Wet macular degeneration: what the trials show about eye injections, longer intervals and the newest drugs

If you or someone close to you has been diagnosed with "wet" age-related macular degeneration, the treatment usually arrives as a schedule rather than a single procedure: an injection into the eye, then another, then another, sometimes for years. The questions are practical: does this protect sight, can injections be less frequent, and what about the new drugs in the news? Here is what the large trials have shown, in whom, and what they leave open.

This material is for information only and does not replace a consultation with a doctor.

What is "wet" macular degeneration, in plain terms?

The macula is the small central area of the retina that handles reading, faces and fine detail. In the "wet", or neovascular, form of age-related macular degeneration, fragile new blood vessels grow beneath the retina and leak fluid. Central vision can become blurred or distorted. The main driver of that vessel growth is a signalling protein called vascular endothelial growth factor A (VEGF-A), and almost every treatment discussed below works by blocking it.

The condition is common at the population level. A meta-analysis of 39 population studies with 129,664 people put the prevalence of any age-related macular degeneration at about 8.7% and of the late forms at about 0.37% between the ages of 45 and 85.

What did the original injection trials show?

Two randomised trials published in 2006 set the standard. In MARINA, 716 patients with minimally classic or occult lesions received monthly ranibizumab injections or sham injections. At 12 months, about 95% of treated patients had lost fewer than 15 letters on the eye chart, compared with 62% on sham, and mean vision improved by 6.5–7.2 letters on ranibizumab while it fell by 10.4 letters on sham. ANCHOR, in 423 patients with predominantly classic lesions, compared ranibizumab with verteporfin photodynamic therapy. The direction was the same, though the exact figures differed: fewer people lost 15 letters on ranibizumab, and mean vision rose on ranibizumab and fell on photodynamic therapy.

What these trials do not say matters as much. They lasted two years and used strict monthly dosing. When researchers re-examined 65 patients from ANCHOR, MARINA and the HORIZON extension a mean of 7.3 years after entry, 37% saw 20/70 or better, 37% saw 20/200 or worse, and 34% had lost 15 letters or more. Macular atrophy (thinning of the retina) was found in 98% of eyes. The injections had not removed the disease. A subgroup that received 11 or more injections after leaving HORIZON had a better letter-score change, but that was an observation inside the cohort, not a randomised test of continuous treatment.

Does the specific drug matter?

Less than one might expect. In the CATT trial, 1,208 patients were randomly assigned to ranibizumab or bevacizumab, a related antibody used off-label. When given on the same schedule, the two drugs produced equivalent gains in vision at one year: bevacizumab 8.0 versus ranibizumab 8.5 letters monthly, and 5.9 versus 6.8 letters as needed. Serious systemic adverse events (mostly hospitalisations) were somewhat more frequent with bevacizumab, 24.1% versus 19.0%, but they were spread across disease categories not previously linked to the drug, and the authors called for further study rather than drawing a conclusion.

Can the injections be spaced further apart?

Brolucizumab, faricimab and aflibercept 8 mg have been tested against aflibercept 2 mg every eight weeks in people starting treatment. The implant further down was studied in people already responding to injections, against monthly ranibizumab.

• Brolucizumab (HAWK and HARRIER). Vision gains were non-inferior to aflibercept at week 48, and just over half of eyes on the 6 mg dose (56% and 51%) stayed on 12-week dosing through week 48. A later independent review of the same trials found definite or probable intraocular inflammation in 4.6% of brolucizumab-treated eyes, sometimes with retinal vasculitis and vessel occlusion, and a loss of at least 15 letters linked to that inflammation in 0.74%; with aflibercept the inflammation rate was 1.1%.

• Faricimab (TENAYA and LUCERNE). This antibody blocks both VEGF-A and angiopoietin-2. In 1,329 patients aged 50 or older, faricimab given at intervals of up to 16 weeks produced vision changes non-inferior to aflibercept every eight weeks (treatment differences of 0.7 and 0.0 letters), with comparable rates of ocular adverse events.

• Higher-dose aflibercept 8 mg (PULSAR). In 1,011 patients, 8 mg every 12 or 16 weeks was non-inferior to 2 mg every eight weeks at week 48 (+6.7 and +6.2 versus +7.6 letters), with similar rates of ocular adverse events.

• A refillable implant (Archway). In 418 patients already responding to injections, a surgically implanted reservoir refilled every 24 weeks was equivalent to monthly ranibizumab for vision. The trade-off was surgery: prespecified ocular adverse events of special interest occurred in 19.0% of implant patients versus 6.0% on monthly injections, including endophthalmitis in 1.6%.

Two cautions run through all of these. First, non-inferiority means "not worse by more than a pre-set margin", usually four letters; it does not mean any drug is better for vision. Second, the longer intervals were reached by protocol in trial conditions, and not every eye in every trial could stay on them.

What is new right now?

On 28 September 2026 the company Kodiak Sciences announced that two investigational drugs, tarcocimab tedromer and tabirafusp alfa tedromer (tabirafusp-ted, which the company describes as blocking both VEGF and interleukin-6), met their primary endpoint in the phase 3 DAYBREAK trial. According to its registry entry, DAYBREAK compares each drug with aflibercept 2 mg in people with wet macular degeneration, with vision at week 48 as the primary outcome. The announcement reports non-inferiority on vision. At the time of writing these are company-reported results: they have not been published in a peer-reviewed journal, and neither drug has been approved. Whether adding an interleukin-6 blocker changes the course of the disease beyond what VEGF blockade does is an open question that this trial was not designed to answer.

What about supplements?

They address a different situation. The AREDS2 trial enrolled 4,203 people aged 50–85 with intermediate disease or advanced disease in one eye, all of whom were offered the original AREDS formula of antioxidant vitamins and zinc. Adding lutein and zeaxanthin, omega-3 fatty acids, or both did not significantly reduce progression to advanced disease in the primary analysis. Supplements are discussed for slowing progression from intermediate disease; they are not a treatment for active wet macular degeneration.

What to do with this information

• If wet macular degeneration has been diagnosed, note that the trials in which vision was preserved were trials of regular treatment. Whether to start and how often to return is a decision for the retinal specialist.

• If the number of visits is the main difficulty, the interval question is worth raising with the retinal specialist. Several options have been shown to allow longer intervals in many, though not all, eyes, and each has its own safety profile.

• Sudden distortion of straight lines or a new blurred spot in central vision is a reason for prompt examination rather than waiting for the next routine appointment.

For another common age-related change in vision and how its treatments were tested, see our article on presbyopia.

This material is for information only and does not replace a consultation with a doctor.

References

• Wong WL, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014. PMID 25104651

• Rosenfeld PJ, et al. Ranibizumab for neovascular age-related macular degeneration (MARINA). N Engl J Med. 2006. PMID 17021318

• Brown DM, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration (ANCHOR). N Engl J Med. 2006. PMID 17021319

• Rofagha S, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON (SEVEN-UP). Ophthalmology. 2013. PMID 23642856

• CATT Research Group; Martin DF, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011. PMID 21526923

• Dugel PU, et al. HAWK and HARRIER: phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020. PMID 30986442

• Monés J, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab: post hoc review of HAWK and HARRIER. Ophthalmology. 2021. PMID 33207259

• Heier JS, et al. Faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE). Lancet. 2022. PMID 35085502

• Lanzetta P, et al. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR). Lancet. 2024. PMID 38461841

• Holekamp NM, et al. Archway randomized phase 3 trial of the Port Delivery System with ranibizumab. Ophthalmology. 2022. PMID 34597713

• Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration (AREDS2). JAMA. 2013. PMID 23644932

• DAYBREAK: tarcocimab tedromer and tabirafusp tedromer compared with aflibercept in wet AMD. ClinicalTrials.gov. NCT06556368