Avmapki Fakzynja Co-pack
avutometinib and defactinib
Sources:FDA multi-discipline review ↗
Species
MonkeyRatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey (avutometinib); rat and dog (defactinib)
“The nonclinical development program for avutometinib and defactinib consisted of studies in mice, rats, dogs, and monkeys to evaluate the primary and safety pharmacology, pharmacokinetics, general toxicology, and genotoxicity.”
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 compounds were tested
“The Applicant conducted GLP-compliant, daily oral repeat-dose general toxicology studies of defactinib in rats and dogs for up to 13-weeks duration.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat, monkey and dog)
“The Applicant evaluated the toxicity of avutometinib in GLP-compliant, daily oral repeat-dose general toxicology studies in rats and monkeys for up to 13-weeks duration.”
Pivotal GLP studies
13-week oral studies: avutometinib in rats and monkeys; defactinib in rats and dogs
“The Applicant conducted GLP-compliant, daily oral repeat-dose general toxicology studies of defactinib in rats and dogs for up to 13-weeks duration.”
Route in tox
Oral, daily
“The Applicant evaluated the toxicity of avutometinib in GLP-compliant, daily oral repeat-dose general toxicology studies in rats and monkeys for up to 13-weeks duration.”
Skipped studiesopen answer page →
Genotoxicity
Defactinib: Ames and chromosome aberration negative; positive in vitro and in vivo rat micronucleus (aneugenic)
“Defactinib was not mutagenic in the bacterial reverse mutagenesis (Ames) assay and was not clastogenic in an in vitro Chinese hamster lung cell chromosome aberration assay. Defactinib was positive in the in vitro micronucleus assay through an aneugenic mechanism and in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication)
“The Applicant did not conduct carcinogenicity studies with avutometinib; it is also not warranted to support the marketing application of AVMAPKI FAKZYNJA CO-PACK for the proposed indication.”
Reproductive & developmental
Not conducted for either drug; embryo-fetal toxicity assessed by weight of evidence
“The Applicant did not conduct any reproductive toxicology studies with avutometinib and defactinib.”
Safety pharmacology
Avutometinib: weak hERG inhibitor, little or no QT risk
“In safety pharmacology studies, avutometinib was found to be a weak inhibitor of the hERG channel current. As such, the data suggests that avutometinib may pose little or no risk for QT interval effects.”
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 Avmapki Fakzynja Co-pack 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: Avutometinib: skin and lymphoid organs; also eye, kidney, heart, liver (rat) and GI tract, ovary (monkey) (FDA multi-discipline review, p. 35)
NOAEL / key findings
Avutometinib: skin and lymphoid organs; also eye, kidney, heart, liver (rat) and GI tract, ovary (monkey)
“The major target organs of toxicity in rats and monkeys included the skin and lymphoid organs. Additional organs in rats included the eye, kidney, heart, and liver, and in monkeys, gastrointestinal organs, and ovary.”
Risksopen answer page →
Immune & cytokine safety
Avutometinib: lymph node follicular hyperplasia, plasma cells and inflammatory infiltrates in rats and monkeys
“Histopathology findings of hyperplasia of the lymph follicle, increased plasma cells of the medulla, and inflammatory cell infiltrates in the sinus of the lymph nodes were noted in both species.”
Biodistribution & persistence
Defactinib: distributes to pigmented skin and uveal tract, suggesting melanin affinity
“radioactivity was reported in the pigmented tissues (pigmented skin, eye [uveal tract, lens]), indicating a possible affinity of defactinib to melanin.”
Modality-specific risk
GI, skin, ocular, renal, hematologic and hepatic toxicities, all also seen clinically
“Consistent with nonclinical findings, gastrointestinal, skin, ocular, renal, hematologic, and clinical chemistry (elevations in liver enzymes) toxicities have occurred clinically.”