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.”
Species: general tox
Mouse and dog
“The parent compound was adequately tested in a standard battery of general toxicology studies in mouse and dog.”
Species: DART
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; additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Species: carcinogenicity
Not conducted pre-approval; mouse and rat studies required postmarketing
“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; additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Surrogate used in
No surrogate used; vamorolone tested directly
“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.”
Genotox: Ames
Negative
“In vitro, vamorolone was negative for increased reverse mutations in Ames tests in bacteria and for chromosomal aberrations, polyploidy and endoreduplication in mouse lymphoma cells and a micronucleus assay in CHO-K1 cells, respectively.”
Genotox: in vitro mammalian
Mouse lymphoma cells and CHO-K1 micronucleus assay: negative
“In vitro, vamorolone was negative for increased reverse mutations in Ames tests in bacteria and for chromosomal aberrations, polyploidy and endoreduplication in mouse lymphoma cells and a micronucleus assay in CHO-K1 cells, respectively.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Vamorolone did also not increase the formation of micronuclei in polychromatic erythrocytes of mouse bone marrow in vivo.”
Carcinogenicity model
Not conducted; mouse and rat studies to be conducted as postmarketing requirements
“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; additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies to be conducted after approval (postmarketing requirements)
“given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
hERG / QT
No hERG inhibition up to 20 µM; applicant-claimed 45-fold margin over free plasma level at MRHD
“The core battery of safety pharmacology studies of vamorolone revealed no inhibition of hERG currents up to 20 µM vamorolone in vitro. The applicant claims that this 20 µM concentration translates into a 45-fold safety margin compared to the free vamorolone plasma level of 0.44 µg/ml at the MRHD.”
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”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Alterations in Endocrine Function
- Immunosuppression and Increased Risk of Infection
- Alterations in Cardiovascular/Renal Function
- Gastrointestinal Perforation
- Behavioral and Mood Disturbances
- Effects on Bones
- Ophthalmic Effects
- Immunizations
- Effects on Growth and Development
- Myopathy
- Kaposi's Sarcoma
- Thromboembolic Events
- Anaphylaxis
InfectionsNephrotoxicityCardiovascularGastrointestinalMusculoskeletalThrombosis & embolismHypersensitivity & infusion reactions
US prescribing information, 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral dog study with recovery period (length not stated)
“After cessation of vamorolone administration, compensatory lymphocyte hyperplasia was observed in thymus and spleen of mice, whereas the lymphoid depletion did not completely reverse in the recovery periods of the 28 days and 39 weeks toxicity studies in dogs.”
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”
DART package
Species: DART
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; additionally, 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”
PPND / ePPND: when
Not conducted: patient population almost exclusively male, so no DART battery needed
“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”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval; mouse and rat studies required postmarketing
“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; additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Carcinogenicity model
Not conducted; mouse and rat studies to be conducted as postmarketing requirements
“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; additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies to be conducted after approval (postmarketing requirements)
“given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: NOAEL exposures negligible in mice and non-existent in dogs versus MRHD
“Safety margins based on the Cmax- and AUC0-last-related exposure at the respective NOAELs determined in repeat-dose toxicity studies were negligible in adult or juvenile mice or not existent in dogs when compared to corresponding levels in human DMD patients at the MRHD.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
mdx mouse (dystrophin-deficient) proof-of-concept studies with vamorolone
“In vivo proof-of-concept studies were conducted in mdx mice, which harbor a nonsense point mutation in exon 23 that results in production of a truncated and nonfunctional dystrophin protein.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: mdx comparison against a low prednisolone dose (5 mg/kg/day) hampers reliable evaluation of benefits and side effects
“Despite similar molecular weights, oral vamorolone doses between 5 to 30 mg/kg/day were compared with a low 5 mg/kg/day prednisolone dose in mdx mice and in another mouse model of acute lung inflammation, which hampers to reliably evaluate the benefits and side effects of the two corticosteroids.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; mouse and rat studies deferred to postmarketing requirements
Why: Seriousness of the indication; deferral previously agreed with the CHMP · Serious disease
“additionally, given the seriousness of the indication, carcinogenicity studies in two species (mouse and rat) are to be conducted as post marketing requirements.”
“Accordingly, the applicant plans to defer carcinogenicity studies post-approval as previously agreed with the CHMP (EMA/CHMP/SAWP/545127/2019).”
DARTAccepted
No standard battery of developmental and reproductive toxicity studies
Why: Patient population almost exclusively male; consistent with ICH S5 and earlier CHMP protocol assistance · Within the guideline · Other reason
“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”
“The absence of a standard battery of developmental and reproductive toxicology studies for the MAA is considered acceptable in accordance with the ICH S5 guideline and earlier CHMP protocol assistance (EMA/CHMP/SAWP/545127/2019).”
GLPCriticised but acceptedBeyond the letter
In vitro hERG assay exploratory and non-GLP, conducted outside the OECD mutual acceptance of data area
Why: Not justified by the applicant; reassurance from dog telemetry showing no cardiovascular or respiratory effects · Weight of evidence
“However, the documentation of the hERG measurements is rather of exploratory nature and the applicant did not adequately justify the lack of GLP compliance, although the study was conducted in 2010, i.e., after implementation of the pertinent ICH S7A and B guidelines in 2001 and 2005.”
“Nevertheless, oral vamorolone doses up to 50 mg/kg did not impair cardiovascular and respiratory function in telemetered dogs.”
Safety marginAccepted with a conditionBeyond the letter
No or negligible exposure margins at the NOAELs in mice and dogs versus the maximum recommended human dose
Why: Limitation reflected in section 5.3 of the SmPC
“Safety margins based on the Cmax- and AUC0-last-related exposure at the respective NOAELs determined in repeat-dose toxicity studies were negligible in adult or juvenile mice or not existent in dogs when compared to corresponding levels in human DMD patients at the MRHD.”
“This limits the predictive value of the toxicology programme and has meanwhile been considered in section 5.3 of the SmPC.”
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