Regenxbio provided additional long-term data from the ongoing phase 1/2a trial of RGX-314 for the treatment of wet age-related macular degeneration (AMD).
In the phase 1/2a trial of RGX-314, 42 patients with 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 immune suppressive oral corticosteroid therapy before or after administration of RGX-314.
Patients in the study are being assessed each month for 24 months and will receive safety follow-up for 5 years after RGX-314 administration. Efficacy assessments for the study include reduction in 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 protein expression levels as measured from aqueous samples by electrochemiluminescence immunoassay (ECL).
As of April 6, 2020, RGX-314 continued to be well-tolerated across all cohorts, with no drug-related serious adverse events (SAEs) reported. Sixteen SAEs that were not related to RGX-314, including two ocular procedure-related SAEs, were reported in ten patients. 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.
Across all 42 patients in the study, the most common nonserious adverse events in the study eye were generally assessed as mild (90%). 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 postoperative visual acuity reduction (17% of patients). In 67% of patients across all cohorts, and in 83% of patients in Cohorts 3-5, mild to moderate retinal pigmentary changes were observed on imaging, the majority of which were in the peripheral inferior retina. There was no evidence of clinical symptoms or changes to visual acuity related to retinal pigmentary changes. Retinal hemorrhage was observed in 17% of patients and is an anticipated event in patients with severe wet AMD.
“I am impressed by the overall outcomes in patients after a one-time administration of RGX-314. I believe that RGX-314 is the leading gene therapy program for a major retinal disease such as wet AMD and could be an important potential one-time treatment option for AMD patients who require frequent and burdensome anti-VEGF injections,” Allen C. Ho, MD, Director of Retina Research at Wills Eye Hospital and Mid Atlantic Retina and investigator surgeon in the RGX-314 trial, said in a company news release. “Real-world evidence demonstrates that patients lose vision over time with our current standard of care and incur significant treatment burden with frequent clinic visits and injections.”
“The clinical profile of RGX-314 appears very promising as a one-time treatment strategy for wet AMD as we continue to learn about the consistent and durable effects of our anti-VEGF gene therapy,” added Steve Pakola, MD, Chief Medical Officer of Regenxbio. “We are encouraged that all patients in Cohort 5 who were anti-VEGF injection-free at six months remained anti-VEGF injection-free at nine months. We also have further evidence of dose-dependent intraocular protein levels in this phase I/IIa study. We are on track to have one-year data from our later cohorts in mid-2020 and look forward to initiating a pivotal program for the subretinal delivery of RGX-314 in the second half of 2020. We are also continuing our preparations to initiate a Phase II trial for the in-office suprachoroidal delivery of RGX-314 in wet AMD patients in the first half of this year.”
Summary of Long-term Data for Cohort 3 Over Two Years
Positive long-term potential efficacy signals were sustained over 2 years in Cohort 3. The mean change in visual acuity across all six patients in Cohort 3 was markedly improved over two years, with a mean BCVA improvement of +14 letters, and the mean change in CRT was stable, with an increase of +2 µm.
Patients in Cohort 3 also demonstrated long-term reductions in anti-VEGF treatment burden over 2 years with a mean annualized rate of 2.8 anti-VEGF injections after administration of RGX-314, which is a reduction of over 60% from the mean annualized injection rate during the 12 months prior to administration of RGX-314. Three out of six (50%) patients received no anti-VEGF injections over 2 years following one-time administration of RGX-314. One patient received four anti-VEGF injections after RGX-314 administration and then did not receive anti-VEGF injections from 9 months through 2 years.
The four patients who did not receive anti-VEGF injections after 9 months demonstrated a mean BCVA improvement of +14 letters, with a range of +6 letters to +25 letters. In addition, these patients had stable retinal thickness with a mean change of +9 µm.
Additionally, long-term intraocular RGX-314 protein expression was stable in patients in Cohort 3 over 2 years. The mean RGX-314 protein expression level in Cohort 3 was 227.2 ng/ml at 2 years, compared to 217.8 ng/ml at 6 months. The mean RGX-314 protein expression level in the four patients who did not receive anti-VEGF injections after nine months was 291.7 ng/ml at 2 years, compared to 273.6 ng/ml at 6 months.
Summary of Data for Cohorts 4 and 5
Consistent with previous results, intraocular RGX-314 protein expression levels increased in a dose-dependent manner across cohorts when measured at 6 months after administration of RGX-314; the mean protein expression level in Cohort 4 and Cohort 5 was 653.6 ng/ml and 848.7 ng/ml, respectively.
Patients in Cohort 5 continued to demonstrate a meaningful reduction in anti-VEGF treatment burden over 9 months following administration of RGX-314, with 8/11 (73%) patients remaining anti-VEGF injection-free, and a reduction across the cohort of over 80% from the mean annualized injection rate during the 12 months prior to RGX-314 administration.