Recent Happenings in the Geographic Atrophy Space

Geographic atrophy (GA) has long been a major cause of visual impairment worldwide, with a global prevalence of more than 5 million and nearly 1 million cases in the United States alone (Figure).¹ Significant morbidity, combined with an incidence that is rising with our aging population, has led to an explosion of experimental therapies designed to address this growing need. Here, we share the ongoing investigations for therapies targeting GA (Table).

Click to view larger

Figure. More than 5 million patients worldwide have geographic atrophy, as seen here in this fundus photograph.

Click to view larger

C3 INHIBITION

Pegcetacoplan (Syfovre, Apellis) is a pegylated complement C3 inhibitor that blocks the initial convergence of the three complement pathways, resulting in significant downregulation of downstream complement cascade activity.^2-4

The 18-month results of the phase 3 OAKS and DERBY trials, along with evidence of the drug’s consistent safety profile, were included in the new drug application (NDA)submitted in June 2022 and granted priority review designation by the FDA in July 2022.^5,6

Subsequently, the 24-month results showed that the extrafoveal GA lesion growth rate was reduced by 22% with monthly injections (P < .0001) and 18% with every-other-month injections (P = .0002) in the OAKS study, and 19% (P = .0004) and 16% (P = .0030) in the DERBY study, respectively.^3,4,7 The FDA accepted the company’s major NDA amendment to include this data, pushing the Prescription Drug User Fee Act target action date to February 2023.⁸

The GALE extended phase 3 study, initiated to assess long-term safety and efficacy, plans to enroll 1,200 participants with projected completion in 2025.⁹

NGM621 (NGM Biopharmaceuticals) is a humanized IgG1 monoclonal antibody with a high affinity for C3. NGM621’s inhibition of C3 creates blockage at the intersection of all three pathways. The phase 2 CATALINA trial enrolled 320 participants who were randomized into monthly injections, every-other-month injections, or sham groups.^10,11 The primary endpoints include the rate of change of GA lesion areas and the incidence and severity of ocular and systemic adverse events. The estimate for primary completion is December 2022, with final completion estimated for April 2023.

In February 2022, the FDA granted fast track designation to NGM621, which provides opportunities for close and frequent communication with the FDA throughout the development process as well as the potential for accelerated approval.¹²

C5 INHIBITION

Avacincaptad pegol (Zimura, Iveric Bio) is a pegylated aptamer that inhibits cleavage of C5 into terminal fragments C5a and C5b-9, which block the complement cascade and the formation of the membrane attack complex.

The phase 3 GATHER1 study included 286 participants and, at 12 months, demonstrated a mean reduced GA growth rate of 27.4% in the 2 mg dose group (P = .0072) and 27.8% in the 4 mg dose group (P = .0051) compared with sham controls.¹³ At 18 months, the rate was reduced by 28% and 30% in the 2 mg and 4 mg groups, respectively. Of note, the study found that the treatment groups developed choroidal neovascularization at a rate of 9.0% in the 2 mg dose group and 9.6% in the 4 mg dose group at 12 months, compared with 2.7% in the sham group. At 18 months, these rates increased to 11.9% and 15.7%, respectively, while the sham rate remained unchanged.¹³

The phase 3 GATHER2 trial also met its primary endpoint with a favorable safety profile.¹⁴ Patients in the investigative arm experienced a mean rate of GA growth of 1.745 mm compared with 2.121 mm in the sham group (P = .0039).¹⁴

Based on this data, the company submitted the first part of its NDA to the FDA for rolling review in November and is already collaborating with DelSiTech to develop an injectable silica-based sustained-release formulation of avacincaptad pegol.^15,16 The FDA granted breakthrough therapy designation for avacincaptad pegol in November.¹⁷

ORAL THERAPY

ALK-001 (Alkeus Pharmaceuticals) is a chemically modified form of vitamin A in which hydrogen is replaced by deuterium, resulting in the reduced formation of dimers.¹⁸ Replacing natural vitamin A with this modified version inhibits the formation of toxic vitamin A aggregates in the eye. ALK-001 is administered as an oral capsule once per day.

Initially investigated for the treatment of Stargardt disease, ALK-001 was studied in a phase 2 trial that found that the treatment was able to safely slow disease progression without interrupting the normal visual cycle.¹⁹

The ongoing phase 3 SAGA trial is investigating the safety, tolerability, and efficacy of ALK-001 in the treatment of GA.²⁰ The trial randomized approximately 300 participants into two groups, daily ALK-001 or placebo, for 24 months. Initial results are expected in August 2023.²⁰

The drug was granted breakthrough therapy designation from the FDA in July 2021.²¹

C1Q INHIBITION

ANX007 (Annexon Biosciences) is a monoclonal antibody antigen-binding fragment that binds to C1q, disrupting the entire classical complement pathway. Phase 1 trials with participants with primary open-angle glaucoma completed in 2020 showed that ANX007 was well-tolerated at all dose levels and achieved target C1q suppression.^22-24

In the phase 2 ARCHER study, 270 participants are randomized to receive intravitreal ANX007 injections monthly or every-other-month or receive monthly sham injections for one year.²⁵ The primary endpoint is GA lesion growth rate over 12 months as measured by fundus autofluorescence, with secondary endpoints including safety, BCVA, low-luminance BCVA, and low-luminance visual acuity deficit. Topline data is expected in the first half of 2023, with full data expected at the end of the year after a 6-month off-treatment period.²⁶

GENE THERAPY

HMR59 (Hemera Biosciences/Janssen Pharmaceuticals) is an ocular gene therapy, delivered via a single intravitreal injection, that is designed to cause retinal cells to increase the expression of a soluble form of CD59. The phase 1 dose-escalating safety and tolerability study, which enrolled 17 patients, is complete with data pending.²⁷

GT005 (Gyroscope Therapeutics/Novartis) is an AAV2 vector gene therapy but acts on complement factor I (CFI), a key regulator of the complement system that inactivates proteins implicated in complement overactivation. The therapy received FDA fast track designation in September 2020.²⁸ Novartis acquired GT005 in December 2021, changing the name of the therapy to PPY-988.^29,30

Preliminary results of the phase 1/2 FocuS study showed that subretinal delivery of GT005 was well-tolerated with no serious adverse events.^31,32 The initial data also showed that the therapy provided sustained increases in vitreous CFI and downstream modulation of complement biomarkers, consistent with reduced complement activity. The trial is active but not recruiting, and the final two cohorts will receive GT005 through the Orbit Subretinal Delivery System (Gyroscope Therapeutics).³³

Additional phase 2 trials EXPLORE and HORIZON are recruiting.^34,35 Both trials administer GT005 at two doses and assess the progression of GA as measured by fundus autofluoresence for 48 weeks.^34,35