Acuity and microperimetry: why Europe refused a drug the US approved

The US approved pegcetacoplan, the first drug for geographic atrophy, in February 2023 on scans showing slower lesion growth. The European Medicines Agency's assessment report explains why Europe refused it: over 24 months no prespecified measure of function, acuity and microperimetry included, showed a meaningful difference or even a positive trend to weigh against the risks of regular injections. The MHRA's UK rejection was reported in January 2025.

Chart and scan disagree earlier in the disease too. A study published in September in the American Journal of Ophthalmology suggests why: in early atrophic AMD, with lesions far smaller than the trials', acuity tracked distance from the fovea and microperimetry tracked lesion size.

What the trials measured

OAKS and DERBY randomised 1,258 patients with geographic atrophy of 2.5 to 17.5 mm² to pegcetacoplan monthly or every other month, or sham, for 24 months, measured on fundus autofluorescence. The FDA's label gives modelled growth over 24 months of 3.98 mm² with sham in OAKS and 4.00 mm² in DERBY, and 0.70 to 0.87 mm² less with pegcetacoplan, 17.4% to 21.9% slower.

Every key secondary endpoint measured function: acuity, reading speed, a reading-independence index and, in OAKS only, microperimetry. None showed a meaningful difference or a positive trend. A late, post hoc OCT analysis found photoreceptor loss slowing even more. The committee's answer:

the observed reduction of the GA lesion growth rate (regardless of the specific measurement) remains an anatomical endpoint that can in itself not demonstrate clinically relevant patient benefit.

What the US and Europe each accepted

Europe had agreed lesion area could be the primary measure if the trials showed at least a positive trend in visual function. Its experts, in June 2024, called lesion size an acceptable primary outcome and microperimetry the best available test of retinal function in geographic atrophy, with acuity measured but not as the primary endpoint. The committee accepted that acuity can miss loss while the fovea is spared, but acuity fell 6.94 letters over two years with sham, so a real effect should at least have shown as a trend.

It refused by majority, weighing the missing benefit against the risks of regular injections, including wet AMD, inflammation and endophthalmitis. Eleven members dissented: with the fovea spared so long, a benefit may not have been possible to show within the trials, and post hoc microperimetry showed the preserved retina still responded to light. The majority judged them inconsistent between doses, at around one scotomatous point.

The FDA has also approved a treatment on an OCT primary endpoint. Encelto's label, for macular telangiectasia type 2, gives the rate of ellipsoid zone loss on SD-OCT over 24 months: 0.075 against 0.166 mm² with sham in one trial, 0.111 against 0.160 in the other. Its secondary microperimetry endpoint differed in the first (p = 0.02), not the second (p = 0.83).

Microperimetry and acuity in early atrophy

The Utah study took 87 eyes with early atrophic AMD, lesions no larger than 1.27 mm². In the 38 with atrophy on autofluorescence, each doubling of lesion size went with 3.55 dB lower mesopic sensitivity on microperimetry aimed at the lesion. Acuity, low luminance acuity and reading followed distance from the fovea, about 4 to 5 letters per mm for acuity, with no consistent link to lesion size. We could read only its abstract, and nothing here goes beyond it.

In a Dutch study of 102 AMD patients, most with late AMD in at least one eye, acuity in the better-seeing eye explained 38% of the variation in daily visual functioning, and adding mesopic microperimetry on a fixed 37-point grid raised that only to 46%. The authors suggest acuity gives stronger evidence of clinical efficacy.

Why it matters in practice

• A 6/6 beside atrophy on the OCT is consistent with a spared fovea, not proof of one, and says nothing about the atrophy's size. Check the fovea on the OCT and record how far the atrophy sits from it.
• The Vision Academy's consensus recommends low luminance acuity alongside standard acuity: the ETDRS chart through a 2.0 log unit neutral density filter, simple, inexpensive and relatively rapid, though not yet standardised. In the Utah eyes it followed the fovea too.
• A patient asking about the US injections for geographic atrophy can be told the first was refused in Europe and the UK: no benefit to sight was shown to set against the risks of injections. Our interactive simulation of dry AMD shows its stages.
• ARCHER II, a phase 3 trial of vonaprument in 659 patients, is judged on the proportion losing 15 letters or more by month 15, with primary completion estimated for October 2026.

The caveats

• Both regulators accepted that the drug slowed lesion growth. Europe's final assessment covered every other month dosing only, monthly dosing having been dropped over adverse events.
• DERBY narrowly missed its prespecified 12-month primary endpoint. The difference was larger at 24 months, but that was not the prespecified test.
• The Utah and Dutch studies are cross-sectional, with different patients and microperimetry methods.
• The Vision Academy is funded by Bayer, and Bayer part-funded the Dutch study.

Sources

1. 1.Syfovre: EPAR, refusal public assessment report (EMA/328209/2025) · European Medicines Agency, 14 August 2025
2. 2.Structure-function associations in eyes with early atrophic age-related macular degeneration · American Journal of Ophthalmology, 26 September 2026
3. 3.Visual acuity provides a more meaningful measure of vision-related functioning than mesopic microperimetry in age-related macular degeneration patients: a cross-sectional study · Translational Vision Science & Technology, 1 February 2026
4. 4.SYFOVRE (pegcetacoplan injection), prescribing information · US Food and Drug Administration, 17 February 2023
5. 5.ENCELTO (revakinagene taroretcel-lwey), prescribing information · US Food and Drug Administration
6. 6.ARCHER II: vonaprument (ANX007) in geographic atrophy, NCT06510816 · ClinicalTrials.gov, 4 May 2026
7. 7.First treatment for late-stage dry AMD rejected by UK drug regulator · Macular Society, 22 January 2025
8. 8.Additional measures of macular function beyond visual acuity · Graefe's Archive for Clinical and Experimental Ophthalmology, 8 November 2023