Izervay
avacincaptad pegol
Species
MonkeyRatDogRabbit
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit and dog (IVT ocular studies); rat and cynomolgus monkey (7-day IV); monkey the only pharmacologically relevant species
“The monkey is the only species identified that could be considered relevant showing 1/10th of the ARC1905 in an in vitro activity assay against human C5.”
Why that species
Human C5 aptamer: monkey 1/10th and rat 1/1000th of human activity; rabbit/dog expected very low activity but accepted for ocular tolerability
“The ocular studies were conducted in rabbit and dogs, which, as the Applicant indicated, are species in which ARC1905 is expected to have very low activity.”
Surrogate molecule
No surrogate; clinical aptamer (ARC1905) tested in non-pharmacologically-relevant ocular species plus IV monkey
“There are no animal species in which the human anti-C5 aptamer can be tested in ocular toxicity studies for effects stemming from C5 binding.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Study title: A 1-Month (Single-Dose) and 9-Month (Ten-Dose) Toxicity Study of ARC1905 Given by Intravitreal Injections to Rabbits”
Pivotal GLP studies
GLP 1-month and 9-month (10 monthly doses) IVT studies in rabbit and dog +/- Lucentis; 7-day IV rat and monkey studies
“Repeat-dose IVT toxicity studies were conducted in New Zealand White rabbits (0, 0.15, 0.5, and 1.5 mg/eye) and Beagle dogs (0, 0.3, 1, and 3.0 mg/eye).”
Route in tox
Intravitreal (ocular studies); IV bolus plus continuous infusion (systemic studies)
“Repeat-dose IVT toxicity studies were conducted in New Zealand White rabbits (0, 0.15, 0.5, and 1.5 mg/eye) and Beagle dogs (0, 0.3, 1, and 3.0 mg/eye).”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, chromosomal aberration in mammalian cells, mouse micronucleus; all negative
“Avacincaptad pegol was negative for genotoxicity based on a standard battery of studies including the bacterial reverse mutation assay, chromosomal aberration in mammalian cells and in vivo mouse bone marrow micronucleus assays.”
Carcinogenicity
Not conducted (waiver accepted; low systemic exposure, C5-inhibitor class experience)
“Carcinogenicity No studies were conducted. The Applicant submitted a justification to support a waiver request not to conduct the carcinogenicity studies”
Reproductive & developmental
EFD studies in rat and rabbit (IV, NOAEL 1.2 mg/kg/day); FEED and PPND waived
“In the embryofetal development (EFD) toxicity studies in rats and rabbits, there was no avacincaptad pegol-related adverse effects on any measured maternal or fetal parameter at doses up to 1.2 mg/kg/day (NOAEL).”
Safety pharmacology
Dedicated: hERG assay, rat CNS study, monkey telemetry CV/respiratory (NOAEL 100 mg/kg IV); transient APTT prolongation
“The NOAEL for cardiovascular and respiratory findings in this study was the high dose, 100 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Rabbit NOEL 0.5 mg/eye, NOAEL >=1.5 mg/eye; dog NOAEL 1.0 mg/eye; reversible retinal ganglion cell vacuolation, optic tract vacuolation in dog
“In the rabbit, based on the retinal vacuolation, the NOEL for avacincaptad pegol is 0.5 mg/eye for single and repeated IVT injections (0.66X the recommended clinical dose).”
Risksopen answer page →
Immune & cytokine safety
Main pharmacology-related risk is increased susceptibility to infections (C5 inhibition); no complement activation by the aptamer in monkeys; panuveitis with Lucentis combination
“Therefore, it seems that the main adverse reaction due to an exaggerated pharmacological effect of complement inhibition is an increased susceptibility to infections.”
Biodistribution & persistence
Ocular tissue distribution in rabbit after single IVT 3 mg/eye; low systemic exposure (rabbit 51 ng/mL, dog 489 ng/mL); no accumulation in rabbit
“An ocular tissue distribution study was conducted in male Dutch-Belted rabbits following a single IVT injection of avacincaptad pegol (3 mg/eye) to both eyes”
Modality-specific risk
Retinal/optic tract vacuolation from PEGylated aptamer uptake; transient APTT/PT prolongation (oligonucleotide class); macrophage vacuolation after high IV dosing
“The presence of the vacuoles most likely reflects uptake of the PEGylated aptamer within the retinal cells”