Introduction
Izervay (avacincaptad pegol) is a novel complement C5 inhibitor approved by the FDA in August 2023 for the treatment of geographic atrophy secondary to age-related macular degeneration. This oligonucleotide therapeutic represents a significant advancement in the management of this progressive retinal condition, offering the first pharmacologic approach to slow the progression of geographic atrophy lesions.
Mechanism of Action
Izervay works through targeted inhibition of complement C5 protein. The drug is a pegylated RNA aptamer that binds specifically to complement component C5 with high affinity. By inhibiting C5 cleavage, Izervay prevents the formation of both C5a (anaphylatoxin) and C5b, thereby interrupting the terminal complement cascade. This mechanism reduces the inflammatory and cell-damaging effects of complement activation in the retinal pigment epithelium and choroid, which are believed to contribute to geographic atrophy progression.
Indications
Izervay is indicated for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. This approval is based on clinical trials demonstrating reduced GA lesion growth rate. It is not indicated for neovascular (wet) AMD.
Dosage and Administration
- Standard dosage: 2 mg (0.1 mL) intravitreal injection every month
- Administration: Administered by intravitreal injection by qualified healthcare professionals
- Preparation: Use aseptic technique to prepare the injection
- Special populations:
- Renal impairment: No dosage adjustment required - Hepatic impairment: No dosage adjustment required - Elderly: No dosage adjustment required
Pharmacokinetics
- Absorption: Local ocular administration with minimal systemic exposure
- Distribution: Primarily confined to the vitreous humor and retina
- Metabolism: Undergoes nuclease-mediated metabolism to nucleotides
- Elimination: Systemic elimination half-life approximately 6-10 days
- Systemic exposure: Minimal systemic absorption following intravitreal administration
Contraindications
- Hypersensitivity to avacincaptad pegol or any component of the formulation
- Ocular or periocular infections
- Active intraocular inflammation
Warnings and Precautions
- Endophthalmitis and retinal detachments: Intravitreal injections may be associated with endophthalmitis, retinal detachment, and intraocular inflammation
- Increased intraocular pressure: Transient increases in intraocular pressure may occur post-injection
- Neovascular AMD: Monitor for emergence of neovascular AMD
- Pregnancy: No human data; use only if potential benefit justifies potential risk
- Lactation: Unknown if excreted in human milk; consider developmental and health benefits
Drug Interactions
Formal drug interaction studies have not been conducted. However, theoretical interactions include:
- Other complement inhibitors (potential additive effects)
- Immunosuppressive therapies
- No known pharmacokinetic interactions with systemic medications due to limited systemic exposure
Adverse Effects
Most common adverse reactions (≥5%):- Conjunctival hemorrhage (13%)
- Increased intraocular pressure (9%)
- Choroidal neovascularization (7%)
- Vitreous floaters (6%)
- Eye pain (5%)
- Endophthalmitis (<1%)
- Retinal detachment (<1%)
- Intraocular inflammation
Monitoring Parameters
- Visual acuity at each visit
- Intraocular pressure monitoring pre- and post-injection
- Dilated fundoscopic examination to assess:
- Geographic atrophy progression - Development of neovascular AMD - Ocular inflammation
- Patient-reported visual symptoms
- Signs of ocular infection
Patient Education
- Report any eye pain, redness, sensitivity to light, or vision changes immediately
- Understand the progressive nature of geographic atrophy and treatment goals
- Attend all scheduled injection appointments
- Be aware of potential risks including infection and increased eye pressure
- Do not rub or touch the treated eye immediately after injection
- Keep follow-up appointments to monitor treatment response and safety
- Inform all healthcare providers about Izervay treatment
References
1. FDA Approval Letter: Izervay (avacincaptad pegol). August 2023. 2. 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. 3. Khanani AM, Patel SS, Ferrone PJ, 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;402(10411):1449-1458. 4. Izervay [package insert]. Irvine, CA: Iveric Bio, An Astellas Company; 2023. 5. Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, et al. 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.