ASRS Day 1: Results from the INFINITY and ALTITUDE studies

Rachel Israilevich, BS
Sidney Kimmel Medical College
Thomas Jefferson University School of Medicine

One of the highlights of Saturday’s Diabetic Retinopathy Symposium at ASRS was the presentation of first-time data from the INFINITY Phase II trial presented by Dr. Charles Wykoff. The previous OPTIC Phase I trial was successful in demonstrating safety, tolerability, and efficacy with a single intravitreal injection of ADVM-022, a novel biofactory approach to gene therapy designed for continuous intraocular delivery of aflibercept, in patients with neovascular age-related macular degeneration (nAMD). The Phase II INFINITY enrolled 34 patients in 3 arms (aflibercept, low dose ADVM-022 [2×1011 vg/eye], and high-dose ADVM-022 [6×1011 vg/eye]) to evaluate the safety, efficacy, and durability of ADVM-022 in patients with diabetic macular edema (DME). The primary endpoint was the time to worsening of DME disease activity in the study eye, measured at week 24. At this time point, 89% of eyes in the control group required rescue aflibercept injections versus 25% and 39% of eyes in the high dose and low dose groups, respectively (p=0.042). Visual acuity improvements were preserved until after week 24, where a downward trajectory related to adverse events was noted. Central subfield thickness (CST) improved across all three arms. From a safety perspective, non-ocular adverse events were similar between study arms. However, INFINITY was unmasked due to unexpected adverse ocular events. Nearly all of the ADVM-022 treated patients developed dose-dependent inflammation, including anterior chamber inflammation, iris-related events, and posterior uveitis. While these events were consistent with those recorded in OPTIC, the proportion and intensity of these events increased. Additionally, nearly all patients receiving gene therapy required steroids by multiple administration routes (ocular, intraocular, oral, or systemic) beyond the 10-week prophylactic period. The most significant adverse event was the development of hypotony in 3 patients, all within the high dose group, which required vitrectomy and silicone oil placement. The mechanism underlying this dose-limiting toxicity is unknown, but current hypotheses under investigation include the risk of the study population, particularly the impact of diabetes on ciliary body function, the toxic effect or immune response to gene therapy, a local anti-VEGF effect, or a combination of these and other events. Additional efforts are being deployed to ensure patient safety and better understand this dose-limiting toxic effect in the high-dose group. In conclusion, the results of this study support the biological efficacy of ADVM-022, and highlight the impact of ADVM-022 dose and disease state in determining the therapeutic window. Moving forward, the development of ADVM-022 will focus on lower doses and the treatment of nAMD rather than DME.

To continue the discussion on leading trials in retinal gene therapy, Dr. Dennis Marcus shared early results from the Phase II ALTITUDE study. This study is evaluating the suprachoroidal delivery of RGX-314 in eyes with proliferative diabetic retinopathy (PDR) and NPDR. RGX-314 utilizes a novel AAV-8 vector encoding an anti-VEGF monoclonal antibody fragment with potential for long-term, therapeutic anti-VEGF expression in retinal cells. This vector is injected into the suprachoroidal space, and is hypothesized to induce less inflammation compared to earlier vectors and deliver gene products more efficiently. The primary objective of this study is to evaluate the proportion of patients with ≥2 step improvement in severity on the DRSS at one year, with secondary objectives including the safety and tolerability of RGX-314 and development of diabetic ocular complications. Eyes were randomized in a 3:1 ratio of suprachoroidal RGX-314 (2.5×1011 GC/eye) versus non-sham observation control group without any prophylactic steroids. From a safety perspective, the preliminary results demonstrated good tolerability for RGX-314. Only one significant adverse event was noted in the fellow eye and was not considered drug-related. Most importantly, no intraocular inflammation was observed across the whole cohort. At month 3 following treatment, the rate of ≥2 step DRSS improvement in the RGX-314 group was 33% versus 0% in the control group. One eye in the RGX group even demonstrated a 4-step DRSS improvement. Rates of DRSS 2-step improvement in PANORAMA (aflibercept intravitreal injection for severe non-PDR) and RIDE/RISE (ranibizumab intravitreal injection for DME) ranged from 32%-45% with monthly injections, whereas RGX-314 demonstrated similar results following a single injection. In summary, suprachoroidal RGX-314 is being well-tolerated in ALTITUDE’s Cohort 1 with no incidence of intraocular inflammation. ALTITUDE is currently enrolling patients for Cohorts 2 and 3 to investigate higher doses of RGX-314 (5.0×1011 GC/eye). The suprachoroidal space offers the potential for administration of lower drug doses with high bioavailability in the posterior segment, and these promising results will hopefully help lead us towards treatment options with a reduced injection burden.