Regenxbio reported positive 1 year data from patients in Cohorts 4 and 5 of the phase 1/2a trial of RGX-314 for the treatment of wet age-related macular degeneration (AMD). The company plans to initiate a pivotal program for subretinal delivery of RGX-314 in patients with wet AMD by the end of 2020. In addition, Regenxbio announced that a phase 2 trial of RGX-314 for the treatment of wet AMD delivered to the suprachoroidal space (AAVIATE) is active and expected to enroll patients in the third quarter 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 company news release. “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 1 year. Results from the phase 1/2a 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.”
Dr. Pakola continued: “I am also pleased to announce that our AAVIATE trial, a phase 2 trial of RGX-314 for the treatment of wet AMD utilizing the SCS Microinjector, is active and we expect to dose the first patient this quarter. The targeted, in-office suprachoroidal delivery approach may provide additional options for patients in all settings of patient care. We anticipate providing an interim data update from the first cohort in late 2020.”
“Based on the overall results to date from the phase 1/2a trial, I believe that RGX-314 has the potential to profoundly impact all aspects of clinical management for patients with wet AMD,” Robert Avery, MD, Founder of California Retina Consultants and Research Foundation and investigator surgeon in the phase 1/2a RGX-314 trial, said in the news release. “Wet AMD affects a large number of adults, and often results in loss of vision over time due to non-compliance with the current standard of care of frequent anti-VEGF injections. I am encouraged that RGX-314 has the potential to become a one-time gene therapy treatment option for a broad range of patients.”
Study Design and Safety Update from Phase 1/2a Trial of RGX-314 for the Treatment of Wet AMD using Subretinal Delivery
In the phase 1/2a trial of RGX-314, 42 patients with long-standing severe wet AMD requiring frequent anti-vascular endothelial growth factor (anti-VEGF) injections were treated across five dose cohorts, with doses ranging from 3×109 GC/eye to 2.5×1011 GC/eye. Patients were 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.
Patients in the study are being assessed each month for 2 years and will receive safety follow-up for 5 years after RGX-314 administration. Efficacy assessments for the study include number of anti-VEGF intravitreal injections, change in vision as 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, 2020, RGX-314 was generally well-tolerated across all cohorts. Eighteen serious adverse events (SAEs) were reported in 11 patients, including 17 that were not related to RGX-314. One possibly drug-related SAE of significant decrease in vision was reported in Cohort 5 at Month 11 in a patient who had retinal pigmentary changes that involved the macula. The most common nonserious adverse events in the eye were generally assessed as mild (77%). These included post-operative conjunctival hemorrhage (69% of patients), postoperative inflammation (36% of patients), eye irritation (17% of patients), eye pain (17% of patients), and post-operative visual acuity reduction (17% of patients). 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 which were in the peripheral inferior retina. Retinal hemorrhage was observed in 24% of patients and is an anticipated event in patients with severe wet AMD. There have been no reports of clinically determined immune responses, drug-related ocular inflammation, or post-surgical inflammation beyond what is expected following routine vitrectomy.
Summary of Data from Cohorts 4 and 5 of Phase 1/2a Trial of RGX-314 for the Treatment of Wet AMD using Subretinal Delivery
Today’s update includes data from Cohorts 4 and 5 as of July 13, 2020. Each cohort enrolled 12 patients each at doses of 1.6×1011 GC/eye and 2.5×1011 GC/eye, respectively.
Patients in Cohort 4 and Cohort 5 at 1 year after administration of RGX-314 demonstrated stable visual acuity with a mean BCVA change of +4 letters and -2 letters from baseline, respectively, as well as decreased retinal thickness, with a mean change in CRT of -61 µm and -79 µm, respectively.
There was a clinically significant and meaningful reduction in anti-VEGF treatment burden in both Cohorts 4 and 5 compared to the 12 months prior to RGX-314 administration. Patients in Cohort 4 received a mean of 4.1 injections over 1 year following administration of RGX-314, a 61% reduction in treatment burden. Patients in Cohort 5 received a mean of 1.4 injections over one year following administration of RGX-314, a reduction in treatment burden of 85%.
In Cohort 4, three out of twelve (25%) patients received no anti-VEGF injections over 1 year, and these patients demonstrated a mean BCVA improvement of +6 letters and a mean reduction in CRT of -62 µm at 1 year. In Cohort 5, eight out of the eleven (73%) patients observed through one year have received no anti-VEGF injections after administration of RGX-314 and these patients demonstrated a stable mean BCVA change of 0 letters and a mean reduction in CRT of -95 µm at 1 year.
Consistent with previous results, intraocular RGX-314 protein expression levels were observed in a dose-dependent manner across each cohort at 1 year after administration of RGX-314. The mean protein expression levels in Cohort 4 and Cohort 5 were 420.9 ng/ml and 457.5 ng/ml, respectively.
Study Design for Phase 2 Trial for RGX-314 for Treatment of Wet AMD Using Suprachoroidal Delivery (AAVIATE)
Regenxbio also announced that a phase 2 trial, AAVIATE, to evaluate the suprachoroidal delivery of RGX-314 in patients with wet AMD, will begin dosing patients in the third quarter of 2020. AAVIATE is a multicenter, open-label, randomized, active-controlled, dose-escalation study that will evaluate the efficacy, safety and tolerability of suprachoroidal delivery of RGX-314 using the SCS Microinjector, a targeted, in-office route of administration.
AAVIATE will enroll 40 patients with severe wet AMD who are responsive to anti-VEGF treatment. 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 two dose levels of RGX-314 will be evaluated: 2.5×1011 GC/eye and 5×1011 GC/eye. Patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314.
The primary endpoint of the study is mean change in vision, as measured by BCVA, at 40 weeks from baseline compared to monthly ranibizumab. Other endpoints include mean change in CRT and number of anti-VEGF intravitreal injections.
The company expects to report interim data from the first cohort of this trial by the end of 2020.