Exblifep
cefepime and enmetazobactam
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
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Why that species
Metabolic profiles in rats, dogs and rabbits similar to humans
“The metabolic profiles of enmetazobactam in rats, dogs, rabbits and humans were similar which supports the selection of these animal species as the primary toxicology species.”
Surrogate molecule
No surrogate; the clinical compounds were tested alone and in combination
“Enmetazobactam given alone to rats at doses of 125, 250 and 500 mg/kg/day and at doses of 60, 120 and 240 mg/kg/day to dogs was in general well tolerated.”
Species: general tox
Rat and dog (enmetazobactam alone and with cefepime)
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Species: DART
Rat (male and female fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive and developmental toxicology studies (male and female fertility studies in rats, embryofetal development studies in rats and rabbits, and a pre-postnatal development study in rats)”
Species: carcinogenicity
Not conducted (intended therapy duration ≤14 days)
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Surrogate used in
No surrogate used; enmetazobactam tested directly in rat, dog and rabbit
“The metabolic profiles of enmetazobactam in rats, dogs, rabbits and humans were similar which supports the selection of these animal species as the primary toxicology species.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week dog combination study)
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Pivotal GLP studies
28-day IV enmetazobactam rat and dog studies; 28-day rat and 13-week dog cefepime-enmetazobactam combination studies
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
Route in tox
Intravenous, once daily
“All studies used once daily IV administration and included a recovery phase.”
Skipped studiesopen answer page →
Genotoxicity
Enmetazobactam negative in Ames, CHO chromosomal aberration and mouse bone marrow micronucleus assays
“Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Carcinogenicity
Not conducted (intended duration of therapy ≤14 days)
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Reproductive & developmental
Rat and rabbit EFD: no malformations; reduced maternal weight gain and fetal body weights
“In embryo-fetal development (EFD) studies in rats and rabbits, enmetazobactam was not associated with fetal malformations, but did cause maternal toxicity in the form of reduced body weight gain and fetal toxicity as reduced fetal body weights in both studies.”
Safety pharmacology
hERG IC50 1,254.22 µg/mL (63-fold over MRHD Cmax); low QT risk
“The hERG study revealed an IC50 -value of 1,254.22 µg/mL, corresponding to 3,990.30 μM, for enmetazobactam which translates into a 63-fold safety margin compared to the Cmax level of 19.8 µg/ml at the MRHD. Thereby, the potential risk for QT prolongation in humans is low.”
Genotox: Ames
Enmetazobactam: negative
“Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Genotox: in vitro mammalian
Enmetazobactam CHO chromosomal aberration: negative
“Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Genotox: in vivo
Enmetazobactam mouse bone marrow micronucleus: negative
“Enmetazobactam was negative for genetic toxicity in vitro in a bacterial reverse mutation assay and a chromosomal aberration assay in Chinese Hamster ovary cells, and in vivo in a mouse micronucleus assay in bone marrow cells.”
Carcinogenicity model
Not conducted (intended therapy duration ≤14 days)
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Carcinogenicity timing
Not conducted and not planned for enmetazobactam: intended therapy duration of 14 days or less
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
hERG / QT
Enmetazobactam hERG IC50 1,254.22 µg/mL, 63-fold over MRHD Cmax; low QT risk
“The hERG study revealed an IC50 -value of 1,254.22 µg/mL, corresponding to 3,990.30 μM, for enmetazobactam which translates into a 63-fold safety margin compared to the Cmax level of 19.8 µg/ml at the MRHD. Thereby, the potential risk for QT prolongation in humans is low.”
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 Exblifep 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study) (FDA integrated review, p. 42)
NOAEL / key findings
Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study)
“In the 28-day study in dogs, the increased liver enzymes correlated with microscopic evidence of single-hepatocyte necrosis, and in the combination toxicology study, liver enzyme increases correlated with granular hepatocellular inclusions.”
Risksopen answer page →
Immune & cytokine safety
Guinea pig maximization test: no skin sensitization
“At 24 and 48 hours after the challenge patch removal, the guinea pigs induced and challenged with AAI101 did not exhibit any skin responses and received the same Magnusson and Kligman grades (0% positive reaction) as the vehicle control group.”
Biodistribution & persistence
No melanin binding; no preferential retention in skin, eye or uveal tract
“There was no preferential distribution to or retention in the skin, the eye or the uveal tract, i.e., no specific binding of [14C]-enmetazobactam and drug related radioactivity to melanin was indicated.”
Modality-specific risk
Hepatotoxicity (liver primary target of enmetazobactam)
“Based on the 28-day Repeated Dose Toxicity (RDT) studies of enmetazobactam and the 28-day and 13-week combination studies in rats and dogs, the liver appears to be a primary target of toxicity for enmetazobactam.”
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 applicable (small molecule)
“Immunogenicity Assessment—Impact of PK/PD, Efficacy, and Safety Not Applicable”
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 Exblifep 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study) (FDA integrated review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IV beagle dog study (enmetazobactam, cefepime and combination) with 8-week recovery
“AAI101, cefepime and AAI101 + cefepime: 13-week intravenous toxicity study in beagle dog followed by an 8-week recovery period”
Pivotal GLP studies
28-day IV enmetazobactam rat and dog studies; 28-day rat and 13-week dog cefepime-enmetazobactam combination studies
“general toxicology studies (28-day IV-dose studies in rats and dogs, a 28-day combination toxicology study with cefepime and enmetazobactam in rats, and a 13-week combination toxicology study with cefepime and enmetazobactam in dogs)”
DART package
Species: DART
Rat (male and female fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive and developmental toxicology studies (male and female fertility studies in rats, embryofetal development studies in rats and rabbits, and a pre-postnatal development study in rats)”
Reproductive & developmental
Rat and rabbit EFD: no malformations; reduced maternal weight gain and fetal body weights
“In embryo-fetal development (EFD) studies in rats and rabbits, enmetazobactam was not associated with fetal malformations, but did cause maternal toxicity in the form of reduced body weight gain and fetal toxicity as reduced fetal body weights in both studies.”
PPND / ePPND: when
PPND in rat (enmetazobactam, IV) completed and reviewed with the marketing application
“In the pre-postnatal development study in rats with enmetazobactam, maternal body weights and the body weights of first-generation offspring were reduced, and pinna detachment in first-generation offspring was delayed with maternal doses of 500 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Not conducted (intended therapy duration ≤14 days)
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Carcinogenicity model
Not conducted (intended therapy duration ≤14 days)
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Carcinogenicity timing
Not conducted and not planned for enmetazobactam: intended therapy duration of 14 days or less
“Carcinogenicity studies of enmetazobactam have not been conducted and are not planned based on the intended duration of therapy (≤ 14 days).”
Safety marginopen answer page →
Safety margin at NOAEL
28-day dog: highest enmetazobactam dose without liver effects 2.8x MRHD exposure
“The exposure margin for the highest enmetazobactam dose not associated with increased liver enzymes and liver histopathology in the 28-day dog study was 2.8-times the maximum recommended human dose of enmetazobactam.”
NOAEL / key findings
Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study)
“In the 28-day study in dogs, the increased liver enzymes correlated with microscopic evidence of single-hepatocyte necrosis, and in the combination toxicology study, liver enzyme increases correlated with granular hepatocellular inclusions.”
Efficacy evidenceopen answer page →
Efficacy evidence
Neutropenic murine thigh infection model (ESBL K. pneumoniae) and hollow-fiber infection model
“dose-fractionation studies in hollow fiber and neutropenic murine thigh infection models identified %fT >2 µg/mL (i.e., the percentage of time that unbound drug concentrations exceed the threshold concentration of 2 µg/mL) as the PK-PD index that best correlates with enmetazobactam’s activity.”
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
EMA: thigh-model PK-PD target (45% fT>CT) acceptable; thigh-model AUC similar to patient AUC adds support
“From these findings, an enmetazobactam non-clinical target of 45% fT>CT was selected which is acceptable. AUC also correlated relatively well with enmetazobactam activity (Figure 65), and the AUC studied in the thigh model that provided activity is fairly similar to the AUC in patients, providing some additional support.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
No exposure margin for enmetazobactam liver effects; combination-study NOAELs below MRHD exposure in dogs and rats
Why: No margin in rats or for dog NOAELs, and liver effects seen clinically; findings described in the SmPC · Human data
“For the NOAELs in the combination studies of enmetazobactam given together with cefepime, the margin to the exposure at the MRHD was 0.71 in dogs and 0.86 or lower in rats.”
“Anyway, as there is no margin to the clinical exposure for any of the dose levels in rats or for the NOAELs for corresponding effects in dogs, and risk for increased liver enzymes and liver effects has been observed in the clinic, information on the non-clinical liver effects have been included in the SmPC.”
DARTAcceptedBeyond the letter
Male fertility study did not continue dosing through mating until conception, deviating from ICH S5(R3)
Why: Dosing shortfall was less than 3 days; unlikely to change the male fertility outcome · Other reason
“Note: The study design for this study deviated from recommendations in the ICH S5(R3) Guideline. Males in the study were administered vehicle or test article for 1-month during the premating period, but dosing was not continued during the mating period at least until verification of conception as recommended in the Guideline.”
“Conception for untreated females mated with treated males occurred over a range of 2.0 to 2.7 days after the start of mating, so the deficiency in dosing duration was less than 3 days. This minor deviation was considered unlikely to produce a different study outcome with regard to male fertility.”
OtherVerdict not stated
Combination toxicity studies used an enmetazobactam/cefepime ratio different from the clinical ratio
Why: Exact ratio not defined during preclinical development
“The Applicant acknowledges that the combination ratio was dissimilar between non-clinical and clinical studies, as the exact ratio was not defined during the preclinical development.”
Safety marginVerdict not stated
Exposure margins for enmetazobactam in reproductive and developmental studies very low or undetermined
“The safety margins from animal to human exposure ratio for enmetazobactam in the reproduction and development studies were very low or undetermined.”
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