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”
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).”
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.”