macular degeneration 1). It is the second approved drug for GA, following the complement C3/C3b inhibitor pegcetacoplan (Syfovre) 2).
GA (geographic atrophy) is an advanced form of age-related macular degeneration that causes irreversible vision loss due to atrophy of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris 1). The global prevalence of GA is approximately 8.7%, affecting about 5 million people worldwide (1–1.6 million in the U.S.) 1). It is a leading cause of central vision loss in people over 55, with a prevalence of 3.5% at age 75 and about 22% at age 90 and older 1). Approximately 20% of legal blindness cases in the U.S. and about 26% in the U.K. are attributed to GA 3). In Japan, it occurs in men and women over 50 (male:female ≈ 3:1), starting with metamorphopsia and central scotoma, and progressing to corrected visual acuity below 0.1.
It is a pegylated RNA aptamer that inhibits complement C5. Approved by the FDA in 2023 as a treatment for geographic atrophy, it slows the enlargement of GA lesions, but has not been shown to restore atrophied tissue or improve vision at this time. See the [Standard Treatment] section (#5-標準的な治療法) for details.
The main subjective symptoms of GA are as follows1).
GA causes slower vision loss than neovascular age-related macular degeneration, but its long-term impact on visual function is significant2). Over 2 years, approximately 75% of affected eyes lose 5 letters, about 50% lose 10 letters (3 lines), and about 25% lose 15 letters (6 lines)3). GA progression negatively affects quality of life (both vision-related and health-related), and is associated with difficulties in independent living and mental health3). Increased depression and anxiety have also been reported4).
Over 2 years, approximately 75% of eyes lose 5 letters (1 line), about 50% lose 10 letters (3 lines), and about 25% lose 15 letters (6 lines) of vision3). A single lesion involving the fovea carries a high risk of vision loss, while multiple lesions have faster enlargement but relatively slower impact on vision4).
Fundus Examination
Atrophic area: Well-demarcated hypopigmented area with scalloped borders.
Surrounding findings: Drusen and pigment changes are observed around the lesion.
Lesion phenotype: Well-defined zone of atrophy of the RPE and/or choriocapillaris2).
FAF and OCT
Fundus autofluorescence (FAF): Dark hypoautofluorescence due to lack of lipofuscin. The surrounding hyperautofluorescence pattern predicts the rate of GA enlargement.
OCT (outer retina): Loss of outer nuclear layer, ellipsoid zone (EZ), and interdigitation zone; loss of RPE; increased choroidal hypertransmission. EZ integrity is useful for predicting visual prognosis4).
GA is an advanced form of age-related macular degeneration, and its risk factors overlap with those of overall age-related macular degeneration.
Non-modifiable risk factors:
Modifiable risk factors:
Pathological background: Drusen accumulation induces photoreceptor and RPE degeneration, progressing to atrophy 1). Abnormal activation of the complement system plays a key role in the onset and progression of GA 1)3). Precursor lesions of GA include retinal pigment epithelium abnormalities (pigment mottling, hyperpigmentation, hypopigmentation) and soft drusen.
A combination of multimodal imaging is recommended for the diagnosis of GA 2).
The characteristics of each examination are shown below.
| Examination Method | Main Purpose | Notes |
|---|---|---|
| Fundus Autofluorescence (FAF) | Measurement of GA area | Standard measurement method. Can also predict progression rate. |
| OCT (SD/SS) | Outer retinal / RPE assessment | EZ integrity predicts visual prognosis4) |
| Microperimetry | Quantification of retinal sensitivity | Allows assessment of residual function4) |
ACP administration: 2 mg (0.1 mL of 20 mg/mL solution) administered as an intravitreal injection once monthly1).
The efficacy of ACP was evaluated in two randomized, double-masked trials: GATHER1 (Phase 2/3) and GATHER2 (Phase 3).
| Study | GA enlargement suppression rate | Statistics |
|---|---|---|
| GATHER1 (12 months, square root transformation) | 27.4% reduction | p=0.00727) |
| GATHER1 (18 months, observed values) | 32.2% reduction | 95%CI 0.480–1.8338) |
| GATHER2 (12 months, observed values) | 17.7% reduction | p=0.0041) |
In the 12-month results of GATHER2 by Khanani et al. (2023), the ACP group (n=271) showed a significant suppression of GA growth rate compared to the sham group (n=269): 0.336 vs. 0.392 mm/year (difference 0.056 mm/year; 95%CI 0.016–0.096; p=0.006)6).
The 24-month data from GATHER2 showed a 14% reduction in the monthly dosing group and a 19% reduction in the group that switched from monthly to every-other-month dosing after 12 months2).
No significant improvement in best-corrected visual acuity was shown in either GATHER1 or GATHER21)2). However, a post-hoc analysis suggested that loss of 15 or more letters in best-corrected visual acuity occurred in 4.0% of the ACP group vs. 7.6% in the sham group, and the risk of sustained 15-letter loss was reduced by 56% (HR 0.44; 95%CI 0.21–0.92)1)5).
The complement C3/C3b inhibitor pegcetacoplan (Syfovre) showed a 21% reduction in GA enlargement at 12 months with monthly dosing in the OAKS/DERBY Phase 3 trials (OAKS trial)2).
The main adverse effects (pooled GATHER1/GATHER2) are shown below1).
| Adverse effect | ACP group | Sham group |
|---|---|---|
| Subconjunctival hemorrhage | 13% | 9% |
| Increased intraocular pressure | 9% | 1% |
| Blurred vision | 8% | 5% |
| Macular neovascularization conversion | 7% | 4% |
| Eye pain | 4% | 3% |
No cases of endophthalmitis or ischemic optic neuropathy were reported over 12 months1). Elevated intraocular pressure was mainly transient and related to the injection procedure1).
Risk of macular neovascularization conversion: In GATHER1, the ACP 2mg group had 9.0% vs sham 2.7%; in GATHER2, ACP 2mg group had 6.7% vs sham 4.1%1). If macular neovascularization (choroidal neovascularization) develops, treatment with anti-VEGF therapy is necessary2).
Contraindications: Patients with ocular or periocular infections, or active intraocular inflammation.
The GATHER trials did not show significant improvement in best-corrected visual acuity1)2). However, a post-hoc analysis suggested a 56% reduction in the risk of sustained vision loss of 15 letters or more (HR 0.44), indicating a potential contribution to long-term vision maintenance5).
In the integrated data from the GATHER study, macular neovascularization conversion was observed in 7% of the treatment group and 4% of the sham group 2). When macular neovascularization occurs, it is managed with anti-VEGF therapy. Regular OCT monitoring is essential.
Abnormal activation of the complement system plays a central role in the onset and progression of GA.
The complement system consists of three pathways: the classical pathway, the lectin pathway, and the alternative pathway 1). All three pathways converge at the cleavage of C3 by C3 convertase (C3 → C3a + C3b) 1). Subsequently, C5 convertase cleaves C5 into C5a (anaphylatoxin) and C5b 1).
With aging, the expression of complement system-related genes is upregulated 1). Genetic polymorphisms in CFH, CFB, C3, and ARMS2 are associated with GA susceptibility 1)2).
ACP is a chemically synthesized single-stranded oligonucleotide, and pegylation provides biological stability and delayed clearance 1).
It binds with high affinity to C5 and inhibits its cleavage into C5a and C5b 1).
Theoretical advantage of C5 inhibition: It preserves C3a (which has anti-inflammatory and host defense functions) upstream of C5 while blocking inflammasome recruitment and MAC formation 1). In contrast to C3 inhibitors, which may impair host defense functions from upstream, C5 inhibition is considered a more selective target 1).
C5 cleavage products, C5a and MAC, are thought to promote GA progression through inflammatory damage to the RPE 1). Inhibiting C5 prevents MAC formation and C5a generation while preserving the anti-inflammatory and host defense functions of upstream C3a. Since C3 inhibition raises concerns about increased infection risk, C5 is considered a safer target 1).
In the 24-month data from GATHER2, GA area enlargement was suppressed by 14% in the monthly dosing group and by 19% in the group that switched to every-other-month dosing after 12 months 2). This suggests that switching to every-other-month dosing may not reduce the GA suppression rate, and optimization of dosing intervals remains a future challenge.
A post-hoc analysis suggested a 56% reduction in the risk of sustained vision loss of 15 letters or more (HR 0.44), but this is a post-hoc exploratory analysis and not a definitive conclusion 1)5). Prospective trials with visual endpoints as primary outcomes are needed for verification.
The utility of EZ (ellipsoid zone) integrity as a biomarker is being explored 1). Research on predicting visual function from OCT biomarkers using machine learning is also progressing 4). The importance of early detection and early treatment intervention for GA is emphasized 1), and these biomarkers are expected to be established as prognostic tools.
Elucidating the mechanism by which complement inhibition increases the risk of developing macular neovascularization (choroidal neovascularization) remains an important unresolved issue 1). There is a hypothesis that the complement system is also involved in the suppression of angiogenesis, and understanding this balance is thought to influence future drug design.
