Krazati
adagrasib
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Why that species
Selected based on in vitro and in vivo metabolism studies
“The rat and dog were selected as preclinical species for toxicology studies based on results from in vitro and in vivo metabolism studies, which is supported.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Species: general tox
Sprague-Dawley rat and beagle dog (28-day and 13-week)
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Species: DART
Rat and rabbit (EFD only); no fertility or pre/postnatal studies (ICH S9)
“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Surrogate used in
No surrogate used; rat and dog selected on metabolism data
“The rat and dog were selected as preclinical species for toxicology studies based on results from in vitro and in vivo metabolism studies, which is supported.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Pivotal GLP studies
GLP 28-day and 13-week oral studies in Sprague-Dawley rats and Beagle dogs
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Route in tox
Oral
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat micronucleus assays
“Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
No fertility, early embryonic or PPND studies (ICH S9); rat and rabbit EFD conducted
“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed. This is considered acceptable as adagrasib is intended for treatment of advanced cancer, and the ICH S9 guideline applies.”
Safety pharmacology
hERG IC50 3.8 uM, about 48-fold above human free Cmax
“Adagrasib inhibited hERG potassium channel currents with an IC50 of 3.8 μM in a safety pharmacology assessment, which is approximately 48-fold higher than the human free steady-state Cmax of ~0.08 μM based on ~98% protein-binding at the recommended dose.”
Genotox: Ames
Negative
“In the standard genotoxicity battery, adagrasib was not mutagenic in a bacterial reverse mutation (Ames) assay nor clastogenic in an in vitro micronucleus assay.”
Genotox: in vitro mammalian
In vitro micronucleus: not clastogenic; endoreduplication increased almost 4% at 9 µg/mL with S9
“In the standard genotoxicity battery, adagrasib was not mutagenic in a bacterial reverse mutation (Ames) assay nor clastogenic in an in vitro micronucleus assay. However, it is noted that following a 3-hour incubation of cells with adagrasib in the presence of S9, there was increased endoreduplication by almost 4% at 9 μg/mL.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“An in vivo bone marrow micronucleus study in rats was unremarkable.”
Carcinogenicity model
Not conducted: not needed for advanced cancer indication
“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not conducted; not needed for advanced cancer (ICH S9)
“The FDA’s Assessment: The FDA agrees that carcinogenicity studies are not needed to support the use of adagrasib in the currently proposed indication per ICH S9.”
hERG / QT
hERG IC50 3.8 µM, ~48-fold human free Cmax
“Adagrasib inhibited hERG potassium channel currents with an IC50 of 3.8 μM in a safety pharmacology assessment, which is approximately 48-fold higher than the human free steady-state Cmax of ~0.08 μM based on ~98% protein-binding at the recommended dose.”
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 Krazati 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 in rats and dogs: heart, lungs, adrenal gland, kidney and liver (FDA multi-discipline review, p. 42)
NOAEL / key findings
Target organs in rats and dogs: heart, lungs, adrenal gland, kidney and liver
“In both rats and dogs, the target organs were heart, lungs, adrenal gland, kidney, and liver.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid tissue changes not considered an immunotoxicity risk; no dedicated immunotoxicity studies
“It is further clarified that adagrasib-induced microscopic changes in lymphoid tissues, do not appear to translate into an immunotoxicity risk is supported. Omission of specific immunotoxicity studies is therefore accepted.”
Biodistribution & persistence
Distributed to nearly all rat tissues by 8 h; affinity for melanin-pigmented tissues
“Following single oral administration to rats, 14C-adagrasib-derived radioactivity distributed to nearly all tissues by 8 hours post-dose. Adagrasib demonstrated affinity for melanin-pigmented tissues.”
Modality-specific risk
Phospholipidosis (macrophage infiltration and vacuolation) in multiple tissues
“Toxicology studies of up to 13 weeks duration in both species revealed microscopic findings of macrophage infiltration and vacuolation in several tissues, suggestive of phospholipidosis”
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
- Gastrointestinal Adverse Reactions
- QTc Interval Prolongation
- Hepatotoxicity
- Interstitial Lung Disease / Pneumonitis
GastrointestinalCardiovascularHepatotoxicityImmune-mediated reactionsPulmonary toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US: first-in-human study 849-001 in patients with KRAS G12C-mutated advanced solid tumors
“Efficacy data supporting this NDA were generated in Study 849-001, an open-label, multi-center, first-in-human (FIH), Phase 1/2, multiple expansion cohort study of adagrasib in patients with advanced solid tumors malignancies with KRAS G12C mutation. Study 849-001 was designed and conducted in accordance with FDA draft guidance issued in August 2018 (FDA 2018) and conducted in the United States.”
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 Krazati 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 in rats and dogs: heart, lungs, adrenal gland, kidney and liver (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week oral rat study with 28-day recovery; 13-week dog study also had a 28-day recovery
“Study Title: A 13-Week Study of MRTX849 by Oral Gavage in Rats with a 28-Day Recovery Period”
Pivotal GLP studies
GLP 28-day and 13-week oral studies in Sprague-Dawley rats and Beagle dogs
“The Applicant evaluated the safety of adagrasib in GLP-compliant 28-day and 13-week repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs, using the intended oral route of administration.”
DART package
Species: DART
Rat and rabbit (EFD only); no fertility or pre/postnatal studies (ICH S9)
“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed.”
Reproductive & developmental
No fertility, early embryonic or PPND studies (ICH S9); rat and rabbit EFD conducted
“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed. This is considered acceptable as adagrasib is intended for treatment of advanced cancer, and the ICH S9 guideline applies.”
PPND / ePPND: when
No PPND or fertility studies: not needed for advanced cancer (ICH S9)
“DRF and definitive EFD studies were performed in Wistar rat and NZW rabbits. No fertility, early embryonic development or PPND studies were performed. This is considered acceptable as adagrasib is intended for treatment of advanced cancer, and the ICH S9 guideline applies.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted: not needed for advanced cancer indication
“Dedicated carcinogenicity studies were not conducted with adagrasib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not conducted; not needed for advanced cancer (ICH S9)
“The FDA’s Assessment: The FDA agrees that carcinogenicity studies are not needed to support the use of adagrasib in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and dog 28-day/13-week exposure margins 0.3 to 2.4; NOAEL exposures similar to or below MRHD exposure
“It should be taken into consideration that low margins of exposure ranging from 0.3 to 2.4 were observed in the 28-day and 13-week repeat-dose studies in rat and dog. And in general, the observed exposure at NOAEL levels were similar or below the exposure level at the maximum human recommended dose.”
NOAEL / key findings
Target organs in rats and dogs: heart, lungs, adrenal gland, kidney and liver
“In both rats and dogs, the target organs were heart, lungs, adrenal gland, kidney, and liver.”
Efficacy evidenceopen answer page →
Efficacy evidence
KRAS G12C-mutant human tumor xenografts in mice: activity in 14 of 17 lung xenograft models, none in G12C-negative models
“In a panel of KRAS G12C-mutant and KRAS G12C-negative tumor xenograft models, adagrasib had anti-tumor activity in 14 of 17 KRAS G12C-mutant lung xenograft models. In contrast, adagrasib did not exhibit anti-tumor activity in KRAS G12C-negative tumor models.”
Why that model
Human tumor xenografts in immunodeficient mice are an established model of human tumor biology
“In vivo pharmacology studies were conducted in mice as human xenografts growing in immunodeficient mice are a well-established and useful model in studying human tumour biology.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo pharmacodynamic studies adequately show potent, selective KRAS G12C inhibition
“The in vitro and in vivo primary pharmacodynamic studies provided adequate evidence that adagrasib is a potent and selective inhibitor of KRAS G12C.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
Low exposure margins (0.3 to 2.4) in 28-day and 13-week rat and dog studies; NOAEL exposures similar to or below human exposure
Why: Severe toxicity at exposures similar to or below clinical exposure reflected in SmPC section 5.3 and the RMP
“It should be taken into consideration that low margins of exposure ranging from 0.3 to 2.4 were observed in the 28-day and 13-week repeat-dose studies in rat and dog. And in general, the observed exposure at NOAEL levels were similar or below the exposure level at the maximum human recommended dose.”
“Furthermore, the severe toxicity signals at high dose levels which resulted in similar or even lower exposure levels compared to the clinical exposure (mortalities and animals needing to be euthanised) has been included in the SmPC section 5.3 and the RMP.”
GenotoxicityAcceptedBeyond the letter
No definitive GLP genotoxicity assays with major human metabolites M11 and M68
Why: Parent not genotoxic and metabolites structurally related; totality of data suggests low genotoxicity risk · Weight of evidence
“The Applicant did not conduct definitive GLP genotoxicity assays with M68 and M11.”
“Given that adagrasib, was not genotoxic in in vitro and in vivo GLP genotoxicity assays (see discussion below) and that metabolites M11 and M68 are structurally related to adagrasib, the totality of the data suggests that there is low risk of genotoxicity with the metabolites.”
Safety pharmacologyQuestioned
Blood pressure in the 28-day dog study measured indirectly at the tail root, a method not fit for safety pharmacology
“Of note in the 28-day repeat-dose study (study No TX-MRTX849-009) in dogs indirect blood pressure recordings were performed from the tail roots or other appropriate sites. However, this method is not considered fit for purpose to obtain accurate measurements and to detect blood pressure fluctuations in a safety pharmacology context.”
Similar precedents
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