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Initial Data Positive for Wet Age-Related Macular Degeneration Treatment

REGENXBIO also announced the scheduling of a phase 2 trial testing RGX-314 for wet AMD.

Positive RGX-314 data from an early phase trial is allowing investigators to move forward with a new treatment for wet age-related macular degeneration (wet AMD).

REGENXBIO reported positive one-year results from cohorts 4 and 5 in the phase 1 and 2a trial testing RGX-314 for wet age-related macular degeneration and is now planning on initiating a program for subretinal delivery in patients with wet AMD by the end of 2020.

"Today's results provide further evidence of the clinical profile of RGX-314 as a promising one-time gene therapy treatment paradigm for patients with wet AMD," Steve Pakola, MD, Chief Medical Officer of REGENXBIO, said in a statement. "The data demonstrated stable to improved visual acuity and retinal thickness, as well as a meaningful reduction in anti-VEGF injection burden, in these higher dose levels at one year. Results from the Phase I/IIa trial will inform the design of the pivotal program of RGX-314 in patients with wet AMD, which we look forward to initiating by the end of this year."

In the phase 1/2a trial, the investigators examined 42 patients with long-standing severe wet AMD requiring frequent anti-vascular endothelial growth factor (anti-VEGF) injections treated across 5 dose cohorts.

The doses ranged from 3x10 9 GC/eye to 2.5x10 11 GC/eye and patients enrolled into all dose cohorts independent of their neutralizing antibody titers to AAV and did not receive prophylactic or supplemental immune suppressive corticosteroid therapy for RGX-314.

The 4 and 5 cohorts enrolled 12 patients each at doses of 1.6x10 11 GC/eye and 2.5x10 11 GC/eye, respectively.

Patients in the study will be assessed monthly for 2 years. Each participants will receive safety follow-up for 5 years following treatment administration.

The investigators assessed a number of efficacy measures including the number of anti-VEGF intravitreal injections, change in vision measured by Best Corrected Visual Acuity (BCVA), change in central retinal thickness (CRT) as measured by spectral domain optical coherence tomography (SD-OCT), and RGX-314 protein expression levels as measured from aqueous samples by electrochemiluminescence immunoassay (ECL).

As of July 13, the study drug was generally well-tolerated across all dosing cohorts. However, there were 18 serious adverse events reported in 11 patients, including 17 that were not related to RGX-314.

One possibly drug-related serious adverse event of significant decrease in vision was reported in cohort 5 at month 11 in a patient who had retinal pigmentary changed that involved the macula. The investigators found 77% of the most common nonserious adverse events in the eye were generally classified as mild.

This included post-operative conjunctival hemorrhage (69% of patients), post-operative inflammation (36%), eye irritation (17%), eye pain (17%), and post-operative visual acuity reduction (17%).

In 67% of patients across all cohorts, and in 83% of patients in Cohorts 3 through 5, retinal pigmentary changes were observed on imaging. The majority of these were in the peripheral inferior retina.

The investigators also observed retinal hemorrhage in 24% of patients, which is an anticipated event for patients with severe wet AMD.

There were no reports of clinically determined immune responses, drug-related ocular inflammation, or post-surgical inflammation beyond what is expected after routine vitrectomy.

Patients in the 2 cohorts demonstrated stable visual acuity with a mean BCVA change of 4 letters and -2 letters from baseline at the one-year mark. The patients also showed decreased retinal thickness with a mean change in CRT of 61 µm and -79 µm, respectively.

There was also a clinically significant and meaningful reduction in anti-VEGF treatment burden in both cohorts compared to the 12 months prior to RGX-314 administration.

The patients in cohort 4 received a mean of 4.1 injections over a one-year period following the administration of RGX-314. This represents a 61% reduction in treatment burden.

For the patients in cohort 5, they received a mean of 1.4 injections over the same time period, representing a 85% reduction in treatment burden.

In the fourth cohort, 25% (n = 3) of patients received no anti-VEGF injections over one-year and demonstrated a mean BCVA improvement of 6 letters and a mean reduction in CRT of -62 µm at one-year.

At the fifth cohort, 73% (n = 8) of patients received no anti-VEGF injections after treatment for 1 year, demonstrating a stable mean BCVA change of 0 letters and a mean reduction in CRT of -95 µm at one-year.

Intraocular RGX-314 protein expression levels were observed in a dose-dependent manner across each cohort at one-year after administration of RGX-314 and the mean protein expression levels in Cohort 4 and Cohort 5 were 420.9 ng/ml and 457.5 ng/ml, respectively.

REGENXBIO also announced a phase 2 trial of RGX-314 for wet AMD delivered to the suprachoroidal space is active and they will begin to enroll patients in the third quarter of 2020, involving 40 patients with severe wet AMD.

The multi-center, open-label, randomized, active-controlled, dose-escalation study will evaluate the efficacy, safety, and tolerability of suprachoroidal delivery of RGX-314 using the SCS Microinjector.

Patients will be randomized to one-time RGX-314 SCS delivery versus monthly 0.5 mg ranibizumab intraocular injection at a 3:1 ratio and 2 dose levels of RGX-314 will be evaluated: 2.5x1011 GC/eye and 5x1011 GC/eye.

The investigators will seek a primary endpoint of the mean change in vision, measured by BCVA, at 40 weeks compared to monthly ranibizumab, as well as secondary endpoints of the mean change in CRT and the number of anti-VEGF intravitreal injections.