A patient enrolled in the phase 2 INFINITY trial exploring ADVM-022 for diabetic macular edema experienced a suspected unexpected serious adverse reaction, which has led to an unmasking of the study.
A patient enrolled in the phase 2 INFINITY trial exploring ADVM-022 for diabetic macular edema (DME) experienced a suspected unexpected serious adverse reaction (SUSAR) of hypotony with panuveitis and loss of vision following a single intravitreal injection of the gene therapy. The study, which completed patient dosing in December 2020, is being unmasked to allow for further study of this adverse event, according to a statement from Adverum Biotechnologies, the company developing the therapy.
“The safety of every patient who is participating in our clinical studies with our gene therapy is the utmost priority for us at Adverum,” Laurent Fischer, MD, chief executive officer of Adverum, said in a statement. “We are fully committed to thoroughly assessing this case and ongoing monitoring of this patient and all patients treated with ADVM-022 with our investigators, data monitoring committee, scientific advisory board, and healthcare authorities.”
ADVM-022 is an AAV.7m8-mediated gene therapy that encodes a sequence for aflibercept (Eylea), a VEGF inhibitor approved for wet age-related macular degeneration (AMD), DME, diabetic retinopathy, and macular edema following retinal vein occlusion. Aflibercept is a recombinant fusion protein that consists of the binding sites for VEGFR1 and VEGFR2 fused to the Fc portion of IgG1.
The INFINITY trial enrolled 36 patients with DME across 3 arms (NCT04418427). In the first group, patients received ADVM-022 as a single intravitreal (IVT) injection at 6 x 10^11 vg/eye and in the second the gene therapy was administered at 2 x 10^11 vg/eye. In the third arm, which was a control group, patients received aflibercept alone at 2 mg IVT. Those receiving ADVM-022 were subsequently randomized to receive a sham injection or aflibercept at 2 mg IVT, if required.
As a single IVT injection, the goal of the therapy was to significantly reduce treatment burden for patients with DME and a primary measure in the study was the durability of treatment. The study follow-up period was 48 weeks after randomization. The primary end point was time to DME worsening, with secondary outcome measures focused on safety, the need for rescue aflibercept, visual acuity, and other measures.
The SUSAR event occurred 30 weeks following the initial randomization in an individual receiving the highest dose of ADVM-022. Adverum alerted the FDA and all clinical sites of the SUSAR and was working closely with the data monitoring committee to uncover a potential cause. Additional updates are expected as analyses continue.
The SUSAR event was announced just a few days prior to the ARVO 2021 meeting, wherein Adverum promised updates from the phase 1 OPTIC trial exploring ADVM-022 for patients with wet AMD. In earlier findings from the study released at the 2020 AAO meeting, most patients treated with a high-dose of ADVM-022 (14 of 15) did not require additional injections of a VEGF therapy, with up to 86 weeks of follow up. In the low-dose arm, 10 of 15 patients were injection free at the time of the analysis. The annualize VEGF injection frequency was reduced by 99% with high-dose ADVM-022 and by 85% in the low-dose group, representing a significant reduction in treatment burden.
In the OPTIC study, ADVM-022 was well tolerated. There were mild ocular adverse events in 78% of patients, with 22% having moderate events. Ocular inflammation was observed but was responsive to steroid eye drops, which were utilized prophylactically. There was no vasculitis, retinitis, choroiditis, vascular occlusions, or endophthalmitis in the study.