After submitting an amended IND, Adverum’s gene therapy is set to be evaluated in the phase 2 LUNA trial.
Adverum Biotechnologies is advancing their adeno-associated virus (AAV) vector gene therapy candidate ixoberogene soroparvovec (Ixo-vec; ADVM-022) into phase 2 studies for the treatment of wet age-related macular degeneration (wet AMD).1
“On the heels of receiving the European Medicines Agency PRIME designation in the European Union, highlighting the unmet medical need in the current treatments for wet AMD, we are delighted to advance Ixo-vec into phase 2 development... We have also optimized our manufacturing strategy and have a scalable approach designed to provide an ample supply of Ixo-vec to support our clinical development program through biologics license application filing,” Laurent Fischer, MD, president and chief executive officer, Adverum Biotechnologies, said in a statement.1
Ixo-vec is set to be evaluated in the phase 2 LUNA trial, initiating in the next few months, following Adverum’s completion of an investigational new drug (IND) amendment with the FDA. In order to support the therapy’s development and extend the company’s cash runway into 2025, Adverum also announced restructuring and layoffs to cut costs.
Ixo-vec recently showed efficacy in improving visual outcomes and producing sustained aflibercept expression in the phase 1 OPTIC trial (NCT03748784).2 Investigators in OPTIC found that the mean annualized rate of anti-vascular endothelial growth factor (VEGF) injections was reduced by 81% in all participants treated at this dose and 93% in participants with low NAbs titers. The annual rate of central subfield thickness (CST) fluctuation also was reduced by 70% (± 50 µm) in participants treated at this dose level with low NAbs titers. Additionally, 3-year follow-up data demonstrated that ixo-vec was well-tolerated, with no cases of inflammation requiring topical corticosteroids.
“We are excited to initiate our Phase 2 LUNA trial this quarter. We designed the LUNA trial after a thorough review of data generated in all 55 study participants treated to date with a single injection of ADVM-022, some of whom have now demonstrated continuous and stable aflibercept expression for over three years. We have deepened our understanding of AAV mediated ocular gene therapy, including the inflammatory response to AAV, and this is informing our strategy to mitigate immunogenicity,” Richard Beckman, MD, chief medical officer, Adverum, added to the statement.1 “The LUNA trial is designed to build on the strong efficacy profile demonstrated in the OPTIC trial in wet AMD and to establish the most effective pairing of an Ixo-vec dose and prophylactic steroid regimen to optimize the risk benefit in patients with this debilitating disease. We look forward to sharing greater detail on the LUNA trial after we dose the first subject.”
The multicenter, double-blind, randomized, parallel-group LUNA trial will evaluate 2 doses of ixo-vec, the previously assessed 2x1011 vg/eye and a new, lower, 6x1010 vg/eye dose in up to 72 patients with wet AMD. The trial will also assess 4 new enhanced prophylactic steroid regimens that combine local steroids and systemic steroids including topical difluprednate (Durezol) and IVT Ozurdex to assess the contributions of local versus systemic AAV exposure on ocular inflammation.
Participants will be randomized between doses and 4 prophylactic steroid regimens across approximately 40 sites in the US and Europe. Similar to the OPTIC trial, LUNA will primarily evaluate mean change in best corrected visual activity from baseline to 1 year and incidence and severity of adverse events (AEs). The study will also assess the effectiveness and tolerability of the prophylactic steroid regimens and protein expression of aflibercept at 10 and 26 weeks.
“Results from the OPTIC trial demonstrate that ADVM-022 at the 2E11 dose has the potential to provide an effective and durable treatment with manageable safety for patients with neovascular AMD, with sustained aflibercept levels through three years. This has resulted in a dramatic reduction in the number of required anti-VEGF injections, thus addressing an important area of unmet medical need. I look forward to participating as a LUNA investigator and studying the new, lower 6E10 dose. The LUNA study is also designed to help us determine a safe and effective prophylactic steroid regimen for patients,” investigator Arshad M. Khanani, MD, FASRS, managing partner and director, clinical research, Sierra Eye Associates, and clinical associate professor, University of Nevada, Reno School of Medicine, added to the statement.1
Ixo-vec's safety profile has previously been in question, with the phase 2 INFINITY clinical trial (NCT04418427) placed on hold in August 2021.3 The hold was due to a dose-limiting toxicity of a Suspected Unexpected Serious Adverse Reaction of hypotony in a treated patient with diabetic macular edema (DME) as well as other treatment-related AEs of intraocular pressure decrease. Following the clinical hold, Adverum decided to stop developing ixo-vec for DME and focus solely on the wet AMD indication.