Summary

Current treatment of neovascular AMD relies on repeated intravitreal injections of anti-VEGF agents given monthly, every 8 weeks, or at extended intervals of up to 16 weeks under treat-and-extend or personalized-interval regimens, with continuous office monitoring. Real-world patients receive fewer injections than trial participants and have smaller visual gains: in 49,485 treatment-naive United States eyes, the mean gain at 1 year was 0.95 letter after a mean of 7.3 injections; in the eight-country AURA study (2,227 patients), mean gains were +2.4 letters at year 1 and +0.6 letters at year 2 with 5.0 and 2.2 injections; and in LUMINOUS (3,379 treatment-naive patients with 1-year data), the mean gain was 3.1 letters with 5.0 injections. In one United States retina practice, 2,003 of 9,007 patients (22.2%) were lost to follow-up for 12 months or longer after an injection. In CATT, vision gains from the first 2 years were not maintained at 5 years. Agent-specific safety limitations include intraocular inflammation with retinal vasculitis or occlusion after brolucizumab (definite or probable intraocular inflammation in 4.6% of brolucizumab-treated eyes in HAWK and HARRIER) and endophthalmitis in 11 of 555 participants (2.0%) who received the port delivery system with ranibizumab, which carries a boxed warning and was voluntarily recalled in 2022 before reintroduction in 2024. Payer prior authorization requests for anti-VEGF agents were approved in 96.2% of cases but delayed care by more than 24 hours in 59.6% of approvals.

Real-world undertreatment and visual outcomes: United States retina database

“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 visual outcomes: AURA multi-country study

“Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively.” (opens the source at this quote in a new tab)
“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. Anti-VEGF treatment resulted in an initial improvement in visual acuity; however, this was not maintained over time.” (opens the source at this quote in a new tab)

Real-world visual outcomes: LUMINOUS treatment-naive patients

“The mean (SD) visual acuity (VA; letters) gain at 1 year was 3.1 (16.51) (n = 3,379; BLVA, 51.9 letters [Snellen: 20/92]) with a mean (SD) of 5.0 (2.7) injections and 8.8 (3.3) monitoring visits.” (opens the source at this quote in a new tab)

Nonadherence and loss to follow-up

“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)
“Loss to follow-up is not uncommon in patients with neovascular AMD.” (opens the source at this quote in a new tab)

Loss to follow-up in a United States retina practice

“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)

Long-term vision loss despite anti-VEGF treatment

“The CATT 5-year follow-up study demonstrated that vision gains during the first 2 years were not maintained at 5 years.” (opens the source at this quote in a new tab)
“The PRN regimens using ranibizumab appear to have efficacy and safety comparable to fixed monthly regimens over 1 year of treatment, but they do not maintain the initial visual gains with longer follow-up.” (opens the source at this quote in a new tab)

Injection frequency and treatment burden: sponsor description

“These treatments are injected in a physician’s office either monthly, bi-monthly or in some patients every three to four months, which can cause inconvenience and often leads to reduced compliance and poor outcomes.” (opens the source at this quote in a new tab)

Brolucizumab: intraocular inflammation, retinal vasculitis, and occlusion

“On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%).” (opens the source at this quote in a new tab)
“There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion).” (opens the source at this quote in a new tab)

Brolucizumab every 4 weeks in recalcitrant disease

“However, the incidence of intraocular inflammation, including retinal vasculitis and retinal vascular occlusion, was 11.5% for brolucizumab and 6.1% for aflibercept.” (opens the source at this quote in a new tab)

Port delivery system with ranibizumab: endophthalmitis and device complications

“Importantly, after using the implant, there was a 2% risk of endophthalmitis in clinical trials (a rate three times higher than monthly intravitreal injections of ranibizumab).” (opens the source at this quote in a new tab)
“Other risks included vitreous hemorrhage, rhegmatogenous retinal detachment, implant dislocation, septum dislodgement, conjunctival erosion, conjunctival retraction, and conjunctival blebs.” (opens the source at this quote in a new tab)

Prior authorization delays for anti-VEGF agents

“Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service.” (opens the source at this quote in a new tab)
“The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes.” (opens the source at this quote in a new tab)

Monitoring visits during extended-interval dosing in the faricimab phase 3 trials

“Finally, the assessment of the potential for faricimab to reduce treatment burden and improve quality of life might also be limited by the fact that at the time of the primary analysis, all patients returned for monthly visits to maintain masking.” (opens the source at this quote in a new tab)

Brolucizumab: postmarketing event rates per 10 000 injections and timing of inflammation onset

“On August 28, 2020, postmarketing data indicated that Novartis had received reports of evidence of associated retinal vasculitis and retinal vascular occlusion at a rate of 4.71 per 10 000 brolucizumab injections, while individual events of retinal vasculitis and retinal vascular occlusion were reported at rates of 3.61 and 2.35 per 10 000 injections, respectively.” (opens the source at this quote in a new tab)
“Approximately three quarters of cases of each event occurred within the initial 6 months after the first injection.” (opens the source at this quote in a new tab)
“Notably, patients whose first IOI-related event occurred more than 12 months after the first injection had no reported vision loss at the end of the study.” (opens the source at this quote in a new tab)

Visual acuity change by anti-VEGF injection count over 1 year

“At the lower range, those patient eyes that received 4 anti-VEGF injections or fewer in the first year of treatment generally lost vision, approximately 2 to 3 letters at 1 year.” (opens the source at this quote in a new tab)
“In the mid range, a linear relationship was found between mean letters gained and mean number of anti-VEGF injections, up to 10 injections over 1 year, after which the relationship plateaued at approximately 3 to 4 letters gained.” (opens the source at this quote in a new tab)
“Patient eyes that received 4 anti-VEGF injections or fewer over 1 year generally showed worse mean baseline VA than those patient eyes that received a greater number of injections over 1 year.” (opens the source at this quote in a new tab)
“Those who received 1 anti-VEGF injection had a mean baseline age of 81.1 years, whereas those who received 13 injections over 1 year had a mean baseline age of 78.4 years” (opens the source at this quote in a new tab)

Variable-frequency regimens and the gap from registration-trial outcomes

“Registration trials for ranibizumab (monthly) and aflibercept (every 2 months after 3 monthly loading doses) and the monthly ranibizumab and bevacizumab arms of CATT show an average 1-year improvement of 8.5 letters across these studies” (opens the source at this quote in a new tab)
“The 2015 American Society of Retina Specialists Preferences and Trends Survey of more than 2700 retina specialists in 60 countries revealed that more than 90% of retina specialists, both in the United States and internationally, use OCT-guided variable frequency anti-VEGF treatment protocols for nAMD.” (opens the source at this quote in a new tab)
“Multiple prospective RCTs have demonstrated that variable frequency anti-VEGF therapy for nAMD results in a less favorable visual outcome compared with fixed, frequent anti-VEGF suppression.” (opens the source at this quote in a new tab)
“Consequently, attempts to limit treatment burden through the adoption of variable frequency anti-VEGF treatment regimens must be approached cautiously.” (opens the source at this quote in a new tab)

Loss to follow-up and nonpersistence: national registry rates and risk factors

“This big data retrospective cohort study from the IRIS Registry of 185 138 eyes of 156 327 patients who were documented with treatment-naive neovascular AMD and subsequently were treated with anti-VEGF therapy in the United States disclosed an LTFU rate of 11.6%.” (opens the source at this quote in a new tab)
“Risk factors for being LTFU included increasing age, male sex, Black or African American race or ethnicity, diabetes, unilateral involvement, and Medicaid health insurance. The rate of nonpersistence in this same cohort was 14.3%.” (opens the source at this quote in a new tab)
“Health insurance is also a risk factor because patients with Medicaid insurance were more likely to be LTFU and nonpersistent, whereas patients with Medicare insurance were less likely to be LTFU and nonpersistent than patients with private insurance.” (opens the source at this quote in a new tab)
“Among patients who were LTFU, the average time from the first intravitreal injection to the last visit was 2.4 years and was 4.4 years for patients not LTFU.” (opens the source at this quote in a new tab)

Visual acuity at last visit by follow-up status

“Compared with patients without nonpersistence during the same follow-up period, a lower percentage of patients with nonpersistence showed VA of 20/40 or better (35% vs. 43%; P < 0.001) at the last visit” (opens the source at this quote in a new tab)
“Compared with patients without nonpersistence during the same follow-up period, a higher percentage of patients with nonpersistence lost > 5 ETDRS letters (40% vs. 36%; P < 0.001; Table 5) in the treated eye.” (opens the source at this quote in a new tab)
“Twelve percent of patients who were LTFU did later undergo follow-up (defined as after the first year and within 4 years of the last anti-VEGF intravitreal injection).” (opens the source at this quote in a new tab)

Duravyu (vorolanib intravitreal insert)

Limitations of current therapies