Veopoz
pozelimab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only; not evaluated in rodents
“Thirteen- and 26-week repeat-dose toxicity studies were conducted with pozelimab in cynomolgus monkeys. As pozelimab is not pharmacologically active in rat or mouse, it was not evaluated in a rodent species.”
Why that species
Binds human and monkey C5 with high affinity but not mouse, rat or rabbit C5
“Pozelimab (REGN3918) is a human monoclonal antibody that binds with high affinity to complement factor 5 (C5) from human and monkey but not mouse, rat, or rabbit.”
Surrogate molecule
No surrogate in toxicology; C5 humanized transgenic mice used only for pharmacology; clinical antibody tested in monkeys
“serum samples from pozelimab-treated C5 humanized mice (i.e., transgenic mice expressing human C5) and monkeys resulted in > 80% inhibition of classical pathway-induced hemolysis.”
Species: general tox
Cynomolgus monkey only (13- and 26-week studies); no rodent species (not pharmacologically active)
“Thirteen- and 26-week repeat-dose toxicity studies were conducted with pozelimab in cynomolgus monkeys. As pozelimab is not pharmacologically active in rat or mouse, it was not evaluated in a rodent species.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development with juvenile dosing of offspring)
“Pozelimab is not pharmacologically active in rat or mouse. Thus, an enhanced pre- and postnatal development study was conducted with pozelimab in pregnant cynomolgus monkeys, with juvenile dosing of the offspring for three months post-weaning.”
Species: carcinogenicity
Not conducted; ECAC agreed studies not necessary
“The Executive Carcinogenicity Assessment Committee concurred with the Applicant’s proposal that nonclinical carcinogenicity studies with pozelimab are not necessary to support a BLA for this product.”
Surrogate used in
No surrogate in toxicology; C5 humanized transgenic mice used for pharmacology (ex vivo hemolysis) only
“serum samples from pozelimab-treated C5 humanized mice (i.e., transgenic mice expressing human C5) and monkeys resulted in > 80% inhibition of classical pathway-induced hemolysis.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Thirteen- and 26-week repeat-dose toxicity studies were conducted with pozelimab in cynomolgus monkeys.”
Pivotal GLP studies
GLP 13-week monkey study: IV 5, 20, 100 mg/kg or SC 100 mg/kg once weekly; plus 26-week IV study
“Dose and frequency of dosing: IV: 5, 20, 100 mg/kg; SC: 100 mg/kg; once weekly”
Route in tox
IV and SC
“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genetic toxicology studies with pozelimab have not been conducted, in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted; weight-of-evidence assessment concluded low carcinogenic potential; ECAC concurred
“Carcinogenicity studies with pozelimab have not been conducted. The Applicant conducted a carcinogenicity risk assessment for pozelimab and concluded that the carcinogenic potential is low.”
Reproductive & developmental
No fertility effects in 26-week study; monkey ePPND with juvenile dosing: no maternal, infant or juvenile effects up to 50 mg/kg/week
“No adverse effects of pozelimab were observed on male or female fertility parameters in the 26- week repeat-dose toxicity study at doses up to 100 mg/kg/week. Additionally, no adverse effects of pozelimab were observed on maternal or infant health or on juvenile development at doses up to 50 mg/kg/week”
Safety pharmacology
Incorporated into 13- and 26-week monkey studies; no effects on ECG, neurological or respiratory function
“Nonclinical studies conducted with pozelimab include pharmacology studies, pharmacokinetics, 13- and 26-week repeat-dose toxicity studies in cynomolgus monkeys with incorporated safety pharmacology endpoints”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genetic toxicology studies with pozelimab have not been conducted, in accordance with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genetic toxicology studies with pozelimab have not been conducted, in accordance with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genetic toxicology studies with pozelimab have not been conducted, in accordance with ICH S6(R1).”
Carcinogenicity model
Not conducted; carcinogenicity risk assessment concluded low potential
“Carcinogenicity studies with pozelimab have not been conducted. The Applicant conducted a carcinogenicity risk assessment for pozelimab and concluded that the carcinogenic potential is low.”
Carcinogenicity timing
Not required: ECAC concurred studies not necessary for the BLA (weight-of-evidence)
“Carcinogenicity Assessment Committee concurred with the Applicant’s proposal that nonclinical carcinogenicity studies with pozelimab are not necessary to support a BLA for this product.”
hERG / QT
No hERG or thorough QT study; 145 kDa antibody not expected to interact with hERG
“No dedicated thorough QT study was conducted. Pozelimab, a monoclonal antibody with a molecular weight of 145kDa, is not expected to interact with hERG channel.”
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 Veopoz 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 100 mg/kg/week (highest dose) in 13- and 26-week monkey studies; no adverse findings; clinical margins 12-15 (FDA multi-discipline review, p. 36)
NOAEL / key findings
NOAEL 100 mg/kg/week (highest dose) in 13- and 26-week monkey studies; no adverse findings; clinical margins 12-15
“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks). Clinical safety margins are 12-15 relative to the predicted drug exposure”
Risksopen answer page →
Immune & cytokine safety
ADA in 9 of 36 treated monkeys (26-week study); ADA did not notably affect exposure
“Nine of 36 treated animals were positive for ADA post-dose (7/12 LD animals, 2/12 HD animals). Positive ADA response did not notably affect drug exposure.”
Biodistribution & persistence
TCR: no plasma membrane staining; cytoplasmic staining unlikely relevant; off-target toxicity risk minimal
“No plasma membrane staining with pozelimab was observed. Given the low likelihood that pozelimab will enter the cytoplasm of cells and in the absence of adverse effects in the 13- and 26-week toxicity studies, the risk of off-target binding by pozelimab resulting in clinically relevant toxicity is minimal.”
Modality-specific risk
Serious infections, including meningococcal infections, from complement inhibition
“The increased risk of serious infections, including meningococcal infections associated with administration of pozelimab, will be included in the labeling as a Warning and Precaution.”
Anti-drug antibodies: animals
Monkey ADA generally did not affect drug exposure or hasten elimination
“Positive ADA responses generally did not affect drug exposure or hasten elimination”
Anti-drug antibodies: patients
None of 9 evaluable patients developed anti-pozelimab antibodies during 48 weeks
“Nine of the 10 patients 3 years of age and older with CD55-deficient PLE in the clinical study were evaluable for anti-pozelimab antibodies. None of these patients developed anti-pozelimab-bbfg antibodies during the 48-week treatment with pozelimab-bbfg.”
Label warnings
Boxed warning: Serious meningococcal infections
- Serious Meningococcal Infections
- Other Bacterial Infections
- Systemic Hypersensitivity Reactions
- Immune Complex Formation
InfectionsHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and 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
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.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Veopoz 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 100 mg/kg/week (highest dose) in 13- and 26-week monkey studies; no adverse findings; clinical margins 12-15 (FDA multi-discipline review, p. 36)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV infusion) with 13-week recovery
“A 26-Week Intravenous Infusion Toxicity, Toxicokinetic, and Fertility Assessment Study in Sexually Mature Cynomolgus Monkeys with a 13-Week Recovery Phase”
Pivotal GLP studies
GLP 13-week monkey study: IV 5, 20, 100 mg/kg or SC 100 mg/kg once weekly; plus 26-week IV study
“Dose and frequency of dosing: IV: 5, 20, 100 mg/kg; SC: 100 mg/kg; once weekly”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development with juvenile dosing of offspring)
“Pozelimab is not pharmacologically active in rat or mouse. Thus, an enhanced pre- and postnatal development study was conducted with pozelimab in pregnant cynomolgus monkeys, with juvenile dosing of the offspring for three months post-weaning.”
Reproductive & developmental
No fertility effects in 26-week study; monkey ePPND with juvenile dosing: no maternal, infant or juvenile effects up to 50 mg/kg/week
“No adverse effects of pozelimab were observed on male or female fertility parameters in the 26- week repeat-dose toxicity study at doses up to 100 mg/kg/week. Additionally, no adverse effects of pozelimab were observed on maternal or infant health or on juvenile development at doses up to 50 mg/kg/week”
PPND / ePPND: when
ePPND in cynomolgus monkey with juvenile dosing of offspring completed before the marketing application
“Thus, an enhanced pre- and postnatal development study was conducted with pozelimab in pregnant cynomolgus monkeys, with juvenile dosing of the offspring for three months post-weaning.”
Carcinogenicity
Species: carcinogenicity
Not conducted; ECAC agreed studies not necessary
“The Executive Carcinogenicity Assessment Committee concurred with the Applicant’s proposal that nonclinical carcinogenicity studies with pozelimab are not necessary to support a BLA for this product.”
Carcinogenicity model
Not conducted; carcinogenicity risk assessment concluded low potential
“Carcinogenicity studies with pozelimab have not been conducted. The Applicant conducted a carcinogenicity risk assessment for pozelimab and concluded that the carcinogenic potential is low.”
Carcinogenicity timing
Not required: ECAC concurred studies not necessary for the BLA (weight-of-evidence)
“Carcinogenicity Assessment Committee concurred with the Applicant’s proposal that nonclinical carcinogenicity studies with pozelimab are not necessary to support a BLA for this product.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 100 mg/kg/week (13-week SC, 26-week IV): 12-15x predicted clinical exposure
“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks). Clinical safety margins are 12-15 relative to the predicted drug exposure following the proposed IV loading dose and subsequent weekly weight-based dosing regimen.”
NOAEL / key findings
NOAEL 100 mg/kg/week (highest dose) in 13- and 26-week monkey studies; no adverse findings; clinical margins 12-15
“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks). Clinical safety margins are 12-15 relative to the predicted drug exposure”
Efficacy evidenceopen answer page →
Efficacy evidence
Ex vivo hemolysis inhibition in serum from pozelimab-treated C5 humanized mice and normal monkeys
“Following administration to C5 humanized mice and normal monkeys, pozelimab blocked classical and alternative pathway-initiated hemolysis in serum samples ex vivo.”
Why that model
CD55 knockout mouse lacks the CHAPLE phenotype, so no acceptable animal disease model
“Importantly, though a CD55 knockout mouse model exists, it does not display the CHAPLE disease phenotype, and thus is not considered an acceptable animal disease model in which one could demonstrate potential clinical effectiveness of pozelimab in subjects with CHAPLE disease.”
Reviewer's view of the efficacy data
FDA: nonclinical data give strong mechanistic support as confirmatory evidence of effectiveness
“Nonclinical data provide strong mechanistic support as confirmatory evidence of effectiveness for pozelimab in the treatment of subjects with CHAPLE disease.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for chronic use; weight-of-evidence risk assessment reviewed by ECAC
Why: Low carcinogenic potential by risk assessment; not pharmacologically active in rat or mouse · Weight of evidence · No relevant species
“Carcinogenicity Carcinogenicity studies with pozelimab have not been conducted. The Applicant conducted a carcinogenicity risk assessment for pozelimab and concluded that the carcinogenic potential is low.”
“Additionally, pozelimab is not pharmacologically active in rat or mouse. The Executive Carcinogenicity Assessment Committee concurred with the Applicant’s proposal that nonclinical carcinogenicity studies with pozelimab are not necessary to support a BLA for this product.”
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