Dramatic results seen with gene therapy for age-related macular degeneration

MONTREAL -- Gene therapy for neovascular age-related macular degeneration (nAMD) achieved stable vision and retinal anatomy for up to 5 years, with dramatic reductions in treatment burden, according to studies reported here.

Five-year follow-up of 15 patients treated with the phase III dose of VEGF-targeting ixoberogene soroparvovec (ixo-vec) showed a mean loss of 6.1 letters in best corrected visual acuity (BCVA) versus an expected loss of 12 to 17 letters on the basis of clinical trials of standard nAMD therapy. Baseline central subfield thickness (CST) declined by 131.6 µm. The patients required fewer than two supplemental injections annually, an 87% cumulative reduction over the baseline average of 10.

No patients developed hypotony, vasculitis, retinitis, choroiditis, or vascular occlusion, and one patient developed intraocular inflammation after complex cataract surgery, reported Szilard Kiss, MD, of Weill Cornell College of Medicine in New York City, at the American Society of Retina Specialists meeting.

"There was nearly a 90% reduction in the need for rescue injections [of aflibercept (Eylea)]," said Kiss. "Durable aqueous aflibercept levels were seen out to 5 years, as well as robust and durable clinical activity, with the low dose being well tolerated out to 5 years. Ixo-vec is currently undergoing evaluation in two phase III trials."

Another study showed that patients who received a single dose of 4D-150, also targeting VEGF, had stable vision and CST during 2 years of follow-up, with an 80-90% reduction in treatment burden. In a subgroup of 15 patients with recently diagnosed nAMD, two-thirds required no supplemental treatment over the 2 years of follow-up. Had the patients received standard therapy with aflibercept every 8 weeks, they would have required 12 intravitreal injections over 2 years, said Carl Awh, MD, of Tennessee Retina in Nashville.

A third study showed as much as a nine-letter improvement in BCVA over 5 years with surabgene lomparvovec (sura-vec, ABBV-RGX-314). Administered by subretinal injection, the therapy reduced treatment burden by about two-thirds in patients who received dose levels being evaluated in an ongoing phase III trial, reported Robert Avery, MD, of California Retina Consultants in Santa Barbara.

Noting the consistency of the three studies, session co-moderator Sunir Garg, MD, of Wills Eye Hospital in Philadelphia, said, "Now that we have longer follow-up -- I realize in smaller groups of patients -- can you say that after a year, if you haven't needed a shot, are you going to remain injection free out to year 5? And those who require supplemental injections during the first year are the types of patients who need it over time?"

"I don't think so," said Awh, "because we know this disease tends to change a bit over time. Many of our patients who are stable at the same rate of treatment, they come back at the same interval, and [at some point] they come back and they're worse. I think we can never really relax our vigilance, but we will have a lot more comfort in monitoring patients, knowing that their eye will never have zero drug in it."

Co-moderator Timothy Murray, MD, of Murray Ocular Oncology and Retina in Coral Gables, Florida, homed in on another aspect of the studies' consistency: "We seem to be moving away a little bit from the concern for vision and focusing on the potential to decrease injections. How important is long-term vision? Are we going to potentially let some vision fall by the wayside?"

"Vision is important," said Kiss. "Our patients don't care about what their OCTs [optical coherence tomography] look like. Ultimately, they care about what vision is. When you look at the [ixo-vec] trial, there was no potential to gain vision because patients had been treated for over 3 years with 10 injections [per year]. We are going to look at vision and the potential gain for vision in the phase III trials."

Referencing historical data showing a 12- to 17-letter vision loss at 5 years with standard therapy, Kiss pointed to the stable vision over 5 years with ixo-vec without the need for repeated injections. "Vision is still paramount," he noted.

Ixo-Vec

Kiss reported findings from the long-term extension of the phase I OPTIC trial of ixo-vec (formerly ADVM-022). The therapy consists of a therapeutic transgene delivered by a capsid vector to the retina to induce continuous stable production of aflibercept. OPTIC included 30 patients who had required frequent intravitreal injections of anti-VEGF therapy for nAMD for 3-4 years. The study population comprised two 15-patient cohorts treated with one of two doses of ixo-vec.

Both doses of the gene therapy achieved stable early aflibercept levels that predicted long-term protein expression. In the patients treated with the phase III dose, BCVA decreased by 6.1 letters over 5 years, but exclusion of two "outliers" who had large decreases in BCVA resulted in a net gain of 0.9 letters. A baseline CST of 407.1 µm decreased rapidly after injection of ixo-vec and remained stable throughout follow-up.

Two ongoing phase III trials with a total of 568 patients are comparing ixo-vec and aflibercept 2 mg in both treated and untreated nAMD. Initial results from the ARTEMIS trial are expected in early 2027, said Kiss.

4D-150

Administered by routine intravitreal injection, 4D-150 consists of an adeno-associated vector (AAV) that delivers a dual transgene payload to the retina, inducing production of aflibercept and an inhibitory RNA against VEGF-C. Awh focused on a 30-patient cohort of the phase I/II PRISM trial, representing a broad range of nAMD characteristics. Mean duration of nAMD was 1.8 years, and the patients had received an average of 4.4 intravitreal injections in the previous 12 months.

Both CST and BCVA remained stable throughout 2 years of follow-up after administration of 4D-150. Almost half (46%) of the patients required no supplemental treatment during the 2 years, and 69% required no more than two injections. In 15 patients with recently diagnosed nAMD, 87% required no more than two supplemental injections, including 66% who remained injection free.

No 4D-150-related serious adverse events (SAEs) occurred, nor any cases of hypotony, endophthalmitis, retinal vasculitis, or choroidal effusion, said Awh. Safety follow-up for 4 years showed a 2.8% incidence of intraocular inflammation, none after the first 28 weeks.

Sura-Vec

The therapeutic construct consists of an AAV that delivers a gene that induces production of an anti-VEGF fragment antibody. During the first 2 years of follow-up, the gene therapy demonstrated dose-dependent increases in therapeutic protein, said Avery.

A phase I/IIb clinical trial enrolled and treated 37 patients who had a baseline BCVA of 19-73 letters, a demonstrated response to anti-VEGF therapy, and four or more intravitreal injections in the 8 months prior to enrollment. The trial had no cap on disease duration.

A single injection of sura-vec led to stable or improved BCVA during the first 2 years, with change in BCVA ranging from -4 to +14 letters across five dose levels. After 5 years of follow-up, mean BCVA associated with the two dose levels selected for phase III investigation were +11 letters and -11 letters. Treatment burden decreased by 64-65% in those two cohorts.

Five ocular SAEs occurred, including two cases of visual impairment that the investigators considered related to sura-vec. Four patients died but none of the deaths were related to the gene therapy, said Avery. The most common ocular adverse event was retinal pigmentary changes in 26 of the 37 patients.

Two phase III trials of sura-vec are ongoing.