Miplyffa
arimoclomol
Species
RatDog
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“The oral administration of BRX-345 (arimoclomol) at 0 (vehicle, control), 200, 400, or 900 mg/kg/day to Wistar rats daily for 6 months (Table 53) resulted in increased daily food intake at 400 mg/kg/day (female) and 900 mg/kg/day (male and female)”
Species: general tox
Rat and dog
“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”
Species: DART
Rat and rabbit
“In the reproductive toxicology studies in rats and rabbits, the rabbit appeared to be the more sensitive species to arimoclomol treatment.”
Species: carcinogenicity
Han Wistar rat (2-year) and Tg rasH2 mouse (26-week)
“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”
Surrogate used in
No surrogate used; arimoclomol tested directly in rats and dogs
“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week dog)
“Dose and frequency of dosing: 0, 25, 50 and 160 mg/kg/day (80 mg/kg in 2 divided doses) daily for 52 weeks”
Pivotal GLP studies
26-week rat and 52-week dog oral studies
“Histological examinations did not detect any lesions or toxic effect of chronic administration of the test article for 6 months in the rat or 12 months in the dog.”
Route in tox
Oral (capsules in dogs)
“Route of administration: Oral capsules”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma forward mutation and in vivo mouse micronucleus assays
“Arimoclomol was not genotoxic in the Ames assay at up to 5,000 µg/plate, was not mutagenic in the mouse forward mutation assay at up to 1,000 µg/ml, or in the in vivo mouse micronucleus assay at doses up to 2,500 mg/kg/day.”
Carcinogenicity
2-year rat and 26-week rasH2 mouse: no increase in tumors
“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”
Reproductive & developmental
Rat FEED: reduced fertility, fewer corpora lutea and pre-implantation loss at 1,000 mg/kg/day; fertility NOAEL 750 mg/kg/day
“In fertility and early embryonic development study (FEED) in rats, an arimoclomol dose of 1,000 mg/kg/day reduced fertility and the fecundity index in male and female rats, resulted in reduction in the number of corpora lutea, and increased pre-implantation loss in female rats. The NOAEL for the fertility study in rats is considered to be 750 mg/kg/day, which is equivalent to a 4-fold safety margin for the 600 mg/day clinical dose.”
Safety pharmacology
10% QTc increase in 2-week dog studies at ~28-fold human exposure
“Additional findings in the canine 2-week repeat dose toxicity studies noted a 10% increase in the QTc interval at the end of the dosing at exposures corresponding to about 28-fold the human exposure.”
Genotox: Ames
Negative
“Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).”
Genotox: in vitro mammalian
Negative: chromosomal aberration (CHO cells) and mouse lymphoma forward mutation
“Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).”
Genotox: in vivo
Negative: mouse and rat bone marrow micronucleus
“Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).”
Carcinogenicity model
2-year Han Wistar rat; 26-week Tg rasH2 mouse; no tumor increase
“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”
Carcinogenicity timing
6-month TgRasH2 mouse and 2-year rat: missing from the original NDA, final reports included in the resubmission before approval
“In their resubmission, the Applicant (Zevra) included the reports of two final carcinogenicity studies (6-month TgRas H2 transgenic mouse study and a 2-year study in rats), and additional reports of in vitro and in vivo nonclinical studies that were conducted to define a mechanism of action for arimoclomol.”
hERG / QT
Weak: 16% hERG inhibition at 70 µM; no effect on canine Purkinje fiber action potential
“However, arimoclomol had no effect on action potential in canine Purkinje fibers and a 16% inhibition of hERG (human Ether-a-go-go Related Gene) at 70 µM, suggestive of weak inhibitory potential at the rapidly activating delayed rectifier potassium channel (IKr).”
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 Miplyffa 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: NOAEL 200 mg/kg/day in rats and 160 mg/kg/day in dogs (FDA integrated review, p. 199)
NOAEL / key findings
NOAEL 200 mg/kg/day in rats and 160 mg/kg/day in dogs
“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid and bone marrow depletion, spleen and thymus atrophy at MTD or higher
“Dosed at the maximum tolerated dose or higher, arimoclomol affected hematology parameters(e.g. reduced mean corpuscular volume, hemoglobin concentration and erythrocyte count), lymphoid and bone marrow depletion, and atrophy/reduced weight of the spleen and thymus.”
Biodistribution & persistence
Low-level distribution to skin, brain and eyes, eliminated within 24 hours
“Low level distribution of arimoclomol to the skin, brain and eyes was observed with elimination occurring within 24 hours.”
Modality-specific risk
Immune, liver, developing kidney, GI irritation, fertility and embryo-toxicity effects
“The main concerns to human safety are the potential for arimoclomol to result in adverse clinical signs and mortality, with effects on the immune system, effects on the liver, developing kidneys, gastrointestinal (GI) irritation, reduced male and female fertility, and embryo-toxicity.”
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
- Hypersensitivity Reactions
- Embryofetal Toxicity
- Increased Creatinine without Affecting Glomerular Function
Hypersensitivity & infusion reactionsEmbryo-fetal toxicityNephrotoxicity
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 Miplyffa 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: NOAEL 200 mg/kg/day in rats and 160 mg/kg/day in dogs (FDA integrated review, p. 199)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week Beagle dog (oral); recovery phase not stated
“Oral BRX-345 (arimoclomol) at 0 (vehicle, control), 25, 50, or 160 mg/kg/day was administered to male and female Beagle dogs daily for 52 weeks.”
Pivotal GLP studies
26-week rat and 52-week dog oral studies
“Histological examinations did not detect any lesions or toxic effect of chronic administration of the test article for 6 months in the rat or 12 months in the dog.”
DART package
Species: DART
Rat and rabbit
“In the reproductive toxicology studies in rats and rabbits, the rabbit appeared to be the more sensitive species to arimoclomol treatment.”
Reproductive & developmental
Rat FEED: reduced fertility, fewer corpora lutea and pre-implantation loss at 1,000 mg/kg/day; fertility NOAEL 750 mg/kg/day
“In fertility and early embryonic development study (FEED) in rats, an arimoclomol dose of 1,000 mg/kg/day reduced fertility and the fecundity index in male and female rats, resulted in reduction in the number of corpora lutea, and increased pre-implantation loss in female rats. The NOAEL for the fertility study in rats is considered to be 750 mg/kg/day, which is equivalent to a 4-fold safety margin for the 600 mg/day clinical dose.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal development study (PPND) in rats, arimoclomol was evaluated at 0, 500, 750 and 1000 mg/kg.”
Carcinogenicity
Species: carcinogenicity
Han Wistar rat (2-year) and Tg rasH2 mouse (26-week)
“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”
Carcinogenicity model
2-year Han Wistar rat; 26-week Tg rasH2 mouse; no tumor increase
“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”
Carcinogenicity timing
6-month TgRasH2 mouse and 2-year rat: missing from the original NDA, final reports included in the resubmission before approval
“In their resubmission, the Applicant (Zevra) included the reports of two final carcinogenicity studies (6-month TgRas H2 transgenic mouse study and a 2-year study in rats), and additional reports of in vitro and in vivo nonclinical studies that were conducted to define a mechanism of action for arimoclomol.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 200 mg/kg/day ~2-fold, dog NOAEL 160 mg/kg/day ~10-fold the 600 mg/day clinical dose
“The arimoclomol NOAEL of 200 mg/kg/day in the rat will provide a two-fold safety margin for the 600 mg/day clinical dose, whereas the NOAEL of 160 mg/kg/day in the dog provides a 10-fold safety margin for the clinical dose.”
NOAEL / key findings
NOAEL 200 mg/kg/day in rats and 160 mg/kg/day in dogs
“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”
Efficacy evidenceopen answer page →
Efficacy evidence
NPC patient fibroblasts and Npc1-/- mutant mice (hepatic GSL, motor deficits)
“Arimoclomol was shown to increase NPC1 protein expression in fibroblast cell lines from NPC patients in vitro at considerably higher concentrations than those achieved clinically, and reduced hepatic GSL accumulation and improved neurological motor ability deficit in NPC -/- mutant mice in one in vivo non-GLP study and one publication.”
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
Unconvincing for arimoclomol alone in patient-derived cells and NPC animal models
“Given the limitations of the data presented in the Applicant’s resubmission, the data that support the effects of arimoclomol when used alone in patient-derived cells and in animal models of NPC are unconvincing.”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelQuestioned
Nonclinical efficacy and mechanism data for arimoclomol alone in patient-derived cells and NPC animal models judged unconvincing
“Given the limitations of the data presented in the Applicant’s resubmission, the data that support the effects of arimoclomol when used alone in patient-derived cells and in animal models of NPC are unconvincing.”
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