Evenity
romosozumab
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent toxicology species as romosozumab binds to human, rat, and cynomolgus monkey sclerostin with similar affinity and is pharmacologically active in these species.”
Why that species
Binds human, rat and cynomolgus sclerostin with similar affinity and is pharmacologically active in both species
“The Sprague Dawley rat and cynomolgus monkey were selected as the main rodent and non-rodent toxicology species as romosozumab binds to human, rat, and cynomolgus monkey sclerostin with similar affinity and is pharmacologically active in these species.”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in rats and monkeys (rodent versions r13c7/m13c7 used in pharmacology/PK)
“In some studies, rodent versions of the humanized antibody AMG785 (rat 13c7 (r13c7) and mouse 13c7 (m13c7)) were used because AMG785 causes anti-drug antibody (ADA) formation in those species.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Romosozumab has been evaluated in repeat-dose toxicity studies in rats (up to 26 weeks with 14 weeks recovery) and in monkeys (up to 26 weeks with 14 weeks recovery).”
Pivotal GLP studies
Repeat-dose studies up to 26 weeks (14-week recovery) in rats and monkeys; rat carcinogenicity and reproductive studies
“The program includes repeat-dose studies up to 26 weeks with 14 weeks recovery in rats and monkeys; reproductive toxicity studies in rats, a carcinogenicity study in rats”
Route in tox
Subcutaneous (all studies); intravenous in some repeat-dose studies
“The subcutaneous (SC) route of administration was utilized in all toxicology studies to match the intended clinical administration route, with intravenous dosing included in some repeat-dose studies to obtain higher systemic exposures.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (recombinant protein not expected to interact with DNA)
“Genotoxicity testing was not performed. The product is a recombinant IgG2 protein of naturally occurring amino acids and is not expected to react with DNA or other chromosomal material.”
Carcinogenicity
Rat carcinogenicity study: 2/54 osteosarcomas in high-dose males (19x), not significant; judged unlikely to raise human osteosarcoma risk
“A low incidence of osteosarcoma (2/54) was observed in high dose males at 19x human exposure. However, the lack of statistical significance of this finding and the large exposure multiple suggests that romosozumab is unlikely to increase the human risk of osteosarcoma.”
Reproductive & developmental
Rat FEED, EFD and PPND: reduced 6th cervical vertebra ventral processes at 100-300 mg/kg (17-56x)
“Findings in the definitive FEED and EFD studies included reduced ventral processes of the 6th cervical vertebrae at doses of 100 and 300 mg/kg (17-56x human exposure).”
Safety pharmacology
Single-dose rat neurobehavioral and monkey cardiovascular/respiratory studies
“Safety pharmacology endpoints were evaluated in a single dose neurobehavioral study in rat and in a single dose combined cardiovascular/respiratory study in cynomolgus monkey.”
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 Evenity 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 adverse effects at up to 100 mg/kg weekly SC for 26 weeks in rats and monkeys (37x and 90x human exposure); findings pharmacologic (bone)
NOAEL / key findings
No adverse effects at up to 100 mg/kg weekly SC for 26 weeks in rats and monkeys (37x and 90x human exposure); findings pharmacologic (bone)
“No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 37 and 90 times, respectively, the systemic exposure observed in humans”
Risksopen answer page →
Immune & cytokine safety
No adverse consequences of ADAs in rats and monkeys; immune complex disease in a few rabbits
“There were no adverse consequences of ADAs in rats and monkeys. In the rabbit, adverse consequences of the immune response to romosozumab (immune complex disease) occurred in a few animals.”
Biodistribution & persistence
TCR: binding to osteocytes in human, monkey and rabbit bone (not rat) and to monkey aorta/pulmonary artery
“A tissue cross-reactivity immunohistochemistry study showed binding of AMG785 to osteocytes in human, cynomolgus monkey, and rabbit, but not rat bone. Binding was also observed in aorta or pulmonary artery in a monkey.”
Modality-specific risk
Clinical cardiovascular signal without nonclinical support; Wnt-driven osteosarcoma risk; hypocalcemia; skeletal developmental effects
“However, there were no adverse findings from the nonclinical program that lend support to the cardiovascular findings observed in the clinical trials.”
Similar precedents
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