At the 24-week analysis, patients who received the high dose achieved an 89% decrease in annualized antiVEGF injection rates.
4D Molecular Therapeutics’ 4D-150, an investigational dual-mechanism gene therapy being evaluated for the treatment of wet age-related macular degeneration (AMD) in the phase 1/2 PRISM clinical trial (NCT05197270), has continued to demonstrate the ability to reduce the need for antivascular endothelial growth factor (VEGF) injections in newly announced interim data.
As of the January 19, 2024, data cutoff, 51 patients with severe wet AMD were enrolled in the phase 2 dose expansion cohort and were assigned in a 2:2:1 ratio to be treated with either a high dose of 4D-150 (3x1010 vg/eye, single intravitreal dose), a low dose of 4D-150 (1x1010 vg/eye, single intravitreal dose), or a 2 mg intravitreal dose of standard of care treatment aflibercept every 8 weeks (control arm). At the 24-week analysis, patients who received the high dose achieved an 89% decrease in annualized antiVEGF injection rates and patients who received the low dose achieved an 85% decrease in annualized antiVEGF injection rates. Furthermore, 84% of patients who received the high dose had been administered either 0 or 1 supplemental aflibercept injection; for patients who were treated with the low dose of 4D-150, 90% received 0 or 1 supplemental aflibercept injections. Among patients who were treated with the high dose of 4D-150, 63% had 0 supplemental aflibercept injections; among patients who were treated with the low dose, 50% had 0 supplemental aflibercept injections. The study also averaged the week 20 and week 24 adjusted mean change from baseline inbest corrected visual acuity (BCVA) and central subfield thickness (CST) for the treatment arms against thecontrol arm.
Patients who received the high dose showed a –1.8 change in Early Treatment Diabetic Retinopathy Study (ETDRS) letters for BCVA and patients who received the low dose showed a +1.8 change in ETDRS letters for BCVA. For CST, patients in the high dose arm showed a –8.3 µm change and patients in the low dose arm showed a +29.9 µm change.
As of the aforementioned data cutoff, safety results from all ophthalmic exams through up to 48 weeks of follow-up revealed no serious adverse events (SAEs) related to 4D-150 or SAES in the study eyes. None of the patients who received the high dose experienced intraocular inflammation. One patient who was treated at the low dose showed 1+ anterior mixed (pigmented & white blood) cells in a single eye at the week 16 exam, but this case had resolved by the following exam. The patient completed a prophylactic topical corticosteroid taper by week 26. Furthermore, 38 of 39 (97%) patients completed a 20-week prophylactic topical corticosteroid taper as scheduled and all patients are off steroids as of the data cutoff. No cases of hypotony, endophthalmitis, retinal vasculitis, choroidal effusions, or retinal artery occlusions were reported.
“We are pleased by the robust clinical activity demonstrated in this severe disease activity patient population with high treatment burden,” Robert Kim, MD, the chief medical officer of 4D Molecular Therapeutics, said in a statement. “We believe these positive interim Phase 2 results demonstrate a differentiated product profile for the treatment of wet AMD, including in these most difficult to treat patients that have not been studied adequately in prior clinical trials. We look forward to discussions with regulators to align on a phase 3 development plan expedited by FDA regenerative medicine advanced therapy and EMA PRIME designations to advance 4D-150 with the goal of providing a compelling new treatment option for millions of patients suffering from these blinding VEGF-driven retinal diseases.”
Alongside the above results, the company also announced some long-term findings from the phase 1 portion of PRISM. It noted that for all 15 patients treated in the phase 1, who now have up to 104 weeks of follow-up, safety outcomes have been maintained, with the patients showing no new inflammation and no change in steroid status. All 3 patients who were previously reported to be free of supplemental injections through at least 52 weeks after receiving the high dose have maintained injection-free status through 80 to 104 weeks of follow-up.
CGTLive™ has previously spoken with Arshad Khanani, MD, the director of clinical research and director of Fellowship at Sierra Eye Associates, about the PRISM trial. In a May 2023 interview, he gave background information about the current standard of care for wet AMD and explained how 4D-150 has the potential reduce treatment burden for patients with this disease.
“[The] majority of the patients need frequent injections—and that's the biggest unmet need, where the treatment burden is so high for many of these patients that they don't get the adequate number of injections that they need,” Khanani said. “And that's why in [the] real world, we see visual acuity outcomes that are worse than what we see in clinical trials. So there is really an unmet need for having durable agents and sustained delivery of anti-VEGF. Gene therapy is one modality to address this treatment burden and hopefully stabilize visual acuity and improve long-term outcomes in the real world.”