Geographic atrophy: new treatments and the regulators’ decisions

In the United States the advanced dry form of macular degeneration has had its first approved drug¹. In Europe the same molecule received a negative opinion in 2024 from the European Medicines Agency (EMA), confirmed after a re-examination². For a second drug with a similar mechanism, the company withdrew its application for authorisation before the decision⁹.

Two agencies, two answers, and a fundamental question: what must a drug demonstrate for atrophic macular degeneration, called geographic atrophy? In the studies these drugs really did slow the growth of lesions in the retina, but the main indicators of visual function did not change^1,6.

In this article

1. What atrophic macular degeneration is
2. The drugs that restrain complement
3. Vision, the weak point
4. Why the EMA said no
5. What it means for European patients
6. Frequently asked questions
7. Sources

What atrophic macular degeneration is

In age-related macular degeneration the advanced forms are two: the wet one, with abnormal vessels that leak fluid, and the advanced dry one, geographic atrophy. In the latter, areas of the central retina thin and stop working; in images of the back of the eye they appear as patches with sharp edges, like regions on a map. We described the two forms and their symptoms in our article on macular degeneration.

How it evolves is shown by the data of AREDS2, a large American study of people with age-related macular degeneration³. Among the eyes that did not have it at the start, geographic atrophy appeared in 19% within five years. At the start of the study two lesions in three did not touch the exact centre of the macula, the fovea; but when the atrophy arose away from the centre, within four years it came to involve it in 57% of eyes. The authors describe an enlargement that does not stop and that leads to a rapid loss of central vision. In eyes with newly appeared atrophy, moreover, the risk of also developing the wet form was 29% in four years³.

The drugs that restrain complement

Complement is a part of the immune system: a cascade of proteins that are activated one after another. Several lines of research indicate that its faulty regulation plays a central role in geographic atrophy, and the two drugs we are discussing act precisely here: pegcetacoplan blocks the C3 protein, avacincaptad pegol the C5 protein⁴. Both are injected into the eye, every month or every two months^1,5.

The second drug was tested in the GATHER2 trial: 447 people with an atrophy that did not yet touch the centre of the macula, randomly assigned to monthly or sham injections for a year; in the second year those who were treated were divided between injections every month and every two months⁵. Over two years the lesion grew on average by 4.46 square millimetres with monthly injections and by 4.20 with those every two months, against 5.18 with sham injections: a difference of 14 and 19%⁵. Neovascularisation, that is, the onset of the wet form, affected 11.6% of those treated and 9% of the control group⁵.

Vision, the weak point

A ‘living’ systematic review, updated as new studies come out, summarised the results of the two drugs: inhibition of C3 or C5 probably reduces the growth of lesions, but probably does not change visual acuity at 12 months, and at 24 months the evidence is uncertain⁶. Side effects in the eye are more frequent than with sham injections and the treatment probably increases cases of the wet form, while those on the rest of the body are similar⁶.

Some later analyses look for signals on visual function. In the two GATHER trials, a post hoc analysis found that in 12 months 4.0% of treated eyes had lost 15 letters or more against 7.6% of those with sham injections, and that fewer treated eyes fell below the vision threshold required for driving⁷. In the GALE extension of the first drug, open-label and compared with a projection rather than with a control group, the reduction in lesion growth reached as much as 32%, and at 36 months there were 18% fewer new blind spots in the macula, measured with microperimetry⁸. These are interesting data, but a post hoc analysis and an extension without a control group have to be read with caution.

Why the EMA said no

On 27 June 2024 the EMA gave a negative opinion on the application for authorisation of pegcetacoplan; the company asked for a re-examination and on 19 September 2024 the negative opinion was confirmed, with the refusal of the authorisation in December². In its public assessment the Agency acknowledges that the studies show a slowing of lesion growth, but considers that it did not lead to clinically relevant benefits for patients: an effect on everyday life was not seen in the studies. To this is added the significant risk of side effects linked to regular injections into the eye, including the appearance of other forms of macular degeneration or of inflammation. For this reason, according to the EMA, it was not possible to establish a positive balance between benefits and risks².

For avacincaptad pegol the story ended earlier: the company withdrew the application on 24 October 2024, when the EMA’s provisional opinion was that the drug could not be authorised⁹. Here too the Agency acknowledged the slowing of lesions, but considered that it did not translate into clinically relevant benefits on visual function; the company gave the Agency’s doubts about efficacy as the reason for the withdrawal⁹. For those taking part in clinical trials with these drugs, both companies have told the EMA that there are no consequences^2,9.

What it means for European patients

In practice, in the European Union neither drug is authorised for geographic atrophy^2,9. In the United States pegcetacoplan has been approved¹; in Europe the Agency asked for proof of a benefit that patients can perceive, and questions remain open about the effects on vision and about safety^2,4.

For people with geographic atrophy this does not mean that there is nothing to be done. The ophthalmologist follows the progression of the disease and checks that the wet form does not appear, which is treated instead with anti-VEGF injections³. For the difficulties of daily life there is visual rehabilitation, which we discuss in the article Does macular degeneration cause blindness?.

Frequently asked questions

Can geographic atrophy be cured?

In the European Union the two drugs studied are not authorised^2,9. In the studies they slow the growth of lesions, but probably do not change visual acuity^1,6: they do not bring back sight that has already been lost.

Why is the drug approved in the United States but not in Europe?

In the United States the drug was approved on the basis of studies that showed its effect on the lesions¹; the EMA considered that, without a clinically relevant benefit for patients and with the risks of repeated injections, the balance was not positive².

How fast does geographic atrophy get worse?

It depends on the lesions. In AREDS2, those far from the centre, those made up of several patches, those of intermediate size and cases in which both eyes were affected grew faster³.

Do supplements help in geographic atrophy?

A post hoc analysis of the AREDS and AREDS2 studies, on about 1,200 people with atrophy, found that the supplements studied slowed the advance of the atrophy towards the centre of the macula, but not the overall enlargement of the lesion¹⁰. We discuss this in our article on AREDS and AREDS2.

The story shows what European regulators ask for: it is not enough for images of the retina to change, people who are ill must notice it in everyday life^2,9. So far the drugs studied have not crossed that threshold; the studies of the coming years will tell whether a treatment manages to.