Voyxact
sibeprenlimab
Sources:FDA integrated review ↗
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.”
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.”
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 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: 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.”