Investigative Gene Therapy RGX-314 Reduces Anti-VEGF Dosing in AMD Patients


The REGENXBIO drug's promising phase 1 results has led to the addition of a fourth patient dosing cohort and a phase 2 trial initiation.

Kenneth T. Mills

Kenneth T. Mills

Clinical-stage biotechnology company REGENXBIO has announced promising results in its phase 1 trial for investigative gene therapy RGX-314 in patients with wet age-related macular degeneration (wet AMD).

The trial results, anticipated to be presented at the American Association of Ophthalmology (AAO) annual meeting in Chicago, IL, this October, indicate that patients with AMD may eventually be able to improve visual acuity without the aid of anti-vascular endothelial growth factor (anti-VEGF) therapy.

According to the interim data update, 18 patients with wet AMD were administered 1 dose of RGX-314 across 3 dose cohorts. Patients included in the trial had a history of frequent anti-VEGF treatment (as defined by at least 4 injections in the 8 months prior to the trial) and a documented history of response to anti-VEGF.

The cohort trial doses, to 6 patients each, were 3x10^9, 1x10^10, and 6x10^10 genome copies (GC)/eye. Patients were assessed every month to a six-month primary endpoint. The interim clinical updates as of July 27 reported on patients having been treated for an average of 11, 9, and 6 months in each cohort, respectively.

Researchers gauged patients in all cohorts for dose-dependent protein expression levels and reduction in anti-VEGF injections, as well as maintenance of central retinal thickness (CRT) by spectral domain optical coherence tomography (SD-OCT).

Thus far, all treated patients have reported RGX-314 protein expression to date, and dose-dependent increases in protein expression levels at approximately 1 month following administration have been observed.

CRT maintenance, as measured by SD-OCT, has been observed in patients from baseline to 6 months in all 3 cohorts. Notably, in the third cohort, mean CRT decreased by -14 µm in that observed period—despite these patients receiving fewer anti-VEGF injections on average than patients in the first 2 cohorts.

On average, patients received 35-plus anti-VEGF treatments since their wet AMD diagnosis. In the 6 months following administration of RGX-314, average injection rates among patients in Cohort 3 decreased 53% compared to prior history. Cohort 2 also reported an anti-VEGF treatment decrease of 8% versus prior history. Half (50%) of the patients treated in Cohort 3 have been free of any anti-VEGF injections since being administered the investigative gene therapy.

Best corrected visual acuity (BCVA), as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letters, was maintained across all cohorts from baseline to 6 months. Patients in Cohort 3 reported a mean gain of 8 ETDRS letters.

There were no drug-related adverse events (AEs) or serious AEs reported at the interim study results, with the most common AEs in all dose cohorts being assessed as “mild.” Researchers reported no immune responses, drug-related ocular inflammation, or post-surgical inflammation beyond the anticipated standards of routine vitrectomy.

Based on the results and a filed amendment from REGENXBIO, the US Food and Drug Administration (FDA) cleared the company to proceed with the initiation of a fourth dosing cohort of 6 patients, at a dose of 1.6x10^11 GC/eye. The first patient in the new cohort was dosed last week.

The early indications of a safe, effective gene therapy gives credence to an expansion in a phase 2 trial, Kenneth T. Mills, REGENXBIO president and chief executive officer, said in a statement. The hope is to get the therapy to patients as “quickly as possible.”

"We are very encouraged by the positive interim data for RGX-314 and the potential of NAV gene therapy as a one-time treatment for wet AMD, particularly as this is a non-rare patient population with a significant treatment burden," Mills said.

The phase 2 trial is planned for a 2019 start date, with final determinations of the study currently underway.

The state of gene therapy for ophthalmologic indications is at the cusp of an “explosion,” Stephen R. Russell, MD, told MD Magazine® during an interview at the American Society of Retinal Specialists (ASRS) annual meeting in Vancouver, BC, this July.

Russell, a professor of vitroretinal diseases at the University of Iowa Hospital & Clinics, told MD Mag the variety of genes being targeted and the mechanism by which they are being targeted in dozens of clinical trials is robust.

“We’ll have to see,” Russell said. “It’ll be a gene-by-gene guerilla warfare, as we try to figure out how to do these treatments, as to what will be a reasonable expectation.”

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