Ensacove
ensartinib
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
“To assess the safety of ensartinib, the Applicant conducted repeat-dose toxicology studies up to 13 weeks in duration in rats and dogs.”
Why that species
Dog chosen as non-rodent because its liver microsomal metabolism most resembled human
“Because dog microsomes shared greater metabolic similarities with human microsomes (major metabolites, rate of metabolism, and relative abundance), they were selected by the Applicant as the non-rodent toxicologic species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 13-week GLP-compliant toxicology studies, ensartinib was administered QD via oral gavage to rats (12.5, 25, or 50 mg/kg) and dogs (5, 10, or 20/15 mg/kg).”
Species: general tox
Rat and dog (13-week GLP oral gavage studies)
“In the 13-week GLP-compliant toxicology studies, ensartinib was administered QD via oral gavage to rats (12.5, 25, or 50 mg/kg) and dogs (5, 10, or 20/15 mg/kg).”
Species: DART
Rat (EFD only); fertility studies not conducted per ICH S9
“Fertility and early embryonic development studies were not conducted or needed to support the use of ensartinib in the proposed indication per ICH S9. Embryo and Fetal Development Toxicity Study of X-36 Administered Via Oral Gavage in Sprague Dawley Rats”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
Surrogate used in
No surrogate used; ensartinib itself tested
“Ensartinib exhibited in vivo antitumor activity in an immunodeficient murine model of human NSCLC harboring EML4-ALK.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“To assess the safety of ensartinib, the Applicant conducted repeat-dose toxicology studies up to 13 weeks in duration in rats and dogs.”
Pivotal GLP studies
13-week GLP oral gavage studies in rats and dogs
“In the 13-week GLP-compliant toxicology studies, ensartinib was administered QD via oral gavage to rats (12.5, 25, or 50 mg/kg) and dogs (5, 10, or 20/15 mg/kg).”
Route in tox
Oral (gavage)
“In the 13-week GLP-compliant toxicology studies, ensartinib was administered QD via oral gavage to rats (12.5, 25, or 50 mg/kg) and dogs (5, 10, or 20/15 mg/kg).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and in vivo rat micronucleus assays
“Ensartinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human lymphocyte chromosome aberration assay or an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
Reproductive & developmental
Rat EFD: embryo-fetal mortality, growth alterations and malformations at exposures approximately equal to the human exposure at 225 mg/day
“Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC”
Safety pharmacology
Reversible 10% QTc increase in male dogs at 20/15 mg/kg/day (~1.6x human AUC) in the 13-week study
“male dogs dosed with 20/15 mg/kg/day ensartinib (approximately 1.6-fold the human exposure based on AUC at the clinical dose of 225 mg/day) in the 13-week toxicology study exhibited a statistically significant 10% increase in QTc prolongation compared to controls, which resolved during the recovery period.”
Genotox: Ames
Negative
“Ensartinib was not mutagenic in an in vitro Ames assay.”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration: polyploidy at ≥1.8 µg/mL (~72x free human Cmax) but not clastogenic or aneugenic
“Ensartinib induced a greater number of polyploid lymphocytes in an in vitro human lymphocyte chromosome aberration assay at concentrations as low as 1.8 µg/mL (~2.8µM; approximately 72 times the free human Cmax of 39nM at the recommended dose of 225 mg/day), but was not clastogenic or aneugenic in vitro.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Further, ensartinib did not increase micronuclei in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
hERG / QT
Reversible 10% QTc increase in male dogs at 20/15 mg/kg/day (~1.6x human AUC) in the 13-week study
“male dogs dosed with 20/15 mg/kg/day ensartinib (approximately 1.6-fold the human exposure based on AUC at the clinical dose of 225 mg/day) in the 13-week toxicology study exhibited a statistically significant 10% increase in QTc prolongation compared to controls, which resolved during the recovery period.”
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 Ensacove 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: Dog target organs: skin, liver and thymus; severe ear skin lesions at 20 mg/kg forced a dose holiday and reduction to 15 mg/kg (FDA integrated review, p. 121)
NOAEL / key findings
Dog target organs: skin, liver and thymus; severe ear skin lesions at 20 mg/kg forced a dose holiday and reduction to 15 mg/kg
“Dogs exhibited severe skin lesions particularly on the ear at 20 mg/kg, which led to dose holiday on Days 12-17 and reduced dosing at 15 mg/kg on Day 18. • The target organs of toxicity were skin, liver, and thymus.”
Risksopen answer page →
Immune & cytokine safety
Splenic lymphoid depletion and marked bone marrow hypocellularity in the 4-week dog study
“Additional findings in the 4-week dog study included increased creatine kinase, histologic lymphoid depletion in the spleen, and up to marked hypocellularity of the bone marrow.”
Biodistribution & persistence
Persists in testes at 24 h; distributes to melanin-containing skin; eye not evaluated
“While ensartinib was eliminated from most tissues after 24 hours, 87% of the Cmax was still detected in the testes. Ensartinib was detected in the skin (melanin-containing tissue), but distribution to the eye was not evaluated in this study.”
Modality-specific risk
Skin toxicity, consistent with clinical rash and pruritus
“Consistent with nonclinical findings, rash and pruritus were observed clinically with ensartinib, and the ensartinib label includes a warning for skin reactions.”
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
- Interstitial Lung Disease/Pneumonitis
- Hepatotoxicity
- Dermatologic Adverse Reactions
- Bradycardia
- Hyperglycemia
- Visual Disturbances
- Increased Creatine Phosphokinase
- Hyperuricemia
- Embryo-Fetal Toxicity
- FD&C Yellow No. 5 (Tartrazine)
Immune-mediated reactionsPulmonary toxicityHepatotoxicitySkin reactionsCardiovascularMetabolic & endocrineOcular toxicityMusculoskeletalEmbryo-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 Ensacove 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: Dog target organs: skin, liver and thymus; severe ear skin lesions at 20 mg/kg forced a dose holiday and reduction to 15 mg/kg (FDA integrated review, p. 121)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week oral rat and dog studies; rat study with 4-week recovery
“To assess the safety of ensartinib, the Applicant conducted repeat-dose toxicology studies up to 13 weeks in duration in rats and dogs. Repeat-Dose Toxicity 13-Week Oral Gavage Toxicity and Toxicokinetic Study with X-396 in Rats with a 4 Week Recovery (Study # X396-TOX-006).”
Pivotal GLP studies
13-week GLP oral gavage studies in rats and dogs
“In the 13-week GLP-compliant toxicology studies, ensartinib was administered QD via oral gavage to rats (12.5, 25, or 50 mg/kg) and dogs (5, 10, or 20/15 mg/kg).”
DART package
Species: DART
Rat (EFD only); fertility studies not conducted per ICH S9
“Fertility and early embryonic development studies were not conducted or needed to support the use of ensartinib in the proposed indication per ICH S9. Embryo and Fetal Development Toxicity Study of X-36 Administered Via Oral Gavage in Sprague Dawley Rats”
Reproductive & developmental
Rat EFD: embryo-fetal mortality, growth alterations and malformations at exposures approximately equal to the human exposure at 225 mg/day
“Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“Carcinogenicity studies were not conducted or needed to support the use of ensartinib in the currently proposed indication per International Council for Harmonisation (ICH) S9.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin stated; severe dog skin lesions at exposures ~equal to human AUC at 225 mg/day
“At exposures approximately equal to the clinical exposure based on AUC at 225 mg/day, dogs exhibited severe skin lesions particularly on the ear, which led to dose reduction.”
NOAEL / key findings
Dog target organs: skin, liver and thymus; severe ear skin lesions at 20 mg/kg forced a dose holiday and reduction to 15 mg/kg
“Dogs exhibited severe skin lesions particularly on the ear at 20 mg/kg, which led to dose holiday on Days 12-17 and reduced dosing at 15 mg/kg on Day 18. • The target organs of toxicity were skin, liver, and thymus.”
Efficacy evidenceopen answer page →
Efficacy evidence
H3122 (EML4-ALK) human NSCLC xenograft in nude mice
“Female nude mice injected subcutaneously with H3122 lung cancer cells harboring EML4-ALK E13/A20 received 0 or 25 mg/kg of ensartinib QD or 25 mg/kg BID for 3 weeks via oral gavage.”
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: nonclinical data support the potential effectiveness of ensartinib
“The nonclinical data support the potential effectiveness of ensartinib based on the following findings (see Section 13 for detailed reviews of these study reports).”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin for dog skin toxicity: severe skin lesions at exposures approximately equal to clinical AUC at 225 mg/day
“At exposures approximately equal to the clinical exposure based on AUC at 225 mg/day, dogs exhibited severe skin lesions particularly on the ear, which led to dose reduction.”
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