Serious adverse reaction halts gene therapy for diabetic macular edema

Adverum Biotechnologies announced that they are no longer developing ADVM-022 for diabetic macular edema (DME) after a dose-limiting toxicity was observed at the 6 x 1011 vg/eye high dose in the phase 2 INFINITY clinical trial (NCT04418427).

In April 2021, a patient in the INFINITY trail experienced a Suspected Unexpected Serious Adverse Reaction (SUSAR) of hypotony in an eye treated with the high dose of ADVM-022. Adverum unmasked the trial following the SUSAR. Despite close monitoring, other patients treated with the high dose experienced additional adverse events (AEs) including steroid-refractory, rapid, clinically relevant decreases in intraocular pressure. These AEs, which occurred 16 to 32 weeks after ADVM-022 administration, required additional treatment.

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“Our primary focus remains patient safety. We deeply appreciate the continued expertise shared by the DMC, the SAB, retina specialists, and investigators to guide best patient care decisions. Gene therapy is a new and very promising, yet challenging field, as we work to develop durable treatments for patients,” said Laurent Fischer, MD, president and chief executive officer, Adverum Biotechnologies, in a statement. “Our team is grateful for all of the patients and investigators participating in our clinical studies for their critical roles as we strive to shift the treatment paradigm through developing a one-time intravitreal gene therapy for patients.”

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No patients treated with the low, 2 x 1011 vg/eye dose of ADVM-022 experienced similar AEs. Additionally, none of the 30 patients with wet age-related macular degeneration (AMD) in the phase 1 OPTIC trial (NCT03748784) experienced similar AEs after treatment with the high or low dose of ADVM-022, although patients in that study are now being closely monitored.

Adverum presented long-term safety and efficacy data from OPTIC at the Association for Research in Vision and Ophthalmology (ARVO) 2021 Virtual Meeting earlier this year. These follow-up data, which ranged from 52 weeks to 1.5 years, revealed that 60% of patients were injection-free for over a year and patients treated with the low dose (n = 15) had an 85% reduction in annualized injection frequency. 

Based off these data, the company anticipates initiating a phase 2 trial of ADVM-022 in wet AMD. Further long-term data will be presented at a scientific conference in Fall 2021.

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“The data show marked differences for ADVM-022 in patients with wet AMD versus DME. Our fully dedicated team and expert advisors are working relentlessly to better understand the root cause of the events experienced by certain high-dose patients in INFINITY and potential risk factors in these patients with DME,” Fischer added. “Following completion of our analysis and discussions with advisors and regulators, we are planning a Phase 2 clinical trial in wet AMD patients to explore additional low doses with alternative prophylactic regimens to support the best possible path for delivering ADVM-022 safely to patients.”

All 34 patients in INFINITY were more closely monitored following the SUSAR. The 12 patients in the high-dose cohort received prophylactic aggressive immunomodulatory regimens following the event.

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Despite these actions, 5 more patients experienced similar AEs, although they all had a history of severe vascular disease. Three patients needed surgery on the treated eye. The first patient that experienced the SUSAR 30 weeks after treatment has been treated and some ocular pressure and vision have been restored.

“Dose finding has been a challenge for the field of gene therapy, and while AAV remains a very safe delivery system, we should expect as with any biologic product that unexpected dose-limiting toxicities may be encountered,” said Szilárd Kiss, MD, associate professor of ophthalmology and scientific advisory board member, Adverum. “It is important to learn from the data generated by this field to bring new treatments with durable efficacy and well-managed safety to patients.”

This article has been adapted from Gene Therapy Live.

Reference

1. Adverum provides update on ADVM-022 and the INFINITY trial in patients with diabetic macular edema. News release. News release. Adverum Biotechnologies. July 22, 2021. https://investors.adverum.com/news/news-details/2021/Adverum-Provides-Update-on-ADVM-022-and-the-INFINITY-Trial-in-Patients-with-Diabetic-Macular-Edema/default.aspx

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