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.”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”