Wayrilz
rilzabrutinib
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
“the rat and dog were considered appropriate primary models for nonclinical safety studies, based on the similarity of oral bioavailability and metabolite profiles in these species to”
Why that species
BTK ~99% homologous between human and mouse, rat, dog and rabbit, with identical binding sites
“This is because mouse, rat, dog, and rabbit BTK are nearly identical to the human version of the protein (approximately 99% homologous amino acid sequence), with no differences in the sites where rilzabrutinib binds.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Study 1281-16100: Nine-Month Oral GLP Toxicity Study of Rilzabrutinib in Beagle Dogs”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“repeat-dose toxicity studies in rats (13-day; 2-week; 1-, 3-, and 6-month), and dogs (4-day; 2- and 12-week, 1-, 3-, and 9-month)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive toxicology studies (male and female fertility study in rats; embryo-fetal toxicity in rats and rabbits, pre- and postnatal development toxicity study in rats)”
Species: carcinogenicity
Tg rasH2 mouse (6-month) and rat (2-year)
“Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors.”
Surrogate used in
No surrogate used; rodent and dog BTK nearly identical to human at the binding site
“This is because mouse, rat, dog, and rabbit BTK are nearly identical to the human version of the protein (approximately 99% homologous amino acid sequence), with no differences in the sites where rilzabrutinib binds.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Study 1281-16100: Nine-Month Oral GLP Toxicity Study of Rilzabrutinib in Beagle Dogs”
Pivotal GLP studies
6-month rat and 9-month dog studies
“repeat-dose toxicity studies in rats (13-day; 2-week; 1-, 3-, and 6-month), and dogs (4-day; 2- and 12-week, 1-, 3-, and 9-month)”
Route in tox
Oral gavage
“Dose and frequency of dosing 0, 15, 30, and 50 mg/kg/day Route of administration Oral gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and rat bone marrow micronucleus assays
“Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
6-month Tg.rasH2 mouse and 2-year rat: no drug-related tumors
“Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors.”
Reproductive & developmental
Adverse visceral and skeletal fetal findings in rats at a maternally toxic dose (22x human exposure)
“However, adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22 times the human exposure (based on AUC) at the MRHD (see Animal Data).”
Safety pharmacology
No adverse CNS, respiratory or cardiovascular (including QTc) effects at doses up to 500 mg/kg
“The in vivo studies were conducted at doses up to 500 mg/kg, which did not show any adverse rilzabrutinib-related effects in the CNS, respiratory or cardiovascular systems (including QTc).”
Genotox: Ames
Negative (not mutagenic in Ames assay)
“Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”
Genotox: in vitro mammalian
Human peripheral lymphocyte chromosomal aberration assay: negative
“Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”
Genotox: in vivo
Rat bone marrow micronucleus assay: negative
“Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was not clastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity model
6-month Tg rasH2 mouse (up to 300 mg/kg/day); 2-year rat; no drug-related tumors
“Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors.”
Carcinogenicity timing
2-year rat and 26-week Tg.rasH2 mouse studies completed and submitted with the marketing application
“In this submission the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice.”
hERG / QT
hERG IC50 ~621-fold above projected free Cmax (3.75 ng/mL) at 400 mg BID; adequate margin
“At a projected Cmax of 150 ng/mL, corresponding to a 400 mg BID dose, the estimated maximum free drug concentration would be only 3.75 ng/mL (assuming a free fraction of 2.5%). This free drug concentration is approximately 621-fold below the hERG IC50, providing an adequate 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 Wayrilz 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: Rat NOAEL 50 mg/kg/day; mortality, meninges/neuropil inflammation and stomach hemorrhage/inflammation at higher doses (FDA integrated review, p. 121)
NOAEL / key findings
Rat NOAEL 50 mg/kg/day; mortality, meninges/neuropil inflammation and stomach hemorrhage/inflammation at higher doses
“The no observed adverse effect level (NOAEL) was defined at 50 mg/kg/day based on mortality, inflammation of meninges/neuropil and hemorrhage/inflammation of stomach at higher doses”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies submitted
“No dedicated immunotoxicity studies were submitted in Module 4.2.3.7.2 of this dossier.”
Biodistribution & persistence
Higher concentrations in pigmented tissues (uveal tract, skin) than non-pigmented, suggesting melanin binding
“Rilzabrutinib concentrations in the pigmented tissues (eye uveal, skin) were higher than nonpigmented tissues suggesting rilzabrutinib may interact with melanin.”
Modality-specific risk
Neurotoxicity in rats: neutrophil influx into meninges and neuropil, with unknown long-term clinical effects
“Deficiencies included findings of neurotoxicity in animal models based on influx of neutrophils into meninges and neuropil and the unknown long-term clinical effects when considering the potential for chronic use in ITP.”
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
- Serious Infections
- Hepatotoxicity, Including Drug-Induced Liver Injury
- Embryo-Fetal Toxicity
InfectionsHepatotoxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human study in healthy volunteers (PRN1008-001)
“Study PRN1008-001 (FIH study in HV): Mean apparent volume of distribution (Vz/F) ranged from 6720 to 4890 L.”
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 Wayrilz 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: Rat NOAEL 50 mg/kg/day; mortality, meninges/neuropil inflammation and stomach hemorrhage/inflammation at higher doses (FDA integrated review, p. 121)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week (9-month) dog study with 4-week recovery
“For the 9-month dog study with a 4-week recovery period (study DVR0377) Beagle dogs were treated”
Pivotal GLP studies
6-month rat and 9-month dog studies
“repeat-dose toxicity studies in rats (13-day; 2-week; 1-, 3-, and 6-month), and dogs (4-day; 2- and 12-week, 1-, 3-, and 9-month)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive toxicology studies (male and female fertility study in rats; embryo-fetal toxicity in rats and rabbits, pre- and postnatal development toxicity study in rats)”
Reproductive & developmental
Adverse visceral and skeletal fetal findings in rats at a maternally toxic dose (22x human exposure)
“However, adverse visceral and skeletal findings occurred in rat fetuses at a maternally toxic dose at exposures 22 times the human exposure (based on AUC) at the MRHD (see Animal Data).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal developmental toxicity study, pregnant rats were given rilzabrutinib by oral gavage at doses of 50, 150, or 300 mg/kg/day during the periods of gestation, parturition, and lactation (gestation day 7 to lactation day 21).”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month) and rat (2-year)
“Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors.”
Carcinogenicity model
6-month Tg rasH2 mouse (up to 300 mg/kg/day); 2-year rat; no drug-related tumors
“Rilzabrutinib was not carcinogenic in a 6-month study in Tg.rasH2 mice at doses up to 300 mg/kg/day. In a 2-year rat carcinogenicity study at doses of 10, 30 or 100 and 5, 15 or 50 mg/kg/day in males and females, respectively, there were no rilzabrutinib-related tumors.”
Carcinogenicity timing
2-year rat and 26-week Tg.rasH2 mouse studies completed and submitted with the marketing application
“In this submission the sponsor included reports of two animal carcinogenicity studies, one in rats and one in mice.”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic rat NOAEL (50 mg/kg/day) exposure approximated clinical AUC at MRHD 400 mg BID
“The no observed adverse effect level (NOAEL) was defined at 50 mg/kg/day based on mortality, inflammation of meninges/neuropil and hemorrhage/inflammation of stomach at higher doses with corresponding AUC0-24 2060 and 5760 ng*h/mL in males and females. Exposures at the NOAEL approximated the clinical exposures at the MRHD of 400 mg BID, based on AUC.”
NOAEL / key findings
Rat NOAEL 50 mg/kg/day; mortality, meninges/neuropil inflammation and stomach hemorrhage/inflammation at higher doses
“The no observed adverse effect level (NOAEL) was defined at 50 mg/kg/day based on mortality, inflammation of meninges/neuropil and hemorrhage/inflammation of stomach at higher doses”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse anti-CD41 antibody-induced ITP model; also rat collagen-induced arthritis and canine pemphigus
“In a murine model for ITP, rilzabrutinib pretreated animals were stressed with an intraperitoneal injection of an anti-CD41 antibody to induce thrombocytopenia (DVR0288).”
Why that model
BTK ~99% conserved across mouse, rat, dog, rabbit and human, with identical binding sites
“This is because mouse, rat, dog, and rabbit BTK are nearly identical to the human version of the protein (approximately 99% homologous amino acid sequence), with no differences in the sites where rilzabrutinib binds.”
Reviewer's view of the efficacy data
EMA: in the pivotal ITP model, drug did not prevent the platelet drop or accelerate recovery
“Hence, in the pivotal animal model, rilzabrutinib was not able to prevent full drop in platelets, was not able to reduce the drop velocity of platelets and was not able to significantly accelerate the recovery in platelet numbers.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Chronic rat NOAEL exposure only approximated clinical AUC at the maximum recommended dose
“Exposures at the NOAEL approximated the clinical exposures at the MRHD of 400 mg BID, based on AUC.”
Impurity or metaboliteCriticised but accepted
Impurities qualified with a generic 4-fold dose margin, which the reviewer found unexplained
Why: Dose margins revised from results of study TXC1711 (ICH Q3A(R2)) · Within the guideline
“A generic acceptability criterium of 4 to regard impurities as qualified is not explained any further.”
“Dose margins of rilzabrutinib impurities qualified under ICH Q3A(R2) were revised based on the results from study TXC1711. This is acknowledged and listed impurities (specifically PRN3232, PRN3590 and PRN1418) are considered qualified at their respective proposed specification levels.”
Juvenile toxAcceptedBeyond the letter
Juvenile rat study programme dropped from the paediatric plan
Why: Paediatric waiver extended; not needed for an adult indication · Other reason
“A programme of juvenile animal studies was initiated in rats aged 10 days to support paediatric development of rilzabrutinib from 1 year of age, but subsequently deleted from the PIP due to extension of the waiver to patients below 10 years of age.”
“It is agreed that additional JAS is not needed to support the current MAA for the treatment of adult patients.”
DARTAccepted
Milk transfer and offspring toxicokinetics not assessed in the pre- and postnatal study
Why: ICH S5 does not strictly demand toxicokinetic assessment in maternal milk · Within the guideline
“Transfer of Rilzabrutinib into maternal milk was not assessed.”
“It is agreed that ICH S5 (see 3.5.) does not strictly demand the toxicokinetic assessment of substances in maternal milk.”
Similar precedents
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