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Early Promise for Gene Therapy in AMD

SAN FRANCISCO — Patients with severe neovascular age-related macular degeneration (AMD) had long-term vision stabilization and anatomic improvement following a single treatment with an investigational gene therapy, a preliminary study showed.

In a subgroup of patients with the longest follow-up, three of six in the dose cohort required no rescue anti-VEGF medication for more than 1.5 years following treatment with RGX-314, which consists of an adenovirus-associated vector (AAV) to deliver an antibody fragment targeting VEGF. In another cohort with shorter follow-up, nine of 12 patients remained free of rescue medication for up to 6 months.

None of 42 patients treated in five dose cohorts had drug-related serious adverse events (SAEs), as reported here at the American Academy of Ophthalmology meeting.

“Subretinal RGX-314 was well tolerated with dose-dependent increases in ocular protein, and in cohort five, there was a high clinical response, as three-quarters of the patients are injection free at 5 or 6 months,” said Jeffrey Heier, MD, of Ophthalmic Consultants of Boston.

Investigation of RGX-314 will proceed with a phase IIb trial involving patients with neovascular AMD, a phase II trial in diabetic retinopathy, and evaluation of in-office suprachoroidal delivery of the agent.

Preliminary data for another gene-therapy strategy for neovascular AMD showed that the first six patients had stabilization of best corrected visual acuity (BCVA) at 24 weeks and a reduction in central retinal thickness (CRT) following a single intravitreal injection of ADVM-022, an AAV carrying an aflibercept (Eylea) payload.

Asked how long the therapy might allow patients to go without additional treatment, Heier said some patients treated with RGX-314 have been followed almost 2 years without retreatment, and studies of other types of gene therapy have maintained efficacy for several years. “It remains to be seen, but it’s certainly encouraging,” he stated.

In response to other questions, Heier said the minimal amount of inflammation seen thus far could reflect the subretinal delivery approach and the AAV8 vector, which elicits fewer neutralizing antibodies as compared with other vectors. Additionally, no patient has required immunosuppressive treatment thus far.

Background, Clinical Data

RGX-314 targets the angiogenesis that drives neovascular AMD by using the AAV to deliver a gene encoding for an anti-VEGF fab protein. The novel approach to targeting VEGF has the aim of longer-lasting control of AMD with a single subretinal injection, thereby reducing the number of injections as compared with currently available options.

Heier reported findings from the first five dose cohorts, ranging from 3 x 109 to 2.5 x 1011 genome copies/eye. The first three cohorts included six patients each, and cohorts four and five enrolled 12 patients each.

The ongoing phase I/II trial has a safety-related primary endpoint. Patients are followed monthly with assessments that include reduction in anti-VEGF injections (rescue medication), change in BCVA and CRT, and protein expression levels. Rescue medication could be administered as needed at the discretion of the treating physician.

The 42 patients had a mean age of 80, baseline BCVA of 55.7 letters, and baseline CRT of 399.1 µm. They had received anti-VEGF injections for an average of 56.1 months, and they had received an average of 9.6 injections a year.

The safety analysis showed a total of 15 SAEs in nine patients, none of which was considered drug related, said Heier. Two patients died, also of causes unrelated to treatment with RGX-314. Two procedural SAEs were reported, one case each of peripheral retinal detachment and endophthalmitis following aqueous sample collection.

Pharmacokinetic/pharmacodynamic data showed dose-dependent increases in RGX-314 protein in aqueous samples obtained 1 month after injection. The data correlated with better visual and anatomic outcomes in follow-up to 1.5 years. Patients in the first two cohorts had little or no improvement in BCVA and CRT, whereas patients in cohort three had BCVA improvement of nine letters and mean CRT reduction of 40 µm.

Heier said patients in cohort three required 2.6 injections of rescue medication on annualized basis, including three patients who had received no additional treatment. In the two most recently enrolled cohorts, five of 12 patients in cohort four remained injection free at 6 months, and nine of 12 in cohort five remained injection free for 5 to 6 months. Patients who remained injection free in cohorts four and five had improvement in BCVA averaging two and five letters and reductions in CRT averaging 61 and 80 µm, respectively.

ADVM-022 Results

The ongoing trial of ADVM-022 was preceded by preclinical studies showing that a single intravitreal injection of the therapy led to sustained aflibercept protein expression for 30 months within the range of single-dose aflibercept, said Szilard Kiss, MD, of Weill Cornell Medical College in New York City. Additional research showed that administration of ADVM-022 more than a year before laser-induced choroidal neovascularization (CNV) was as effective as administration of aflibercept at the same time as CNV.

The first six patients in the trial had a mean age of 79, mean interval since AMD diagnosis of 3.3 years, and average anti-VEGF injections of 9.3 per year. They had a mean BCVA of 65.8 letters and mean CRT of 369.2 µm.

No SAEs were reported, and no drug-related non-ocular adverse events occurred. Six patients had a total of 19 ocular adverse events, 14 considered mild and five judged to be moderate in severity. The most common were anterior chamber cells (four, two moderate), anterior chamber flare (four), vitreous cells (three, one moderate), intermediate uveitis (two moderate), and keratic precipitates (two).

Through 24 weeks of follow-up, the six patients had a mean loss of two letters in BCVA and a mean reduction in CRT of 52.7 µm.

The latest data from a median follow-up of 34 weeks showed no grade 3 or serious adverse events, mean BCVA change from baseline of -1.5 letters, and no rescue injections.

“ADVM-022 offers transformative potential to greatly reduce treatment burden and improve retinal anatomy with a single intravitreal injection in neovascular AMD,” said Kiss.

The RGX-314 trial was supported by RegenxBio.

The ADVM-022 trial was supported by Adverum Biotechnologies.

Heier disclosed relevant relationships with Aerie, Aerpio, Apellis, Clearside, Daiichi, Genentech/Roche, Graybug, Gyroscope, Hemera, Janssen, KalVista, Kanghong, Novartis, Ophthotech, Optos, Optovue, Regeneron, RegenxBio, Stealth Biotherapeutics, Thrombogenics, Tyrogenex, 4DMT, Adverum, Aldeyra, Alkahest, Allegro, Allergan, Annexon, Array, Asclepix, Eloss, Galimedix, Generation Bio, Interface, iRenix, jCyte, Kala, Kodiak, NGM Biopharmaceuticals, Notal Vision, Ocugenix, Ocular Therapeutix, Omeicos, Orbit/Gyroscope, Retrotope, Santen, Scifluor, Shire, Takeda, and Voyant.

Kiss disclosed relevant relationships with Adverum, RegenxBio, Genentech/Roche, Fortress Bio, Optos, and Novartis, as well as an intellectual property interest.