Livmarli
maralixibat
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
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Why that species
Pharmacokinetic programme considered to justify the toxicity species; very low bioavailability, local mode of action
“Maralixibat has to be characterised as a substance of very low bioavailability, with a local mode of action. Overall, the study programme appears to be appropriate and complete, justifying from pharmacokinetic point of view the species involved in toxicity testing.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week rat toxicity study, maralixibat at 750 mg/kg/day in males and 2000 mg/kg/day in females caused deaths due to bleeding, which was attributed to vitamin K deficiency.”
Species: general tox
Rat (up to 6 months) and dog (up to 12 months)
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD); juvenile rat studies
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. Two juvenile animal toxicity studies were performed in rats.”
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride.”
Surrogate used in
No surrogate used; maralixibat tested directly (ASBT highly conserved across species)
“The ASBT transporter protein is highly conserved across species, with the human and mouse proteins showing 81% identity and 89% similarity at the amino acid level”
Study lengthopen answer page →
Longest pivotal study
52 (1-year dog)
“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day”
Pivotal GLP studies
Oral repeat-dose studies in rats up to 6 months and dogs up to 12 months
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Route in tox
Oral
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosome aberration and in vivo rat micronucleus assays
“Maralixibat was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, or the in vivo rat micronucleus assay.”
Carcinogenicity
2-year rat and 26-week TgRasH2 mouse: no drug-related tumors
“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND: no adverse findings
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. Two juvenile animal toxicity studies were performed in rats. No adverse findings were observed in the reproductive and developmental toxicology studies.”
Safety pharmacology
No effects on rat CNS, dog cardiovascular or guinea pig respiratory function; no hERG inhibition up to 1 µM
“had no significant effect on neurobehavioral functions in rats, cardiovascular function in dogs, or respiratory function in guinea pigs. Maralixibat at concentrations up to 1 µmol/L did not inhibit hERG current.”
Genotox: Ames
Negative
“Maralixibat was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, or the in vivo rat micronucleus assay.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Maralixibat was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, or the in vivo rat micronucleus assay.”
Genotox: in vivo
Rat micronucleus: negative
“Maralixibat was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using Chinese hamster ovary cells, or the in vivo rat micronucleus assay.”
Carcinogenicity model
2-year rat; 26-week Tg rasH2 mouse (no drug-related tumors)
“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride.”
Carcinogenicity timing
Tg.RasH2 mouse completed; 2-year rat in progress at approval, submission a postmarketing requirement
“Therefore, submission of the 2-year rat carcinogenicity study should be a Postmarketing Requirement. The study results will be included in subsection 13.1 of the labeling, in addition to the results of the completed carcinogenicity study in Tg.RasH2 mice.”
hERG / QT
No hERG inhibition up to 1 µM
“Maralixibat at concentrations up to 1 µmol/L did not inhibit hERG current.”
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 Livmarli 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: 1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC) (FDA integrated review, p. 68)
NOAEL / key findings
1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC)
“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Low bioavailability limits tissue distribution; rat liver and pancreas levels ~10x plasma
“Due to maralixibat’s low bioavailability, distribution to other tissues is low, although maralixibat was also found in the liver and pancreas of the rat at levels approximately 10 times higher than plasma.”
Modality-specific risk
Fat-soluble vitamin reduction with no no-effect dose; FSV monitoring in patients advised
“However, none of the toxicity studies established a no-effect dose for reductions in the serum or liver levels of fat-soluble vitamins. Therefore, the animal data could be relevant to the risk in humans, suggesting a need for monitoring of the levels of FSVs in patients.”
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
- Hepatotoxicity
- Gastrointestinal Adverse Reactions
- Fat Soluble Vitamin (FSV) Deficiency
- Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age)
HepatotoxicityGastrointestinalMetabolic & endocrine
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 Livmarli 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: 1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC) (FDA integrated review, p. 68)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
1-year (52-week) dog (oral capsule) with 8-week recovery
“4-week recovery period was allowed after the initial 6 months of treatment; 8-week recovery period was allowed after the 1 year of treatment.”
Pivotal GLP studies
Oral repeat-dose studies in rats up to 6 months and dogs up to 12 months
“repeat-dose oral toxicology studies in rats for up to 6 months and in dogs for up to 12 months”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD); juvenile rat studies
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. Two juvenile animal toxicity studies were performed in rats.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND: no adverse findings
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. Two juvenile animal toxicity studies were performed in rats. No adverse findings were observed in the reproductive and developmental toxicology studies.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“Reproductive and developmental toxicology studies included a fertility study in male and female rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg rasH2 mouse (26-week)
“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride.”
Carcinogenicity model
2-year rat; 26-week Tg rasH2 mouse (no drug-related tumors)
“Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride.”
Carcinogenicity timing
Tg.RasH2 mouse completed; 2-year rat in progress at approval, submission a postmarketing requirement
“Therefore, submission of the 2-year rat carcinogenicity study should be a Postmarketing Requirement. The study results will be included in subsection 13.1 of the labeling, in addition to the results of the completed carcinogenicity study in Tg.RasH2 mice.”
Safety marginopen answer page →
Safety margin at NOAEL
1-year dog NOAEL 5 mg/kg/day: 96- to 358-fold human AUC
“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”
NOAEL / key findings
1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC)
“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”
Efficacy evidenceopen answer page →
Efficacy evidence
Rat partial bile duct ligation (pBDL) cholestasis model: reduced serum bile acids, liver enzymes and bilirubin
“In the rat partial bile duct ligation (pBDL) model of cholestasis, maralixibat alone at oral doses of 0.3, 1, and 10 mg/kg/day or the combination of maralixibat (1 mg/kg/day) and UDCA (1 mg/kg/day) reduced serum bile acids (sBA), ALP, AST, ALT, GGT, and total bilirubin after 14 days of treatment.”
Why that model
No animal model of Alagille syndrome; induced cholestasis (pBDL) used to simulate reduced bile flow
“ALGS is a cholestatic liver disease for which no animal model has been established. Therefore, the Applicant evaluated the potential effectiveness of maralixibat in a rat cholestasis model that involved partial bile duct ligation (pBDL), to simulate the reduced bile flow in Patients with ALGS and other cholestatic liver diseases.”
Reviewer's view of the efficacy data
EMA: in vivo data (naive and pBDL rats, dogs, monkeys) consistent with inhibition of bile acid reuptake
“The pharmacodynamic effects of maralixibat in vivo were investigated in naïve rats, partial bile duct ligated (pBDL) rats as a cholestasis model, dogs and monkeys and in vivo primary pharmacology data are in line with the ability of orally administered maralixibat to inhibit the re-uptake of bile acids and to increase the faecal excretion thereof.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Only the Tg.RasH2 mouse study completed before approval; 2-year rat carcinogenicity study in progress and made a postmarketing requirement
Why: Prior FDA agreement; two-species carcinogenicity routinely expected for use beyond 6 months, so rat study made a PMR
“A 2-year rat carcinogenicity study is currently in progress. The incomplete status of the carcinogenicity testing program is in accordance with the FDA’s prior agreement with the Applicant.”
“Carcinogenicity studies in two rodent species are routinely expected to support the approval of drugs for which the duration of use is expected to exceed 6 months. Therefore, submission of the 2-year rat carcinogenicity study should be a Postmarketing Requirement.”
Safety marginAcceptedBeyond the letter
Safety margins calculated on dose rather than systemic exposure
Why: Very low bioavailability (in general below 1%) · Pharmacology or kinetics
“As the bioavailability of maralixibat is very low (in general below 1%) the use of doses instead of systemic exposure for calculation of safety margins is acceptable as well.”
DARTCriticised but acceptedBeyond the letter
Rat reproductive studies used dietary dosing; PPND study did not prevent pup access to maternal diet, confounding pup body weights
“Unfortunately, no measure was taken to prevent access of offspring to the maternal diet in the PPND study, where adverse effects on pups’ body weights were considered due to consuming the maternal diet at the time when the offspring start to eat on their own.”
“In line with the proposed indication “Treatment of cholestatic liver disease in patients with Alagille syndrome (ALGS) 2 months of age and older”, a full range of reproductive and juvenile toxicity studies were submitted, which do not raise any concerns.”
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