Prolia
denosumab
Species
Monkey
Longest study
52 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
“Since denosumab recognizes and neutralizes RANKL in non human primates, the cynomolgus monkey was identified as a relevant species and the main studies have been conducted in ovariectomized animals.”
Why that species
Binds and neutralizes human and monkey RANKL (binding epitope fully conserved); does not recognize rodent RANKL
“This absence is acceptably justified by the fact that the RANKL domain to which denosumab binds is entirely conserved between cynomolgus monkeys and humans.”
Surrogate molecule
Yes: huRANKL knock-in mice and OPG-Fc surrogate in rodents, used for pharmacology, fracture healing and neonatal bone/tooth studies
“Several studies have been conducted with a transgenic huRANKL knock-in mouse model expressing chimeric RANKL that can be recognized and neutralized by denosumab.”
Study lengthopen answer page →
Longest pivotal study
52 weeks
“In 6/12-Month Repeated-dose Study in Monkeys (102090) denosumab was administrated at doses of 0, 1, 10, and 50 mg/kg.”
Pivotal GLP studies
Cynomolgus monkey 1-month and 6/12-month SC studies, once monthly at 0, 1, 10, 50 mg/kg
“SC injection, 0, 1, 10 and 50 mg/kg once/month for 6 or 12 months)”
Route in tox
Subcutaneous (once monthly)
“SC injection, 0, 1, 10 and 50 mg/kg once/month for 6 or 12 months)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not necessary for a recombinant protein
“No studies were conducted. Denosumab is a recombinant protein and contains no inorganic or synthetic organic linkages or other non-protein portions.”
Carcinogenicity
Not conducted per regulatory guidance; no preneoplastic lesions in OVX monkeys treated up to 16 months
“No carcinogenicity studies were conducted in accordance with available regulatory guidance. Ovariectomized monkey treated for up to 16 months with denosumab showed no evidence of pre neoplastic lesions.”
Reproductive & developmental
Monkey PPND (50 mg/kg throughout pregnancy): fetal loss, stillbirths, postnatal mortality, absent lymph nodes, abnormal bone growth; fertility unaffected
“In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth”
Safety pharmacology
Single-dose monkey CV/respiratory study plus ECG within repeat-dose study; no ECG evidence of cardiotoxicity after 53 weeks
“There was no ECG evidence of cardiotoxicity after 53 weeks of treatment with denosumab.”
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 Prolia 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: No target organ toxicity at doses up to 50 mg/kg in 6/12-month monkey study (EMA assessment report, p. 16)
NOAEL / key findings
No target organ toxicity at doses up to 50 mg/kg in 6/12-month monkey study
“In 6/12-Month Repeated-dose Study in Monkeys (102090) denosumab was administrated at doses of 0, 1, 10, and 50 mg/kg. Overall, no effects on organ weights or macroscopic or microscopic evidence of target organ toxicity were noted.”
Risksopen answer page →
Immune & cytokine safety
Highly immunogenic in monkeys (ADA in most studies); no major immunomodulatory changes; no dedicated immunotoxicity studies
“Studies on immunomodulatory effects were incorporated in some pharmacology and toxicology studies in cynomolgus monkeys. These studies did not reveal any major differences compared to controls.”
Biodistribution & persistence
Wide distribution in monkey without bone sequestration; limited BBB, testis and placental crossing
“There were indications that denosumab has limited potential to cross the blood/brain barrier, the blood/testis barrier as well as the placental barrier, although this data is confounded by the presence of radiolabel in blood vessels and an unknown contribution of free radiolabel.”
Modality-specific risk
RANKL inhibition: hypocalcemia, impaired bone growth/tooth eruption, lymph node agenesis, impaired lactation, embryo-fetal harm
“RANK/RANKL knockout mice also exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy)”