Vonjo
pacritinib
Sources:FDA integrated review ↗
Species
MouseDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and dog
“Mice and dogs were considered the most relevant nonclinical species for toxicological evaluations based on the similarity of their pacritinib metabolic profile to humans and the sufficient bioavailability observed in these nonclinical species.”
Why that species
Metabolic profile similar to humans and sufficient bioavailability
“Mice and dogs were considered the most relevant nonclinical species for toxicological evaluations based on the similarity of their pacritinib metabolic profile to humans and the sufficient bioavailability observed in these nonclinical species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“there were no cardiovascular effects attributed to the administration of pacritinib in the repeat-dose toxicity study in dogs dosed up to 14.2 mg/kg BID for 39 weeks.”
Species: general tox
Mouse (26-week) and dog (39-week); rat up to 13 weeks
“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks) and rabbits (embryo-fetal development) during repeat-dose toxicology studies.”
Species: DART
Mouse (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive toxicology was assessed in mice in two fertility and early embryonic development studies (BALB/c and CD-1), an embryo-fetal development study (CD-1) and a pre- and postnatal development study (CD-1). An embryo-fetal development study was also conducted in New Zealand white rabbits.”
Species: carcinogenicity
Rat (2-year) and Tg(HRAS) transgenic mouse (26-week)
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Surrogate used in
No surrogate used; pacritinib tested directly
“there were no cardiovascular effects attributed to the administration of pacritinib in the repeat-dose toxicity study in dogs dosed up to 14.2 mg/kg BID for 39 weeks.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”
Pivotal GLP studies
26-week mouse and 39-week dog oral studies
“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”
Route in tox
Oral (capsules in dogs)
“39-Week Oral (Capsules) Toxicology Study in Beagle Dogs (RPT241)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (CHO) and in vivo mouse micronucleus assays
“pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice”
Carcinogenicity
2-year rat and 26-week Tg(HRAS) mouse: not carcinogenic
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Reproductive & developmental
Mouse EFD: post-implantation loss, lower fetal weight and cleft palate at maternally toxic high dose
“The NOAEL for embryo-fetal development was also considered the MD based on higher post-implantation loss, lower mean fetal body weights, and altered external fetal morphology (cleft palate) observed in the presence of maternal toxicity at the HD.”
Safety pharmacology
hERG IC50 3 µM, substantially above free plasma concentrations at clinical exposure
“Pacritinib inhibited human ether-à-go-go-related gene (hERG) potassium channel with a mean IC50 of 3μM, substantially higher than free plasma concentrations at clinical exposure”
Genotox: Ames
Negative (Ames)
“pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice”
Genotox: in vivo
Mouse micronucleus: negative
“pacritinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in mice”
Carcinogenicity model
2-year rat; 26-week hemizygous Tg(HRAS) mouse
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Carcinogenicity timing
2-year rat and 26-week Tg(HRAS) mouse studies completed before the marketing application
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
hERG / QT
hERG IC50 3 µM, substantially above free clinical Cmax (240 nM at 200 mg BID)
“Pacritinib inhibited human ether-à-go-go-related gene (hERG) potassium channel with a mean IC50 of 3μM, substantially higher than free plasma concentrations at clinical exposure (human maximum concentration [Cmax] at 200 mg twice daily [BID], free fraction 240nM).”
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 Vonjo 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: 39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose (FDA integrated review, p. 118)
NOAEL / key findings
39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose
“The Reviewer agreed with the Applicant’s interpretation that the NOAEL was the MD (20 mg/kg/day) based on the mortality, weight loss and GI toxicity observed at the HD.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid tissue depletion with white blood cell changes consistent with bone marrow suppression in mice, rats and dogs
“Lymphoid tissue depletion and concomitant changes in white blood cell parameters, consistent with bone marrow suppression, were observed in mice, rats, and dogs”
Biodistribution & persistence
Mouse: lung exposure 19-fold and brain exposure 2-fold that of plasma
“Pacritinib exposure levels within these three tissues were highest in the lungs (increased 19-fold versus plasma, area under the concentration-time curve [AUC]) followed by the brain (increased 2-fold versus plasma, AUC) and plasma.”
Modality-specific risk
Toxicities at exposures significantly below clinical exposure (no safety margins)
“The toxicities observed in nonclinical studies occurred at exposures that were significantly lower than those anticipated at the proposed therapeutic dose (Table 27).”
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
- Diarrhea
- Thrombocytopenia
- Prolonged QT Interval
- Major Adverse Cardiac Events (MACE)
- Thrombosis
- Secondary Malignancies
- Risk of Infection
- Symptom Exacerbation Following Interruption or Discontinuation of Treatment
- Interactions With CYP3A4 Inhibitors or Inducers
BleedingGastrointestinalThrombocytopeniaCardiovascularThrombosis & embolismSecondary malignancyInfections
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 Vonjo 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: 39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose (FDA integrated review, p. 118)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral (capsule) GLP study in beagle dogs; reversibility not assessed
“The reversibility of findings in dogs was not assessed. The NOAEL (MD, 11.8 μg·h/mL, and 3.4 μg·h/mL AUC024, Day 270, in males and females) represents a 0.06× (M) and 0.02× (F) exposure margin to the anticipated clinical dose (200 mg BID, 213 μg·h/mL AUC).”
Pivotal GLP studies
26-week mouse and 39-week dog oral studies
“Toxicological characterization of pacritinib was assessed in mice (1, 4, and 26 weeks), rats (1, 4, and 13 weeks), dogs (1, 4, and 39 weeks)”
DART package
Species: DART
Mouse (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive toxicology was assessed in mice in two fertility and early embryonic development studies (BALB/c and CD-1), an embryo-fetal development study (CD-1) and a pre- and postnatal development study (CD-1). An embryo-fetal development study was also conducted in New Zealand white rabbits.”
Reproductive & developmental
Mouse EFD: post-implantation loss, lower fetal weight and cleft palate at maternally toxic high dose
“The NOAEL for embryo-fetal development was also considered the MD based on higher post-implantation loss, lower mean fetal body weights, and altered external fetal morphology (cleft palate) observed in the presence of maternal toxicity at the HD.”
PPND / ePPND: when
PPND in CD-1 mouse completed before the marketing application
“Reproductive toxicology was assessed in mice in two fertility and early embryonic development studies (BALB/c and CD-1), an embryo-fetal development study (CD-1) and a pre- and postnatal development study (CD-1).”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg(HRAS) transgenic mouse (26-week)
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Carcinogenicity model
2-year rat; 26-week hemizygous Tg(HRAS) mouse
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Carcinogenicity timing
2-year rat and 26-week Tg(HRAS) mouse studies completed before the marketing application
“Pacritinib was not carcinogenic in either a 2-year rat study or during a 26-week hemizygous Tg(HRAS) transgenic mouse study, demonstrating low carcinogenic potential secondary to inhibition of JAK2/FLT3 activity.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL below clinical exposure: 6-month mouse 0.02x, 9-month dog 0.02–0.06x human AUC
“Six-month mouse 200 mg/kg/day 4.8 μg·h/mL 0.02× Nine-month dog 20 mg/kg/day 11.8 μg·h/mL (males) 3.4 μg·h/mL (females) 0.06× 0.02×”
NOAEL / key findings
39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose
“The Reviewer agreed with the Applicant’s interpretation that the NOAEL was the MD (20 mg/kg/day) based on the mortality, weight loss and GI toxicity observed at the HD.”
Efficacy evidenceopen answer page →
Efficacy evidence
Two murine myelofibrosis models driven by excessive JAK2 activity (nude mice bearing Ba/F3-JAK2 cells)
“Two proof-of-concept studies were conducted in murine models of myelofibrosis whose pathology is driven by excessive JAK2 activity, recapitulating the dysregulated JAK/STAT pathway described in human myelofibrosis.”
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 models showed pacritinib can alleviate to some degree myeloproliferative disease symptoms
“In general, results generated with these mouse models provided evidence that pacritinib can alleviate to some degree the various symptoms associated with myeloproliferative disease.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Chronic dog NOAEL exposure only 0.06x (males) and 0.02x (females) the clinical AUC
“The NOAEL (MD, 11.8 μg·h/mL, and 3.4 μg·h/mL AUC024, Day 270, in males and females) represents a 0.06× (M) and 0.02× (F) exposure margin to the anticipated clinical dose (200 mg BID, 213 μg·h/mL AUC).”
CarcinogenicityQuestioned
Rat and transgenic mouse carcinogenicity exposures considerably below human exposure at the recommended dose
Why: Higher doses not tolerated due to excessive JAK2/FLT3 activity
“However, a notable limitation of the carcinogenicity assessment is that pacritinib exposures achieved in rats and mice were considerably lower than the exposure observed at the recommended human dose, due to a lack of tolerability primarily from excessive JAK2/FLT3 activity at higher doses.”
“The inability to evaluate pacritinib at multiples of clinical exposure limits the robustness of assessing carcinogenic potential from off-target kinases where pacritinib and the M1/M2 metabolites have lower inhibitory potencies than for JAK2/FLT3 (Section III.13.1.1).”
RecoveryVerdict not stated
Reversibility of findings not assessed in the chronic dog study
“The reversibility of findings in dogs was not assessed.”
Impurity or metaboliteAcceptedBeyond the letter
Major human metabolite M2 (~10% of parent) not predominant in any nonclinical species
Why: No safety concerns identified with M1 and M2 metabolites in nonclinical studies
“However, it is notable that the M2 metabolite, a principal metabolite in humans present at ~10% of the parent pacritinib, is not a predominant metabolite in any of the nonclinical species.”
“No safety concerns were identified with the pacritinib M1 and M2 metabolites in nonclinical studies.”
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