AXPAXLI (axitinib intravitreal implant)

Age-related macular degeneration (AMD) is a spectrum of macular disorders characterized by drusen of at least medium size (63 μm or more) or retinal pigment epithelium abnormalities, typically in people aged 50 years or older. It is a multifactorial disease related to aging, genetic susceptibility (principally the CFH and ARMS2 loci), and environmental factors, of which cigarette smoking is the primary modifiable risk factor. Late AMD has two forms, geographic atrophy and neovascular AMD (nAMD), in which abnormal vessels grow in the macula and leak, causing subretinal and intraretinal fluid, hemorrhage, and fibrosis. An estimated 80% of patients with AMD have the non-neovascular form, but the neovascular form accounts for nearly 90% of severe visual acuity loss (20/200 or worse) from AMD.

In the United States, an estimated 1.49 million people aged 40 years and older were living with late AMD (neovascular AMD and/or geographic atrophy) in 2019, a crude prevalence of 0.94%, rising from 0.02% at ages 40 to 44 years to 11.39% at 85 years or older. The manufacturer's annual report, citing a market research report, states that 1.7 million people in the United States and 14.8 million globally had wet AMD in 2025. The annual incidence of neovascular AMD in White Americans aged 50 years and older was estimated at 1.8 per 1000, and the 3-year incidence of exudative AMD among Americans aged 65 years and older at 9.4 to 11.4 per 1000. In the IRIS Registry, 918,759 patients with nAMD were identified between 2016 and 2021, with a mean age at presentation of 80.2 years. Globally, the pooled prevalence of late AMD in people aged 45 to 85 years was 0.37%, and the number of people with any AMD was projected at 196 million in 2020 and 288 million in 2040. The number of people with vision impairment due to AMD rose from 3.64 million in 1990 to 8.06 million in 2021 and is projected to reach about 21.34 million in 2050. The second eye is frequently affected: in CATT, choroidal neovascularization developed in the fellow eye within 2 years in 75 of 365 participants (20.6%) treated with ranibizumab and 60 of 362 (16.6%) treated with bevacizumab, and the cumulative incidence of second-eye involvement was 54% over 5 years in the Fight Retinal Blindness! registry.

Untreated nAMD causes progressive central vision loss. In a meta-analysis of 4362 untreated participants from interventional studies, mean visual acuity loss was about 4 lines after 24 months, severe vision loss (more than 6 lines) increased from 21.3% at 6 months to 41.9% by 3 years, and the proportion with visual acuity worse than 20/200 increased from 19.7% at baseline to 75.7% by 3 years. In the sham-injection arm of MARINA, visual acuity decreased by 10.4 letters, 62.2% of participants lost fewer than 15 letters at 12 months, and 22.7% had severe vision loss (30 letters or more) at 24 months. Without treatment, exudative macular neovascularization typically results in extensive fibrosis. Late AMD was associated with higher all-cause mortality in a meta-analysis (hazard ratio 1.20, 95% CI 1.02 to 1.41), and in AREDS2, participants with nAMD in one eye had higher mortality than those with no or few drusen (hazard ratio 1.56).

AMD was the leading cause of blindness among White Americans (54.4% of cases) in 2000 and accounts for an estimated 46% of severe visual loss (20/200 or worse) in people older than 40 years in the United States; globally, 1.85 million people were blind due to AMD in 2020. Vision loss continues despite anti-VEGF therapy. In CATT, mean visual acuity at 5 years was 3 letters below baseline and 20% of eyes had visual acuity of 20/200 or worse; in SEVEN-UP, at a mean of 7.3 years, 37% of study eyes had visual acuity of 20/200 or worse and macular atrophy was detected in 98%; and in a meta-analysis of 12 real-world studies (1274 eyes with 10-year follow-up), mean visual acuity declined by 8.11 letters over 10 years. In CATT, the cumulative proportion of eyes with scar was 56% at 5 years, and the cumulative incidence of geographic atrophy was 38% at 5 years. In an English population-based cohort, AMD was associated with higher risks of falls (hazard ratio 1.25) and fractures (hazard ratio 1.18).

The humanistic burden tracks visual acuity in the better-seeing eye: time trade-off utility fell from 0.89 with 20/20 to 20/25 vision to 0.40 with counting fingers to light perception in 80 participants. In a five-country study, 401 participants with bilateral nAMD reported 45% worse vision-related functioning and 42% more depression symptoms than 471 controls, with fall rates of 16% versus 8% and need for assistance with daily activities of 29% versus 7%. Among Medicare beneficiaries, nAMD (n = 1228) was associated with higher odds of diagnosed vision loss (odds ratio 5.39) and of difficulty with instrumental activities of daily living (odds ratio 1.41). Published prevalence of depressive symptoms in AMD ranges from 15.7% to 44%, and in a French nationwide cohort treated nAMD was associated with a 19% increased risk of disability and mood disorders.

Economic burden includes drug, medical, productivity, and caregiver costs. In 2024, fee-for-service Medicare Part B spent $3.0 billion on Eylea (including Eylea HD) for 329,500 users and $1.9 billion on Vabysmo for 173,300 users, and Medicare beneficiaries received 36,398,293 intravitreal anti-VEGF injections from 2014 to 2023. In U.S. commercial claims, mean annual all-cause cost per patient with nAMD was $24,520, and costs were 73% higher for patients with 4 to 6 injections and 342% higher for those with 10 or more injections than for those with 1 to 3 injections per year. A prevalence-based model estimated per-person annual costs of nAMD in the United States at $55,752, including productivity and well-being losses. Informal care is common: in a nine-country survey, 82.1% of 910 participants received support from a caregiver, and in a U.S. study, participants reported that caregivers took time away from work (22%) to provide transportation to appointments.

Treatment burden contributes to undertreatment. Participants in a U.S. time-and-motion study reported almost 12 hours per visit including recovery, 24.2% of participants with nAMD or diabetic macular edema in a multinational survey needed 1 day or more to recover from injections, and in a UK study of 300 participants receiving anti-VEGF treatment, 56% of those providing qualitative data (n = 132) reported anxiety related to treatment. Real-world injection counts are lower than in registration trials: a mean of 7.3 injections in year 1 with a mean gain of 0.95 letter in 49,485 U.S. eyes, and in the IRIS Registry a mean of 7.2 injections in year 1 falling to 4.2 to 4.6 per year in years 3 to 6, with a net loss of 4.6 letters from baseline after 6 years and treatment discontinuation in 38.8% of eyes. Loss to follow-up was 11.6% of 156,327 treatment-naive IRIS Registry participants and 22.2% of 9007 participants in one U.S. practice, and a systematic review of 37 studies reported nonpersistence in up to 50% of patients by 24 months and nonadherence in 32% to 95%. Reasons for undertreatment include the burden of injections and monitoring visits on patients and caregivers.