Voyxact
sibeprenlimab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Given >99% homology with human APRIL and comparable binding affinity, the cynomolgus monkey was considered a pharmacological relevant species for safety evaluation.”
Why that species
APRIL binding comparable in cynomolgus monkey, rabbit and human; no binding detected in mouse or rat
“In cross-species comparison studies, binding affinity for APRIL was comparable between cynomolgus monkeys, rabbits, and humans whereas binding to APRIL could not be detected in rodents (mouse or rat).”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkeys (mouse surrogate mAb 4540 used in a mouse IgAN efficacy model)
“The impact of blocking APRIL interaction with its receptors was evaluated in a grouped ddY (gddY) IgA mouse nephropathy model using the mAb 4540 mouse surrogate and in healthy cynomolgus monkeys with sibeprenlimab.”
Species: general tox
Cynomolgus monkey only (>99% APRIL homology, comparable binding)
“Given >99% homology with human APRIL and comparable binding affinity, the cynomolgus monkey was considered a pharmacological relevant species for safety evaluation.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study)
“The potential maternal and developmental effect on pregnant cynomolgus monkeys and their offspring was evaluated in an enhanced pre- and postnatal development study.”
Species: carcinogenicity
Not conducted; rodent carcinogenicity studies deemed not warranted
“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
Surrogate used in
Yes: mouse surrogate mAb 4540 for in vivo efficacy (gddY IgAN model); toxicology used sibeprenlimab in monkeys
“The impact of blocking APRIL interaction with its receptors was evaluated in a grouped ddY (gddY) IgA mouse nephropathy model using the mAb 4540 mouse surrogate and in healthy cynomolgus monkeys with sibeprenlimab.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A 26-week IV study (25 to 100 mg/kg biweekly) showed no adverse effects at the highest dose of 100 mg/kg/dose.”
Pivotal GLP studies
Cynomolgus 26-week IV (25-100 mg/kg biweekly) and 26-week SC (25-100.5 mg/kg biweekly) GLP studies
“A 26-week IV study (25 to 100 mg/kg biweekly) showed no adverse effects at the highest dose of 100 mg/kg/dose. A 26-week study with SC dosing (25 to 100.5 mg/kg biweekly) demonstrated a similar safety profile”
Route in tox
Intravenous and subcutaneous
“A 26-week study with SC dosing (25 to 100.5 mg/kg biweekly) demonstrated a similar safety profile and with ~70% bioavailability compared to the IV route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (antibody lacks ability to interact directly with DNA)
“Genotoxicity studies were not conducted for sibeprenlimab, a monoclonal antibody, which lacks the ability to directly interact with DNA.”
Carcinogenicity
Not conducted; carcinogenicity risk assessment accepted, rodent studies not warranted
“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
Reproductive & developmental
Monkey ePPND (101 mg/kg SC every 2 weeks, GD 20 to delivery): no adverse embryofetal or postnatal effects
“subcutaneous administration of sibeprenlimab once every 2 weeks to pregnant cynomolgus monkeys from gestation Day 20 through delivery did not result in any adverse effects on embryofetal or postnatal development at one tested dose of 101 mg/kg”
Safety pharmacology
Incorporated into GLP repeat-dose monkey studies; no neurological, cardiovascular, ECG or respiratory effects
“No adverse effects related to sibeprenlimab were observed in qualitative neurological assessments, and there were no significant effects on heart rate, blood pressure, electrocardiogram parameters, or on respiratory function at any dose levels tested.”
Genotox: Ames
Not conducted (antibody does not interact directly with DNA)
“Genotoxicity studies were not conducted for sibeprenlimab, a monoclonal antibody, which lacks the ability to directly interact with DNA.”
Genotox: in vitro mammalian
Not conducted (antibody does not interact directly with DNA)
“Genotoxicity studies were not conducted for sibeprenlimab, a monoclonal antibody, which lacks the ability to directly interact with DNA.”
Genotox: in vivo
Not conducted (antibody does not interact directly with DNA)
“Genotoxicity studies were not conducted for sibeprenlimab, a monoclonal antibody, which lacks the ability to directly interact with DNA.”
Carcinogenicity model
Not conducted; carcinogenicity risk assessment reviewed under the IND instead
“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
Carcinogenicity timing
Not required: rodent studies deemed not warranted after risk assessment
“Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
hERG / QT
No standalone study; no significant ECG, heart rate or blood pressure effects in monkey repeat-dose studies
“No adverse effects related to sibeprenlimab were observed in qualitative neurological assessments, and there were no significant effects on heart rate, blood pressure, electrocardiogram parameters, or on respiratory function at any dose levels tested.”
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 Voyxact 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 every 2 weeks IV (high dose) in IV monkey study (FDA integrated review, p. 101)
NOAEL / key findings
NOAEL 100 mg/kg every 2 weeks IV (high dose) in IV monkey study
“The no-observed-adverse-effect level (NOAEL) was established at the high dose of 100 mg/kg/2-week”
Risksopen answer page →
Immune & cytokine safety
ADAs in 20% of monkeys at 25 and 50 mg/kg SC, none at high dose, no exposure effect
“ADAs were observed in 20% of male and female monkeys in the 25 and 50 mg/kg/dose groups, but not in the highest dose groups. No effect on exposure was observed.”
Biodistribution & persistence
Placental transfer in monkeys: infant drug levels 3.7-fold maternal at postpartum Day 28
“Sibeprenlimab demonstrated placental crossing capability, with infant drug concentrations measuring 3.7-fold higher than maternal levels at postpartum Day 28.”
Modality-specific risk
Pharmacologic immunoglobulin reduction (especially IgA), reversible and without adverse effects in monkeys
“All studies showed the anticipated pharmacological effect, i.e., decreases in immunoglobulin levels (particularly IgA) that were reversible and not associated with any adverse effects on clinical chemistry or histopathology.”
Anti-drug antibodies: animals
26-week SC monkey study: ADA in 20% at 25 and 50 mg/kg, none at high dose; no effect on exposure
“ADAs were observed in 20% of male and female monkeys in the 25 and 50 mg/kg/dose groups, but not in the highest dose groups. No effect on exposure was observed.”
Anti-drug antibodies: patients
ADA in 34% (88/256) of patients; 23.9% of these neutralizing
“During the treatment period in the VISIONARY Study, 88 of 256 (34%) evaluable patients treated with VOYXACT developed ADA. Among the 88 patients who tested positive for ADA, 21 patients (23.9%) developed ADA that had neutralizing activity.”
Label warnings
- Immunosuppression and Increased Risk of Infections
- Immunosuppression and Immunization Risks
Infections
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
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 Voyxact 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 every 2 weeks IV (high dose) in IV monkey study (FDA integrated review, p. 101)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey (IV) with 4-month recovery
“A 6-Month Study of VIS649 by Intravenous Injection in Cynomolgus Monkeys With a 4-Month Recovery Period”
Pivotal GLP studies
Cynomolgus 26-week IV (25-100 mg/kg biweekly) and 26-week SC (25-100.5 mg/kg biweekly) GLP studies
“A 26-week IV study (25 to 100 mg/kg biweekly) showed no adverse effects at the highest dose of 100 mg/kg/dose. A 26-week study with SC dosing (25 to 100.5 mg/kg biweekly) demonstrated a similar safety profile”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study)
“The potential maternal and developmental effect on pregnant cynomolgus monkeys and their offspring was evaluated in an enhanced pre- and postnatal development study.”
Reproductive & developmental
Monkey ePPND (101 mg/kg SC every 2 weeks, GD 20 to delivery): no adverse embryofetal or postnatal effects
“subcutaneous administration of sibeprenlimab once every 2 weeks to pregnant cynomolgus monkeys from gestation Day 20 through delivery did not result in any adverse effects on embryofetal or postnatal development at one tested dose of 101 mg/kg”
PPND / ePPND: when
ePPND in cynomolgus monkey completed before the marketing application
“The potential maternal and developmental effect on pregnant cynomolgus monkeys and their offspring was evaluated in an enhanced pre- and postnatal development study.”
Carcinogenicity
Species: carcinogenicity
Not conducted; rodent carcinogenicity studies deemed not warranted
“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
Carcinogenicity model
Not conducted; carcinogenicity risk assessment reviewed under the IND instead
“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
Carcinogenicity timing
Not required: rodent studies deemed not warranted after risk assessment
“Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 6-month IV and SC studies, highest doses tested: 13-fold (IV) and 10-fold (SC) AUC margins at MRHD of 400 mg
“Based on the AUC exposures at the highest doses tested in monkeys with IV and SC dosing for 6 months, these studies established 13-fold and 10-fold safety margins, respectively, for clinical exposures at the MRHD of 400 mg (Table 42).”
NOAEL / key findings
NOAEL 100 mg/kg every 2 weeks IV (high dose) in IV monkey study
“The no-observed-adverse-effect level (NOAEL) was established at the high dose of 100 mg/kg/2-week”
Efficacy evidenceopen answer page →
Efficacy evidence
gddY IgA nephropathy mouse model with mouse surrogate mAb 4540; IgA reduction in healthy monkeys with sibeprenlimab
“The impact of blocking APRIL interaction with its receptors was evaluated in a grouped ddY (gddY) IgA mouse nephropathy model using the mAb 4540 mouse surrogate and in healthy cynomolgus monkeys with sibeprenlimab.”
Why that model
Sibeprenlimab does not bind rodent APRIL, so a mouse surrogate antibody was used in rodent models
“Due to lack of binding to rodent APRIL, direct effects of sibeprenlimab were assessed in rodent models using a mouse surrogate antibody (mAb 4540).”
Reviewer's view of the efficacy data
FDA: in vitro and in vivo pharmacology characterize the mechanism and support proof-of-concept efficacy for IgAN
“In vitro and in vivo pharmacology studies were conducted to characterize the mechanism of action and support proof of concept efficacy for the intended clinical indication, which are briefly described below.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No rodent carcinogenicity studies for a chronic IgA nephropathy indication; carcinogenicity risk assessment instead
Why: Carcinogenicity risk assessment reviewed under the IND · Weight of evidence
“A carcinogenicity risk assessment was submitted by the applicant, which was reviewed under the IND. Rodent carcinogenicity studies were deemed not to be warranted to establish an adequate assessment of carcinogenicity risk for sibeprenlimab.”
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