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.”
Species: general tox
New Zealand White rabbit and Beagle dog (repeat-dose intravitreal)
“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).”
Species: DART
Rat and rabbit (EFD only); fertility and pre/postnatal studies 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).”
Species: carcinogenicity
Not conducted (waiver)
“No studies were conducted. The Applicant submitted a justification to support a waiver request not to conduct the carcinogenicity studies”
Surrogate used in
No surrogate used; no species allows testing of C5-related ocular effects
“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.”
Genotox: Ames
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.”
Genotox: in vitro mammalian
Chromosomal aberration in mammalian cells: 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.”
Genotox: in vivo
Mouse bone marrow micronucleus: 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 model
Not conducted: waiver based on mechanism of action, route, literature, class effects and existing data
“The Applicant justification to omit the conduct of nonclinical carcinogenicity studies is based on avacincaptad pegol mechanism of action, route of administration, a supportive literature review, an analysis of pharmacological class effects, and nonclinical and clinical data collected to date.”
Carcinogenicity timing
Not required: carcinogenicity waiver accepted on weight of evidence
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
hERG / QT
Negative: hERG IC50 >100 µM; minimal QTc risk
“The IC50 was not determined but considered to be > 100 μM, supporting minimal risk for QTc prolongation.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Izervay don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA pharmacology/toxicology review, p. 7)
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”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Endophthalmitis and Retinal Detachments
- Neovascular AMD
- Increase in Intraocular Pressure
Ocular toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Rabbit and dog repeat-dose intravitreal studies; interim data up to week 13 submitted under the initial IND
“Repeat-dose ocular toxicity studies were conducted in New Zealand White rabbits and Beagle dogs. An interim report (with data up to week 13) was submitted under the initial IND.”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Izervay don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Rabbit intravitreal study, 10 monthly doses through Week 37, with 4-week recovery (dog study of the same design)
“On Week 37 (after 10 monthly doses), mild retinal vacuolation was observed in the high dose group. The finding did not increase in severity between Doses 1 and 10. The finding was again reversible following a 4-week recovery period (Day 281).”
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).”
DART package
Species: DART
Rat and rabbit (EFD only); fertility and pre/postnatal studies 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).”
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).”
PPND / ePPND: when
Not conducted: PPND (and FEED) waived; weight of evidence showed studies not necessary for the dosing regimen and indication
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
Carcinogenicity
Species: carcinogenicity
Not conducted (waiver)
“No studies were conducted. The Applicant submitted a justification to support a waiver request not to conduct the carcinogenicity studies”
Carcinogenicity model
Not conducted: waiver based on mechanism of action, route, literature, class effects and existing data
“The Applicant justification to omit the conduct of nonclinical carcinogenicity studies is based on avacincaptad pegol mechanism of action, route of administration, a supportive literature review, an analysis of pharmacological class effects, and nonclinical and clinical data collected to date.”
Carcinogenicity timing
Not required: carcinogenicity waiver accepted on weight of evidence
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog intravitreal NOAEL 1.0 mg/eye = 0.66x the recommended clinical dose
“The NOAEL is considered to be 1.0 mg/eye (0.66X the recommended clinical dose) even though optic tract vacuolation at 3.0 mg/eye was not associated with any adverse histopathology or significant ERG findings.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro and ex vivo complement functional assays plus in vivo complement inhibition in monkey
“Avacincaptad pegol has demonstrated complement inhibitory activity in several in vitro and ex vivo functional assays and in vivo in the monkey.”
Why that model
Human C5-specific aptamer: monkey has 1/10th and rat 1/1000th of activity against human C5
“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. The rat has 1/1000th of the in vitro activity against human C5.”
Reviewer's view of the efficacy data
FDA: monkey data imply ~10 µg/mL needed for complete C5 inhibition; clinical Cmax 68.3 ng/mL is over 140x lower
“Based on this fact, it seems we can assume plasma concentrations of approximately 10 μg/mL will be required in humans for complete C5 inhibition. The clinical Cmax was 68.3 ng/mL, over 140X lower than the estimated concentration for complete C5 inhibition.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
Ocular toxicity studies in rabbit and dog, species in which the aptamer has very low activity; no monkey ocular study
Why: Monkey has no advantage over rabbit or dog for the ocular studies · Other reason
“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.”
“Therefore, the monkey has no advantage over the rabbit or dog, and the reviewer considers that the rabbit and dog are acceptable species.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; waiver granted
Why: Mechanism of action, intravitreal route, literature, pharmacological class effects and nonclinical and clinical data · Weight of evidence · Class precedent · Pharmacology or kinetics
“The Applicant justification to omit the conduct of nonclinical carcinogenicity studies is based on avacincaptad pegol mechanism of action, route of administration, a supportive literature review, an analysis of pharmacological class effects, and nonclinical and clinical data collected to date.”
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
DARTAcceptedBeyond the letter
Fertility/early embryonic and pre-/postnatal development studies waived; only rat and rabbit EFD studies conducted
Why: Weight of evidence shows the studies are not necessary for the intended dosing regimen and indication · Weight of evidence
“Nonclinical recommendations for (1) submission for a waiver request for FEED (fertility and early embryonic developmental) and PPND (pre-and postnatal developmental), along with the justification and supporting data, (2) conduct of embryofetal development studies in relevant species”
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
Safety marginVerdict not stated
Ocular NOAEL below the clinical dose: dog 1.0 mg/eye (0.66X the recommended clinical dose)
“The NOAEL is considered to be 1.0 mg/eye (0.66X the recommended clinical dose) even though optic tract vacuolation at 3.0 mg/eye was not associated with any adverse histopathology or significant ERG findings.”
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