Agamree
vamorolone
Species
MouseDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and dog
“The parent compound was adequately tested in a standard battery of general toxicology studies in mouse and dog.”
Why that species
Mouse: pharmacologically responsive with metabolic profile similar to human; dog: established experience with glucocorticoid effects
“Mice were selected as pharmacologically responsive species and because of their similar metabolic profile to humans, whereas dogs were chosen due to the established experience with glucocorticoid effects in this species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The parent compound was adequately tested in a standard battery of general toxicology studies in mouse and dog.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Oral administration of vamorolone (0, 2, 10, or 50 mg/kg/day) for 39 weeks to dogs resulted in spermatocyte and spermatid degeneration in the testes and oligospermia and germ cell debris in the epididymis in males at the high dose and absence of corpora lutea in the ovaries in females at all doses.”
Pivotal GLP studies
6-month mouse and 9-month dog oral studies
“Vamorolone was evaluated in oral repeated-dose toxicity studies for up to 6 months in mice and 9 months in dogs”
Route in tox
Oral
“Vamorolone was evaluated in oral repeated-dose toxicity studies for up to 6 months in mice and 9 months in dogs”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma gene mutation and mouse micronucleus assays
“Vamorolone was negative in an adequately conducted battery of genotoxicity studies that consisted of an in vitro bacterial reverse mutation assay, an in vitro mammalian gene mutation assay in mouse lymphoma cells, and an in vivo micronucleus assay in mouse.”
Carcinogenicity
Not conducted; mouse and rat studies are postmarketing requirements
“given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Reproductive & developmental
Not conducted (patient population almost exclusively male)
“Because the intended patient population is almost exclusively male, a standard battery of reproductive and developmental toxicology studies was not needed to support a marketing application”
Safety pharmacology
No hERG inhibition up to 20 µM; no cardiovascular or respiratory effects in telemetered dogs up to 50 mg/kg
“Vamorolone did not inhibit human ether-a-go-go-related gene (hERG) potassium currents up to the highest concentration of 20 µM in vitro. Accordingly, oral vamorolone doses up to 50 mg/kg did not impair cardiovascular and respiratory function in telemetered dogs.”
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 Agamree 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 small molecules 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: Targets: liver, adrenals, lymphoid tissues, reproductive tissues, skeletal muscle; NOELs at or below clinical exposure (FDA integrated review, p. 120)
NOAEL / key findings
Targets: liver, adrenals, lymphoid tissues, reproductive tissues, skeletal muscle; NOELs at or below clinical exposure
“In the general toxicology studies, the target tissues of vamorolone were liver, adrenal glands, lymphocytes and lymphoid tissues, male and female reproductive tissues, and skeletal muscle; plasma exposures at the no effect level for the findings in these tissues were similar to or less than that in humans at the proposed clinical dose of 6 mg/kg (Table 44).”
Risksopen answer page →
Immune & cytokine safety
Glucocorticoid immunosuppression: TDAR inhibited in female mice and abolished in male mice at 100 mg/kg/day
“As expected from the immunosuppressive activity of vamorolone and other glucocorticoids, 100 mg/kg/day vamorolone and prednisolone doses ≥10 mg/kg/day comparably inhibited the TDAR in female mice, while TDAR was completely abolished in male animals.”
Biodistribution & persistence
Wide distribution (QWBA), highest in GI tract and liver; slight distribution to retinal melanin
“A subsequent Quantitative Whole Body Autoradiography (QWBA) study revealed wide tissue distribution of 14C-labelled vamorolone in pigmented rats with highest radioactivity levels in the gastrointestinal tract and liver. A slight distribution to melanin-containing pigmented layer of the retina was also detected.”
Modality-specific risk
Corticosteroid class toxicities: adrenal cortical atrophy, lymphoid depletion, skeletal muscle atrophy, suppressed bone formation
“Many vamorolone-related adverse effects observed in the nonclinical studies were consistent with known adverse effects associated with long-term use and/or high doses of corticosteroids, such as cortical atrophy, lymphoid depletion, skeletal muscle atrophy, and suppression of bone formation”