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.”
Species: general tox
Sprague Dawley rat and cynomolgus monkey (up to 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).”
Species: DART
Rat only (fertility/EFD, EFD, pre- and postnatal development)
“A full reproductive and developmental toxicity package has been performed in rats, including preliminary and definitive embryo-fetal development (EFD) studies, a combined fertility and EFD study, and a pre-and post”
Species: carcinogenicity
Sprague Dawley rat (98-week)
“For romosozumab, a carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week of romosozumab, equivalent to 1-19x human exposure.”
Surrogate used in
Yes: rat and mouse versions (r13c7, m13c7) used in some studies because romosozumab induces ADA in those species
“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.”
Genotox: Ames
Not conducted (ICH S6; protein not expected to alter DNA)
“Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.”
Genotox: in vitro mammalian
Not conducted (ICH S6; protein not expected to alter DNA)
“Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.”
Genotox: in vivo
Not conducted (ICH S6; protein not expected to alter DNA)
“Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.”
Carcinogenicity model
Sprague-Dawley rat, SC 3, 10 or 50 mg/kg weekly from 8 to 98 weeks of age (up to 19x human AUC)
“In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison).”
Carcinogenicity timing
98-week Sprague Dawley rat carcinogenicity study completed before the marketing application
“A carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week, equivalent to 1-19x human exposure.”
hERG / QT
No hERG assay; no effect on BP, heart rate, ECG or QT/QTc in monkeys at >200-fold clinical exposure
“The results of these studies indicate that romosozumab had no effect on cardiovascular (blood pressure, heart rate, ECGs, QT/QTc) functions after subcutaneous dosing with exposure margins exceeding 200-fold to the clinical exposure.”
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
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: 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.”
Anti-drug antibodies: animals
Immunogenic in rats and monkeys; ADA-positive animals with reduced exposure removed from analyses; no adverse ADA consequences
“To ensure robust assessment of the toxicity of romosozumab in longer term studies, rats and monkeys positive for binding ADAs with high S/N and reduced serum romosozumab concentration and/or presence of neutralizing antibodies were removed from study and data analyses. There were no adverse consequences of ADAs in rats and monkeys.”
Anti-drug antibodies: patients
18.1% of 5914 patients developed ADA; 4.7% of these neutralizing
“Among 5914 subjects treated with EVENITY, 18.1% developed antibodies to romosozumab-aqqg. Of the subjects who developed antibodies to romosozumab-aqqg, 4.7% had antibodies that were classified as neutralizing using an in vitro biological assay.”
Label warnings
Boxed warning: Potential risk of myocardial infarction, stroke and cardiovascular death
- Major Adverse Cardiac Events (MACE)
- Hypersensitivity Reactions
- Hypocalcemia
- Osteonecrosis of the Jaw
- Atypical Subtrochanteric and Diaphyseal Femoral Fractures
CardiovascularHypersensitivity & infusion reactionsMetabolic & endocrineMusculoskeletal
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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week rat and 26-week monkey studies, each with 14-week recovery
“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”
DART package
Species: DART
Rat only (fertility/EFD, EFD, pre- and postnatal development)
“A full reproductive and developmental toxicity package has been performed in rats, including preliminary and definitive embryo-fetal development (EFD) studies, a combined fertility and EFD study, and a pre-and post”
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).”
PPND / ePPND: when
PPND in rat completed before the marketing application (with rat FEED and EFD)
“Reproductive toxicity was evaluated in rat fertility and early embryonic development (FEED), embryofetal development (EFD) and pre- and postnatal development (PPND) studies.”
Carcinogenicity
Species: carcinogenicity
Sprague Dawley rat (98-week)
“For romosozumab, a carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week of romosozumab, equivalent to 1-19x human exposure.”
Carcinogenicity model
Sprague-Dawley rat, SC 3, 10 or 50 mg/kg weekly from 8 to 98 weeks of age (up to 19x human AUC)
“In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison).”
Carcinogenicity timing
98-week Sprague Dawley rat carcinogenicity study completed before the marketing application
“A carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week, equivalent to 1-19x human exposure.”
Safety marginopen answer page →
Safety margin at NOAEL
No adverse effects at 100 mg/kg weekly for 26 weeks: 37x (rat) and 90x (monkey) human AUC at 210 mg monthly
“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 following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison)”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Ovariectomized rat and monkey models of postmenopausal osteoporosis treated with romosozumab
“In ovariectomized rats and monkeys (animal models of postmenopausal osteoporosis), romosozumab increased bone mass and bone strength without negatively affecting bone quality.”
Why that model
Romosozumab binds rat, monkey and human sclerostin with similar affinity and is pharmacologically active in rats and monkeys
“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.”
Reviewer's view of the efficacy data
EMA: cross-species activity justifies the sclerostin rationale and use of rats and monkeys for primary and safety pharmacology
“As romosozumab binds to human, cynomolgus monkey, and rat sclerostin with a similar strong affinity and was shown to be pharmacologically active in rats and cynomolgus monkeys in vivo, the rationale for inhibition of sclerostin in the treatment of osteoporosis”
Flexibilityopen answer page →
Flexibility accepted
GLPAcceptedBeyond the letter
Bioanalytical method validations for pivotal toxicity studies not formally GLP
Why: Some studies followed GLP principles such as QA audit; no impact on results · Other reason
“None of the method validations applied in pivotal toxicity studies were formally performed under GLP. It is acknowledged that some of the studies are performed according to GLP principles, e.g. QA audit of different steps of the study.”
“The classification of the studies as non-GLP is not considered to have any impact on the results from the studies.”
OtherVerdict not stated
Rodent surrogate antibodies (r13c7, m13c7) used in some studies instead of romosozumab
Why: Romosozumab causes anti-drug antibody formation in rodents
“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.”
OtherAcceptedBeyond the letter
No initial data on prolonged treatment and vascular calcification or atherosclerosis; mechanistic studies added during review
Why: Weight of evidence shows no mechanistic link between sclerostin inhibition and vascular calcification or atherosclerosis · Weight of evidence
“The applicant did not provide data on the effect of prolonged romosozumab treatment on vascular calcification in normal and diseased vasculature such as in the atherosclerosis mouse model. As such, it is not clear, if a sclerostin specific antibody would possibly amplify the atherosclerotic effects.”
“A weight of evidence assessment of all available non-clinical data indicates no obvious mechanistic association between sclerostin inhibition and vascular calcification or promotion of atherosclerosis, in normal and/or diseased tissue. Further non-clinical testing is, thus, not likely to contribute to the overall benefit / risk assessment in humans.”
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