Brexafemme
ibrexafungerp
Species
RatDog
Longest study
26 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
“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”
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 compound was tested
“The 13-week studies were conducted with the citrate salt form which is the ibrexafungerp form in the current clinical formulation and these studies included 14-day recovery periods.”
Species: general tox
Rat and dog
“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“In contrast to the results of the embryo-fetal study in rabbits, ibrexafungerp was not associated with fetal malformations in a rat embryo-fetal study. Also, ibrexafungerp did not inhibit male or female fertility in a fertility study in rats or produce adverse effects on the survival, growth, behavior, or reproductive ability of first-generation offspring in a pre-postnatal study in rats.”
Species: carcinogenicity
Not conducted (limited duration of use for VVC)
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
26 (26-week rat)
“Daily administration of oral ibrexafungerp for 26 weeks in rats, at the highest dose of 80 mg/kg/day (approximately 10 times the RHD based on AUC comparison), was associated with marked, but reversible, phospholipidosis and foamy histiocytes in alveolar tissue in the lung and labored breathing, marked irritation and metaplasia in gastric mucosa, and peripheral nerve degeneration accompanied by hind-limb paralysis.”
Pivotal GLP studies
1-month and 13-week oral studies in rats and dogs
“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”
Route in tox
Oral gavage
“Administration of SCY-078 citrate by once daily oral gavage for 13 weeks was well tolerated in dogs at dose levels of 15, 30, and 60 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat bone marrow micronucleus assays
“Ibrexafungerp was negative for genotoxicity in both nonclinical in vitro assays (Ames assays and a chromosome aberration assay in mammalian cells) and in vivo studies (micronucleus study in rat bone marrow cells).”
Carcinogenicity
Not conducted (limited duration of use for VVC)
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Reproductive & developmental
Rabbit EFD: limb, ear and body-wall malformations at about 5x human exposure
“In pregnant rabbits, oral ibrexafungerp administered during organogenesis was associated with fetal malformations including absent forelimb(s), absent hindpaw, absent ear pinna, and thoracogastroschisis at dose exposures greater or equal to approximately 5 times the human exposure at the RHD.”
Safety pharmacology
hERG IC50 about 1.4-fold the clinical Cmax
“Results from an in vitro hERG assay indicated that the ibrexafungerp IC50 for hERG inhibition was 1.4-fold higher than the plasma Cmax value associated with the recommended clinical dose of 600 mg/day ibrexafungerp in fed patients.”
Genotox: Ames
Negative (Ames)
“Ibrexafungerp was negative for genotoxicity in both nonclinical in vitro assays (Ames assays and a chromosome aberration assay in mammalian cells) and in vivo studies (micronucleus study in rat bone marrow cells).”
Genotox: in vitro mammalian
Chromosome aberration assay in mammalian cells: negative
“Ibrexafungerp was negative for genotoxicity in both nonclinical in vitro assays (Ames assays and a chromosome aberration assay in mammalian cells) and in vivo studies (micronucleus study in rat bone marrow cells).”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Ibrexafungerp was negative for genotoxicity in both nonclinical in vitro assays (Ames assays and a chromosome aberration assay in mammalian cells) and in vivo studies (micronucleus study in rat bone marrow cells).”
Carcinogenicity model
Not conducted (limited duration of use for VVC)
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Carcinogenicity timing
Not performed due to the limited duration of use for VVC
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
hERG / QT
hERG IC50 only ~1.4-fold above clinical Cmax at 600 mg/day
“Results from an in vitro hERG assay indicated that the ibrexafungerp IC50 for hERG inhibition was 1.4-fold higher than the plasma Cmax value associated with the recommended clinical dose of 600 mg/day ibrexafungerp in fed patients.”
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 Brexafemme 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: Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month) (FDA multi-discipline review, p. 42)
NOAEL / key findings
Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month)
“Several ibrexafungerp-related toxicities with potential clinical relevance occurred in a dose-dependent manner in the 1-month toxicology study in rats including degeneration of skeletal muscle cells and stomach glandular mucosa and single-cell necrosis of hepatocytes.”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid necrosis in high-dose rats (1-month study)
“Thymus: Very slight lymphoid necrosis in the thymus was observed in 3/10 HD males and moderate lymphoid necrosis was observed in 1/10 HD females.”
Biodistribution & persistence
Extensive tissue distribution (large intestine, pituitary, bone marrow, liver); no radioactivity in brain/CNS
“Extensive distribution to tissues was observed with the highest concentrations in large intestine, pituitary gland, bone marrow, and liver followed by lung and kidney, minimal concentrations in male reproductive organs, and no detectable radioactivity in brain and CNS tissues.”
Modality-specific risk
Embryofetal toxicity (rabbit malformations)
“Ibrexafungerp was associated with serious dose-related fetal malformations in rabbits at exposures 5- to 13-times the expected clinical exposure.”
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 evaluated (small molecule, no immune response expected)
“Ibrexafungerp is a small molecule that is not expected to provoke a host immune response; therefore, immunogenicity was not specifically evaluated.”
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 Brexafemme 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: Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month) (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week rat (oral); high-dose findings described as reversible (recovery length not stated)
“Daily administration of oral ibrexafungerp for 26 weeks in rats, at the highest dose of 80 mg/kg/day (approximately 10 times the RHD based on AUC comparison), was associated with marked, but reversible, phospholipidosis and foamy histiocytes in alveolar tissue in the lung and labored breathing”
Pivotal GLP studies
1-month and 13-week oral studies in rats and dogs
“Oral-dose toxicology studies with ibrexafungerp included 1-month and 13-week studies in rats and dogs.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“In contrast to the results of the embryo-fetal study in rabbits, ibrexafungerp was not associated with fetal malformations in a rat embryo-fetal study. Also, ibrexafungerp did not inhibit male or female fertility in a fertility study in rats or produce adverse effects on the survival, growth, behavior, or reproductive ability of first-generation offspring in a pre-postnatal study in rats.”
Reproductive & developmental
Rabbit EFD: limb, ear and body-wall malformations at about 5x human exposure
“In pregnant rabbits, oral ibrexafungerp administered during organogenesis was associated with fetal malformations including absent forelimb(s), absent hindpaw, absent ear pinna, and thoracogastroschisis at dose exposures greater or equal to approximately 5 times the human exposure at the RHD.”
PPND / ePPND: when
PPND in rat (oral gavage) completed before the marketing application
“A Developmental and Perinatal/Postnatal Reproduction Study of SCY-078 by Oral Gavage in Rats, Including a Postnatal Behavioral/Functional Evaluation/ SCY078- TOX-029”
Carcinogenicity
Species: carcinogenicity
Not conducted (limited duration of use for VVC)
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Carcinogenicity model
Not conducted (limited duration of use for VVC)
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Carcinogenicity timing
Not performed due to the limited duration of use for VVC
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit EFD: NOAEL ~2x and LOAEL ~5x human AUC in fed patients
“The plasma AUC values associated with the No-Observed-Adverse-Effect Level (NOAEL) and Lowest-Observed-Adverse-Effect Level (LOAEL) doses in rabbits are approximately 2- and 5-times respectively the plasma AUC exposures expected for fed patients.”
NOAEL / key findings
Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month)
“Several ibrexafungerp-related toxicities with potential clinical relevance occurred in a dose-dependent manner in the 1-month toxicology study in rats including degeneration of skeletal muscle cells and stomach glandular mucosa and single-cell necrosis of hepatocytes.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro antifungal activity against Candida species (MIC90 0.015-4 ug/mL)
“Ibrexafungerp demonstrated activity with MIC90 values ranging from 0.015 – 4 μg/mL against C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. lusitaniae, C. guillermondii, C. orthopsilosis, C. pelliculosa, C. kefyr, and C. auris.”
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: only C. albicans supported clinically; other Candida species listed on in vitro data alone
“Therefore, the “first list” of microorganisms only includes Candida albicans. The second list which is based solely on in vitro data includes the following fungal organisms”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
No carcinogenicity studies
Why: Limited duration of intended use for VVC · Within the guideline
“Carcinogenicity studies were not performed for ibrexafungerp due to the limited duration of its intended use for the treatment of VVC.”
Safety marginAccepted with a conditionBeyond the letter
Rabbit embryo-fetal NOAEL only about 2-fold, LOAEL about 5-fold, clinical AUC with severe malformations
Why: Contraindication in pregnancy, pregnancy verification and contraception advice in labeling
“The plasma AUC values associated with the No-Observed-Adverse-Effect Level (NOAEL) and Lowest-Observed-Adverse-Effect Level (LOAEL) doses in rabbits are approximately 2- and 5-times respectively the plasma AUC exposures expected for fed patients.”
“A contraindication for use in pregnancy will be included in the labeling. Providers will be advised to verify pregnancy status for females of reproductive potential prior to oral ibrexafungerp treatment and recommend use of effective contraception during treatment and for 4 days after the last dose.”
Safety pharmacologyAcceptedBeyond the letter
hERG IC50 only 1.4-fold the clinical Cmax
Why: No QTc prolongation at high exposures in a clinical study · Human data
“Results from an in vitro hERG assay indicated that the ibrexafungerp IC50 for hERG inhibition was 1.4-fold higher than the plasma Cmax value associated with the recommended clinical dose of 600 mg/day ibrexafungerp in fed patients.”
“A potential for QTc prolongation revealed in an assessment of ibrexafungerp inhibition of hERG activity is not expected to be a clinical concern based on the lack of QTc prolongation with high ibrexafungerp exposures in a Phase 1 study.”
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