With a commitment to creating novel treatments for retinal diseases that have limited therapeutic options, Iveric Bio, an Astellas Company, developed Izervay (avacincaptad pegol intravitreal solution) to treat geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Geographic atrophy impacts an estimated 1.5 million people in the United States and can cause irreversible vision loss.^1,2 Approximately 75% of people living with GA in the United States are believed to be undiagnosed.³ Without treatment, an estimated 66% of people with GA may become blind or severely visually impaired.⁴ Currently, there are limited treatment options for dry AMD and GA.

Geographic atrophy is difficult to treat because it seems to be a multifactorial disease. “We don’t have a complete understanding of all the different pathogenic mechanisms that lead to the development and progression of GA,” says Dhaval Desai, PharmD, chief development officer at Iveric Bio. “This makes it difficult to pick 1 or any combination of targets.”

Geographic atrophy occurs at the end stage of AMD. At this stage of the disease, there is a complete loss of photoreceptors, which leads to irreversible vision loss. “This stage of the disease is marked by cell death; it’s very difficult to reverse or even slow down the dying process,” says Matthew Starr, MD, assistant professor of ophthalmology at Mayo Clinic in Rochester, Minnesota, who was a clinical investigator during clinical trials.

HOW THE DRUG WORKS

Izervay is an intravitreal injection that targets the complement pathway; specifically, it’s a complement C5 inhibitor. It limits the production of C5a and C5b, 2 fragments that may play important roles in cell death, cell lysis, and inflammation, Dr. Starr explains. By targeting this pathway, Izervay may limit cell death in patients with GA.

Izervay is used to limit the growth of atrophy via monthly intravitreal injections for up to 1 year. The length of time it’s given is based on a patient’s response and treating physician, Dr. Starr says. The recommended dose for Izervay is 2 mg (0.1 mL of 20 mg/mL solution).

Patients who are treated with Izervay most likely won’t see any improvement in visual acuity, but they may see a reduction in the growth of GA lesions, Dr. Starr says. Therefore, they may experience vision preservation.

A CLOSER LOOK

Izervay is an RNA aptamer, a PEGylated oligonucleotide that binds to and inhibits complement protein C5. By inhibiting C5, Izervay may prevent the production of C5a and C5b and therefore decrease membrane attack complex (MAC) formation, Desai says.

The complement system protects the eyes against pathogens as part of the body’s immune system. It functions as a cascade, starting with C1 and ending with the MAC. C5 is at the end of the cascade and causes MAC formation, which protects the eye by directly attacking germs that infiltrate it. When the complement system doesn’t work correctly, the MAC can start to attack the eye’s own cells, which can lead to irreparable vision loss that becomes dry AMD and, ultimately, GA. By targeting C5, Izervay may preserve upstream benefits of the complement system and may prevent MAC formation, therefore reducing inflammation and cell death associated with the development and progression of GA.⁵

On average, GA lesions can start to impact central vision within 2.5 years of diagnosis.⁵ “Therefore, reducing and slowing lesion growth as early as possible is meaningful for patients,” Desai says.

WHAT CLINICAL STUDIES SHOWED

Carl J. Danzig, MD, director of vitreoretinal services and retina clinical research at Rand Eye Institute in Deerfield Beach, Florida, who was a principal investigator in clinical trials, was excited to participate in a clinical trial in early 2021 because he viewed treating GA as the biggest unmet need in the retina space.

“At that time, no treatments were available for these patients,” he says. “By reducing GA progression, we are hoping to give patients the best chance of preserving their vision for as long as possible.”

Today, Izervay is the only FDA-approved GA treatment that has been shown in 2 phase 3 clinical trials to significantly reduce the rate of GA progression after 12 months. The rate of GA growth was evaluated at the onset of the study, at 6 months, and at 12 months. In each trial, there was a significant reduction in the rate of GA growth in patients treated with Izervay compared to sham treatments. Izervay slowed the loss of photoreceptors and disease progression as early as 6 months with a 35% reduction in the GATHER1 clinical trial and 18% reduction in the GATHER2 trial in the first year of treatment.

Recently, Iveric Bio announced positive 24-month top-line results from GATHER2, which demonstrated that the Izervay monthly dosing regimen met the primary objective to slow GA growth at 24 months with statistical significance compared to sham treatments. Across the GATHER clinical trial program, the most common adverse reactions (≥2%) reported at 12 months in patients who received Izervay 2 mg and greater than the sham treatment were conjunctival hemorrhage (13%), increased intraocular pressure (9%), and blurred vision (including visual impairment, blurred vision, a reduction in visual acuity, and visual acuity transiently reduced) (8%), choroidal neovascularization (7%), eye pain (4%), vitreous floaters (2%), and blepharitis (2%).

Says Dr. Danzig, “The safety profile across all GATHER trials was favorable, with 0 cases of vasculitis and only 1 case of ischemic optic neuropathy over 2 years.” RP

REFERENCES

1. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027
2. Colijn JM, Liefers B, Joachim N, et al. Enlargement of geographic atrophy from first diagnosis to end of life. JAMA Ophthalmol. 2021;139(7):743-750. doi:10.1001/jamaophthalmol.2021.1407
3. Iveric Bio. Data on file.
4. Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835. doi:10.1097/IAE.0000000000001392
5. Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;S0140-6736(23)01583-0. doi:10.1016/S0140-6736(23)01583-0