Rhapsido
remibrutinib
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“As listed in the table below, general toxicity studies with remibrutinib were conducted in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Why that species
Pharmacologically relevant species with sufficient exposure by the clinical oral route
“The toxicological assessment was performed in pharmacologically relevant species (mouse, rat, rabbit and dog) that were sufficiently exposed to remibrutinib following the intended clinical route of administration (i.e. oral).”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 39-week GLP oral repeat-dose toxicity study in beagle dogs, animals (4/sex/group) were administered doses of 0 (vehicle), 10, 50, and 300 mg/kg/day remibrutinib.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“As listed in the table below, general toxicity studies with remibrutinib were conducted in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“(i) a combined male and female fertility and early embryonic development (FEED) study in rats, (ii) embryo-foetal development (EFD) studies in rats and rabbits, and (iii) a pre- and postnatal development (PPND) study in rats.”
Species: carcinogenicity
Wistar rat (2-year) and Tg.rasH2 mouse (6-month)
“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib.”
Surrogate used in
No surrogate used; remibrutinib tested directly
“As listed in the table below, general toxicity studies with remibrutinib were conducted in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“In a 39-week GLP oral repeat-dose toxicity study in beagle dogs, animals (4/sex/group) were administered doses of 0 (vehicle), 10, 50, and 300 mg/kg/day remibrutinib.”
Pivotal GLP studies
26-week rat and 39-week dog GLP repeat-dose studies
“GLP repeat-dose toxicity studies were conducted in rats (up to 26-week daily dosing; dose levels in 26-week rat study were 30, 300, and 1000 mg/kg/day) and dogs (up to 39-week daily dosing; dose levels in 39-week dog study were 10, 50, and 300 mg/kg/day).”
Route in tox
Oral gavage
“In a 26-week GLP toxicity study, Wistar rats (20/sex/group) were dosed by oral gavage with 0, 30, 300, and 1000 mg/kg/day remibrutinib.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat micronucleus assays
“Remibrutinib was considered negative for genotoxicity in an Ames test, an in vitro micronucleus assay in peripheral human lymphocytes, and an in vivo micronucleus assay in rats.”
Carcinogenicity
2-year rat and 6-month Tg.rasH2 mouse: no evidence of tumorigenicity
“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib. No evidence of tumorigenicity was observed in male and female Tg.rasH2 mice at doses up to 1500 mg/kg/day or in rats at exposures approximately 8x and 98x the MRHD in males and female rats, respectively.”
Reproductive & developmental
Rat fertility and EFD unaffected; rabbit maternal toxicity and adverse developmental outcomes at ≥300 mg/kg/day; rat PPND stillbirths, pup deaths at 1000 mg/kg/day
“Remibrutinib did not affect fertility and was nonteratogenic in rats. In rabbits, remibrutinib treatment resulted in maternal toxicity and adverse developmental outcomes at doses ≥300 mg/kg/day. In the rat pre- and postnatal development study, remibrutinib treatment resulted in increased number of stillborn pups, dead pups, and a smaller litter size at 1000 mg/kg/day.”
Safety pharmacology
hERG inhibition only at >230-fold unbound clinical Cmax; no adverse cardiovascular effects in single-dose dog study
“The GLP study indicated hERG inhibition at concentration which was over 230-fold higher than the unbound clinical Cmax, providing a wide safety margin. In a GLP single-dose dog study, remibrutinib was well tolerated at high doses with no adverse cardiovascular effects or mortality.”
Genotox: Ames
Negative (Ames)
“Remibrutinib was considered negative for genotoxicity in an Ames test, an in vitro micronucleus assay in peripheral human lymphocytes, and an in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
In vitro micronucleus in human peripheral lymphocytes: negative
“Remibrutinib was considered negative for genotoxicity in an Ames test, an in vitro micronucleus assay in peripheral human lymphocytes, and an in vivo micronucleus assay in rats.”
Genotox: in vivo
In vivo rat micronucleus: negative
“Remibrutinib was considered negative for genotoxicity in an Ames test, an in vitro micronucleus assay in peripheral human lymphocytes, and an in vivo micronucleus assay in rats.”
Carcinogenicity model
2-year Wistar rat; 6-month Tg.rasH2 mouse
“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib.”
Carcinogenicity timing
104-week Wistar rat and 26-week Tg.rasH2 mouse completed before the marketing application; both negative
“A 104-week oral carcinogenicity study of remibrutinib in Wistar rats (50/sex/dose) showed no evidence of carcinogenicity at oral doses of 0 (water), 0 (vehicle), 30, 100, and 300 mg/kg/day remibrutinib once daily.”
hERG / QT
hERG inhibition only at >230-fold unbound clinical Cmax
“The GLP study indicated hERG inhibition at concentration which was over 230-fold higher than the unbound clinical Cmax, providing a wide safety margin.”
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 Rhapsido 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: lymph nodes, thyroid, liver, pancreas (islet fibrosis) and blood (prolonged bleeding, inhibited platelet aggregation) (FDA integrated review, p. 121)
NOAEL / key findings
Targets: lymph nodes, thyroid, liver, pancreas (islet fibrosis) and blood (prolonged bleeding, inhibited platelet aggregation)
“Target organs of toxicity were identified as the lymph nodes (underdeveloped germinal centers, sinusoidal red blood cells), thyroid gland (follicular hypertrophy), liver (hepatocellular hypertrophy, multinucleated hepatocytes, pigment), pancreas (islet fibrosis, pigment), and blood (prolongation of bleeding, inhibition of platelet aggregation).”
Risksopen answer page →
Immune & cytokine safety
Inhibited primary antibody responses to some antigens, attributed to BTK role in B cells
“Remibrutinib inhibited primary antibody responses to certain, but not all, tool antigens in rodent pharmacology studies at pharmacologically relevant exposure, considered related to the role of BTK in B cells.”
Biodistribution & persistence
Broad tissue distribution except brain, eye lens, spinal cord and white fat
“A single oral dose of remibrutinib resulted in broad distribution in all tissues except for the brain, lens of the eye, spinal cord, and white fat, with a Tmax of 0.5 to 8 hours.”
Modality-specific risk
Infection and bleeding risk from inhibited antibody responses and platelet function
“Important potential risks at pharmacologically relevant exposure are related to effects of remibrutinib on primary antibody responses (potential risks of infection, impact on at least some antibody responses) as well as on specific platelet functions (potential risk of bleeding).”
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
- Risk of Bleeding
- Live Attenuated Vaccines
Bleeding
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 Rhapsido 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: lymph nodes, thyroid, liver, pancreas (islet fibrosis) and blood (prolonged bleeding, inhibited platelet aggregation) (FDA integrated review, p. 121)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral, GLP); no recovery groups
“In a 39-week GLP oral repeat-dose toxicity study in beagle dogs, animals (4/sex/group) were administered doses of 0 (vehicle), 10, 50, and 300 mg/kg/day remibrutinib. No recovery groups were included in the study.”
Pivotal GLP studies
26-week rat and 39-week dog GLP repeat-dose studies
“GLP repeat-dose toxicity studies were conducted in rats (up to 26-week daily dosing; dose levels in 26-week rat study were 30, 300, and 1000 mg/kg/day) and dogs (up to 39-week daily dosing; dose levels in 39-week dog study were 10, 50, and 300 mg/kg/day).”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“(i) a combined male and female fertility and early embryonic development (FEED) study in rats, (ii) embryo-foetal development (EFD) studies in rats and rabbits, and (iii) a pre- and postnatal development (PPND) study in rats.”
Reproductive & developmental
Rat fertility and EFD unaffected; rabbit maternal toxicity and adverse developmental outcomes at ≥300 mg/kg/day; rat PPND stillbirths, pup deaths at 1000 mg/kg/day
“Remibrutinib did not affect fertility and was nonteratogenic in rats. In rabbits, remibrutinib treatment resulted in maternal toxicity and adverse developmental outcomes at doses ≥300 mg/kg/day. In the rat pre- and postnatal development study, remibrutinib treatment resulted in increased number of stillborn pups, dead pups, and a smaller litter size at 1000 mg/kg/day.”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In a pre- and postnatal development study, pregnant rats received daily oral doses of remibrutinib at 0 (vehicle), 100, 300, and 1000 mg/kg/day from GD 6 to Lactation Day 21.”
Carcinogenicity
Species: carcinogenicity
Wistar rat (2-year) and Tg.rasH2 mouse (6-month)
“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib.”
Carcinogenicity model
2-year Wistar rat; 6-month Tg.rasH2 mouse
“A 2-year oral study in Wistar rats and a 6-month oral study in Tg.rasH2 mice were conducted to assess the carcinogenic potential of remibrutinib.”
Carcinogenicity timing
104-week Wistar rat and 26-week Tg.rasH2 mouse completed before the marketing application; both negative
“A 104-week oral carcinogenicity study of remibrutinib in Wistar rats (50/sex/dose) showed no evidence of carcinogenicity at oral doses of 0 (water), 0 (vehicle), 30, 100, and 300 mg/kg/day remibrutinib once daily.”
Safety marginopen answer page →
Safety margin at NOAEL
Repeat-dose toxicity (26-week rat, 39-week dog) exposure multiples 15- to 146-fold human steady-state AUC
“No remibrutinib-related adverse effects were observed in the 39-week dog toxicity study (doses up to 300 mg/kg/day), and adverse effects on the endocrine pancreas observed at all tested dose levels in the 26-week rat toxicity study (doses up to 1,000 mg/kg/day) were considered unlikely to translate to human. Exposure multiples ranged from 15- to 146-fold in terms of steady-state AUC0-24h.”
NOAEL / key findings
Targets: lymph nodes, thyroid, liver, pancreas (islet fibrosis) and blood (prolonged bleeding, inhibited platelet aggregation)
“Target organs of toxicity were identified as the lymph nodes (underdeveloped germinal centers, sinusoidal red blood cells), thyroid gland (follicular hypertrophy), liver (hepatocellular hypertrophy, multinucleated hepatocytes, pigment), pancreas (islet fibrosis, pigment), and blood (prolongation of bleeding, inhibition of platelet aggregation).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse reverse passive Arthus and passive cutaneous anaphylaxis models of skin mast cell degranulation
“In vivo, remibrutinib showed a response in two animal models relevant to CSU, a mouse reverse passive Arthus model and a mouse passive cutaneous anaphylaxis model.”
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
FDA: mouse Arthus and PCA mast-cell degranulation models considered relevant for CSU
“In vivo, remibrutinib showed a response in two models of skin mast cell degranulation induced by FcγR and FcεR mediated hypersensitivity, a mouse reverse passive Arthus model, and a mouse passive cutaneous anaphylaxis model. These models are relevant for CSU.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
No NOAEL in 26-week rat study: endocrine pancreas fibrosis, haemorrhage and pigment at all doses
Why: Spontaneous changes in aging rats exacerbated by BTK inhibitors, with no translation to other species · Class precedent · Pharmacology or kinetics
“Whereas a NOAEL was established at the highest tested dose level of 300 mg/kg/day in the 39-week dog study, no NOAEL was established in the 26-week rat study due to an increased incidence and severity of endocrine pancreas fibrosis, haemorrhage and pigment at all tested dose levels (i.e., doses of 30, 300, and 1000 mg/kg/day).”
“However, these changes are considered unlikely to translate to humans since they represent spontaneously occurring changes in aging rats, known to be exacerbated by BTK inhibitors with no translation to other species (Erickson et al 2017, Bhaskaran et al 2018).”
Juvenile toxAccepted with a conditionBeyond the letter
Ocular and neurobehavioral findings in juvenile rats; repeat juvenile toxicity study in older rats required postmarketing
Why: Juvenile rat results to be reviewed before the paediatric trial starts
“Given ocular and neurobehavioral findings in the completed juvenile toxicity study in rats, an additional PREA PMR will be issued for a repeat juvenile toxicity study in older rats that approximate children 6 years of age.”
“The results of the juvenile rat study will need to be submitted and reviewed prior to initiation of clinical study CLOU064F12302.”
Similar precedents
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