Summary

With current anti-VEGF therapy, the expected outcome in pivotal trials is prevention of moderate vision loss in most treated eyes and a mean BCVA gain in the first year, followed by maintenance with continued treatment. In MARINA, mean BCVA increased by 7.2 letters with monthly ranibizumab 0.5 mg versus a 10.4-letter decrease with sham at 12 months; in ANCHOR, 96.4% of eyes receiving ranibizumab 0.5 mg lost fewer than 15 letters versus 64.3% with verteporfin. Newer agents achieve similar mean gains with fewer injections: at 2 years, adjusted mean BCVA change with faricimab was +3.7 and +5.0 letters in TENAYA and LUCERNE, with 59.0% and 66.9% of participants on every-16-week dosing at week 112, and at 96 weeks in PULSAR, least squares mean BCVA change was +5.6 and +5.5 letters with aflibercept 8 mg every 12 and 16 weeks versus +6.6 letters with aflibercept 2 mg every 8 weeks. The port delivery system maintained vision with 98.4% of participants needing no supplemental injection in the first 24-week interval, and Portal interim data suggest maintenance for 4 years in a small cohort. Long-term outcomes are lower. At 5 years in CATT, 50% of eyes had visual acuity of 20/40 or better and mean acuity was 3 letters below baseline; at 7.3 years in SEVEN-UP, mean acuity was 54 letters; and in the Fight Retinal Blindness! registry, eyes in Australia and New Zealand that completed 10 years of treatment lost a mean of 0.9 letters with a median of 53 injections, whereas Swiss eyes lost 14.9 letters with a median of 42. In routine care, outcomes are closer to maintenance than gain (mean +0.95 letter at 1 year in a United States database). The sponsor's stated goals for 4D-150 are maintenance of vision with substantially reduced treatment burden after a single injection, and the 4FRONT primary endpoint is noninferiority of BCVA change to aflibercept 2 mg every 8 weeks at 52 weeks.

Prevention of vision loss and first-year gains in pivotal ranibizumab trials

“At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons).” (opens the source at this quote in a new tab)
“The benefit in visual acuity was maintained at 24 months.” (opens the source at this quote in a new tab)

“Of the 423 patients enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P<0.001 for each comparison).” (opens the source at this quote in a new tab)

Maintenance of vision with extended dosing: faricimab and aflibercept 8 mg

“The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]).” (opens the source at this quote in a new tab)

“Aflibercept 8 mg delivered sustained disease control in patients with nAMD, maintaining improvements in visual and anatomic outcomes through week 96 with extended dosing intervals and similar safety profile to aflibercept 2 mg.” (opens the source at this quote in a new tab)

Durability with continuous delivery: port delivery system

“Interim results from Portal suggest 4-year maintenance of visual/anatomic outcomes with PDS 100 mg/mL, with the PDS preferred to monthly injections.” (opens the source at this quote in a new tab)
“Of Ladder-to-Portal previous monthly ranibizumab patients, 92% preferred the PDS over injections.” (opens the source at this quote in a new tab)

Long-term visual outcomes: CATT at 5 years

“At the 5-year visit, 50% of study eyes had VA 20/40 or better and 20% had VA 20/200 or worse.” (opens the source at this quote in a new tab)
“However, 50% of eyes had VA 20/40 or better, confirming anti-VEGF therapy as a major long-term therapeutic advance for neovascular AMD.” (opens the source at this quote in a new tab)

Long-term visual outcomes: SEVEN-UP at 7 years

“At a mean 7.3 years after ANCHOR or MARINA enrollment, mean visual acuity was 54 letters, study eyes having received a mean 1.6 injections per year since the HORIZON study.” (opens the source at this quote in a new tab)

Long-term visual outcomes: 10-year registry data

“The mean VA in 132 eyes (28%) from ANZ patients who completed 10 years of treatment dropped by 0.9 letters from baseline (95% confidence interval [CI], -4.9 to 3.1; P = 0.7) with 42% achieving ≥20/40, whereas the 37 eyes (12%) from Swiss subjects lost 14.9 letters (95% CI, -24 to -5.7; P < 0.001) with 35% achieving ≥20/40.” (opens the source at this quote in a new tab)
“Eyes with nAMD may achieve satisfactory long-term visual outcomes if they receive adequate treatment.” (opens the source at this quote in a new tab)

Long-term outcomes in polypoidal choroidal vasculopathy

“At 6 years, initial visual gains from aflibercept therapy were not maintained; however, nearly half of the eyes had BCVA ≥ 69 letters, and a large proportion achieved polypoidal lesion regression.” (opens the source at this quote in a new tab)

Expected outcomes for 4D-150: phase 3 primary endpoint

“The 4FRONT global Phase 3 registration program consists of two multicenter, randomized, double masked, aflibercept Q8W comparator-controlled trials, with the primary endpoint of BCVA noninferiority of 4D-150 3E10 vg/eye to aflibercept 2mg Q8W at 52 weeks.” (opens the source at this quote in a new tab)
“4D-150 demonstrated consistent and durable benefit across all three patient cohorts as evidenced by maintenance of visual acuity, control of retinal anatomy and reduction of treatment burden at all time points with up to 2 years of follow-up.” (opens the source at this quote in a new tab)

Maintenance of every-12-week brolucizumab dosing through 96 weeks

“The probability that an eye could be maintained on an q12w interval after loading to the DAA at week 92 was 39.7% and 45.4% for the brolucizumab 3 mg and 6 mg treatment groups in HAWK, respectively, and 38.6% for the brolucizumab 6 mg group in HARRIER.” (opens the source at this quote in a new tab)
“In those eyes receiving treatment q12w at the week 44 DAA in HAWK, an 80.5% (brolucizumab 3 mg) and 81.5% (brolucizumab 6 mg) probability of remaining on an q12w interval until the final DAA at week 92 was found, whereas the probability was 75.4% for the brolucizumab 6 mg group in HARRIER.” (opens the source at this quote in a new tab)
“Starting at week 16 (the first DAA), and up to week 92 (the last DAA), HAWK had 8 DAAs and HARRIER had 14 DAAs at which patients could only be adjusted from q12w to q8w therapy.” (opens the source at this quote in a new tab)

Visual acuity maintained to week 96 and the effect of high baseline acuity

“These BCVA gains, comparable across treatment arms and studies, were maintained until week 96, with both the brolucizumab 6 mg group and the aflibercept group gaining between 5.3 and 6.6 ETDRS letters from baseline.” (opens the source at this quote in a new tab)
“These visual acuity gains may have been influenced by a ceiling effect resulting from a high mean baseline BCVA of 60 ETDRS letters (60.6 letters [HAWK] and 61.2 letters [HARRIER], resulting from the upper limit of 78 letters for the BCVA inclusion criterion).” (opens the source at this quote in a new tab)

Interpretation limit on the reported every-12-week proportion

“Unlike real-world clinical practice, eyes in the brolucizumab treatment group that were switched from q12w to q8w therapy based on a DAA were not permitted to move back to q12w treatment.” (opens the source at this quote in a new tab)
“As a consequence, the probability for patients to remain on an q12w regimen at week 96 may be underestimated.” (opens the source at this quote in a new tab)

Duration of anti-VEGF expression reported across AAV gene therapy programs

“Collectively, these programs demonstrate that AAV gene therapy can provide durable anti-VEGF expression for up to 24 months post-injection, significantly reducing treatment burden” (opens the source at this quote in a new tab)

Visual outcomes before anti-VEGF therapy as a benchmark

“Two years after diagnosis, fewer than 10% of patients retained vision of 20/40 or better with no treatment and fewer than 15% of patients treated with photodynamic therapy retained 20/40 or better.” (opens the source at this quote in a new tab)

Mean acuity relative to baseline at five years

“Mean visual acuity at 5 years was 3 letters worse than baseline, highlighting an unmet need for further therapeutic advances.” (opens the source at this quote in a new tab)

Expected gain in eyes with poor baseline vision

“Only eyes with 20/200 or less at baseline exhibited a gain in mean VA following treatment, yet these groups were only able to reach the still significantly limited VA of 20/160 after 2 years of treatment.” (opens the source at this quote in a new tab)