Release date:2023/1/31 16:58:31

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) caused by the loss of photoreceptors, retinal pigment epithelium (RPE) and underlying choriocapillaris, which can lead to progressive and irreversible loss of visual function. The etiology of GA is complex, with known associated factors including persistent oxidative stress, chronic inflammation, genetic and environmental factors.

GA is responsible for 10-20% of cases of legal blindness, affecting more than 5 million people wordwilde. Currently there is only one drug approved or effective treatment to prevent either the onset or progression of GA - SYFOVRE™ (pegcetacoplan injection), however, in recent years, significant progress has been made in understanding the pathogenesis of GA, which has led to a number of new potential therapies currently undergoing clinical trial evaluation.

Investigational drugs in clinical trials for geographic atrophy
Drug Target Company Phase
Pegcetacoplan C3 Apellis FDA Approved
Zimura (avacincaptad pegol) C5 Iveric Bio NDA
NGM621 C3 NGM Bio Phase II
GT005 —— Gyroscope Therapeutics/Novartis Phase II
HMR59 —— Hemera/Johnson & Johnson Phase II
RG6147 HtrA1 Roche Phase II
GEM103 CFH Gemini Therapeutics Phase II
ANX007 C1q Annexon Biosciences Phase II
GS030 —— GenSight Biologics Phase I/II
OpRegen —— Lineage Cell Therapeutics Phase I/II
ONL1204 Fas ONL Therapeuticas Phase I
Galegenimab HtrA1 Roche Terminated
EA-2351 —— Endogena Therapeutics Preclinical
Table. Investigational drugs in clinical trials for geographic atrophy

Pegcetacoplan (SYFOVRE™ )

Pegcetacoplan, a pegylated bicyclic peptide therapy targeting complement C3, was approved by the FDA in May 2021 for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH).  On Feb. 17, the U.S. Food and Drug Administration (FDA) has approved SYFOVRE™ (pegcetacoplan injection) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). SYFOVRE is the first and only FDA-approved treatment for GA, a leading cause of blindness that impacts more than one million people in the U.S. and five million people worldwide. SYFOVRE is expected to be the first drug and a blockbuster for GA.

In the Phase 3 DERBY and OAKS studies, the top-line data at 24 months showing increased effects over time with intravitreal pegcetacoplan, in GA secondary to AMD.

DERBY and OKAS are multicenter, randomized, double-masked, sham-controlled phase III clinical trials enrolling 637 and 621 patients, respectively, designed to evaluate the efficacy and safety of pegcetacoplan for the treatment of patients with GA secondary to AMD. The primary endpoint was the change in the total area of GA lesions in patients at month 12. At the end of 12 months of treatment, patients continued to receive concealed treatment for 24 months. In addition, all patients who complete the DERBY or OAKS studies will be invited to participate in the GALE open-label extension study lasting 3 years to further evaluate the long-term efficacy and safety of pegcetacoplan.

Pre-specified analyses showed that clinically meaningful reductions in GA lesion areas were achieved with either monthly or every two months injections of pegcetacoplan at month 24.


Figure. Pegcetacoplan showed clinically meaningful reductions in GA lesion growth from baseline to month 24. Source: Apellis official website

In addition, the efficacy of pegcetacoplan was better at months 18-24 than at the first 6 months. The safety profile of Pegcetacoplan was also consistent with previously disclosed results, with no cases of endophthalmitis reported at months 18-24.


Figure. Pegcetacoplan treatment effetcs accelerated between months 18 & 24, Source: Apellis official website

Zimura (avacincaptad pegol)

Zimura, a PEGylated RNA aptamer designed to inhibit complement C5 protein, alleviates GA-AMD disease progression by inhibiting cleavage of complement factor C5 and formation of terminal fragments C5a and C5b to reduce activation of multiple proteins that regulate inflammation and slow retinal pigment epithelial cell RPE degeneration. On November 3, 2022, Iveric Bio announced that it has submitted to the FDA the first part of its NDA for rolling review of Zimura for the treatment of GA secondary to AMD.


Figure. Zimura mechanism of action, Source: Iveric official website

This NDA is based on the positive results of 2 phase III clinical trials (GATHER1 and GATHER2). 286 and 448 patients were enrolled in the GATHER1 and GATHER2 studies, respectively, to evaluate the efficacy and safety of Zimura for the treatment of patients with GA secondary to AMD. The co-primary endpoint was the mean rate of change in GA lesion area at month 12.

Results from both studies showed that patients in the Zimura group had a significantly lower mean growth rate of GA lesion area compared to the placebo group.

In the GATHER1 study, the mean growth rate of GA lesion area was reduced by 27.38% (p=0.0072) in the Zimura (2 mg) group and by 27.81% (p=0.0051) in the Zimura (4 mg) group of patients compared to the placebo group.


Figure. Primary endpoint results of the GATHER1 study. Source: Iveric official website

In the GATHER2 study, patients in the Zimura (2 mg) group had a 14.3% reduction in the mean growth rate of GA lesion area compared to the placebo group (p=0.0064).Iveric Bio also analyzed the mean change in patients' best-corrected visual acuity (BCVA) and low luminance best-corrected visual acuity (LL BCVA) at month 12. The data showed that patients in the Zimura group had better BCVA improvement than the placebo group and were consistent with the GATHER1 study, but no significant improvement in patients' LL BCVA was observed.


Figure. Primary endpoint results of the GATHER2 study. Source: Iveric official website

Other Therapeutics for GA

However, Complement Inhibitors have not progressed well in the treatment of GA.

In October 2022, a phase II clinical trial of NGM Bio's anti-C3 antibody NGM621 for the treatment of GA secondary to AMD failed miserably: over 52 weeks of treatment, the rate of change in GA lesion area was reduced by 6.3% (P=0.435) and 6.5% (P=0.422) in patients treated with NGM621 once every 4 weeks and once every 8 weeks, respectively, with no statistically significant difference compared to the placebo group.

In June 2021, Gemini Therapeutics announced that its intravitreal injection of recombinant human complement factor H (CFH) GEM103 failed to slow GA progression in the phase IIa ReGatta study in patients with GA secondary to AMD.

In addition, there are also gene therapies in the GA pipeline, such as GS030, HMR59 and GT005.

GS030 is an optogenetic gene therapy that delivers genetic instructions for the photosensitive optic protein ChrimsonR to ganglion cells in the central recess of the patient's retina through an optimized adeno-associated virus (AAV) vector. The patient then applies proprietary photostimulation goggles that project light of the correct wavelength and intensity onto the retina, activating the photosensitive protein and allowing the ganglion cells to send the signal to the brain.

HMR59 is a one-time, outpatient intravitreal injection therapy that works by enhancing the ability of retinal cells to make soluble CD59 (CD59 is a protein that protects the retina from damage caused by the body's complementary immune response and is typically low in AMD patients).

GT005 is an AAV2-based one-time investigational gene therapy designed to restore balance to an overactive complement system by increasing CFI protein production for subretinal administration in the treatment of GA secondary to AMD (CFI protein regulates the activity of the complement system, and over-activation of complement can lead to inflammation that damages healthy tissue and is strongly associated with the onset and progression of AMD).


GA is progressive and irreversible, and can lead to central visual impairment and permanent vision loss. Over the years, the investigation of GA has never stopped. With the development of medical technology and the advancement of GA-related research and experiments, we will eventually find a way to treat or even cure GA.

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