Identification
- Summary
Avacincaptad pegol is an RNA aptamer inhibiting the complement C5 indicated for the treatment of geographic atrophy secondary to age-related macular degeneration.
- Brand Names
- Izervay
- Generic Name
- Avacincaptad pegol
- DrugBank Accession Number
- DB15165
- Background
Avacincaptad pegol is an RNA aptamer covalently bound to a branched polyethylene glycol (PEG) molecule. It was developed to treat an advanced form of age-related macular degeneration (AMD) called geographic atrophy (GA).4 AMD is the leading cause of vision loss in developed countries for people over 50 years old, with a global estimate of 170 million individuals affected. AMD eventually progresses to bilateral and irreversible loss of vision, whether or not the patients have the non-neovascular (dry) or the neovascular (wet) form of AMD.2 Although anti-VEGF therapy is available for the neovascular form of AMD, no treatment was approved for GA.2
Avacincaptag pegol was approved by the FDA on August 4, 2023, under the brand name IZERVAY for the treatment of GA secondary to AMD. This approval is based on the positive results obtained from 2 phase 3 clinical trials GATHER1 and GATHER2.5
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Nucleic Acid Based Therapies
Oligonucleotides - Synonyms
- Avacincaptad pegol
Pharmacology
- Indication
Avacincaptad pegol is indicated for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).4
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Dry macular degeneration •••••••••••• •••••••• - Contraindications & Blackbox Warnings
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Complement C5 is cleaved into C5a and C5b, and it is the final step of the complement cascade where a membrane attacking complex (MAC) is formed to cause cell death.1,2 This is thought to be a major contributor to the pathophysiology of age-related macular degeneration (AMD), as immunohistochemical studies demonstrated complement deposition in postmortem eyes of patients diagnosed with AMD.2 Additionally, 50% of patients with AMD were also found to have mutations in genes regulating the complement cascade, further implicating this pathway in deteriorating retinal health.2 By inhibiting the cleavage of complement C5, avacincaptad pegol can dampen the inflammatory processes, thus slowing down retinal cell injuries and degeneration.2
Increased geographic atrophy area (GA) growth is reflective of the loss of photoreceptors and AMD disease progression, and reductions in the rate of geographic atrophy growth were observed from baseline through the first year of treatment across avacincaptad pegol treatment groups in studies GATHER1 and GATHER2.4 Specifically, a GA growth rate reduction of 29% was observed in patients receiving avacincaptad pegol monthly or 20% in patients receiving the treatment every other month.3
- Mechanism of action
Avacincaptad pegol is an RNA aptamer, a PEGylated oligonucleotide that binds to and inhibits complement protein C5. By inhibiting C5, avacincaptad pegol may prevent its cleavage to C5a and C5b thus decreasing membrane attack complex (MAC) formation.4
Target Actions Organism AComplement C5 inhibitorHumans - Absorption
Following a single dose of avacincaptad pegol, maximum avacincaptad pegol plasma concentrations (Cmax) are estimated to occur approximately 7 days post-dose and mean (CV%) free avacincaptad pegol plasma Cmax is estimated to be 68.4 ng/mL (57.8%) in neovascular AMD (nAMD) patients. The AUC0-28 days following a single 2 mg dose is 1064 day∙ng/mL. Based on a population pharmacokinetic analysis of patients with nAMD, the predicted steady-state avacincaptad pegol Cmax is 83.9 ng/mL after monthly intravitreal administration of avacincaptad pegol 2 mg.4
In humans, avacincaptad pegol plasma concentrations are predicted to be approximately 7,000-fold lower than vitreal concentrations.4
- Volume of distribution
Limited information is available on the volume of distribution of avacincaptad pegol
- Protein binding
Limited information is available on the protein binding of avacincaptad pegol
- Metabolism
The metabolism of avacincaptad pegol has not been fully characterized. Avacincaptad pegol is expected to be catabolized by endonucleases and exonucleases to oligonucleotides of shorter lengths.4
- Route of elimination
The elimination of avacincaptad pegol has not been fully characterized. Avacincaptad pegol is expected to be catabolized by endonucleases and exonucleases to oligonucleotides of shorter lengths which may be excreted renally, in a similar manner to the elimination of endogenous RNA.4
- Half-life
The estimated apparent systemic half-life of avacincaptad pegol is approximately 12 days.4
- Clearance
Limited information is available on the clearance of avacincaptad pegol
- Adverse Effects
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There are no adequate and well-controlled studies of IZERVAY administration in pregnant women. The use of IZERVAY may be considered following an assessment of the risks and benefits.4
The administration of avacincaptad pegol to pregnant rats and rabbits throughout the period of organogenesis resulted in no evidence of adverse effects on the fetus or pregnant female at intravenous (IV) doses 5.1 times and 3.2 times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 2 mg once monthly, respectively.4
No studies have been conducted on the carcinogenic potential of avacincaptad pegol.4
Avacincaptad pegol was negative in in vitro (bacterial reverse mutation assay, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
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Ingredient UNII CAS InChI Key Avacincaptad pegol sodium K86ENL12I5 1491144-00-3 Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Izervay Injection 20 mg/1mL Intravitreal Astellas Pharma US, Inc. 2023-08-19 Not applicable US 
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- TT0V5JLG5B
- CAS number
- 1613641-69-2
References
- General References
- Niculescu T, Weerth S, Niculescu F, Cudrici C, Rus V, Raine CS, Shin ML, Rus H: Effects of complement C5 on apoptosis in experimental autoimmune encephalomyelitis. J Immunol. 2004 May 1;172(9):5702-6. doi: 10.4049/jimmunol.172.9.5702. [Article]
- Jaffe GJ, Westby K, Csaky KG, Mones J, Pearlman JA, Patel SS, Joondeph BC, Randolph J, Masonson H, Rezaei KA: C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. Ophthalmology. 2021 Apr;128(4):576-586. doi: 10.1016/j.ophtha.2020.08.027. Epub 2020 Sep 1. [Article]
- Cabral de Guimaraes TA, Daich Varela M, Georgiou M, Michaelides M: Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions. Br J Ophthalmol. 2022 Mar;106(3):297-304. doi: 10.1136/bjophthalmol-2020-318452. Epub 2021 Mar 19. [Article]
- FDA Approved Drug Products: IZERVAY™ (avacincaptad pegol) intravitreal solution [Link]
- Iveric Bio Receives U.S. FDA Approval for IZERVAY™ (avacincaptad pegol intravitreal solution), a New Treatment for Geographic Atrophy [Link]
- External Links
- 2645108
- Wikipedia
- Avacincaptad_pegol
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Dry Macular Degeneration / Macular Degeneration 1 3 Completed Treatment Dry Macular Degeneration / Macular Degeneration 1 2 Active Not Recruiting Treatment Stargardt Disease 1 1 2 Completed Treatment Neovascular Age-Related Macular Degeneration (nAMD) 1 2 Terminated Treatment Macular Degeneration 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Intravitreal 20 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11491176 No 2014-07-11 2034-07-11 US US11273171 No 2014-07-11 2034-07-11 US US10947544 No 2021-03-16 2025-02-14 US US9617546 No 2017-04-11 2025-02-14 US US8236773 No 2012-08-07 2026-11-11 US US7803931 No 2010-09-28 2025-02-14 US US7538211 No 2009-05-26 2025-02-14 US US7579456 No 2009-08-25 2025-02-14 US
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor binding
- Specific Function
- Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C...
- Gene Name
- C5
- Uniprot ID
- P01031
- Uniprot Name
- Complement C5
- Molecular Weight
- 188303.705 Da
References
- FDA Approved Drug Products: IZERVAY™ (avacincaptad pegol) intravitreal solution [Link]
Drug created at May 20, 2019 14:55 / Updated at November 01, 2023 05:14