AMD is the leading cause of irreversible blindness in adults over 50 years old.¹ Approximately 11 million individuals are affected with AMD in the United States, with a global prevalence of 170 million. AMD is therefore the leading cause of visual disability in the industrialized world and the third leading cause globally.¹ Aging is the greatest risk factor; therefore, the prevalence of AMD in the United States is anticipated to increase to 22 million by 2050, while the global prevalence is expected to increase to 288 million by 2040.²

Compared to monogenic inherited retinal diseases such as Stargardt disease or retinitis pigmentosa, AMD is a multifactorial disease with myriad genetic, environmental and age-related factors. Multiple genes have been implicated in the pathogenesis of AMD, such as complement factor H (CFH) and age-related maculopathy susceptibility 2, or ARMS2; however, these genes play complex additive risk roles and do not contribute to AMD in a simplistic monogenic disease fashion. Thus, replacement gene therapy is likely not going to be useful in this disease.

This is not to say that gene therapy cannot play a role in management of AMD. To the contrary, it is certainly plausible that “gene addition” may assist in disease management, affording addition of useful genes that may modify disease course. Rather than provide the “missing gene” as is done in augmentation (replacement) gene therapy for monogenetic, autosomal recessive conditions (such as gene therapy for RPE65-associated retinal degeneration), gene addition involves injection of vector-carrying sequences that may provide long-term sustained expression of useful factors (ie, an anti-VEGF molecule for treatment of wet AMD).

In this article, we will focus on discussing four ongoing clinical gene therapy trial programs for AMD — two focusing on dry AMD and three focusing on wet AMD.

DRY AMD GENE THERAPY

Gyroscope Therapeutics

One of the dry AMD trials is sponsored by Gyroscope Therapeutics. The Gyroscope product candidate, GT005, is an investigational, adeno-associated virus-based (AAV2) gene therapy designed as a one-time treatment that is delivered either subretinally or suprachoroidally. It is intended to slow the progression of geographic atrophy (GA) secondary to AMD.

The FOCUS study is the first in human trial (Phase 1/2) evaluating GT005 with both a subretinal approach (standard transvitreal approach) and a suprachoroidal approach (orbit subretinal delivery system) in patients with GA. The Orbit subretinal delivery system allows access to the subretinal space via suprachoroidal cannulation.

Gyroscope’s EXPLORE trial is a randomized controlled Phase 2 study comparing two doses of GT005 with the subretinal approach in patients with GA who have rare variants in their complement factor I (CFI) gene associated with low levels of the CFI protein in their blood.

HORIZON is also a randomized-controlled Phase 2 study comparing two doses of GT005 with a subretinal delivery in a broader population of patients with GA (without the rare CFI variant).

Dysregulation of the complement system is thought to play an important role in disease pathophysiology of AMD, and supplementation of CFI, a key regulator of the alternative pathway of the complement system, has the potential to provide a treatment option for AMD.³ At the Angiogenesis, Exudation and Degeneration 2021 virtual meeting, Gyroscope presented interim results of the FOCUS Phase 1/2 trial in patients with GA, citing that early data showed the majority of patients had increased vitreous CFI and downstream modulation of complement biomarkers, and that the therapy was well tolerated. The FOCUS, EXPLORE and HORIZON studies are ongoing at the time of publication.

Hemera Biosciences/Janssen

HMR59 (AAVCAGsCD59), developed by Hemera Biosciences (recently acquired by Janssen), is an AAV-based intravitreal therapy being evaluated in the treatment of both dry and wet AMD.

Administered as a single intravitreal injection, HMR59 uses an AAV2 vector and is designed to lead to production of a soluble form of the CD59 protein, sCD59, that blocks the formation of the membrane attack complex and limits further damage to the retina.⁴ Because it affects the complement cascade, HMR59 has the potential to treat dry AMD.

HMR-1001 is a Phase 1 clinical trial that is closed to enrollment and inactive as of January 2020. HMR-1001 evaluated 17 eyes of 17 subjects with advanced dry AMD and GA who received a single intravitreal dose of HMR59, according to the company’s website.

A randomized-controlled Phase 2 multi-center trial evaluating intravitreal AAVCAGsCD59 (two doses) compared to sham injection for the treatment of advanced AMD with GA is planned.

WET AMD GENE THERAPY

Hemera

Studies have shown that patients with AMD have less CD59 present in the retina to protect their cells from damage caused by complement. Hemera’s HMR59 is designed to affect the complement pathway via inhibition of the membrane attack complex (MAC).⁴ Given the plausible relationship of MAC also in wet AMD, Hemera is also studying AAV in wet AMD. Several studies have linked the complement pathway and MAC formation with wet AMD — with MAC-mediated release of growth factors thought to contribute to choroidal neovascularization and conversion to wet AMD.

HMR-1002 is a Phase 1 trial for the treatment of 25 subjects diagnosed with new onset wet AMD who have never received treatment in the affected eye. HMR-1002 enrolled subjects at Ophthalmic Consultants of Boston and Vitreo-Retinal Associates in Worcester, Mass. All patients who met enrollment criteria were treated with a single intravitreal injection of an anti-VEGF medication followed 7 days later by an intravitreal injection of HMR59. Patients were followed monthly and treated with anti-VEGF injections as needed through month 12 followed by a month 24 visit to evaluate long-term safety, according to Hemera’s website.

Adverum

ADVM-022, created by Adverum Biotechnologies, is a novel recombinant AAV2-based therapy utilizing AAV.7m8 capsid (optimized for intravitreal administration) and designed to result in strong expression of the aflibercept protein.⁵ ADVM-022 can be administered via an intravitreal injection in an office setting and is designed to deliver long-term efficacy and reduce the burden and frequency of anti-VEGF injections.

Adverum’s OPTIC trial was a Phase 1, multi-center, open-label, dose-escalation trial evaluating the safety and tolerability of a single IVT injection of ADVM-022. The most recent OPTIC data presented at Angiogenesis 2021 demonstrated that patients who received 2 x 10^11 vg/eye of ADVM-022 experienced an 85% reduction in 1 year of anti-VEGF injections, and two-thirds did not receive any supplemental anti-VEGF injections (median follow up of 1 year). Patients were either treated prophylactically with oral (13 days) or topical (6 weeks) steroids.

Observed post-injection ocular inflammation appeared responsive to and manageable with steroid eyedrops. ADVM-022-related ocular adverse events were mild (78%) to moderate (22%). One AE deemed to be related to ADVM-022, moderate recurrent uveitis, was responsive to steroid eyedrops.⁶

Two Phase 3 trials (planned to begin in Q4 2021) will study the efficacy and safety of two doses of ADVM-022 straddling the 2 x 10^11 vg/eye dose used in the OPTIC trial. In the Phase 3 trials of approximately 450 patients each, patients newly diagnosed with wet AMD will be randomized to one of three arms, receiving a single IVT injection of either 3 x 10^11 vg/eye or 1 x 10^11 vg/eye of ADVM-022 compared to aflibercept IVT every 8 weeks.

The primary endpoint will be non-inferiority to aflibercept based on change from baseline in BCVA at 1 year, according to the company’s website.

Of note, in April 2021, Adverum released data concerning a suspected unexpected serious adverse reaction case of hypotony and panuveitis and vision loss, although this was not in an AMD program but data from the INFINITY trial evaluating ADVM-022 for the treatment of diabetic macular edema. In a statement released on its website, Adverum writes that “The company has unmasked the study and is assessing and monitoring this patient and all patients treated with ADVM-022.”

REGENXBIO

REGENXBIO’s RGX-314 is a gene therapy vector carrying a coding sequence for a soluble anti-VEGF protein. RGX-314 is being studied for its potential to have a single subretinal injection that could allow the eye to make its own supply of anti-VEGF continually. REGENXBIO product candidates all utilize viral vectors from their proprietary gene delivery platform, called their “NAV Technology Platform.” REGENXBIO’s NAV Technology Platform consists of exclusive rights to AAV7, AAV8, AAV9, AAVrh10 and more than 100 other novel AAV vectors (NAV Vectors).

REGENXBIO is currently enrolling for ATMOSPHERE, a randomized, partially masked, controlled, Phase 2b/3 clinical study to evaluate the efficacy and safety of RGX-314 gene therapy in participants with wet AMD. RGX-314 uses an AAV8 vector containing a gene that encodes for a monoclonal antibody fragment that binds to and neutralizes VEGF activity. The study will evaluate two dose levels of RGX-314 relative to an active comparator (ranibizumab). The primary endpoint of this study is mean change in BCVA of RGX-314 relative to ranibizumab.

Approximately 300 participants who meet the inclusion/exclusion criteria, will be enrolled into one of three arms: two different dose subretinal RGX-314 treatment arms and one control arm (receives only intravitreal ranibizumab.)

REGENXBIO is also evaluating suprachoroidal delivery of RGX-314 gene therapy in a Phase 2, randomized, dose-escalation, ranibizumab-controlled study. This study, AAVIATE, will evaluate the efficacy, safety and tolerability of RGX-314 gene therapy delivered via one or two suprachoroidal space injections in participants with wet AMD. Again, two dose levels with suprachoroidal vector delivery will be compared to a control arm receiving intravitreal ranibizumab.

CONCLUSION

The challenges of gene therapy for AMD lie within the fact that the disease is, by definition, multifactorial and genetically complex. However, the immensity of the need for a sustainable therapy cannot be overestimated.

Unlike with augmentation gene therapy efforts targeting typical monogenetic recessive inherited retinal diseases, gene therapy for AMD utilizes gene addition techniques, providing addition of useful genes (ie, genes encoding anti-VEGF molecules) that may modify disease course.

As described in this brief report, multiple efforts are underway in the field of gene therapy targeting both dry and wet forms of AMD. Gene therapy for AMD has been colloquially touted as the “holy grail” of ocular gene therapy due to the sheer prevalence of the disease. A therapy that provided safe and effective sustained treatment for either dry or wet AMD would be a game changer.

Considerably more work must be done in the field, and unanswered questions certainly exist. Can intravitreally dosed ocular gene therapy be performed in a safe and effective manner, and ocular inflammatory responses controlled? Can subretinal or suprachoroidal delivery techniques (if found to be safe and effective) be realistic in large-scale commercialization efforts post FDA approval? And perhaps the key question: Is long-term sustained and chronic suppression of anti-VEGF safe, or will we see progressive degeneration or other adverse effects in these eyes?

Although the answers to all these questions are unknown, these are certainly exciting times as the field of AMD research joins the ocular gene therapy frontier. OM

REFERENCES

1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106-116.
2. Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. Br J Ophthalmol, 96:614-618.
3. Dreismann AK, McClements ME, Barnard AR, et al. Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells. Gene Ther. 2021;28:265-276.
4. Bora PS, Sohn J-H, Cruz JMC, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization. J Immunol. 2005;174:491-497.
5. Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration. Mol Ther. 2019;27:118-129.
6. Adverum Biotechnologies. Virtual KOL/IR Event, November 14, 2020. https://adverum.com/wp-content/uploads/2020/12/November-2020-ADVM-022-OPTIC-Phase-1-Data-Update.pdf . Accessed June 1, 2021.

About the Author

Christine Kay, MD, is a vitreoretinal surgeon and inherited retinal disease specialist at Vitreoretinal Associates in Gainesville, Fla. She is principal investigator in multiple clinical trials, with a particular interest in retinal gene therapy, genetic testing and optimization of surgical gene therapy delivery techniques.

Disclosures: Dr. Kay is a principal investigator and surgeon for Gyroscope and REGENXBIO clinical trials.