Intraretinal Gene Therapy with ADVM-022

Treatment for DME halted because of worrisome adverse events. Cheryl Guttman Krader reports from AAO 2021 in New Orleans, USA

The INFINITY phase 2 clinical trial—investigating ADVM022 treatment for diabetic macular oedema (DME)— launched after the novel intraretinal gene therapy product showed durable efficacy and acceptable safety in the OPTIC study evaluating its use for treating neovascular age-related macular degeneration.

The adverse events emerging in INFINITY indicated ADVM022 had a very different safety profile in eyes with DME. The results from INFINITY highlight the need to consider the severe comorbid nature of patients with DME and prompted the industry sponsor (Adverum Biotechnologies) to focus on nAMD treatment using low doses of ADVM-022.

Reviewing the results from the two clinical trials, David Boyer MD said, “Much to our surprise (because it was not seen in OPTIC), ADVM-022 treatment in patients with DME caused a marked increase in both anterior segment and posterior segment intraocular inflammation (IOI). There were iris-related events, including transillumination defects, synechiae, and pigmentary changes. More importantly, three patients (25%) in the high dose ADVM-022 group developed severe hypotony (IOP ≤5 mmHg), necessitating surgery with silicone oil and an intravitreal corticosteroid implant.”

The difference in safety between the OPTIC and INFINITY trials is being studied and is unknown, he told delegates.

INFINITY DESIGN AND DATA ADVM-022 is designed to provide continuous delivery of aflibercept. INFINITY randomised patients into one of three arms to receive ADVM-022 2x1011 vg (vector genome)/eye, ADVM-022 6x1011 vg/eye, or aflibercept 2 mg. Patients in the ADVM-022 groups were further randomised to an initial aflibercept or sham injection.

The primary endpoint assessed time to worsening of DME disease activity in the study eye necessitating supplemental aflibercept injection. Over 24 weeks of follow-up, very few patients in either ADVM-022 treatment arm needed rescue. BCVA and central subfield thickness remained stable during follow-up to week 34, Dr Boyer reported.

“We also saw tremendous improvement in diabetic retinopathy severity after a single ADVM-022 injection. At 24 weeks, 46% of patients in each of the ADVM-022 groups had a two-step or greater improvement from baseline in the Diabetic Retinopathy Severity Scale score. Rates of a three-step or greater improvement were 36% and 18% in the low dose and high dose groups, respectively,” he said.

The safety data showed intraocular inflammation with ADVM022 was dose-dependent. Significant inflammation based on the presence of anterior chamber and vitreous cells was seen in the 6x1011 vg/eye group. There were very few patients with anterior chamber cells and vitreous cells in the low dose gene therapy. The rate of iris-related events was also higher in the high dose group, and clinically relevant reductions in IOP were observed only in the high dose group, Dr Boyer said.

OPTIC SAFETY REVIEW In OPTIC, ocular adverse events related to ADVM-022 were mostly mild (83%), and none were severe. Ocular inflammation in eyes treated with ADVM-022 2x1011 vg/eye was minimal and responded to topical steroid treatment. The higher dose of ADVM022 was associated with a little more inflammation, but there was no clinical or fluorescein evidence of posterior inflammation with either dose or any cases of clinically relevant low IOP.

David Boyer MD is Senior Partner at Retina-Vitreous Associates Medical Group, Los Angeles, USA. vitdoc@aol.com

Robust, Sustained Aflibercept Expression Levels Observed for Both Doses (N=11)

Within modeled aflibercept pharmacokinetic range post single Aflibercept 2mg at 4- and 6-weeks dosing

100,000

Aflibercept Expression (ng/mL)

10,000

1,000

100

10 6×1011 vg/eye Dose 2×1011 vg/eye Dose

Aflibercept Levels 4 weeks after Bolus Injection*

*** Aflibercept Levels 6 weeks after Bolus Injection*

1

0 12 24 36 48 60 72 84 96 108 Weeks