Phase 1/2 PRISM Trial Reports Positive Interim Data on Intravitreal 4D-150 for nAMD

Christine Kay, MD

Credit: Atsena Therapeutics

Interim results from the phase 1/2 PRISM trial suggest the investigational single-dose intravitreal genetic medicine, 4D-150, was safe and well-tolerated at a range of doses in individuals with neovascular age-related macular degeneration (nAMD).¹

Presented at the American Society of Retina Specialists (ASRS) 41st Annual Meeting, the genetic medicine, comprised of a retinotopic AAV vector (R100) carrying 2 transgenes encoding aflibercept and a miRNA sequence targeting vascular endothelial growth factor (VEGF)-C, was associated with clinically meaningful reductions in anti-VEGF treatment burden at all dose levels.

“We had a safe profile, with no patients with hypotony, intraocular inflammation, and no reintroduction of topical steroid in 14 to 15 patients, and an 81% reduction in the annualized injection-free interval for patients who were on the 3E10 dose of intravitreal gene therapy with the 4D-150 vector,” presenting investigator Christine Kay, MD, Vitreo Retinal Associates, said at ASRS 2023.

The 4D-150 vector is administered via a single-dose intravitreal administration, allowing widespread delivery to all layers of the retina and efficient reduction of retinal cells. The PRISM trial is a phase ½ clinical trial evaluating the safety, tolerability, and clinical efficacy of 4D-150, starting with a dose exploration and moving into a dose expansion phase.

Key inclusion criteria included patients aged ≥50 years, choroidal neovascularization secondary to nAMD, visual acuity between ≥25 and ≤78 ETDRS letters, clinical response to prior anti-VEGF in prior 12 months, and ≥6 anti-VEGF injections within ≤12 months. A total of 15 patients were enrolled in 3 sequential dose cohorts: 3E10, 1E10, and 6E9 vg/eye; n=5 each).

The primary endpoint was the incidence and severity of treatment-emerge adverse events (TEAEs) and serious adverse events (SAEs). Meanwhile, key secondary endpoints included the percent change of annualized anti-VEGF injection rate, the percent of subjects requiring supplemental aflibercept, the number of supplemental aflibercept injections, BCVA change from baseline, CST change from baseline. At the data cutoff of July 3, 2023, all patients had completed follow-up through ≥36 weeks.

Upon analysis, investigators found the dose-response demonstrated in favor of the highest tested dose of 3E10 vg/eye, including a 100% reduction in supplemental anti-VEGF injections (4 of 4 evaluable patients injection-free). In addition, it was associated with a clinically meaningful reduction in mean CST at 36 weeks in patients with a high anti-VEGF need.

Moreover, an assessment of outcomes beyond 36 weeks in the 3E10 vg/eye dose cohort indicated a durable reduction in supplemental anti-VEGF injections, with 3 of 4 evaluable study participants remaining injection-free beyond 1 year and 1 patient remaining injection-free during a maximum follow-up of 80 weeks. There was no observed change in the safety profile.

The analysis showed lower doses (1E10, 6E9 vs/eye) were also highly active, with 5 of 10 patients requiring zero or 1 supplemental anti-VEGF injections, as well as a 71% reduction in mean annualized supplemental anti-VEGF injection rate through 36 weeks.

Regarding safety, the analysis showed intravitreal 4D-150 remained well-tolerated at all doses in all patients, with no Grade ≥1 inflammatory cells, hypotony, dose-limiting toxicities, or TEAEs during follow-up through 36 weeks. 4D-150 will continue to be studied in phase 2 of the PRISM trial in patients with nAMD and in the phase 2 SPECTRA trial in patients with DME.

“We are pleased to see continued evidence of a favorable safety profile and clinical activity, including clinically meaningful reductions in anti-VEGF treatment burden at all dose levels of intravitreal 4D-150 in these high anti-VEGF need patients,” Robert Kim, MD, chief medical officer of 4DMT, said in a statement.² “In addition, 3 of 4 evaluable patients in the 3E10 vg/eye cohort are now anti-VEGF injection-free at one year and beyond, with up to 80 weeks of follow-up, demonstrating encouraging initial evidence of long-term durability. We look forward to continuing to follow these patients and presenting initial interim Phase 2 Dose Expansion data in H1 2024.”

References

1. Kay CN, Khanani AM, Hershberger VS, Hu A, Eichenbaum DA, Jaffe GJ, Chung C, Honarmand S, Nien C, Lee S, Kabra H, Kirn D, Kim R. Interim Results of the Phase 1/2 PRISM Trial Evaluating 4D-150, a Dual-Transgene Intravitreal Genetic Medicine for Neovascular (Wet) Age-Related Macular Degeneration. Paper presentation at the American Society of Retina Specialists 41st Annual Meeting. July 28 - August 1.
2. 4DMT presents additional positive interim data from Intravitreal 4D-150 phase 1/2 prism clinical trial in patients with WET AMD at ASRS 2023. 4D Molecular Therapeutics. July 29, 2023. Accessed July 30, 2023. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-additional-positive-interim-data-intravitreal-4d#top.