Journavx
suzetrigine
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The following studies were submitted: primary and secondary pharmacology, safety pharmacology in the monkey in addition to in vitro human ether-à-go-go-related gene (hERG) assays; absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic (PK) studies; repeat-dose toxicology studies in the rat and monkey for durations of 28 days and 13 weeks”
Why that species
Monkey: NaV1.8 potency and metabolic profile similar to human
“Based on similarities in potency against NaV1.8 and metabolic profile between monkeys and humans, monkeys were considered an appropriate species for use in the pivotal nonclinical safety studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 13-week monkey study, animals were treated with SUZ at 0, 20, 50, and 150 mg/kg via oral gavage.”
Species: general tox
Rat and cynomolgus monkey (28-day and 13-week studies)
“repeat-dose toxicology studies in the rat and monkey for durations of 28 days and 13 weeks”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicities of SUZ were assessed in male and female fertility and early embryonic development studies in rats, embryo-fetal development (EFD) studies in rats/rabbits, and a pre- and postnatal development (PPND) study in rats.”
Species: carcinogenicity
Not conducted (long-term studies not completed)
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
Surrogate used in
No surrogate used; monkey chosen as pharmacologically relevant species (NaV1.8 potency similar to human)
“Based on similarities in potency against NaV1.8 and metabolic profile between monkeys and humans, monkeys were considered an appropriate species for use in the pivotal nonclinical safety studies.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“repeat-dose toxicology studies in the rat and monkey for durations of 28 days and 13 weeks”
Pivotal GLP studies
91-day repeat-dose rat and monkey studies
“In addition, the safety of SUZ and impurities/degradants in the drug substance and drug product was evaluated in 91-day repeat-dose toxicity studies in rats and monkeys.”
Route in tox
Oral (gavage)
“In a 13-week monkey study, animals were treated with SUZ at 0, 20, 50, and 150 mg/kg via oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro TK6 micronucleus and in vivo rat bone marrow micronucleus assays
“Suzetrigine was not mutagenic in the bacterial reverse mutation assay (Ames test), or clastogenic in the in vitro micronucleus assay with a human TK6 lymphoblastoid cell line, or in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not completed (long-term studies not done for acute-use approval)
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
Reproductive & developmental
Rat fertility: no male effects up to 1000 mg/kg; increased preimplantation loss in females at 15 mg/kg
“SUZ doses up to 1000 mg/kg did not affect male reproductive performance when administered at least 28 days before mating and throughout mating. In a female fertility study in rats, increased preimplantation loss was observed at oral SUZ doses of 15 mg/kg when administered prior to mating and through gestation day (GD) 7.”
Safety pharmacology
No effect on hERG (IC50 >10 µM) for suzetrigine and its M6 metabolite
“SUZ and M6-SUZ were evaluated in good laboratory practice (GLP) in vitro human ether-à-go-go-related gene (hERG) assays, and they had no effect on hERG channel activity (IC50 greater than 10µM).”
Genotox: Ames
Negative
“Suzetrigine was not mutagenic in the bacterial reverse mutation assay (Ames test), or clastogenic in the in vitro micronucleus assay with a human TK6 lymphoblastoid cell line, or in the in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
In vitro micronucleus in human TK6 cells: negative with and without S9
“SUZ was negative for the induction of micronuclei in the nonactivated and rat liver S9-activated test systems in this study.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Suzetrigine was not mutagenic in the bacterial reverse mutation assay (Ames test), or clastogenic in the in vitro micronucleus assay with a human TK6 lymphoblastoid cell line, or in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted: long-term carcinogenicity studies not completed
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
Carcinogenicity timing
Long-term carcinogenicity studies not completed at approval; timing not stated
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
hERG / QT
No hERG effect (IC50 >10 µM) for suzetrigine and M6 metabolite
“SUZ and M6-SUZ were evaluated in good laboratory practice (GLP) in vitro human ether-à-go-go-related gene (hERG) assays, and they had no effect on hERG channel activity (IC50 greater than 10µM).”
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 Journavx 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: 91-day rat (females): ovarian cysts, fewer corpora lutea, pituitary and mammary hyperplasia (FDA integrated review, p. 66)
NOAEL / key findings
91-day rat (females): ovarian cysts, fewer corpora lutea, pituitary and mammary hyperplasia
“In the 91-day rat study, oral administration of SUZ to female rats for 91 days resulted in ovarian cyst formation, decreased number of corpora lutea, pituitary gland hyperplasia, and mammary hyperplasia/dilatation.”
Risksopen answer page →
Immune & cytokine safety
Not a skin sensitizer in the mouse local lymph node assay
“SUZ was not a skin sensitizer in a local lymph node assay in the mouse.”
Biodistribution & persistence
Reversible melanin binding: rat uveal tract, pigmented skin and meninges peaked at 1-4 h, undetectable by 72 h
“Radioactivity concentrations in melanin-containing tissues in rats (i.e., the uveal tract, pigmented skin, and meninges) peaked between 1 and 4 hours postdose then declined to undetectable levels by 72 hours postdose.”
Modality-specific risk
Female reproductive toxicity, fertility and developmental effects
“General toxicity studies and reproductive toxicity studies performed in rats suggested SUZ may pose risks with respect to adverse effects on female reproductive tissues, fertility, pregnancy, and development.”
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
- Increased Risk of Adverse Reactions with Concomitant Use with Strong or Moderate CYP3A Inhibitors
- Risk of Drug Interactions with Certain CYP3A Substrates
- Risk of Drug Interactions with Certain Hormonal Contraceptives
- Risk of Adverse Reactions in Patients with Moderate and Severe Hepatic Impairment
Hepatotoxicity
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 Journavx 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: 91-day rat (females): ovarian cysts, fewer corpora lutea, pituitary and mammary hyperplasia (FDA integrated review, p. 66)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week oral monkey study with no recovery group (rat studies also ran 13 weeks)
“In a 13-week monkey study, animals were treated with SUZ at 0, 20, 50, and 150 mg/kg via oral gavage. Of note, no recovery group was included in this study.”
Pivotal GLP studies
91-day repeat-dose rat and monkey studies
“In addition, the safety of SUZ and impurities/degradants in the drug substance and drug product was evaluated in 91-day repeat-dose toxicity studies in rats and monkeys.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive and developmental toxicities of SUZ were assessed in male and female fertility and early embryonic development studies in rats, embryo-fetal development (EFD) studies in rats/rabbits, and a pre- and postnatal development (PPND) study in rats.”
Reproductive & developmental
Rat fertility: no male effects up to 1000 mg/kg; increased preimplantation loss in females at 15 mg/kg
“SUZ doses up to 1000 mg/kg did not affect male reproductive performance when administered at least 28 days before mating and throughout mating. In a female fertility study in rats, increased preimplantation loss was observed at oral SUZ doses of 15 mg/kg when administered prior to mating and through gestation day (GD) 7.”
PPND / ePPND: when
PPND in rat completed and reviewed in the marketing application
“Reproductive and developmental toxicities of SUZ were assessed in male and female fertility and early embryonic development studies in rats, embryo-fetal development (EFD) studies in rats/rabbits, and a pre- and postnatal development (PPND) study in rats.”
Carcinogenicity
Species: carcinogenicity
Not conducted (long-term studies not completed)
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
Carcinogenicity model
Not conducted: long-term carcinogenicity studies not completed
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
Carcinogenicity timing
Long-term carcinogenicity studies not completed at approval; timing not stated
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of suzetrigine.”
Safety marginopen answer page →
Safety margin at NOAEL
91-day rat female NOAEL 1.3x and 13-week monkey NOAEL 2.1x human AUC
“91-day rat female 10 15.1 2.04 1.3 3.3 13-week monkey 150 24.1 2.75 2.1 4.4”
NOAEL / key findings
91-day rat (females): ovarian cysts, fewer corpora lutea, pituitary and mammary hyperplasia
“In the 91-day rat study, oral administration of SUZ to female rats for 91 days resulted in ovarian cyst formation, decreased number of corpora lutea, pituitary gland hyperplasia, and mammary hyperplasia/dilatation.”
Efficacy evidenceopen answer page →
Efficacy evidence
Primary human DRG neurons in vitro (NaV1.8 current and action potential firing inhibition); no in vivo model
“SUZ inhibited action potential firing in primary human DRG in current-clamp manual patch electrophysiology.”
Why that model
At least 80-fold lower potency on rodent NaV1.8, so no in vivo rodent pharmacology studies
“SUZ was at least 80-fold less potent in rodent NaV1.8 (IC50: 56nM) than in human NaV1.8. Therefore, in vivo primary pharmacology studies were not conducted in rodents.”
Reviewer's view of the efficacy data
FDA nonclinical effectiveness assessment rests on in vitro species DRG potency; human and monkey NaV1.8 IC50 0.68 and 0.75 nM
“The half-maximal inhibitory concentration (IC50) values of SUZ against human and monkey NaV1.8 were 0.68nM and 0.75nM, respectively.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
No in vitro chromosomal aberration test with the major human metabolite M6-SUZ; clastogenicity covered by parent in vivo micronucleus assay
Why: Negative M6-SUZ Ames, negative parent genotoxicity battery and QSAR data · Weight of evidence
“An in vitro chromosomal aberration test was not conducted with M6-SUZ. However, the chromosomal aberration potential of M6-SUZ was assessed through the in vivo micronucleus assay that tested the parent SUZ, which was negative for genotoxicity.”
“Together with the negative Ames result of M6-SUZ, negative genetic toxicology battery of SUZ, and in silico quantitative structure-activity relationship (QSAR) data with M6-SUZ, the weight of evidence supported minimal concern for clastogenicity.”
OtherCriticised but acceptedBeyond the letter
Longer-duration monkey studies with few animals and no recovery groups could not adequately assess male reproductive organ weight decreases
Why: Organ weight changes not toxicologically significant and not relevant for the proposed acute indication · Other reason
“Because of the low number of monkeys in the study, the lack of recovery groups, and known variability in male reproductive organ weights in this species, the nonhuman primate data do not provide an ideal model to evaluate the potential risk of SUZ to male reproductive tissues in these longer duration studies.”
“Therefore, the organ weight changes do not appear to be toxicologically significant and do not appear to have relevance for the proposed acute indication.”
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