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.”
Species: general tox
Avutometinib: rat and monkey; defactinib: rat and dog (program used mice, rats, dogs, monkeys)
“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.”
Species: DART
Not conducted for either drug (weight-of-evidence assessment accepted)
“The Applicant did not conduct any reproductive toxicology studies with avutometinib and defactinib.”
Species: carcinogenicity
Not conducted (not warranted for the proposed 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.”
Surrogate used in
Yes: FAK inhibitor VS-4718 used as defactinib surrogate in in vivo LGSOC efficacy models
“defactinib or the FAK inhibitor VS-4718 (used as surrogate for defactinib in in vivo models) were tested in combination with avutometinib in LGSOC models both in vitro and in vivo.”
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.”
Genotox: Ames
Defactinib: negative
“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.”
Genotox: in vitro mammalian
Defactinib: chromosome aberration (CHL) negative; in vitro micronucleus positive (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.”
Genotox: in vivo
Defactinib: rat bone marrow micronucleus positive
“Defactinib was positive in the in vitro micronucleus assay through an aneugenic mechanism and in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (not warranted for the proposed 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.”
Carcinogenicity timing
Not required for the 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.”
hERG / QT
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)
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: 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.”
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
- Ocular Toxicities
- Serious Skin Toxicities
- Hepatotoxicity
- Rhabdomyolysis
- Embryo-Fetal Toxicity
Ocular toxicitySkin reactionsHepatotoxicityMusculoskeletalEmbryo-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 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)
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: Avutometinib: skin and lymphoid organs; also eye, kidney, heart, liver (rat) and GI tract, ovary (monkey) (FDA multi-discipline review, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week oral defactinib studies in rat and dog, each with 4-week recovery (avutometinib also 13-week in rat and monkey)
“Study Title (study # H58-0008): Defactinib: 13-Week repeated oral dose toxicity and toxicokinetics study in rats with a 4-week recovery period Study Title (study # H58-0009): Defactinib: 13-Week repeated oral dose toxicity and toxicokinetics study in Beagle dogs with 4-week recovery period”
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.”
DART package
Species: DART
Not conducted for either drug (weight-of-evidence assessment accepted)
“The Applicant did not conduct any reproductive toxicology studies with avutometinib and defactinib.”
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.”
PPND / ePPND: when
Not conducted: no reproductive toxicology studies with either drug (oncology weight-of-evidence approach)
“The Applicant did not conduct any reproductive toxicology studies with avutometinib and defactinib.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for the proposed 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.”
Carcinogenicity model
Not conducted (not warranted for the proposed 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.”
Carcinogenicity timing
Not required for the 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.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: avutometinib rat myocardial degeneration/necrosis at ≥0.01 mg/kg/day, below human AUC at recommended dose
“In the repeat-dose toxicology studies up to 13-weeks duration in rats, myocardial degeneration and necrosis were observed at doses ≥ 0.01 mg/kg/day (below the human exposure at the recommended dose based on AUC).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
LGSOC patient-derived xenograft mice: avutometinib plus FAK-inhibitor surrogate VS-4718
“In LGSOC patient-derived xenograft (PDX) models in vivo, the combination of avutometinib with the FAK inhibitor surrogate VS-4718 induced tumor regressions with a delay in tumor progression relative to avutometinib or VS-4718 alone”
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: combination could improve antitumor activity over either drug alone
“Cumulatively, the data indicate that the combination of defactinib and avutometinib could improve antitumor activity of either drug alone.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development study for avutometinib or defactinib; weight-of-evidence assessment instead
Why: Weight-of-evidence assessment in lieu of EFD study; FDA agreed reproductive toxicology studies not warranted · Weight of evidence · Pharmacology or kinetics
“The Applicant provided a Weight of Evidence (WoE) assessment for avutometinib in lieu of an embryo fetal development study.”
“The FDA agrees with the Applicant’s conclusions and that reproductive toxicology studies are not warranted to support this application.”
DARTAccepted
No dedicated fertility studies; fertility assessed from reproductive organ findings in general toxicology studies
Why: Advanced cancer indication · Within the guideline · Serious disease
“Dedicated fertility studies have not been conducted with avutometinib, nor were warranted to support this marketing application in the proposed advanced cancer indication.”
Safety pharmacologyCriticised but accepted
Defactinib rat neurobehavioral study inadequate and inconclusive; no additional CNS safety pharmacology study
Why: Detailed clinical observations in repeat-dose studies; stand-alone safety pharmacology not warranted per ICH S9 · Within the guideline
“Since the Applicant included detailed clinical observations in the repeat dose toxicology studies per ICH S9, and stand-alone safety pharmacology studies are not warranted per ICH S9, an additional CNS safety pharmacology study is not needed to support the proposed marketing application.”
“The neurobehavioral study in rats was inadequate, and the results were considered inconclusive.”
Safety marginAccepted with a conditionBeyond the letter
Avutometinib rat myocardial degeneration and necrosis at ≥0.01 mg/kg/day, below human exposure at recommended dose
Why: Cardiovascular findings were not observed in patients; findings added to label section 13.2 · Human data
“In the repeat-dose toxicology studies up to 13-weeks duration in rats, myocardial degeneration and necrosis were observed at doses ≥ 0.01 mg/kg/day (below the human exposure at the recommended dose based on AUC).”
“The cardiovascular findings were added to section 13.2 of the label considering cardiovascular findings were not observed in patients.”
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