Exkivity
mobocertinib
Sources:FDA multi-discipline review ↗
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
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
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
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
Species: general tox
Sprague-Dawley rat and Beagle dog (up to 3 months)
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
Species: DART
Rat (embryo-fetal development)
“To address the potential reproductive effects of mobocertinib, the Applicant conducted a GLP-compliant embryo-fetal development study in rats.”
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted and are not warranted per ICH S9 guidance for nonclinical safety assessment of pharmaceuticals intended for the treatment of advanced cancer”
Surrogate used in
No surrogate used
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
Pivotal GLP studies
3-month (13-week) oral studies in rats and dogs
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
Route in tox
Oral (gavage)
“A 3-Month Oral Study of TAK-788 by Oral Gavage in Sprague-Dawley Rats with a 1-Month Recovery Period/8002352 Amendment 1”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and in vivo rat bone marrow micronucleus assays
“Mobocertinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Mobocertinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“FDA agrees that carcinogenicity studies are not needed to support the use of mobocertinib in the currently proposed indication per ICH S9.”
Reproductive & developmental
Preliminary rat EFD only: embryo-fetal death and decreased fetal weight at 10 mg/kg; no clear malformations
“Mobocertinib induced embryo-fetal mortality due to post-implantation loss (early resorptions) as well as decreased fetal weight at 10 mg/kg (approximately 1.7 times the exposure based on AUC at the human dose of 160 mg).”
Safety pharmacology
Parent and active metabolites inhibited hERG only above 5 µM; no QT prolongation in dog toxicity studies
“Mobocertinib and its metabolites AP32914 and AP32960 inhibited the human ether-a-go-go related gene (hERG) current at concentrations > 5 µM, suggesting a low potential for QT prolongation.”
Genotox: Ames
Negative
“Mobocertinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes.”
Genotox: in vitro mammalian
Chromosome aberration in human peripheral blood lymphocytes: negative
“Mobocertinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Mobocertinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted and are not warranted per ICH S9 guidance for nonclinical safety assessment of pharmaceuticals intended for the treatment of advanced cancer”
Carcinogenicity timing
Not required for advanced cancer per ICH S9
“FDA agrees that carcinogenicity studies are not needed to support the use of mobocertinib in the currently proposed indication per ICH S9.”
hERG / QT
hERG IC50 10 µM (metabolites AP32960 10 µM, AP32914 5.1 µM)
“Mobocertinib, AP32960, and AP32914 inhibited the hERG current in a concentration-dependent manner with IC50 values of 10, 10, and 5.1 µM, respectively.”
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 Exkivity 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: Target organs consistent with clinical findings: pancreas (increased amylase), liver (ALT/AST elevations) and skin (FDA multi-discipline review, p. 42)
NOAEL / key findings
Target organs consistent with clinical findings: pancreas (increased amylase), liver (ALT/AST elevations) and skin
“Findings in one or both species consistent with clinical experience included effects on the pancreas (increased amylase), liver (elevated alanine aminotransferase [ALT], aspartate transaminase [AST]), skin”
Risksopen answer page →
Immune & cytokine safety
Increased lymphoid cellularity in lymph nodes in rats and dogs
“Additional target organs in both species included the reproductive system (atrophy and single cell necrosis), lymph nodes (increased lymphoid cellularity), digestive tract (decreased epithelial thickness), eyes (atrophy of the corneal epithelium), and larynx (decreased epithelial thickness).”
Biodistribution & persistence
Wide distribution in rats, including uveal tract; low brain penetration
“Following single oral administration, [14C]mobocertinib-derived radioactivity distributed widely to rat tissues including the liver, adrenal gland, kidney, alimentary canal, uveal tract, and thyroid but brain penetration was low.”
Modality-specific risk
QT prolongation in patients not predicted by nonclinical hERG and dog ECG data
“Additionally, the in vivo assessments included in the toxicology studies in dogs did not show QT prolongation or any other cardiac electrophysiologic effects, although QT prolongation, including resultant life-threatening arrhythmias, occurred in patients treated with mobocertinib.”
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.
Tox packageopen answer page →
Before first-in-human
First-in-human: where
United States: first-in-human dose escalation and expansion in NSCLC patients at 28 sites
“Part 1 and Part 2: (dose-escalation and expansion cohorts) were conducted at 28 study sites in the U.S.”
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 Exkivity 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: Target organs consistent with clinical findings: pancreas (increased amylase), liver (ALT/AST elevations) and skin (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month oral beagle dog study with 1-month recovery (same duration and recovery in rat)
“A 3-Month Oral Toxicity Study of TAK-788 in Beagle Dogs with a 1-Month Recovery Period”
Pivotal GLP studies
3-month (13-week) oral studies in rats and dogs
“The Applicant evaluated the toxicity profile of mobocertinib in Sprague-Dawley rats and Beagle dogs in GLP-compliant studies with treatment durations up to 3 months.”
DART package
Species: DART
Rat (embryo-fetal development)
“To address the potential reproductive effects of mobocertinib, the Applicant conducted a GLP-compliant embryo-fetal development study in rats.”
Reproductive & developmental
Preliminary rat EFD only: embryo-fetal death and decreased fetal weight at 10 mg/kg; no clear malformations
“Mobocertinib induced embryo-fetal mortality due to post-implantation loss (early resorptions) as well as decreased fetal weight at 10 mg/kg (approximately 1.7 times the exposure based on AUC at the human dose of 160 mg).”
PPND / ePPND: when
Not conducted: not warranted for advanced cancer per ICH S9
“Prenatal and postnatal development studies were not conducted and are not warranted per ICH S9 guidance for nonclinical safety assessment of pharmaceuticals intended for the treatment of advanced cancer”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted and are not warranted per ICH S9 guidance for nonclinical safety assessment of pharmaceuticals intended for the treatment of advanced cancer”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted and are not warranted per ICH S9 guidance for nonclinical safety assessment of pharmaceuticals intended for the treatment of advanced cancer”
Carcinogenicity timing
Not required for advanced cancer per ICH S9
“FDA agrees that carcinogenicity studies are not needed to support the use of mobocertinib in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat EFD: no embryo-fetal loss up to 5 mg/kg (~0.8x clinical AUC at 160 mg); no repeat-dose NOAEL margin stated
“There was no evidence of embryo-fetal loss at doses up to 5 mg/kg (approximately 0.8 times the clinical AUC at the 160 mg human dose)”
NOAEL / key findings
Target organs consistent with clinical findings: pancreas (increased amylase), liver (ALT/AST elevations) and skin
“Findings in one or both species consistent with clinical experience included effects on the pancreas (increased amylase), liver (elevated alanine aminotransferase [ALT], aspartate transaminase [AST]), skin”
Efficacy evidenceopen answer page →
Efficacy evidence
Patient-derived NSCLC xenograft LU0387 (EGFR exon 20 insertion) in immunocompromised mice
“The Applicant investigated the in vivo anti-tumor activity of mobocertinib in immunocompromised mice (10/group) implanted subcutaneously (SC) with patient-derived NSCLC LU0387 tumor fragments expressing an EGFR exon 20 NPH insertion mutation”
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 confirmed the Applicant's in vitro and in vivo pharmacology findings
“FDA confirmed the Applicant’s in vitro and in vivo findings.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
Embryo-fetal development assessed only in a preliminary rat study; no definitive study and no second species
Why: Clear positive rat result at about 1.7 times clinical exposure sufficient to convey developmental risk, consistent with ICH S9 · Within the guideline · Weight of evidence
“Based on the embryolethality observed at 10 mg/kg, a definitive embryo-fetal development study was deemed unnecessary and was not conducted.”
“Rather, consistent with ICH S9, since a GLP-compliant embryofetal development study in rats demonstrated clear positive results at doses resulting in exposures approximately 1.7 times the clinical exposure at the 160 mg human dose, FDA agreed that this study was sufficient to convey the developmental risk to patients.”
Similar precedents
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