4D-150

4D-150 is an investigational intravitreal adeno-associated virus gene therapy given as a single injection. It uses the synthetic R100 capsid, evolved in nonhuman primates for intravitreal delivery to the retina, and carries two transgenes: a codon-optimized sequence encoding aflibercept, which inhibits VEGF-A, VEGF-B, and PlGF, and a microRNA that inhibits expression of VEGF-C. The dose taken into phase 3 is 3E10 vg/eye. Clinical evidence comes from PRISM (NCT05197270), a phase 1/2 trial with several cohorts: a phase 1 dose exploration (15 participants, 5 each at 3E10, 1E10, and 6E9 vg/eye), a randomized phase 2a dose expansion (51 participants randomized 2:2:1 to 3E10 vg/eye [20 participants], 1E10 vg/eye [21], or aflibercept 2 mg every 8 weeks [10]), and an open-label phase 2b population extension (45 participants; 30 at 3E10 vg/eye and 15 at 1E10 vg/eye). In total, 71 participants have received the phase 3 dose. Two phase 3 trials are fully enrolled but have reported no results: 4FRONT-1 (523 participants randomized, North America, treatment-naive) and 4FRONT-2 (more than 500 participants expected, 14 countries, including up to 40% previously treated). Both compare a single injection of 4D-150 with aflibercept 2 mg every 8 weeks for noninferiority in mean BCVA change at 52 weeks, with supplemental aflibercept allowed in both arms.

Injection burden is the outcome on which 4D-150 has been reported most consistently. In the phase 2b cohort at 2 years (data cutoff May 18, 2026), the 30 participants at 3E10 vg/eye received a mean of 2.7 supplemental injections, a 78% reduction versus the 12.0 injections projected for on-label aflibercept 2 mg every 8 weeks, with 46% injection-free and more than 50% receiving 0 or 1 injection; the 15 participants at 1E10 vg/eye received a mean of 3.7 injections (69% reduction). In the recently diagnosed subgroup at 3E10 vg/eye (15 participants), the mean was 1.6 injections (87% reduction) and 66% were injection-free. At week 52 the same 3E10 vg/eye cohort had a mean of 0.97 injections (83% reduction versus 6.0 projected), 70% with 0 or 1 injection, and 57% injection-free, and the recently diagnosed subgroup had 0.33 injections (94% reduction) and 80% injection-free; the reduction at 3E10 vg/eye fell from 83% at 1 year to 82% at 1.5 years and 78% at 2 years. In the randomized phase 2a dose expansion at 24 weeks (data cutoff January 19, 2024), the annualized anti-VEGF injection rate fell 89% at 3E10 vg/eye (20 participants), with 84% receiving 0 or 1 injection and 63% injection-free, and 85% at 1E10 vg/eye (21 participants), with 90% and 50%. In the pooled phase 1/2a population at 3E10 vg/eye (24 participants), reduction versus each participant's injections in the prior 12 months was 83% through year 1 and 79% through year 2 (data cutoff August 22, 2025). In the phase 1 dose exploration, 4 of 5 participants (80%) at 3E10 vg/eye were injection-free at 24 weeks, and the 3 participants injection-free beyond 52 weeks remained so through about 2 to 2.5 years.

Vision results are smaller in magnitude and less certain. The only comparison with a concurrent aflibercept arm is the phase 2a dose expansion at 24 weeks: the adjusted mean BCVA difference versus aflibercept 2 mg every 8 weeks (10 participants), averaged over weeks 20 and 24, was -1.8 letters (95% CI -7.6 to 4.1) at 3E10 vg/eye and +1.8 letters (95% CI -3.8 to 7.4) at 1E10 vg/eye, and the CST differences were -8.3 µm and +29.9 µm; every interval includes zero, and the cohort was powered for injection counts rather than acuity. In the phase 2b cohort, mean BCVA change at week 52 was +2.2 letters with censoring of assessments confounded by cataract or surgery and +1.0 letter without censoring, with a mean CST change of -11 µm; the recently diagnosed subgroup had +3.1 letters and -10 µm. At 24 weeks in the phase 2b cohort, adjusted mean BCVA change was +3.5 letters (95% CI 1.1 to 5.8) at 3E10 vg/eye and -2.2 letters (95% CI -5.9 to 1.4) at 1E10 vg/eye. Two-year BCVA and CST were described as maintained, with values presented only in figures. In the phase 1 cohort at 3E10 vg/eye, mean BCVA was 1 letter above baseline and mean CST 110 µm below baseline through about 2 years.

Reported safety at the phase 3 dose is based on 71 participants. Within approximately the first 28 weeks after dosing, 2 of 71 (2.8%) had 4D-150-related 1+ mild intraocular inflammation, described as transient vitreous cells at a single timepoint, and no new cases were reported thereafter with 2 to more than 4 years of follow-up as of the July 2026 data cutoff. No 4D-150-related hypotony, endophthalmitis, vasculitis, occlusive or non-occlusive retinal vasculitis, or choroidal effusions have been observed, and no 4D-150-related serious adverse events have been reported. Seventy of 71 participants (99%) completed the approximately 20-week prophylactic topical corticosteroid taper on schedule and 70 of 71 (99%) remained completely off steroids. One case of endophthalmitis, presumed bacterial, was attributed to a supplemental aflibercept injection rather than to 4D-150. At the lower 1E10 vg/eye dose in the phase 2b cohort, 1 of 15 participants (1 of 45 in that cohort, about 2%) had mild to moderate vitreous inflammation, with vitreous cells also observed in the untreated fellow eye. Frequency tables for treatment-emergent adverse events have not been released.

No randomized phase 3 results exist for 4D-150, and no peer-reviewed full publication of PRISM was identified; all results come from company announcements and congress presentations. The phase 2b cohort was single-arm and open-label, and its burden reduction was measured against a projected on-label aflibercept schedule (6.0 injections at 52 weeks and 12.0 at 2 years) derived from a single-arm model rather than against observed injections in a comparator arm, while phase 1 and phase 2a burden reduction was measured against each participant's injection count in the prior 12 months. Sources disagree on several values. For the phase 2b cohort at 52 weeks, a September 2024 Kaplan-Meier analysis reported an 89% reduction with 80% receiving 0 or 1 injection and 70% injection-free, whereas the January 2025 cutoff reported 83%, 70%, and 57%. For the phase 3-eligible subgroup of the phase 2a dose expansion, the company announcement reported a BCVA difference of +3.3 letters versus aflibercept while the congress slides for the same subgroup show +2.4 letters. The inflammation-free follow-up interval was described as approximately 1.5 to more than 3.5 years in the November 2025 announcement and as 2 to more than 4 years in the July 2026 announcement. Topline 52-week results are expected in the second quarter of 2027 for 4FRONT-1 and the second half of 2027 for 4FRONT-2.