IZERVAY for geographic atrophy

IZERVAY, a new complement C5 inhibitor, is now FDA-approved for treating GA due to AMD. Studies showed a reduction in the rate of GA growth and risk of vision loss.

It has been one of the most eventful summers for the retina disease community. In July, the American Society of Retina Specialists (ASRS) reported Apellis’ pegcetacoplan injection (Syfovre) was linked to six cases of occlusive retinal vasculitis, a vision-impairing adverse event.¹ Despite the company’s efforts to conduct thorough manufacturing evaluations and review data from its clinical trials, no definitive cause for the adverse events nor how to prevent or manage them was updated.²

While the safety with Syfovre is causing concerns, there is a new hope for patients with geographic atrophy (GA) due to age-related macular degeneration (AMD). On August 4, 2023, the U.S. Food and Drug Administration (FDA) approved a new treatment option called IZERVAY (avacincaptad pegol), developed by Iveric Bio. an Astellas Pharma company.³ This approval brings a welcoming option for those suffering from geographic atrophy.

How IZERVAY works?

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Geographic atrophy (GA) is a condition that leads to vision loss, often linked to age-related macular degeneration (AMD). Recent studies have found that complement activation, a vital part of the immune system, plays a significant role in GA development.⁴

The complement cascade is a process that protects our bodies from harmful invaders. However, in GA, it may harm healthy cells, including those in the retina, leading to vision loss. Specifically, when the cascade is activated, it creates fragments like C3a, C3b, C5a, and C5b, which can damage retina cells. ⁴

IZERVAY (eye-ZER-vey) is a pegylated aptamer; it specifically targets C5 in the complement cascade. By inhibiting C5's cleavage, IZERVAY may prevent the formation of C5a and C5b, decreasing membrane attack complex formation and reducing the risk of retinal cell damage. ⁶

Administered through intravitreal injections directly into the eye, IZERVAY could interrupt the complement cascade, slowing down or even stopping GA progression.⁶

How effective is IZERVAY?

The U.S. Food and Drug Administration (FDA) based its approval of IZERVAY on the results of two Phase 3 clinical trials called GATHER1 and GATHER2. These trials evaluated the safety and efficacy of monthly 2 mg intravitreal (eye injection) administration of IZERVAY in patients with geographic atrophy due to AMD.³

The primary analysis of these trials looked at the rate of GA growth at baseline, 6 months, and 12 months. Over the course of 12 months, patients treated with IZERVAY showed a statistically significant reduction in the rate of GA growth compared to those who received the placebo (sham treatment). The slowing of disease progression was observed as early as 6 months, with reductions ranging from 18% (GATHER2) to 35% (GATHER1) in the first year of treatment.⁵

Like any medication, IZERVAY has potential side effects. The most common adverse reactions listed in its prescribing information were conjunctival hemorrhage (13%), increased IOP (9%), blurred vision (8%), and neovascular age-related macular degeneration (7%). Further, IZERVAY is contraindicated in patients with ocular or periocular infections or active intraocular inflammation.⁶

 (For more prescribing information, please visit the IZERVAY website)

How does reduced geographic atrophy growth affect vision?

From a post-ad hoc analysis finding from the GATHER trials presented at the Association for Research in Vision and Ophthalmology meeting earlier this year, for the first time in an interventional study, a relationship between GA growth and worsening vision loss was demonstrated -- greater vision loss was correlated with increased GA growth.

The post-hoc analysis of the combined data from GATHER1 and GATHER2 indicated a 56% risk reduction in the rate of persistent vision loss in GA patients who received the 2 mg dose of IZERVAY compared to the sham treatment over the first 12 months of treatment.

* Persistent vision loss was defined as a loss of ≥15 letters in Best Corrected Visual Acuity (BCVA) from baseline measured at any two consecutive visits up to month 12.

Closing thoughts

With the recent approval of IZERVAY (avacincaptad pegol) by the U.S. FDA, the future of treating geographic atrophy looks brighter. According to the company, IZERVAY will be available in the US market in two to four weeks, offering an additional option for GA patients that could reduce the rate of GA growth and the risk of vision loss. However, its real-world use will be crucial in confirming the safety profile observed thus far.

As we continue to make progress in new research findings and treatments, we can anticipate even more armaments in the future to battle against this debilitating disease. The path ahead is filled with hope and the potential for transformative advancements in the field.

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1.  Ophthalmology Times. (2023, July 19). ASRS reports six cases of occlusive retinal vasculitis linked to pegcetacoplan injection. Retrieved August 5, 2023, from https://www.ophthalmologytimes.com/view/asrs-reports-six-cases-of-occlusive-retinal-vasculitis-linked-to-pegcetacoplan-injection

2. Apellis Pharmaceuticals. (2023, July 17). Apellis Provides Update on Review of Rare Safety Events with Syfovre®. Retrieved August 5, 2023, from https://investors.apellis.com/news-releases/news-release-details/apellis-provides-update-review-rare-safety-events-syfovrer

3. Iveric Bio. (2023, Aug 5) Iveric Bio Receives U.S. FDA Approval for IZERVAY™ (avacincaptad pegol intravitreal solution), a New Treatment for Geographic Atrophy. Retrieved August 5, 2023, from https://ivericbio.com/iveric-bio-receives-us-fda-approval-for-izervay-avacincaptad-pegol-intravitreal-solution-a-new-treatment-for-geographic-atrophy/

4. Desai, Dhaval, and Pravin U Dugel. “Complement cascade inhibition in geographic atrophy: a review.” Eye (London, England) vol. 36,2 (2022): 294-302. doi:10.1038/s41433-021-01765-x

5. Iveric Bio. (2022, Nov)  The Efficacy of Avacincaptad Pegol in Geographic Atrophy: GATHER1 and GATHER2 Results. Retrieved August 5, 2023, from https://ivericmedical.com/static/RetinaSociety2022_Efficacy-f610417058de3027f34fd055737ebc79.pdf

6. Iveric Bio. (2023, Aug).  IZERVAY Prescribing information. Retrieved August 5, 2023, from https://ivericbio.com/wp-content/uploads/IZERVAY-avacincaptad-pegol-intravitreal-solution-PI_Final_8.4.23.pdf?__hstc=72177612.d872b412a727cb547698bede85f5b39e.1691214561996.1691214561996.1691214561996.1&__hssc=72177612.1.1691214561996&__hsfp=3022105166

7. Iveric Bio. (2023, Apr 23)  Iveric Bio Announces New Functional Vision Loss Reduction Data from Avacincaptad Pegol GATHER Trials Presented at ARVO Annual Meeting. Retrieved August 5, 2023, from https://ivericbio.com/iveric-bio-announces-new-functional-vision-loss-reduction-data-from-avacincaptad-pegol-gather-trials-presented-at-arvo-annual-meeting/