Jaypirca
pirtobrutinib
Species
RatDog
Longest study
13 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
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“In this GLP study, pirtobrutinib was administered to Sprague Dawley rats at 0, 50, or 500 mg/kg in males or 0, 60, 300 mg/kg in females BID via oral gavage for 15 weeks.”
Species: general tox
Rat and dog (up to 3 months)
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted (ICH S9)
“For the reproductive toxicity assessment, the absence of fertility and PPND studies is in line with ICH guideline S9. Administration of pirtobrutinib to pregnant rats during organogenesis resulted in”
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”
Surrogate used in
No surrogate used; pirtobrutinib tested directly
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”
Pivotal GLP studies
3-month GLP oral repeat-dose studies in rats and dogs
“See additional information provided below for the 3-month repeat-dose toxicity studies in rats and dogs.”
Route in tox
Oral (gavage, twice daily)
“In this GLP study, pirtobrutinib was administered to Sprague Dawley rats at 0, 50, or 500 mg/kg in males or 0, 60, 300 mg/kg in females BID via oral gavage for 15 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; aneugenic in in vitro human lymphocyte micronucleus assays; negative in in vivo rat bone marrow micronucleus assay
“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”
Reproductive & developmental
EFD: decreased fetal weight and urinary tract, reproductive tract and bone malformations at ≥375 mg/kg BID
“Doses ≥ 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae).”
Safety pharmacology
No CNS, respiratory or cardiovascular toxicities of concern in safety pharmacology studies
“Safety pharmacology studies did not point to any toxicities of concern in the CNS, respiratory, or cardiovascular systems.”
Genotox: Ames
Negative
“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay but was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes”
Genotox: in vitro mammalian
Human lymphocyte micronucleus: positive (aneugenic) at ~37-fold unbound human Cmax
“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay but was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes (at approximately 37-fold the unbound human Cmax (unbound) at the recommended human dose).”
Genotox: in vivo
Rat bone marrow micronucleus: negative up to 2000 mg/kg
“Pirtobrutinib was not genotoxic in the rat bone marrow micronucleus assay at doses up to 2000 mg/kg.”
Carcinogenicity model
Not conducted (ICH S9); assessment relied on no hyperplasia in studies up to 3 months
“The absence of carcinogenicity studies is in line with ICH guideline S9 and the assessment relied on the lack of hyperplastic changes in chronic studies (up to 3 months).”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); none conducted
“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”
hERG / QT
hERG IC50 32 μM, 55-fold unbound human Cmax at 200 mg
“In this in vitro GLP study, pirtobrutinib inhibited the hERG channel with an IC50 of 32 μM (15 μg/mL). This is 55-fold higher than the preliminary unbound or free human Cmax at 200 mg with 95.4% protein binding, 0.27 μg/mL, in humans.”
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 Jaypirca 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: Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID (EMA assessment report, p. 33)
NOAEL / key findings
Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID
“Minimal to mild corneal lesions were observed in two high dose dogs at systemic exposure below human exposure at 200 mg QD. In addition, pirtobrutinib caused a decrease in B lymphocytes and a decrease in the TDAR following KLH immunisation. The NOAEL was 2.5 mg/kg BID, due to adverse eye effects at 5 mg/kg BID.”
Risksopen answer page →
Immune & cytokine safety
Decreased B lymphocytes and TDAR response to KLH; adverse only for the anti-KLH TDAR in male rats
“Effects on immune system function consisted of a shift in the balance of T, B, and NK lymphocytes, largely due to a decrease in B lymphocytes, and decreased TDAR response to KLH, a foreign antigen. With the exception of the anti-KLH TDAR in male rats, these effects were not considered adverse due to the lack of effect on the overall well-being of the animals.”
Biodistribution & persistence
Radioactivity persisted in uveal tract and liver at 168 h (t1/2 66.4 and 56.1 h)
“The radioactivity declined over time to below the lower limit of quantitation (< 178 ng-eq) by 168 hours post dose for all tissues but the uveal tract and liver (294 and 262 ng-eq, respectively at 168 hours), with a calculated t1/2 of 66.4 and 56.1 hours, respectively.”
Modality-specific risk
Aneugenicity: in vitro micronucleus induction via chromosome loss
“Pirtobrutinib was positive for the induction of micronuclei under the conditions of this study at concentrations ≥ 12 µg/mL. Based on the high level of centromere-positive staining, the micronuclei were induced via a predominantly aneugenic mechanism (chromosome loss).”
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
- Infections
- Hemorrhage
- Cytopenias
- Cardiac Arrhythmias
- Second Primary Malignancies
- Hepatotoxicity, Including Drug-Induced Liver Injury
- Embryo-Fetal Toxicity
InfectionsBleedingCytopeniasCardiovascularSecondary malignancyHepatotoxicityEmbryo-fetal toxicity
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 Jaypirca 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: Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID (EMA assessment report, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month rat and dog oral studies; no recovery phase described
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs”
Pivotal GLP studies
3-month GLP oral repeat-dose studies in rats and dogs
“See additional information provided below for the 3-month repeat-dose toxicity studies in rats and dogs.”
DART package
Species: DART
Rat (EFD only); fertility and pre/postnatal studies not conducted (ICH S9)
“For the reproductive toxicity assessment, the absence of fertility and PPND studies is in line with ICH guideline S9. Administration of pirtobrutinib to pregnant rats during organogenesis resulted in”
Reproductive & developmental
EFD: decreased fetal weight and urinary tract, reproductive tract and bone malformations at ≥375 mg/kg BID
“Doses ≥ 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae).”
PPND / ePPND: when
Not conducted: PPND not required for advanced cancer (ICH S9)
“For the reproductive toxicity assessment, the absence of fertility and PPND studies is in line with ICH guideline S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”
Carcinogenicity model
Not conducted (ICH S9); assessment relied on no hyperplasia in studies up to 3 months
“The absence of carcinogenicity studies is in line with ICH guideline S9 and the assessment relied on the lack of hyperplastic changes in chronic studies (up to 3 months).”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); none conducted
“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 3-month: corneal lesions at 0.42-fold human AUC at 200 mg; toxicity below clinical exposure
“Corneal lesions were only observed in 2 dogs treated for 3 months. To date, this has not been identified as a drug class toxicity and has not been identified as a significant safety finding in the human population but is nevertheless described in the product information as it was observed at 0.42-fold human exposure (at the recommended dose of 200 mg based on AUC).”
NOAEL / key findings
Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID
“Minimal to mild corneal lesions were observed in two high dose dogs at systemic exposure below human exposure at 200 mg QD. In addition, pirtobrutinib caused a decrease in B lymphocytes and a decrease in the TDAR following KLH immunisation. The NOAEL was 2.5 mg/kg BID, due to adverse eye effects at 5 mg/kg BID.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models of lymphoma with WT or C481S mutant BTK
“Pirtobrutinib had anti-tumor activities in vitro against the human lymphoma cell lines tested (Ramos RA1 and TMD8), and in vivo in mouse xenograft models of lymphoma containing WT BTK or C481S mutant BTK.”
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: xenograft models demonstrated tumour growth inhibition
“In vivo xenograft models demonstrated the growth inhibition of tumours after pirtobrutinib treatment.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAcceptedBeyond the letter
Aneugenic in in vitro human lymphocyte micronucleus assays; in vivo rat micronucleus negative
Why: Human exposure below the rat no-effect level for aneugenicity; cancer patient population; FDA disputed the margin estimate · Serious disease · Pharmacology or kinetics
“Pirtobrutinib is an aneugenic genotoxicant; however, human exposure at 200 mg QD is 12-fold lower than the no effect level for this genotoxicity in rats. Thus, this is not a significant risk for cancer patients.”
“The FDA agrees with the Applicant’s assessment, except for the estimation of the exposure margin.”
Safety marginAccepted with a conditionBeyond the letter
Dog corneal lesions at 0.42-fold human AUC at the recommended dose
Why: Not a class toxicity and not a significant finding in humans; described in product information · Human data
“Corneal lesions were only observed in 2 dogs treated for 3 months. To date, this has not been identified as a drug class toxicity and has not been identified as a significant safety finding in the human population but is nevertheless described in the product information as it was observed at 0.42-fold human exposure (at the recommended dose of 200 mg based on AUC).”
Safety marginAccepted with a conditionBeyond the letter
Anti-KLH TDAR eliminated in male rats at 0.69-fold human AUC at the recommended dose
Why: Described in the product information
“Thus, the effect was considered adverse in male rats and is described in the product information as it was observed at 0.69-fold human exposure (at the recommended dose of 200 mg based on AUC).”
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