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4D Molecular Therapeutics to Start Phase III Trial for Retinal Disorder Gene Therapy in Q1 2025

Masked patient and doctor in ophthalmology office

NEW YORK – 4D Molecular Therapeutics (4DMT) plans to launch a Phase III trial of an experimental gene therapy for a form of macular degeneration early next year after a Phase II trial yielded promising early results.

On a call with market analysts Monday, 4DMT CEO and Cofounder David Kirn shared interim data on the therapy, dubbed 4D-150, from the Phase II PRISM trial and said that based on the gene therapy's activity so far, the company wants to move it into a pivotal trial. Kirn added that the firm is in discussion with regulators about the registrational study for 4D-150, which has received regenerative medicine advanced therapy designation from the US Food and Drug Administration and has priority medicines status from the European Medicines Agency.

"These [FDA and EMA] designations, along with these positive data, enable us to rapidly advance our pivotal trial program," Kirn said. "4D-150 has the potential for multiyear durability by driving continuous, local, and steady-state expression of our two transgene products."

4D-150 is an investigational treatment for wet age-related macular degeneration (wet AMD), a retinal disorder caused by abnormal blood vessels stimulated by VEGF. The blood vessels grow into the central area of the retina, resulting in swelling and vision problems.

The one-time treatment, administered intravitreally, uses 4DMT's R100 vector to deliver a dual transgene payload expressing both the aflibercept protein and an RNA interference molecule to inhibit VEGF-C. Together, they're designed to block four VEGF proteins, namely VEGF A, B, C, and PlGF, which the Emeryville, California-based genetic medicines firm believes will reduce patients' need for ongoing treatment and even preserve vision long term.

In the randomized Phase II PRISM study, 4DMT is evaluating the gene therapy's tolerability and clinical activity specifically in patients with severe disease activity and high treatment burden, for which they require repeated anti-VEGF injections, a current treatment option for the disorder. Investigators participating in the study are monitoring safety, change from baseline in best corrected visual acuity (BCVA) and central subfield thickness (CST), and the proportion of patients requiring supplemental Eylea (aflibercept), an anti-VEGF wet AMD treatment marketed by Regeneron.

4DMT has enrolled 51 patients in the PRISM trial, and on Monday, the firm shared data from patients who have received the gene therapy as of the Jan. 19 data cutoff. In the Phase II trial, patients randomized to the gene therapy arm received either a single high or low dose of 4D-150, and in the control group, patients received intravitreal injections of Eylea every eight weeks.

During the call with analysts, 4DMT executives focused on outcomes from patients enrolled in the higher gene therapy dose cohort since that's the dose the firm has chosen to study in the Phase III trial.

Patients in the Phase II trial who received the higher dose of the gene therapy experienced an 89 percent reduction in annualized anti-VEGF injection rate, compared to 85 percent of patients in the low-dose group. Most patients, 84 percent and 90 percent for the high- and low-dose groups, respectively, received either no anti-VEGF injections or just a single injection through 24 weeks.

Around 63 percent of patients did not need supplemental Eylea injections through 24 weeks in the high-dose group. In the low-dose group, 50 percent of patients met that milestone.

In both groups, CST was stable, representing improved retinal anatomical control. Repeated anti-VEGF injections, by contrast, can lead to variability in CST.

"We saw minimal fluctuations, showing the potential of sustained expression from a single injection of 4D-105," said Arshad Khanani, director of clinic research at Sierra Eye Associates in Reno, Nevada, and a principal investigator on the PRISM study. In the control arm, comparatively, "we saw substantial CST fluctuation."

Khanani initially presented the interim data from the PRISM trial Saturday at the Angiogenesis, Exudation, and Degeneration 2024 Conference. On Monday, following the news, 4DMT's stock price was trading at $30.05 per share when the Nasdaq opened, up 72 percent from the closing price the prior day and representing a new 52-week high.

4D-150 also appears to be well tolerated and have a favorable safety profile in patients who have been evaluated for up to 48 weeks after treatment.

There were no treatment-related serious adverse events among patients who received either the low or high dose of the gene therapy. Investigators observed no significant inflammation, and all patients remained off of steroids as of the data cutoff. Almost all, 38 of 39 patients, completed a 20-week prophylactic topical corticosteroid taper on schedule.

Two patients in the study died: one in the high-dose cohort due to metastatic urothelial carcinoma and one in the low-dose cohort due to acute myocardial infarction. Investigators determined that the deaths were not related to the investigational gene therapy.

Based on initial feedback from regulators in the US and EU, 4DMT expects that the pivotal Phase III trial will have a noninferiority design, which allows for the comparison of BCVA between 4D-150 and Eylea. The firm expects to enroll around 225 wet AMD patients in each arm and not limit enrollment to only those with severe disease activity.

While the first part of the PRISM study involves only those with severe disease activity and high treatment burden, the firm is also studying 4D-150's activity in individuals with a range of disease severity in an extension cohort. Separately, 4DMT is studying 4D-150 in patients with diabetic macular edema.

Kirn said that the firm will recruit patients globally for the pivotal Phase III trial and will have additional discussions with regulators in Q2 to finalize the study design. 4DMT will provide an update on its Phase III trial plans in Q3.

In the US, the company is "committed" to commercializing 4D-150 by itself, Kirn added, but is open to partnerships to make the gene therapy available to patients in other countries.

4DMT does not have any commercial products yet. As of Dec. 31, the firm had about $300 million in cash, which Kirn expects will fund operations into the first half of 2026.