4D Molecular Therapeutics’ Wet AMD Gene Therapy 4D-150 Reduces Need for antiVEGF Injections
The gene therapy has continued to demonstrate efficacy in updated data from the phase 2 PRISM trial.
Arshad Khanani, MD
Credit: Sierra Eye Associates
4D Molecular Therapeutics (4DMT)’s 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 efficacy and safety in updated interim data.1
As of the June 24, 2024, data cutoff, the phase 2 PRISM population extension cohort had treated 30 patients with wet AMD at a dose of 3x1010 vg/eye of 4D-150, which is the planned phase 3 dose. The cohort also included an additional 15 patients with wet AMD who were treated at the study’s low dose of 1x1010 vg/eye. At 24 weeks posttreatment, a landmark analysis was conducted. At this time point, the 30 patients who received the planned phase 3 dose showed a mean decrease of 89% in annualized injection rate of standard of care antivascular endothelial growth factor (VEGF) injections. Furthermore, 93% of these patients received 0 or only 1 antiVEGF injection after treatment with the gene therapy and 77% were entirely free of antiVEGF injections. Freedom from injection was assessed as dose-dependent because only 60% of the 15 patients treated at the low dose were injection-free after treatment with 4D-150.
The patients treated at the planned phase 3 dose also showed an overall improvement from baseline of +4.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. For patients in this group who were entirely free of antiVEGF injections, there was a +4.7 ETDRS letter improvement. Improvements in best-corrected visual acuity (BCVA) were also determined to be dose dependent, as the patients treated at the planned phase 3 dose showed a +5.7 letter improvement compared to those treated at the low dose. In addition, 4DMT noted that patients who received the planned phase 3 dose showed a decrease in central subfield thickness (CST) of –32 μm and patients who received the low dose showed a decrease in CST of -9 μm.
In terms of safety, the patients treated at the planned phase 3 dose experienced no cases of anterior chamber inflammation and no cases of significant vitreous inflammation, though it was noted that 1 patient had trace vitreal cells. All 30 of the patients finished their local steroid prophylaxis as scheduled without any later resumption. Among the patients treated at the low dose, there were no cases of significant anterior chamber inflammation, although 1 patient had trace anterior chamber cells. There was a single case of vitreous inflammation reported in the low dose group, which was characterized as mild to moderate in severity, with vitreous cells being found in the patient’s untreated fellow eye. Across the whole group of 45 patients, there were no serious adverse events (SAEs) deemed related to 4D-150 and no SAEs in patients’ treated eyes. Furthermore, there were no cases of hypotony, retinal vasculitis, choroidal effusions, or retinal artery occlusions in any of the patients.
4DMT noted that the cohort did not have inclusion criteria based on CST and that it allowed participation of patients who had received from 1 to 6 antiVEGF injections in the 12 months beforehand. As such, the group of treated patients was characterized as "generally well-balanced" with a baseline mean CST of 329 μm and a mean of 4.4 antiVEGF injections having been received in the 12 months before trial participation.
“The initial benefits of the current treatment paradigm of repeated bolus antiVEGF injections are not maintained long-term in wet AMD patients due to undertreatment and fluctuations in retinal thickness, leading to vision loss over time,” Robert Kim, MD, the chief medical officer of 4DMT, said in a statement.1 “The data presented on 4D-150 continue to show its promise as a potentially safe, routine, and 1-time intravitreal treatment with the long-term objective to preserve vision for millions of wet AMD patients, regardless of their treatment burden or disease severity. We continue to work closely with the FDA and European Medicines Agency, under our regenerative medicine advanced therapy (RMAT) and priority medicines (PRIME) designations, to finalize our phase 3 clinical trial design that we expect to share in September 2024.”
In addition to the updated results from PRISM’s phase 2 portion, 4DMT also reported updated results from the patients treated in the phase 1 portion, with the same data cut-off date of June 24. The 3 patients in the phase 1 portion who received the planned phase 3 dose have now been injection free for approximately 2 to 2.5 years. In addition, their BCVA has remained stable in comparison to baseline for about 2 years, with a +1 letter change. The patients’ mean CST showed a decrease of –110 microns from baseline through approximately 2 years. For all 15 patients treated in the phase 1 portion at any dose, who have up to 2.5 years of follow-up, safety outcomes have been maintained, with the patients showing no new inflammation and no change in steroid status.
Alongside the PRISM study, 4D-150 is also being evaluated for the treatment of diabetic macular edema (DME) in the phase 2 SPECTRA clinical trial (NCT05930561). 4DMT reported that in 22 patients who have been treated in SPECTRA, who now have up to 36 weeks of follow-up, there have been no cases of inflammation, hypotony, retinal vasculitis, choroidal effusions, or retinal artery occlusions. All these patients also finished their topical corticosteroid prophylactic regimens as scheduled, without any resumptions.
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 an interview that took place earlier in 2024, he spoke about the findings from PRISM that had been reported at that time and expressed enthusiasm for the planned pivotal phase 3 study, which 4DMT now expects to begin in the first quarter of next year.1,2
“As clinicians, we are lucky to have good treatment options for patients with neovascular AMD,” Khanani told CGTLive. “But all of those options come with a high treatment burden anywhere from 4 weeks to up to 16 weeks. And we know that patients have injection fatigue and it's hard for them to come to our clinics. This carries a high treatment burden. Based on the data from the phase 2 portion of the PRISM study, we can see that a single injection of 4D-150 can safely and effectively decrease the treatment burden significantly and control disease. I'm hoping that the pivotal trials will start soon and we can have this option available for patients so that we can decrease the treatment burden, and hopefully have better outcomes for our patients with neovascular AMD.”
