Registered trial objective

“Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment.” (opens the source at this quote in a new tab)

Objective of the randomized dose expansion analysis

“Here we report initial results from the PRISM randomized phase 2 dose expansion study” (opens the source at this quote in a new tab)

Registry dates for the overall PRISM trial

Milestone	Registry record
Study start (actual)	“2021-12-09”
Primary completion (estimated)	“2027-03”
Study completion (estimated)	“2031-01”

Study sites

“PRISM is a multicenter, Phase 1/2 open-label dose exploration and randomized dose expansion study evaluating 4D-150 (NCT05197270)” (opens the source at this quote in a new tab)

“Barnet Delaney Perkins Eye Center” (opens the source at this quote in a new tab)
“Emanuelli Research and Development Center, LLC” (opens the source at this quote in a new tab)

Randomized, controlled, outcome assessor-masked dose expansion versus aflibercept

“In Dose Expansion, subjects (n=50) will be randomized to receive one of 2 dose levels of 4D-150 (n=20 for each dose level) based on results from Dose Escalation, or aflibercept (n=10).” (opens the source at this quote in a new tab)
“During Dose Expansion, outcome assessors will be masked to treatment assignment. Other site personnel (including investigator) and subjects will be unmasked to treatment assignment but will be masked to 4D-150 dose level.” (opens the source at this quote in a new tab)

“Powered to detect difference in anti-VEGF injections compared to aflibercept; study participants and site personnel masked to 4D-150 dose (treatment assignment to 4D-150 vs aflibercept not masked).” (opens the source at this quote in a new tab)

Follow-up duration and long-term follow-up

“After receiving one time administration of 4D-150 by intravitreal injection (IVT), subjects will undergo assessments at monthly intervals for 24 months to assess safety and efficacy outcomes. Only subjects that received 4D-150 will then enter a long-term follow-up (LTFU) period to assess long-term safety of 4D-150 gene therapy and duration of clinical activity through year 5 (60 months).” (opens the source at this quote in a new tab)

Position of the dose expansion within the PRISM cohorts

“The trial consists of Dose Escalation, Dose Expansion, Steroid Optimization, and Population Extension Cohorts.” (opens the source at this quote in a new tab)

“The Dose Expansion cohort of the PRISM study is a randomized, controlled Phase 2 clinical trial evaluating 4D-150 in previously treated wet AMD patients with severe disease activity (≥325 µm central subfield thickness (CST) measured by optical coherence tomography (OCT) and presence of subretinal or intraretinal fluid) and a high treatment burden (≥6 anti-VEGF injections in the prior 12 months).” (opens the source at this quote in a new tab)

Registered inclusion criteria for the main trial

“Diagnosed with CNV secondary to AMD (confirmed by reading center)” (opens the source at this quote in a new tab)
“Currently receiving anti-VEGF treatment (e.g. ranibizumab, aflibercept, faricimab or bevacizumab) in the study eye AND has demonstrated a clinical response consistent with anti-VEGF activity within 12 months prior to screening:” (opens the source at this quote in a new tab)
“Medical records available to document history of anti-VEGF therapy (dates, drugs, and dosage) for a minimum of 12 months prior to Screening” (opens the source at this quote in a new tab)

Key eligibility criteria for the dose expansion cohort

Criterion	Quoted poster text
Diagnosis	“Study eye macular neovascularization secondary to AMD”
Visual acuity	“Best corrected visual acuity (BCVA) of 34–83 letters (Snellen 20/200–20/25)”
Prior treatment	“≥6 anti-VEGF injections during the prior 12 months”

Randomized treatment arms

“Enrolled patients were randomized 2:2:1 to receive a single high (3E10 vg/eye) or low (1E10 vg/eye) intravitreal dose of 4D-150 or intravitreal aflibercept 2 mg every 8 weeks (control).” (opens the source at this quote in a new tab)

Arm	Quoted registry description
4D-150 Dose Expansion Dose 1 and Dose 2	“4D-150 will be administered at the assigned dose level as a single dose IVT injection on Day 1.”
4D-150 Dose Expansion Control	“Aflibercept at a fixed regimen will be administered.”
Investigational product	“4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept”

Aflibercept run-in and prophylactic corticosteroid

“Note: Day -7 aflibercept will be administered ≥ 4 weeks from last IVT anti-VEGF” (opens the source at this quote in a new tab)

“Scheduled 20-week corticosteroid taper (4D-150 groups).” (opens the source at this quote in a new tab)

Supplemental aflibercept injection criteria

“BCVA: Loss of ≥10 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from the average of the Day –7 and Day –1 values attributable to intra- or subretinal fluid, or” (opens the source at this quote in a new tab)
“CST: ≥75 μm increase from the average of the Day –7 and Day –1 values, or” (opens the source at this quote in a new tab)
“New vision-threatening hemorrhage due to nAMD” (opens the source at this quote in a new tab)

Registered primary and secondary outcomes

Outcome	Time frame
“Incidence and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), including clinically significant changes in safety parameters”	“52 weeks”
“Time to receiving the first supplemental aflibercept injection”	“52 weeks”
“Percentage of subjects requiring supplemental aflibercept injections over 52 weeks”	“52 weeks”
“Number of supplemental aflibercept injections over 52 weeks”	“52 weeks”
“Change from baseline in BCVA over time (up to 52 weeks) as assessed using the ETDRS Visual Acuity Chart”	“52 weeks”
“Change from baseline in central subfield thickness (CST) over time (up to 52 weeks) measured by spectral domain optical coherence tomography (SD-OCT)”	“52 weeks”
“Percent Change in Annualized Mean Number of anti-VEGF IVT injections before and after the 4D-150 injection”	“Before and after the 4D-150 injection (or Day 1 for the aflibercept only arm)”

Study outcomes as presented for the dose expansion

“Primary: Incidence and severity of adverse events” (opens the source at this quote in a new tab)
“Secondary: Annualized number of supplemental anti-VEGF injections, change from baseline in BCVA, and change from baseline in CST” (opens the source at this quote in a new tab)

Rationale for treatment burden as the key activity measure

“Repeated injections of anti-vascular endothelial growth factor (VEGF) agents slow vision loss in the majority of treatment-compliant patients; however, many patients fail to maintain initial therapeutic benefits owing to noncompliance with the burdensome treatment regimen” (opens the source at this quote in a new tab)

Planned and enrolled participants

Item	Quoted text
Planned dose expansion enrollment (registry)	“In Dose Expansion, subjects (n=50) will be randomized”
Estimated total PRISM enrollment (registry)	“215”

“The trial enrolled 51 patients with severe disease activity and treatment burden:” (opens the source at this quote in a new tab)

Participants included in the pooled Phase 1/2a analyses at the planned Phase 3 dose

“Phase 1/2a (n=24, all patients have reached year 2): Severe, recalcitrant disease activity” (opens the source at this quote in a new tab)

Mixed-effect model for visual acuity and retinal thickness

“Baseline=Day -7. Adjusted mean, difference in adjusted mean, and 95% CI estimated from a mixed–effect model (MMRM) for repeated measures including observed data (weeks 4–24) without imputation of missing values.” (opens the source at this quote in a new tab)

Kaplan-Meier estimates for supplemental injection endpoints at week 52

“Based on Kaplan-Meier method for calculating endpoint with follow-up through 52 weeks (Phase 1/2a).” (opens the source at this quote in a new tab)

Comparator for pooled Phase 1/2a treatment burden reduction

“Compared to mean injections in prior 12 months” (opens the source at this quote in a new tab)

Preliminary Phase 3 eligibility subgroup

“Participants excluded based on BCVA <40 or >78 ETDRS letters (n=6), CST >500 mm (n=1), or both BCVA <40 or >78 ETDRS letters and CST >500 mm (n=1).” (opens the source at this quote in a new tab)

Early terminations and censoring through week 52

“Early termination (death unrelated to study treatment), one of whom had missing data from Week 36 until death at Week 57.” (opens the source at this quote in a new tab)
“Participant censored for supplemental injection assessment owing to protocol deviation (lost to follow up for >3 months after entering a nursing home).” (opens the source at this quote in a new tab)

Corticosteroid taper completion at the 24-week analysis

“97% (38 of 39) completed the 20-week topical corticosteroid taper on schedule; no participant restarted steroids during up to 48 weeks of follow up” (opens the source at this quote in a new tab)

Demographics and baseline disease characteristics by arm

Characteristic	4D-150 3E10 vg/eye (N=20)	4D-150 1E10 vg/eye (N=21)	Aflibercept 2 mg (N=10)	Total (N=51)
Mean ±SD age, years	“77 ±8.0”	“77 ±8.6”	“80 ±4.1”	“77 ±7.7”
Female, n (%)	“8 (40)”	“11 (52)”	“5 (50)”	“24 (47)”
Mean ±SD time since diagnosis, years	“4.0 ±3.0”	“2.9 ±2.2”	“1.9 ±1.5”	“3.1 ±2.5”
Mean ±SD BCVA, ETDRS letters	“68 ±11.3”	“71 ±12.4”	“71 ±13.2”	“70 ±11.9”
Mean ±SD central subfield thickness	“429 ±89.3”	“465 ±114.1”	“419 ±64.3”	“442 ±96.9”
Mean ±SD actual injections in prior 12 months	“9.9 ±2.4”	“9.4 ±2.1”	“9.3 ±0.9”	“9.6 ±2.0”

Summary of disease severity at baseline

“Baseline characteristics consistent with severe disease activity (mean CST, 442 mm) and high treatment burden (mean actual injections in prior 12 months, 9.6)” (opens the source at this quote in a new tab)

Race and prior annualized injection rate by arm

Characteristic	4D-150 3E10 vg/eye (N=20)	4D-150 1E10 vg/eye (N=21)	Aflibercept 2 mg Q8W (N=10)
White, n (%)	“18 (90)”	“21 (100)”	“9 (90)”
Mean prior annualized injection rate	“10.0”	“9.9”	“9.0”

“*Includes Day -7 AFLB injection.” (opens the source at this quote in a new tab)

Summary: randomized 24-week and pooled long-term results

At the 24-week landmark (data cutoff January 19, 2024), the 3E10 vg/eye arm (n=20) had an 89% reduction in annualized anti-VEGF injection rate, 84% of participants received 0 or 1 supplemental injection, and 63% were injection-free; corresponding values in the 1E10 vg/eye arm (n=21) were 85%, 90%, and 50%. The average week 20 and 24 adjusted mean BCVA difference versus aflibercept 2 mg every 8 weeks (n=10) was -1.8 letters (95% CI -7.6 to 4.1) for 3E10 vg/eye and +1.8 letters (95% CI -3.8 to 7.4) for 1E10 vg/eye; confidence intervals include zero, and the study was powered for injection differences, not visual acuity. In the pooled Phase 1/2a 3E10 vg/eye population (n=24), treatment burden reduction versus the prior 12 months was 83% through year 1 and 79% through year 2 (data cutoff August 22, 2025), with a mean of 1.2 supplemental injections per participant in the 18 to 24 month interval.

Treatment burden at week 24 by 4D-150 dose

Outcome	4D-150 3E10 vg/eye and 1E10 vg/eye
Annualized anti-VEGF injection rate	“89% and 85% reduction in annualized anti-VEGF injection rates in the high (3E10 vg/eye) and low (1E10 vg/eye) 4D-150 dose arms, respectively”
0 or 1 supplemental injection	“84% and 90% of patients received 0 or 1 supplemental aflibercept injection in the high and low 4D-150 dose arms, respectively”
Injection-free	“63% and 50% of patients were supplemental aflibercept injection-free in the high and low 4D-150 dose arms, respectively”

BCVA and CST versus aflibercept at weeks 20 and 24

Comparison versus aflibercept 2 mg Q8W	Week 20	Week 24	Average of weeks 20 and 24
BCVA, 4D-150 3E10 vg/eye (ETDRS letters)	“–1.0 (–7.2, 5.3)”	“–2.6 (–9.3, 4.2)”	“–1.8 (–7.6, 4.1)”
BCVA, 4D-150 1E10 vg/eye (ETDRS letters)	“2.3 (–3.6, 8.3)”	“1.3 (–5.2, 7.8)”	“+1.8 (–3.8, 7.4)”
CST, 4D-150 3E10 vg/eye (µm)	“–9.3 (–97.9, 79.3)”	“–7.3 (–101, 86.2)”	“–8.3 (–92.6, 76.0)”
CST, 4D-150 1E10 vg/eye (µm)	“38.1 (–48.9, 125.2)”	“21.7 (–70.4, 113.8)”	“+29.9 (–53.0, 112.8)”

Preliminary Phase 3-eligible subgroup at week 24

“Application of preliminary Phase 3 eligibility criteria for BCVA and CST to the PRISM Dose Expansion Phase 2 study (16 of 20 in high dose 4D-150 arm and 6 of 10 in aflibercept arm met criteria) demonstrated: BCVA: +3.3 letters favoring high dose 4D-150 vs. aflibercept CST: –99.0 µm favoring high dose 4D-150 vs. aflibercept Anti-VEGF treatment burden: 90% reduction in annualized injection rate (88% received 0 or 1 injection, 63% were injection-free)” (opens the source at this quote in a new tab)

Supplemental injection-free subgroup at week 24

“Stable visual acuity observed through Week 24 in both 4D-150 dose groups (n=22 injection-free patients); BCVA equal to or numerically higher than bimonthly aflibercept (n=10 patients) at all six time points through Week 24” (opens the source at this quote in a new tab)
“The average mean change from baseline in CST at Weeks 20 and 24 was -52.2 mm in the 3E10 vg/eye group and -21.4 in the aflibercept group (mean difference, -30.8 mm)” (opens the source at this quote in a new tab)

Pooled Phase 1/2a treatment burden through week 52

“Phase 1/2a Severe (n=24, through 52 weeks): 83% overall reduction in annualized injections 52% received 0 or 1 injection* 44% injection-free*” (opens the source at this quote in a new tab)

“2 control arm patients received supplemental injections” (opens the source at this quote in a new tab)

Pooled Phase 1/2a treatment burden and dose response through year 2

“Phase 1/2a2: Severe, Recalcitrant 83% 79%” (opens the source at this quote in a new tab)
“Phase 1/2a: Severe, Recalcitrant 0.5 1.3 1.2 1.2” (opens the source at this quote in a new tab)
“Phase 1/2a (at 2 years): 79% vs. 69%” (opens the source at this quote in a new tab)

Visual acuity and anatomy through year 2

“Consistent maintenance of visual acuity as measured by best corrected visual acuity through up to 2 years” (opens the source at this quote in a new tab)
“Consistent control of retinal anatomy (central subfield thickness as measured on optical coherence tomography), with fewer fluctuations through up to 2 years” (opens the source at this quote in a new tab)

“79% reduction in a recalcitrant population” (opens the source at this quote in a new tab)

Visual acuity and retinal thickness versus aflibercept by supplemental injection status

Subgroup and dose	Group size as labeled	Average BCVA difference versus aflibercept (95% CI), ETDRS letters	Average CST difference versus aflibercept (95% CI), µm
Supplemental injection-free, 3E10 vg/eye	“4D-150 3x1010 vg/eye (n=12)”	“+0.4 (–5.2, 6.1)”	“–30.8 (–125, 63.2)”
Supplemental injection-free, 1E10 vg/eye	“4D-150 1x1010 vg/eye (n=10)”	“+4.5 (–1.2, 10.3)”	“+8.7 (–90.3, 107.7)”
Supplemental injection received, 3E10 vg/eye	“3E10: Injected post 4D-150 (n=7)”	“+1.5 (–5.7, 8.6)”	“+4.7 (–115, 124.0)”
Supplemental injection received, 1E10 vg/eye	“1E10: Injected post 4D-150 (n=10)”	“+1.3 (–4.3, 6.9)”	“+54.9 (–42.3, 152.0)”

“Excludes participants (n=1 per dose group) with missing data due to early termination.” (opens the source at this quote in a new tab)

Safety at the 24-week landmark analysis

“No significant intraocular inflammation High dose: None 97% (38 of 39 pts) completed 20-week prophylactic topical corticosteroid taper on schedule Low dose: Single eye at week 16 had 1+ anterior mixed (pigmented & white blood) cells, resolved by next visit and completed prophylactic topical corticosteroid taper by week 26 All patients currently off steroids No 4D-150–related serious adverse events (SAEs) or study eye SAEs No hypotony, endophthalmitis, retinal vasculitis, choroidal effusions, or retinal artery occlusions” (opens the source at this quote in a new tab)

Safety across all Phase 3-dose participants through up to 3.5 years

“As previously reported, within approximately the first 6 months (28 weeks) post-4D-150 dosing, 2.8% (2 of 71) of patients had 4D-150-related 1+ (mild) intraocular inflammation (IOI) (SUN/NEI scales), which were transient 1+ vitreous cells noted at a single timepoint Following the first 28 weeks post-4D-150 dosing, no new cases of inflammation with approximately 1.5 to more than 3.5 years of follow-up on all patients as of the data cutoff 99% (70 of 71) completed steroid prophylaxis taper on schedule 99% (70 of 71) remained completely off steroids No 4D-150-related hypotony, endophthalmitis, vasculitis, occlusive/non-occlusive retinal vasculitis or choroidal effusions observed to date” (opens the source at this quote in a new tab)

Summary

The dose expansion is a small randomized Phase 2 study of 51 participants (20, 21, and 10 per arm) in which participants and investigators were not masked to 4D-150 versus aflibercept assignment and only outcome assessors were masked; it was powered for differences in anti-VEGF injections, not for visual acuity, and the BCVA and CST differences versus aflibercept have confidence intervals that include zero (for example, BCVA -1.8 letters, 95% CI -7.6 to 4.1, at 3E10 vg/eye). Comparative results versus the aflibercept arm have been reported only through week 24; later results pool the 3E10 vg/eye Phase 1 and Phase 2a participants (n=24) as a single-arm cohort, with treatment burden reduction calculated against each participant's injections in the prior 12 months rather than against a concurrent control. Two control arm participants received supplemental injections. The population had severe disease and a high prior treatment burden (mean CST 442 µm; 9.6 injections in the prior 12 months), which differs from the treatment-naive or recently diagnosed population of the 4FRONT Phase 3 trials. The Phase 3-eligible subgroup BCVA difference was reported as +3.3 letters in the company announcement, whereas the congress slides for the same subgroup show +2.4 letters. Results are available only from company announcements and congress presentations; no peer-reviewed full publication was identified, and no patient-reported outcomes have been reported.