Redefining retinal care: Ixo-vec gene therapy for nAMD enters phase 3

Frequent intravitreal injections for neovascular age-related macular degeneration present a long-term treatment burden, highlighting the need for innovative, durable solutions like gene therapy. (Image credit: AdobeStock/WS Studio 1985)

The introduction of intravitreal (IVT) anti-VEGF agents revolutionized the treatment of neovascular age-related macular degeneration (nAMD). Repeated IVT injections of anti-VEGF therapies effectively stabilize vision loss in the majority of patients with nAMD who adhere to treatment.^1,2 However, the lifelong requirement for frequent injections and monitoring imposes a substantial burden on patients and caregivers, leading to poor adherence and suboptimal visual outcomes.^2-9 Real-world discontinuation rates for anti-VEGF therapy have been reported as high as 42% by year 3, highlighting the long-term burden of chronic treatment.¹⁰ In addition, recent evidence suggests that the persistent fluctuation of retinal fluid volume, which results from oscillating peaks and troughs in therapeutic concentrations during intermittent anti-VEGF therapy, may lead to poor long-term visual outcomes.^11-13

A variety of approaches have been developed to extend the durability and reduce the burden of treatment for patients with nAMD. These include treat-and-extend regimens,^14,15 longer-acting anti-VEGF agents,¹⁶ port delivery,¹⁷ and injectable depot systems.^18,19 Although these approaches offer the potential for extended intervals between treatments, all require repeat dosing with frequencies of up to several times per year.

In contrast to approaches that aim to extend the interval between treatments, gene therapy offers the potential to fully eliminate or reduce the requirement for ongoing IVT injections. Ocular gene therapy was first used to deliver a functional copy of a missing or dysfunctional gene in patients with inherited retinal disease. In patients with more common chronic retinal diseases, such as nAMD, gene therapy can be used to deliver vectorized transgenes encoding therapeutic proteins, with the aim of achieving sustained therapeutic concentrations and the potential for lifelong clinical benefit.

Ixoberogene soroparvovec (Ixo-vec; Adverum Biotechnologies) is an IVT gene therapy that comprises a novel capsid vector (AAV.7m8) that was selected through in vivo directed evolution for enhanced retinal transduction and a transgene encoding aflibercept, a widely used recombinant anti-VEGF protein (Figure 1), with more than 70 million doses administered worldwide.²⁰

FIGURE 1. Ixo-vec Design Characteristics and Mechanism of Action.
(A) Novel AAV.7m8 capsid and therapeutic transgene encoding aflibercept. (B) Transduction of retina cells following IVT injection. (C) Ixo-vec–mediated aflibercept expression and suppression of choroidal neovascularization.
CNV, choroidal neovascularization; IVT, intravitreal; Ixo-vec, ixoberogene soroparvovec; RPE, retinal pigment epithelium.
(Figure courtesy of Adverum Biotechnologies)

In preclinical studies, IVT administration of Ixo-vec to nonhuman primates was well tolerated and resulted in sustained long-term intraocular expression of aflibercept.^21-23 In addition, administration of a single IVT injection of Ixo-vec 13 months prior to laser photocoagulation suppressed severe exudative lesions in a primate model of choroidal neovascularization, demonstrating durable clinical activity.²² Key findings from the phase 1 and 2 clinical trials evaluating Ixo-vec in patients with nAMD are summarized below.

OPTIC trial: Durable response through 4 years

The phase 1 OPTIC trial (NCT03748784) is a 2-year, open-label, dose-ranging first-in-human study with an optional 3-year extension (NCT04645212).²⁴ Thirty patients with nAMD requiring frequent IVT injections were assigned 1:1 to 2 doses, 2E11 (2×10¹¹ vg/eye) or 6E11 (6×10¹¹ vg/eye). Patients received 6 weeks of prophylactic topical steroid eye drops or 13 days of prophylactic oral steroids. Baseline characteristics of patients receiving Ixo-vec 2E11 (n = 15) included a mean (SD) age of 78.4 (7.4) years, disease duration of 3.6(2.5) years, and 9.9(1.3) annualized anti-VEGF injections in the year prior to enrollment. At baseline, mean (SD) best corrected visual acuity (BCVA) was 65.4(7.4) Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and mean central subfield thickness (CST) was 407.1(172.5) µm. Through 4 years of follow-up, patients experienced an 87% mean reduction in annualized injection burden.

In addition, the proportion of injection-free patients during each 1-year interval increased during the 4 years of follow-up (60%, 53%, 67%, and 73% for years 1 to 4, respectively). Ixo-vec maintained a mean BCVA change of –2.9 ETDRS letters and mean CST improvement of –117.7 μm from baseline through year 4. Early aqueous aflibercept levels were sustained for as long as measured, up to 5 years. Importantly, the safety profile was favorable. There was no new onset of inflammation (greater than or equal to 1+ anterior chamber/vitreous cells) after week 28, and no patients showed any clinically significant ocular inflammation by 1 year. Except for 1 patient who had inflammation following complex cataract surgery, all others remained inflammation-free throughout 4 years.

LUNA trial: Clinical activity demonstrated at lowest dose (6E10) evaluated to date

The phase 2 LUNA trial (NCT05536973) is a randomized, double-masked study that enrolled treatment-experienced patients with nAMD who have demonstrated response to anti-VEGF therapy.²⁵ Sixty patients were randomly assigned to receive 1 of 2 Ixo-vec doses, 6E10 or 2E11, with enhanced corticosteroid prophylactic regimens. These included a 22-week regimen of difluprednate drops or a single IVT dexamethasone injection followed by difluprednate drops, with or without a 10-week course of oral prednisone. On average, patients had a mean (SD) disease duration of 3.0 (2.9) years and received 10.1 (2.6) anti-VEGF injections in the year prior to enrollment. At 52 weeks, a substantial reduction in treatment burden was observed, with 54% (6E10) and 69% (2E11) of patients remaining injection-free; 89% (6E10) and 90% (2E11) needed 2 or fewer supplemental aflibercept injections. Among patients who had received 6 or fewer injections in the prior year, 75% (6E10) and 67% (2E11) remained injection-free, whereas 100% (6E10) and 89% (2E11) needed only 1 or no supplemental injections.

BCVA and CST remained stable at both doses, which were well tolerated by patients in LUNA. There were no Ixo-vec–related serious adverse events (AEs), and none of the 34 patients in the locally administered corticosteroid cohorts had inflammation at week 52. Aqueous aflibercept levels in LUNA were consistent with those in the OPTIC study. When surveyed, 93% of patients in the LUNA trial preferred Ixo-vec over their prior anti-VEGF therapy.

ARTEMIS trial: Enrolling a broader spectrum of patients

Following the promising data from OPTIC and LUNA, the pivotal phase 3 ARTEMIS trial (NCT06856577) is underway.²⁶ ARTEMIS is a multicenter, double-masked, randomized trial evaluating the efficacy and safety of a single IVT injection of Ixo-vec (6E10 vg/eye) compared with aflibercept 2 t every 8 weeks in a broad population of both treatment-naive and treatment-experienced patients with nAMD (Figure 2).

FIGURE 2. Study Design of Ongoing Phase 3 ARTEMIS Trial.

Multicenter, randomized clinical trial evaluating the efficacy and safety of a single IVT injection of Ixo-vec 6E10 compared with aflibercept 2 mg every 8 weeks in a broad patient population with neovascular age-related macular degeneration.
*Supplemental aflibercept injection administered if criteria met.
IVT, intravitreal; Ixo-vec, ixoberogene soroparvovec; LTFU, long-term follow-up.
(Figure courtesy of Adverum Biotechnologies)

The primary end point is mean BCVA change from baseline between Ixo-vec and aflibercept based on an average at weeks 52 and 56, with a noninferiority margin of –4.5 letters. The key secondary end point is the mean number of aflibercept IVT injections received from week 4 to week 56. All patients will receive 3 monthly loading doses of aflibercept prior to Ixo-vec. The study will utilize sham injections to support masking Ixo-vec and aflibercept treatment. Patients in both arms will be eligible for supplemental injections of aflibercept and will receive topical steroid eye drops. Eligible participants are 50 years or older at screening, have active choroidal neovascularization secondary to nAMD, and have an ETDRS BCVA letter score of 35 to 78 (approximate Snellen equivalent, 20/200 to 20/32) in the study eye. Key exclusion criteria include prior gene therapy, recent ocular surgeries, uncontrolled ocular hypertension or glaucoma, evidence of retinal detachment or retinal pigment epithelium tear, systemic conditions such as recent stroke, myocardial infarction, severe diabetes, and a known history of uveitis or viral eye infections.

ARTEMIS is designed to comprehensively assess the sustained efficacy and safety profile of Ixo-vec in a broad patient population that reflects the patients in standard clinical practice.

Conclusion

IVT delivery is emerging as a safe and effective route for ocular gene therapy. In OPTIC and LUNA, Ixo-vec was well tolerated and maintained visual and anatomic end points in patients with nAMD beyond time points when patients receiving conventional anti-VEGF agents start losing vision in real-world settings. Patients in these trials experienced a meaningful reduction in injection burden compared with their prior regimen and preferred this novel therapy when surveyed. Building on these results, the ARTEMIS trial evaluating the efficacy and safety of Ixo-vec in patients with nAMD has been initiated and is actively enrolling.

Glenn Yiu, MD, PhD
E:gyiu@ucdavis.edu
Yiu is a professor of ophthalmology at the University of California, Davis Eye Center in Sacramento, California. He is a consultant for 4DMT, AbbVie, Adverum Biotechnologies, Alcon, Bausch + Lomb, Boehringer Ingelheim, Clearside Biomedical, Endogena Therapeutics, Genentech, Iridex, Janssen Pharmaceuticals, jCyte, Myrobalan Therapeutics, NGM Biopharmaceuticals, Nanoscope, Novartis, Ocuphire, Opthea, Ray Therapeutics, Regenxbio, Samsung Bioepis, Stealth BioTherapeutics, Supra Medical, Surrozen, and West Pharmaceutical Services.

Acknowledgments
Sincere gratitude to all the OPTIC and LUNA study participants, caregivers, investigators, and study teams. Clinical trial principal investigators: Prema Abraham, MD; Sean Adrean, MD; Benjamin Bakall, MD, PhD; Mark Barakat, MD; David Boyer, MD; Brandon Busbee, MD; Jorge Calzada, MD; Nauman Chaudhry, MD; Carl Danzig, MD; Victor Gonzalez, MD; Amir Guerami, MD; Paul Hahn, MD, PhD; Vivienne Hau, MD, PhD; Michael Ip, MD; Atul Jain, MD; Cameron Javid, MD; Chirag Jhaveri, MD; Brian Joondeph, MD; Arshad Khanani, MD; Gregg Kokame, MD; Xihui Lin, MD; James Major, MD, PhD; Sunil Patel, MD, PhD; Dante Pieramici, MD; Carl Regillo, MD; Veeral Sheth, MD; Michael Singer, MD; Benjamin Thomas, MD; Eduardo Uchiyama, MD; John Wells III, MD; Jeremy Wolfe, MD; Charles Wykoff, MD, PhD; Steven Yeh, MD; Glenn Yiu, MD, PhD.

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