Summary

Current standard of care for neovascular AMD consists of repeated intravitreal anti-VEGF injections that suppress, but do not cure, the disease. Labeled maintenance intervals range from every 4 weeks (ranibizumab) to every 8 to 16 weeks (aflibercept 8 mg, faricimab); in PULSAR, participants completing 96 weeks received a mean of 8.2 to 12.8 injections, and through year 2 of TENAYA and LUCERNE the median number of faricimab injections was 10. Outcomes in routine practice are lower than in trials. In 49,485 treatment-naive eyes in a United States retina database, a mean of 7.3 injections in year 1 produced a mean gain of 0.95 letter, and in an 8-country study of 2,227 patients, mean injections fell from 5.0 in year 1 to 2.2 in year 2, with mean gains of +2.4 and +0.6 letters. In one United States practice, 2,003 of 9,007 patients (22.2%) were lost to follow-up after anti-VEGF injections, and a systematic review reported that up to 50% of patients stopped treatment by 24 months. Visits are time intensive: a time-and-motion study reported an average of almost 12 hours per visit from the patient perspective, including recovery. Long-term vision declines despite treatment: in the CATT cohort, mean visual acuity at 5 years was 3 letters below baseline and 11 letters below the 2-year value, and in SEVEN-UP macular atrophy was present in 98% of study eyes at a mean of 7.3 years. Longer-acting options carry specific risks: brolucizumab labeling warns of retinal vasculitis and retinal vascular occlusion, and the port delivery system requires surgical implantation, carries a boxed warning for an up to 3-fold higher rate of endophthalmitis than monthly ranibizumab (11 of 555 patients, 2%), and was voluntarily recalled in 2022 before reintroduction in 2024. Branded anti-VEGF agents account for a large share of Medicare Part B drug spending; ranibizumab and aflibercept accounted for 12% of the Part B budget in 2011 to 2015.

Real-world undertreatment and visual outcomes in the United States

“At 1 year, after a mean of 7.3 anti-VEGF injections, there was a mean gain of 1 letter (0.95 letter; 95% confidence interval [CI] for change in VA, +0.77 to +1.13 letter; P < 0.001).” (opens the source at this quote in a new tab)
“Real-world nAMD patients receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials.” (opens the source at this quote in a new tab)
“Older patients and those with poor baseline VA may be particularly prone to undertreatment.” (opens the source at this quote in a new tab)

Real-world injection frequency and loss of initial visual gains: multi-country study

“Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively. Patients received a mean of 5.0 and 2.2 injections in the first and second year, respectively.” (opens the source at this quote in a new tab)
“In clinical practice, fewer injections are administered than in clinical trials.” (opens the source at this quote in a new tab)

Real-world treatment falls short of trial protocols

“Real-world treatment tends to fall short of clinical trial guidelines and protocols, and it results in worse outcomes.” (opens the source at this quote in a new tab)

“The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance.” (opens the source at this quote in a new tab)

Nonadherence, nonpersistence, and loss to follow-up

“Nonpersistence occurred early, with up to 50% of patients stopping treatment by 24 months. High rates of nonadherence were similarly reported, occurring in 32% to 95% of patients.” (opens the source at this quote in a new tab)

“Among the 9007 patients (mean [SD] age, 81.2 [8.8] years; 5917 [65.7%] female; 7905 [87.8%] white), 2003 (22.2%) were LTFU.” (opens the source at this quote in a new tab)

“LTFU rates ranged from <5% to >75% over up to 10 years.” (opens the source at this quote in a new tab)
“Patients who were LTFU had worse visual outcomes even after resuming care.” (opens the source at this quote in a new tab)

Time burden on patients, caregivers, and practices

“An average patient visit for neovascular AMD was 90 minutes (range: 13 minutes to >4 hours). Patients reported an average time per visit of almost 12 hours, including preappointment preparation (16 minutes), travel (66 minutes), waiting time (37 minutes), treatment time (43 minutes), and postappointment recovery (9 hours).” (opens the source at this quote in a new tab)
“Patients stated that caregivers took time away from work (22%) and personal activities (28%) to provide transportation to appointments.” (opens the source at this quote in a new tab)

Long-term decline in vision despite treatment

“Vision gains during the first 2 years of the trial were not maintained at 5 years.” (opens the source at this quote in a new tab)
“Mean change in VA was -3 letters from baseline and -11 letters from 2 years.” (opens the source at this quote in a new tab)

“Macular atrophy was present in 98% of study eyes, the mean area increasing from 0.83 ± 0.96 mm(2) at the ANCHOR or MARINA year 2 exit to 2.22 ± 1.6 mm(2) at the SEVEN-UP visit, a growth rate of 0.28 mm(2)/year.” (opens the source at this quote in a new tab)

Sponsor-described limitations of bolus anti-VEGF injections

“Each anti-VEGF injection requires an in-office visit, which carries significant burden and discomfort to patients, and when patients miss injections, they may experience vision decline due to undertreatment.” (opens the source at this quote in a new tab)
“Based on real world data for wet AMD, approximately 40% of patients discontinue treatment by year one, and early vision gains are followed by steady long-term vision decline, which is associated with declining injection frequency.” (opens the source at this quote in a new tab)

Cost to Medicare Part B

“Ranibizumab and aflibercept costs account for 12% of the Medicare Part B budget annually.” (opens the source at this quote in a new tab)

“Medicare costs for anti-VEGF injections increased from 2.51 B USD in 2014 to 4.02 B USD in 2019.” (opens the source at this quote in a new tab)

Unresolved challenges for gene therapy approaches

“Although promising, challenges including long-term safety, complex delivery procedures, immune responses, regulatory hurdles, and the need for optimized vectors and clinical protocols must be addressed before widespread adoption and integration into standard care.” (opens the source at this quote in a new tab)

Injection frequency and atrophy: conflicting analyses across trials

“The 2-year CATT analysis revealed an increased association between atrophy incidence and frequent treatment and also demonstrated a reduced incidence from year 1 to 2 among patients switched from monthly to PRN treatment; at the 5-year visit, the differences were no longer significant.” (opens the source at this quote in a new tab)
“Importantly, follow-up analyses of HARBOR and IVAN revealed no difference in atrophy incidence with monthly or continuous versus PRN or discontinuous treatment, in contrast with initial findings.” (opens the source at this quote in a new tab)
“For example, when images from HARBOR were analyzed with SD OCT, no difference in atrophy with monthly versus PRN was noted, in contrast with previous findings on CFP or FA.” (opens the source at this quote in a new tab)

Reducing injection frequency because of atrophy concern carries a risk of vision loss

“Reducing the frequency of anti-VEGF therapy to allay concerns of atrophy could lead to vision loss; however, titration, or dose adjustment, could be used to mitigate concerns about atrophy development.” (opens the source at this quote in a new tab)
“Because undertreatment of MNV is deleterious to vision, caution should be taken when extending treatment intervals because of concern regarding atrophy.” (opens the source at this quote in a new tab)
“No treatment for atrophy currently exists; therefore, physicians rely on cues from atrophy phenotype and risk factors when making treatment decisions.” (opens the source at this quote in a new tab)

4D-150

Limitations of current therapies