Objective of the dose exploration stage

“OBJECTIVE: EVALUATE SAFETY, TOLERABILITY, AND CLINICAL ACTIVITY” (opens the source at this quote in a new tab)

Registered dose escalation objective

“In Dose Escalation, the safety and tolerability of multiple dose levels of 4D-150 will be examined following an open-label, 3+3 dose escalation design (n=3-5 per dose level).” (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”

Data cutoffs of the dose exploration analyses

“All data below are as of the data cutoff date of April 3, 2023” (opens the source at this quote in a new tab)

“As of the data cutoff date of July 3, 2023, all patients had completed follow-up through at least 36 weeks” (opens the source at this quote in a new tab)

Open-label, three-cohort dose exploration with DSMC review

“Dose Escalation will be open-label.” (opens the source at this quote in a new tab)

“Phase 1 Dose Exploration stage (n=15; three dose cohorts of 5 patients each at 3E10, 1E10 and 6E9 vg/eye) followed by a randomized Phase 2 Dose Expansion stage (n=50, randomized 2:2:1 to 3E10 vg/eye or 1E10 vg/eye of 4D-150 or aflibercept)” (opens the source at this quote in a new tab)

Long-term follow-up

“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)

Key inclusion criteria for the dose exploration stage

Criterion	Quoted slide text
Age	“Age ≥50 years”
Diagnosis	“CNV secondary to AMD”
Visual acuity	“≥25 (~20/320) and ≤78 (~20/32) ETDRS letters”
Anti-VEGF response	“Clinical response to anti-VEGF in prior 12 months”
Prior treatment	“≥6 anti-VEGF injections within the last 12 months”

Retinal thickness criterion

“≥300 µm or retinal fluid” (opens the source at this quote in a new tab)

Single intravitreal dose with topical corticosteroid taper

“Patients received a single intravitreal dose of 4D-150. Topical corticosteroids were administered at tapering doses over 20 weeks” (opens the source at this quote in a new tab)

Registered dose escalation arm

“4D-150 Dose Escalation up to 4 dose levels” (opens the source at this quote in a new tab)

Supplemental anti-VEGF injection criteria

“Anti-VEGF Injection Criteria: Loss of ≥10 letters from baseline in BCVA attributable to intraretinal or subretinal fluid; increase in CST >75 μm from baseline, confirmed by central reading center; presence of new vision-threatening hemorrhage due to wet AMD as determined by investigator.” (opens the source at this quote in a new tab)

Primary and key secondary endpoints of the dose exploration stage

“Incidence and severity of TEAEs and SAEs” (opens the source at this quote in a new tab)
“% change, annualized anti-VEGF injection rate” (opens the source at this quote in a new tab)
“% of subjects requiring supplemental aflibercept” (opens the source at this quote in a new tab)
“Number of supplemental aflibercept injections” (opens the source at this quote in a new tab)
“BCVA change from baseline” (opens the source at this quote in a new tab)
“CST change from baseline” (opens the source at this quote in a new tab)

Rationale for endpoint selection

No evidence found.

Planned and enrolled participants

“In Dose Escalation, the safety and tolerability of multiple dose levels of 4D-150 will be examined following an open-label, 3+3 dose escalation design (n=3-5 per dose level).” (opens the source at this quote in a new tab)

“15 patients received a single intravitreal dose of 4D-150 across three dose cohorts (3E10, 1E10, and 6E9 vg/eye; n=5 each)” (opens the source at this quote in a new tab)

Participants evaluable for supplemental injections at the highest dose

“4 OF 4 (100%) EVALUABLE PARTICIPANTS INJECTION-FREE AT HIGHEST DOSE (3x1010 vg/EYE)” (opens the source at this quote in a new tab)

All enrolled participants

“ANALYSIS POPULATION: ALL ENROLLED PARTICIPANTS (N=15)” (opens the source at this quote in a new tab)

Exclusions from BCVA analyses

“Excludes patients with progressive cataract at time of BCVA measurement: aExcludes Patient 5 (not Phase 2 BCVA-eligible and not evaluable)” (opens the source at this quote in a new tab)

Follow-up completion and non-evaluable participants

“As of 3 July 2023, all participants have completed ≥9 months of follow-up” (opens the source at this quote in a new tab)
“Progressive nuclear sclerotic cataract (Day -1), posterior subcapsular cataract (Week 16).” (opens the source at this quote in a new tab)

Demographics and baseline disease characteristics by dose cohort

Characteristic	3E10 vg/eye (N=5)	1E10 vg/eye (N=5)	6E9 vg/eye (N=5)	Total (N=15)
Mean ±SE age, years	“79 ±3.9”	“79 ±4.1”	“76 ±4.9”	“78 ±4.0”
Female, n (%)	“5 (100)”	“3 (60)”	“3 (60)”	“11 (73)”
Mean ±SE BCVA, ETDRS letters	“55 ±7.4”	“65 ±3.4”	“75 ±4.0”	“65 ±3.6”
Mean ±SE central subfield thickness	“424 ±27.0”	“351 ±44.4”	“402 ±85.0”	“392 ±31.8”
Mean ±SE time since diagnosis, years	“3.5 ±0.8”	“2.6 ±0.5”	“4.7 ±1.4”	“3.6 ±1.0”

Prior anti-VEGF treatment burden

“Enrolled participants had a high need for anti-VEGF therapy, with mean annualized injection rates ranging from 8 to 11 across cohorts prior to 4D-150 treatment” (opens the source at this quote in a new tab)

Summary: dose exploration results

At 24 weeks (data cutoff April 3, 2023), 4 of 5 participants (80%) at 3E10 vg/eye and 2 of 5 (40%) at each of 1E10 and 6E9 vg/eye were anti-VEGF injection-free, with changes in annualized injection rate of -84%, -68%, and -80%. At 36 weeks (data cutoff July 3, 2023), all 4 evaluable participants at 3E10 vg/eye were injection-free and the lower doses had a 71% reduction in mean annualized supplemental injection rate. The 3 participants at 3E10 vg/eye who were injection-free beyond 52 weeks remained injection-free through approximately 2 to 2.5 years (data cutoff June 24, 2024), with mean BCVA +1 letter and mean CST -110 µm from baseline in that dose cohort. Aflibercept was detected in the aqueous humor of 10 of 11 samples (91%) at week 12.

Clinical activity at 24 weeks by dose cohort

Dose cohort	Anti-VEGF injection-free	Mean change in annualized anti-VEGF injection rate	Mean ±SE CST change (µm)	Mean ±SE BCVA change (letters)
3E10 vg/eye	“4 of 5 (80%)”	“(-)84%”	“-78 ±49”	“-4.0 ±4.5”
1E10 vg/eye	“2 of 5 (40%)”	“(-)68%”	“+38 ±37”	“+1.4 ±3.5”
6E9 vg/eye	“2 of 5 (40%)”	“(-)80%”	“+3 ±25”	“-1.2 ±4.2”

Clinical activity at 36 weeks

“Dose response demonstrated in favor of highest tested dose of 3E10 vg/eye, including 100% reduction in supplemental anti-VEGF injections (4 of 4 evaluable patients injection-free) and a clinically meaningful reduction in mean central subfield thickness (CST) at 36 weeks in patient population with high anti-VEGF need” (opens the source at this quote in a new tab)
“Lower doses (1E10, 6E9 vg/eye) also highly active, with 5 of 10 patients requiring zero or one supplemental anti-VEGF injections and a 71% reduction in mean annualized supplemental anti-VEGF injection rate through 36 weeks” (opens the source at this quote in a new tab)

Long-term follow-up of the 3E10 vg/eye cohort

“All three Phase 1 patients treated with 3E10 vg/eye previously reported as injection-free beyond 52 weeks remain injection-free through ~2 to 2.5 years of follow-up Mean BCVA remains unchanged from baseline through ~2 years (+1 letter from baseline) Mean CST remains stable, without fluctuations, and decreased from baseline through ~2 years (-110 microns from baseline)” (opens the source at this quote in a new tab)

“A single patient (1 of 4 evaluable patients in the 3E10 vg/eye cohort) met supplemental injection criterion beyond 36 weeks at a single timepoint.” (opens the source at this quote in a new tab)

Aqueous humor aflibercept expression

“4D-150-mediated expression of the aflibercept transgene protein was demonstrated in the aqueous humor (AH) of the eye at 12 weeks after 4D-150 injection in 91% (10 of 11) of patient samples evaluated to date1 Mean AH aflibercept concentrations dose-related, and predicted to be in therapeutic range for all cohorts” (opens the source at this quote in a new tab)

Pooled Phase 1/2a results

“Phase 1/2a (at 2 years): 79% vs. 69%” (opens the source at this quote in a new tab)

Annualized injection rate before and after dosing in the 3E10 vg/eye cohort at the first interim cutoff

“Follow-up was longest for the 3×1010 vg/eye cohort (12-40 weeks), which had a mean annualized anti-VEGF injection rate of 10.8 before 4D-150.” (opens the source at this quote in a new tab)
“Following 4D-150 injection, a 96.7% overall reduction in mean annualized anti-VEGF injection rate was observed, and 4 of 5 eyes were supplemental AFLB injection-free.” (opens the source at this quote in a new tab)
“Aqueous humor samples from the 3 eyes evaluated to date had detectable AFLB.” (opens the source at this quote in a new tab)

Safety through 24 weeks

“No dose-limiting toxicities” (opens the source at this quote in a new tab)
“3x1010 vg/eye group: pigmented anterior chamber cells (mild, n=1), mixed vitreous cells (mild, n=1)” (opens the source at this quote in a new tab)
“No hypotony, no intraocular inflammation requiring intervention, no endophthalmitis, no retinal vasculitis, no choroidal effusions, no retinal artery occlusion” (opens the source at this quote in a new tab)

“14 of 15 patient had no inflammation reported; one patient had a single episode of asymptomatic trace mixed vitreous cells that resolved without intervention 14 of 15 patients completed the protocol-mandated 20-week topical corticosteroid taper and did not receive further steroids; a single patient continued beyond 20 weeks by the treating physician for asymptomatic non-inflammatory trace pigmented cells” (opens the source at this quote in a new tab)

Safety through 36 weeks

“4D-150 was well tolerated, with no reported Grade ≥1 inflammatory cells and no hypotony, dose-limiting toxicities, or treatment-related serious adverse events” (opens the source at this quote in a new tab)
“Patient was well controlled on the basis of both BCVA and CST prior to developing a retinal hemorrhage, which has resolved with no significant change from baseline in BCVA (reported as “not related” to the test article)” (opens the source at this quote in a new tab)

Long-term safety through up to 2.5 years

“Safety results maintained in all 15 patients treated to the cutoff date (up to 2.5 years of follow-up) with no new inflammation and no change in steroid status” (opens the source at this quote in a new tab)

Summary

The dose exploration stage is an open-label, uncontrolled study of 15 participants (5 per dose cohort), so dose-response and efficacy estimates rest on very small numbers; at the 36-week analysis, only 4 participants at 3E10 vg/eye were evaluable for supplemental injections, and BCVA analyses excluded participants with progressive cataract. Treatment burden reduction was measured against each participant's injection history in the prior 12 months, which is subject to regression to the mean in a population selected for 6 or more injections, rather than against a concurrent comparator. Baseline characteristics differed across cohorts (for example, mean BCVA 55, 65, and 75 letters and mean time since diagnosis 3.5, 2.6, and 4.7 years), and the population had severe, recalcitrant disease unlike the recently diagnosed or treatment-naive population of the Phase 3 trials. Long-term results after mid-2024 are reported only pooled with the Phase 2a dose expansion. Results are available only from company announcements and congress presentations, with no peer-reviewed full publication and no patient-reported outcomes identified.