4D Molecular Therapeutics announced positive interim data from the phase 2 PRISM clinical trial evaluating intravitreal 4D-150 in wet age-related macular degeneration (AMD) patients with severe disease activity and a high treatment burden during the Angiogenesis, Exudation, and Degeneration 2024 conference. The data was presented by Arshad M. Khanani, MD, MA, FASRS, and it consisted of 24-week results from the randomized phase 2 dose expansion cohort of the PRISM clinical trial.
Phase 2 PRISM Clinical Trial Dose Expansion Cohort Background & Summary Baseline Characteristics
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).
The trial enrolled 51 patients with severe disease activity and treatment burden:
Mean CST: 442 µm
Mean anti-VEGF injections in the prior 12 months (actual): 9.6
Mean time since diagnosis (years): 3.1
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).
Phase 2 PRISM Topline Interim Results (Data cutoff: January 19, 2024)
A single intravitreal dose of 4D-150 demonstrated favorable safety results through the data cutoff date (all ophthalmic exams through up to 48 weeks of follow-up):
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
24-week landmark analysis for key efficacy endpoints:
Treatment burden reduction:
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
84% and 90% of patients received 0 or 1 supplemental aflibercept injection in the high and low 4D-150 dose arms, respectively
63% and 50% of patients were supplemental aflibercept injection-free in the high and low 4D-150 dose arms, respectively
Visual and retina anatomic outcomes (difference in the average of week 20 & 24 adjusted mean change from baseline vs. aflibercept control arm):
Best corrected visual acuity (BCVA): –1.8 and +1.8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for the 3E10 and 1E10 vg/eye 4D-150 dose arms, respectively
Central subfield thickness (CST): –8.3 and +29.9 µm for the 3E10 and 1E10 vg/eye 4D-150 dose arms, respectively; highlights notable reduction in retinal anatomical variability in high dose arm across all timepoints
PRISM Phase 1 Long-Term Follow-Up Update (Data cutoff: January 19, 2024)
Safety results maintained in all 15 patients treated to date (up to 104 weeks of follow-up) with no new inflammation and no change in steroid status
Three patients treated with high dose (3E10 vg/eye) 4D-150 were previously reported to be injection-free after 52 weeks of follow-up; all 3 patients remained injection-free through 80–104 weeks (up to 2 years) of follow-up
Additional 4D-150 Program Updates:
110 patients have been enrolled and dosed to date with 4D-150 in the following cohorts: PRISM Dose Exploration (N=15), Dose Expansion (N=41, excluding control arm), Population Extension (N=32), and SPECTRA Dose Confirmation (N=22)
No clinically significant treatment-emergent inflammation reported
Enrollment completed ahead of schedule in Phase 2 PRISM Population Extension cohort evaluating 4D-150 in wet AMD patients with broader disease severity (no minimum CST) and lower treatment burden (1-6 anti-VEGF injections in prior 12 months, ≥1 in last 12 weeks), with 32 patients dosed with 3E10 or 1E10 vg/eye of 4D-150
Pivotal study planning ongoing with FDA and EMA under RMAT and PRIME designations
4DMT plans for the first Phase 3 study to be a BCVA non-inferiority study vs aflibercept 2 mg every 8 weeks; 3E10 vg/eye has been selected as study dose
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)
Enrollment and dosing completed in Phase 2 SPECTRA Part 1 Dose Confirmation cohort evaluating 4D-150 in diabetic macular edema (DME), with 22 patients dosed with 3E10 or 1E10 vg/eye of 4D-150
Upcoming 4D-150 Milestones
Additional FDA and EMA interactions planned in Q2 2024, with an update expected in Q3 2024
Phase 2 PRISM Population Extension cohort evaluating 4D-150 in wet AMD patients with broader disease severity: Initial interim 24-week landmark data analysis is expected in H2 2024
Phase 2 SPECTRA Part 1 Dose Confirmation cohort evaluating 4D-150 in DME: Initial interim 24-week landmark data analysis is expected in H2 2024
Initiation of first Phase 3 study is expected in Q1 2025
Slides available here.
Source - Content lightly modified