Complement inhibitors for age-related macular degeneration

Plain language summary title

What are the benefits and risks of medicines that block complement to treat age-related macular degeneration (AMD)?

Key messages

 • After one year of treatment, pegcetacoplan (a medicine that blocks complement) was shown to slow down the growth of patches of diseased retina in the eyes of people with a severe type of ‘dry’ AMD, but there is currently no evidence that it slows down sight loss or improves quality of life.

 • Treating ‘dry’ AMD with pegcetacoplan and other medicines that block complement may result in more cases of ‘wet’ AMD, where abnormal blood vessels grow in the retina; these can leak blood or fluid and cause rapid vision loss, but can be treated if caught quickly.

 • Future research in this area should focus on options and effects that are important to decision-makers, such as:

 - the benefits of blocking complement in different ways and for different periods of time;

 - potential harms and costs;

 - outcomes that are relevant to patients.

What is age-related macular degeneration?

AMD is a leading cause of sight loss in adults, affecting almost 200 million people worldwide. There are two types of AMD: ‘dry’ and ‘wet’. AMD is at least partially due to genetic causes that are not fully understood or treatable. Most genetic changes linked to AMD have been found to affect complement, a major part of our immune system. When complement is too active, it can injure the retina (the light-sensitive film lining the inside of our eyes) and cause AMD.

How is age-related macular degeneration treated?

Currently, there is no cure for AMD, and while there are treatments available for the 'wet' type, no therapies are available for most of the 95% of patients with the 'dry' form. However, a new treatment option, pegcetacoplan, which blocks complement, has recently been approved in the US for treating severe 'dry' AMD.

What did we want to find out?

We wanted to find out if blocking complement with different medicines was better than sham or placebo (a fake treatment) at preventing or slowing down AMD.

What did we do?

We searched for studies that looked at complement blockers compared with sham or placebo in people with AMD across the world. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 10 studies that involved 4052 people with geographic atrophy (a severe form of ‘dry’ AMD) that had lasted for at least a year. The biggest study was in 1881 people and the smallest study was in 30 people. The studies were conducted in countries around the world; most were done in the US or Europe. All studies were funded by pharmaceutical companies. Almost all studied medicines that blocked complement were given as injections into the eye (intravitreally).

The results of two medicines, lampalizumab and pegcetacoplan, were reported across three studies each. We combined the results of these studies to help give us an idea of the true effectiveness of these treatments when given monthly and every-other-month. We also looked at the results of all other studies, including a medicine called avacincaptad pegol.

Main results

We found that pegcetacoplan given every month or every-other-month reduces the growth of patches of diseased retina, but probably makes little to no difference to vision loss. We also found that avacincaptad pegol may reduce the growth of diseased retina, but also probably makes little to no difference in vision loss. We found that lampalizumab makes little to no difference to any of the outcomes of interest to patients and their clinicians.

Like other medicines given in the eye, we found that most medicines that block complement are probably associated with a small increase in the risk of serious eye infection or inflammation. We also found that blocking complement in the eye in most studies probably caused an increase in the risk of abnormal blood vessels growing in the retina; these can leak blood or fluid and cause rapid vision loss but can be treated if caught quickly.

What are the limitations of the evidence?

We are confident in our results for lampalizumab and pegcetacoplan to treat geographic atrophy. People in the studies were randomly placed into the different treatment groups. This means that differences between the groups are due to differences between the treatments rather than between the people. More information is needed to increase our confidence in the anatomical benefits of avacincaptad pegol, but early evidence is encouraging.

These findings relate only to treatment with intravitreal medicines for up to one year at most. Not all studies provided data about everything that patients and their clinicians may be interested in. Participants in the studies had severe ‘dry’ AMD, so our results may not be useful for people whose AMD is less severe or those who have the ‘wet’ form of AMD.

How up-to-date is this evidence?

This review updates our previous review. The evidence is up-to-date to 29 June 2022.

Authors' conclusions: 

Despite confirmation of the negative findings of intravitreal lampalizumab across all endpoints, local complement inhibition with intravitreal pegcetacoplan meaningfully reduces GA lesion growth relative to sham at one year. Inhibition of complement C5 with intravitreal avacincaptad pegol is also an emerging therapy with probable benefits on anatomical endpoints in the extrafoveal or juxtafoveal GA population. However, there is currently no evidence that complement inhibition with any agent improves functional endpoints in advanced AMD; further results from the phase 3 studies of pegcetacoplan and avacincaptad pegol are eagerly awaited. Progression to MNV or exudative AMD is a possible emergent adverse event of complement inhibition, requiring careful consideration should these agents be used clinically. Intravitreal administration of complement inhibitors is probably associated with a small risk of endophthalmitis, which may be higher than that of other intravitreal therapies. Further research is likely to have an important impact on our confidence in the estimates of adverse effects and may change these. The optimal dosing regimens, treatment duration, and cost-effectiveness of such therapies are yet to be established.

Read the full abstract...

Age-related macular degeneration (AMD) is a common eye disease and leading cause of sight loss worldwide. Despite its high prevalence and increasing incidence as populations age, AMD remains incurable and there are no treatments for most patients. Mounting genetic and molecular evidence implicates complement system overactivity as a key driver of AMD development and progression. The last decade has seen the development of several novel therapeutics targeting complement in the eye for the treatment of AMD. This review update encompasses the results of the first randomised controlled trials in this field.


To assess the effects and safety of complement inhibitors in the prevention or treatment of AMD.

Search strategy: 

We searched CENTRAL on the Cochrane Library, MEDLINE, Embase, LILACS, Web of Science, ISRCTN registry,, and the WHO ICTRP to 29 June 2022 with no language restrictions. We also contacted companies running clinical trials for unpublished data.

Selection criteria: 

We included randomised controlled trials (RCTs) with parallel groups and comparator arms that studied complement inhibition for advanced AMD prevention/treatment.

Data collection and analysis: 

Two authors independently assessed search results and resolved discrepancies through discussion. Outcome measures evaluated at one year included change in best-corrected visual acuity (BCVA), untransformed and square root-transformed geographic atrophy (GA) lesion size progression, development of macular neovascularisation (MNV) or exudative AMD, development of endophthalmitis, loss of ≥ 15 letters of BCVA, change in low luminance visual acuity, and change in quality of life. We assessed risk of bias and evidence certainty using Cochrane risk of bias and GRADE tools.

Main results: 

Ten RCTs with 4052 participants and eyes with GA were included. Nine evaluated intravitreal (IVT) administrations against sham, and one investigated an intravenous agent against placebo. Seven studies excluded patients with prior MNV in the non-study eye, whereas the three pegcetacoplan studies did not. The risk of bias in the included studies was low overall. We also synthesised results of two intravitreal agents (lampalizumab, pegcetacoplan) at monthly and every-other-month (EOM) dosing intervals.

Efficacy and safety of IVT lampalizumab versus sham for GA

For 1932 participants in three studies, lampalizumab did not meaningfully change BCVA given monthly (+1.03 letters, 95% confidence interval (CI) −0.19 to 2.25) or EOM (+0.22 letters, 95% CI −1.00 to 1.44) (high-certainty evidence). For 1920 participants, lampalizumab did not meaningfully change GA lesion growth given monthly (+0.07 mm², 95% CI −0.09 to 0.23; moderate-certainty due to imprecision) or EOM (+0.07 mm², 95% CI −0.05 to 0.19; high-certainty). For 2000 participants, lampalizumab may have also increased MNV risk given monthly (RR 1.77, 95% CI 0.73 to 4.30) and EOM (RR 1.70, 95% CI 0.67 to 4.28), based on low-certainty evidence. The incidence of endophthalmitis in patients treated with monthly and EOM lampalizumab was 4 per 1000 (0 to 87) and 3 per 1000 (0 to 62), respectively, based on moderate-certainty evidence.

Efficacy and safety of IVT pegcetacoplan versus sham for GA

For 242 participants in one study, pegcetacoplan probably did not meaningfully change BCVA given monthly (+1.05 letters, 95% CI −2.71 to 4.81) or EOM (−1.42 letters, 95% CI −5.25 to 2.41), as supported by moderate-certainty evidence. In contrast, for 1208 participants across three studies, pegcetacoplan meaningfully reduced GA lesion growth when given monthly (−0.38 mm², 95% CI −0.57 to −0.19) and EOM (−0.29 mm², 95% CI −0.44 to −0.13), with high certainty. These reductions correspond to 19.2% and 14.8% versus sham, respectively. A post hoc analysis showed possibly greater benefits in 446 participants with extrafoveal GA given monthly (−0.67 mm², 95% CI −0.98 to −0.36) and EOM (−0.60 mm², 95% CI −0.91 to −0.30), representing 26.1% and 23.3% reductions, respectively. However, we did not have data on subfoveal GA growth to undertake a formal subgroup analysis. In 1502 participants, there is low-certainty evidence that pegcetacoplan may have increased MNV risk when given monthly (RR 4.47, 95% CI 0.41 to 48.98) or EOM (RR 2.29, 95% CI 0.46 to 11.35). The incidence of endophthalmitis in patients treated with monthly and EOM pegcetacoplan was 6 per 1000 (1 to 53) and 8 per 1000 (1 to 70) respectively, based on moderate-certainty evidence.

Efficacy and safety of IVT avacincaptad pegol versus sham for GA

In a study of 260 participants with extrafoveal or juxtafoveal GA, monthly avacincaptad pegol probably did not result in a clinically meaningful change in BCVA at 2 mg (+1.39 letters, 95% CI −5.89 to 8.67) or 4 mg (−0.28 letters, 95% CI −8.74 to 8.18), based on moderate-certainty evidence. Despite this, the drug was still found to have probably reduced GA lesion growth, with estimates of 30.5% reduction at 2 mg (−0.70 mm², 95% CI −1.99 to 0.59) and 25.6% reduction at 4 mg (−0.71 mm², 95% CI −1.92 to 0.51), based on moderate-certainty evidence. Avacincaptad pegol may have also increased the risk of developing MNV (RR 3.13, 95% CI 0.93 to 10.55), although this evidence is of low certainty. There were no cases of endophthalmitis reported in this study.