Brukinsa
zanubrutinib
Species
RatDog
Longest study
39 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 dog
“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs.”
Why that species
Pharmacologically relevant species based on BTK sequence homology and functional assay
“Rats and dogs were chosen for the in vivo toxicity evaluation, as they are pharmacologically relevant species based on BTK sequence homology and functional assay.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week study in rats, zanubrutinib was administered by oral gavage at 30, 100, 300, or 1000 mg/kg/day with a 4-week recovery period.”
Species: general tox
Rat (26-week) and dog (39-week)
“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs.”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Embryo-foetal development toxicity studies were conducted in both rats and rabbits.”
Species: carcinogenicity
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“In the 39-week study in dogs, zanubrutinib was administered orally at doses of 10, 30, or 100 mg/kg/day with a 4-week recovery period.”
Pivotal GLP studies
6-month rat and 9-month dog oral once-daily studies
“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs. The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”
Route in tox
Oral
“The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“Zanubrutinib was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay or in the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Reproductive & developmental
Rat EFD: fetal heart malformations (2- or 3-chambered hearts) at 30-150 mg/kg/day
“In an embryo-fetal development study in female rats, once daily administration of zanubrutinib at 30, 75, or 150 mg/kg/day on GD 6-17 resulted in fetal heart malformations in the form of 2- or 3-chambered hearts.”
Safety pharmacology
No significant effects in dog telemetry, rat CNS (neurobehavior, temperature) or respiratory studies
“Zanubrutinib had no toxicologically-significant effects on cardiovascular function in a cardiovascular study in telemetered dogs, and had no effects on neurobehavioral function, temperature, or respiratory function in CNS and respiratory studies conducted in male rats.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Zanubrutinib was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay or in the in vivo bone marrow micronucleus assay in rats.”
Genotox: in vitro mammalian
Chromosomal aberration (CHO cells): negative
“BGB-3111 did not induce chromosome aberrations in Chinese Hamster Ovary cells with or without metabolic activation.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“BGB-3111 did not increase the frequency of micronucleated polychromatic erythrocytes in rats after oral administration.”
Carcinogenicity model
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Carcinogenicity timing
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
hERG / QT
hERG IC50 9.11 µM vs steady-state Cmax ~1 µM; low risk
“In the GLP-study (2017), IC50 for BGB-3111 was determined to be 9.11 µM and 50 nM for the positive control terfenadine. Based on this study, the risk of hERG inhibition is low considering the Cmax at steady state being approximately 1 µM.”
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 Brukinsa 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats (FDA multi-discipline review, p. 26)
NOAEL / key findings
Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats
“Drug-related findings included increased white blood cells (WBCs) and differentials, multi-organ inflammation, GI tract necrosis, multi-organ hemorrhage, and lymphoid depletion. The findings were more prominent in the rat, particularly those in the pancreas (e.g. fibrin deposit and hemorrhage).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in dogs (also rats); inflammatory responses with elevated WBCs
“Other findings in the dog included lymphoid depletion and reduced red blood cells (RBCs) and lineages, which may be at least partially related to bleeding noted on histopathology.”
Biodistribution & persistence
Preferential distribution to stomach, small intestine and liver; very low brain and testis levels
“BGB-3111 showed preference for stomach, small intestine and liver. Very low concentration was found in brain and testes, however elimination from testes appeared to be slower than for other tissues.”
Modality-specific risk
Developmental toxicity: cataracts and corneal opacity in offspring at all PPND doses
“All dosing levels were associated with adverse ocular findings, including cataracts and corneal opacity in the offspring.”
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
- Hemorrhage
- Infections
- Cytopenias
- Second Primary Malignancies
- Cardiac Arrhythmias
- Hepatotoxicity, Including Drug-Induced Liver Injury
- Embryo-Fetal Toxicity
BleedingInfectionsCytopeniasSecondary malignancyCardiovascularHepatotoxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Australia, New Zealand, Italy, South Korea, UK and USA: first-in-human dose-selection study in patients with B-cell malignancies
“A first-in-human, Phase 1/2, dose-selection, PK/PD, safety, and efficacy study in adult patients with relapsed/refractory or treatment-naïve B-cell malignancies conducted in Australia, New Zealand, Italy, South Korea, United Kingdom (UK), and USA (N = 385).”
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 Brukinsa 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats (FDA multi-discipline review, p. 26)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral dog study with 6-week recovery
“39-Week Repeat ed Oral Dose Toxicity and Toxicokinet ics Study in Beagle Dogs with 6-Week Recovery Period”
Pivotal GLP studies
6-month rat and 9-month dog oral once-daily studies
“Zanubrutinib was administered once daily to rats and dogs in studies up to 6 months in rats and 9 months in dogs. The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Embryo-foetal development toxicity studies were conducted in both rats and rabbits.”
Reproductive & developmental
Rat EFD: fetal heart malformations (2- or 3-chambered hearts) at 30-150 mg/kg/day
“In an embryo-fetal development study in female rats, once daily administration of zanubrutinib at 30, 75, or 150 mg/kg/day on GD 6-17 resulted in fetal heart malformations in the form of 2- or 3-chambered hearts.”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In a pre- and postnatal development (PPND) study in rats, pregnant females were administered zanubrutinib at 30, 75, or 150 mg/kg/day from GD6 to lactation day (LD) 17.”
Carcinogenicity
Species: carcinogenicity
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Carcinogenicity model
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Carcinogenicity timing
Not conducted; not required for the indication
“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL ~13x (rat, 100 mg/kg/day) and ~3x (dog, 10 mg/kg/day) human AUC
“The systemic exposure (AUC) at the redefined NOAEL of 100 mg/kg/day in rats and 10 mg/kg/day in dogs was approximately 13 and 3-fold human systemic exposure.”
NOAEL / key findings
Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats
“Drug-related findings included increased white blood cells (WBCs) and differentials, multi-organ inflammation, GI tract necrosis, multi-organ hemorrhage, and lymphoid depletion. The findings were more prominent in the rat, particularly those in the pancreas (e.g. fibrin deposit and hemorrhage).”
Efficacy evidenceopen answer page →
Efficacy evidence
REC-1 mantle cell lymphoma subcutaneous xenograft in mice; dose-dependent growth suppression
“The in vivo activity of BGB-3111 was evaluated in a subcutaneous xenograft model of MCL, using the REC-1 cell line.”
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
EMA: mode-of-action proof of concept shown, but not entirely convincing (no ex vivo primary lymphoma data; limited systemic xenograft efficacy)
“However, since ex vivo studies using relevant primary lymphoma cells are missing and the efficacy in the systemic xenograft model appear limited, non-clinical proof of concept is not entirely convincing.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies; absence justified by weight of evidence
Why: Weight-of-evidence argumentation, in line with the relevant guideline · Weight of evidence · Within the guideline
“The absence of carcinogenicity studies with zanubrutinib is justified based on a weight of evidence argumentation and in line with the relevant guideline.”
OtherAcceptedBeyond the letter
No in vivo excretion and metabolism (ADME) study in the dog, the non-rodent toxicology species
Why: Similar in vitro metabolic profiles across rat, dog and human; sufficient safety margins · Pharmacology or kinetics
“The omission of conducting ADME study of BGB-3111 in dog was justified in the next round of assessment by the following points: i) In vitro metabolic profiles (liver microsomes) were similar between rat, dog and humans.”
“The justification was accepted and requesting a new in vivo ADME study in a non-rodent at this stage of development is not considered necessary.”
Efficacy modelQuestioned
No ex vivo studies in primary lymphoma cells; limited efficacy in the systemic xenograft model
“However, since ex vivo studies using relevant primary lymphoma cells are missing and the efficacy in the systemic xenograft model appear limited, non-clinical proof of concept is not entirely convincing.”
Similar precedents
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