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STOCKHOLM -- Two VEGF-targeting gene therapies for neovascular age-related macular degeneration (nAMD) substantially reduced treatment burden while preserving visual acuity, according to results reported here.

Patients treated with ixoberogene soroparvovec (Ixo-vec) had a 90-95% reduction in anti-VEGF injections and at 6 months achieved best corrected visual acuity (BCVA) and change in central subfield thickness (CST) comparable to the patients' previous results with intravitreal aflibercept (Eylea). Adding topical difluprednate to the prophylactic steroid regimen reduced inflammation compared with intravitreal dexamethasone alone, reported Charles Wykoff, MD, PhD, of Retina Consultants of Texas in Houston, at the American Society of Retina Specialists meeting.

"Through week 26, [Ixo-vec] has demonstrated good visual and anatomic outcomes," said Wykoff. "From 76-83% of patients remain injection free, and 91% of patients in the local steroid arms have had no or minimal inflammation at every time point. Ultimately this is going to be a 1-year trial."

VEGF targeting with 4D-150 also led to a 90% decrease in the annualized injection rate and maintained BCVA and CST at 6 months with two different doses of the gene therapy. Three-fourths of patients required no supplemental anti-VEGF injections, reported Raj Maturi, MD, of the Midwest Eye Institute in Carmel, Indiana.

Emphasizing the safety of 4D-150, Maturi said, "There have been no drug-related serious adverse events. There were no cases of hypotony, endophthalmitis, retinal vasculitis, choroidal effusions, or retinal artery occlusions. [Analysis of] intraocular inflammation showed one case [in each dose group] of mild inflammation."

Questions, Uncertainties

Following the two presentations, an unidentified member of the audience asked Wykoff why such "heavy-handed steroid control" is needed.

"The short answer is that I don't think you do, and the data shows that you don't," Wykoff replied. "Previous studies of Ixo-vec showed meaningful levels of inflammation, and that was in one of the very first trials we started without any prophylaxis."

"We have come a long way in our understanding of how to safely deliver gene therapy," he continued. "This trial was designed to understand more completely comprehensive prophylactic regimens. What we have learned is that you don't need oral prednisone, that intravitreal dexamethasone did not help, and that topical difluprednate was sufficient."

In response to a second question, Wykoff said he is unaware of any evidence showing systemic expression of the vector.

Another question pertained to potential alternatives to intravitreal administration (such as suprachoroidal) to reduce the frequency and severity of inflammation.

"Intravitreal holds the most promise in many ways, but it's generally been associated with higher rates of inflammation," said Maturi. "One of the nice things we found so far in the 4D study is that the rates of inflammation were extremely low."

"We may need to be looking for drugs that minimize inflammation long term," he added. "These were only 6-month data. Gene therapy lasts a long time."

Co-moderator Donald D'Amico, MD, of Weill Cornell School of Medicine in New York City, emphasized "the transitional nature of these studies. Studies of production methods, [questions about] whether the pendulum swung maybe too far with inflammatory control. We're in an evolutionary phase of this, and it certainly will be very different when it is finally put into practice."

Ixo-vec

Promising results with Ixo-vec (formerly known as ADVM-022) in nAMD have continued to accumulate, despite a setback in diabetic macular edema (DME). Three cases of irreversible vision loss and near-universal intraocular inflammation led to termination of a trial in DME. In contrast, Ixo-vec treatment for nAMD has led to dramatic reductions in treatment burden and stable visual and anatomic outcomes for .

"Among the 115 patients treated to date, strong, consistent efficacy at controlling exudative disease activity has been demonstrated," said Wykoff.

Ixo-vec consists of the AV2.7m8 capsid engineered for enhanced transduction, carrying a coding sequence for aflibercept. Following a single intravitreal injection, transduced retinal cells become the source of continual aflibercept production.

The latest results came from the phase II LUNA trial evaluating the safety and efficacy of two doses of Ixo-vec (6 × 10¹⁰, 2 × 10¹¹ vg) plus enhanced corticosteroid prophylaxis to reduce intraocular inflammation in patients with previously treated nAMD. Wykoff reported interim findings for 60 patients, 58 of whom had complete data to 26 weeks. The primary endpoints of the ongoing trial are BCVA and adverse events (AEs), both from baseline to 52 weeks.

At enrollment, the annualized anti-VEGF injection rate from the prior year was 10.1, and patients had a mean BCVA of 72.3 and mean CST of 350.6 µm. At 26 weeks, 79% of patients from the two groups combined remained free of supplemental intravitreal injections of aflibercept, including 83% in patients who received the higher dose of Ixo-vec.

Mean annualized anti-VEGF treatment burden decreased from 10.2 and 10.1 to 1.0 and 0.5 in the lower and higher dose groups, respectively. In addition to the 90-95% reduction in treatment burden, 90-93% of patients required no more than one supplemental anti-VEGF injection.

Mean change in BCVA at 26 weeks was -1.1 to -2.2 letters in the two groups, and mean CST decreased by about 12 µm in both groups. Ixo-vec had the greatest impact on CST in patients whose baseline CST exceeded 300 µm, reducing the mean by 30.2 letters versus 7.4 µm in patients with baseline CST ≤300 µm.

Corticosteroid prophylaxis continued for 21 weeks post-dosing. The patients were randomized to receive various single-agent and combination regimens. With topical difluprednate and intravitreal dexamethasone, 91% of patients had inflammation grade 0-0.5+ (on a scale of 0-3+) as compared with 66% of patients who received oral prednisone in addition to dexamethasone. Local corticosteroids achieved inflammation grade 0-0.5+ in 90% of patients versus 91% with the addition of oral prednisone.

4D-150

The 4D-150 construct consists of the R100 capsid carrying a dual-transgene payload of aflibercept and VEGF-C RNA. Designed for single-dose intravitreal administration, the gene therapy inhibits four distinct VEGF proteins: VEGF-A, B, and C, and placental growth factor (PlGF).

Maturi reported findings from a phase II population expansion study of the PRISM trial involving 45 patients allocated 2:1 to a higher and lower dose of the anti-VEGF therapy (3 × 10¹⁰, 1 × 10¹⁰). Key endpoints were safety and tolerability, change in annualized anti-VEGF injection rate, percentage of patients requiring supplemental aflibercept injections, and change from baseline in BCVA and CST.

The patients had a mean age of 77, and baseline characteristics that included a mean BCVA of 72 letters, mean CST of 329 µm, mean time since nAMD diagnosis of 1.4 years, mean actual anti-VEGF injections in the prior 12 months of 4.4, and mean annualized injection rate of 9.0.

The therapy was well tolerated; two cases of intraocular inflammation were observed, one in each dose group. All but two patients completed the prophylactic steroid regimen as scheduled.

After 24 weeks of follow-up, patients assigned to the higher dose of 4D-150 had an 89% reduction in annualized anti-VEGF injection rate, 93% of patients required no more than one injection, and 77% of patients remained injection free. The same outcomes for the lower-dose group were 91%, 100%, and 60%, respectively.

BCVA improved by 3.5 letters with the higher dose versus a decline of 2.2 letters in patients who received the lower dose. Mean CST decreased by 9.2 µm and increased by 6.9 µm with the higher and lower doses of 4D-150. Patients who remained injection free at 24 weeks had greater improvement in BCVA and CST, said Maturi.