Fasenra
benralizumab
Species
Monkey
Longest study
39 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Pivotal nonclinical studies were conducted in Cynomolgus monkeys.”
Why that species
Binds human and cynomolgus IL-5Rα with similar affinity (KD 11 and 42 pM); no cross-reactivity with murine IL-5Rα
“Benralizumab binds to human and cynomolgus monkey IL-5Rα with KD values of 11 and 42 pM, respectively (as measured by BIAcore). Benralizumab did not cross-react with murine IL-5Rα.”
Surrogate molecule
No surrogate (mouse surrogate judged not required); the clinical antibody was tested in cynomolgus monkeys
“Further, the ECAC agreed that development of a mouse surrogate was not required.”
Species: general tox
Cynomolgus monkey only (toxicology studies up to 39 weeks)
“Pivotal nonclinical studies were conducted in Cynomolgus monkeys. In toxicology studies up to 39 weeks duration, NOAELs of 10 mg/kg IV and 30 mg/kg SC were identified.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development; fertility in 39-week study)
“An enhanced pre- and post-natal development studies were conducted with cynomolgus monkeys to evaluate benralizumab’s effects on development.”
Species: carcinogenicity
Not conducted (rodents not pharmacologically relevant)
“Carcinogenicity studies were not conducted since rodents are not pharmacologically relevant species.”
Surrogate used in
No surrogate used; ECAC agreed a mouse surrogate was not required
“Further, the ECAC agreed that development of a mouse surrogate was not required.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In the pivotal 39-week toxicity study, cynomolgus monkeys (6/sex/group) received 0 (IV/SC), 10 (IV), 25 (IV), or 30 (SC) mg/kg benralizumab once every 2 weeks for a total of 20 doses.”
Pivotal GLP studies
39-week cynomolgus study: 10 or 25 mg/kg IV, or 30 mg/kg SC, every 2 weeks (20 doses)
“In the pivotal 39-week toxicity study, cynomolgus monkeys (6/sex/group) received 0 (IV/SC), 10 (IV), 25 (IV), or 30 (SC) mg/kg benralizumab once every 2 weeks for a total of 20 doses.”
Route in tox
IV and SC
“In the pivotal 39-week toxicity study, cynomolgus monkeys (6/sex/group) received 0 (IV/SC), 10 (IV), 25 (IV), or 30 (SC) mg/kg benralizumab once every 2 weeks for a total of 20 doses.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not applicable to a therapeutic protein
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Carcinogenicity
Not conducted (rodents not pharmacologically relevant); risk assessment accepted by CDER ECAC
“Carcinogenicity studies were not conducted since rodents are not pharmacologically relevant species. AstraZeneca submitted a carcinogenicity risk assessment that was evaluated by the CDER Executive Carcinogenicity Assessment Committee.”
Reproductive & developmental
Monkey ePPND: not teratogenic; NOAEL for maternal toxicity and teratogenicity 30 mg/kg
“Benralizumab was not teratogenic in cynomolgus monkeys. The NOAEL for maternal toxicity and teratogenicity was identified at 30 mg/kg.”
Safety pharmacology
Incorporated into monkey toxicity studies (cardiovascular, respiratory, CNS) up to 30 mg/kg; no toxicity
“These studies included assessment of potential effect of benralizumab on cardiovascular, respiratory and central nervous systems, following single and repeated subcutaneous and intravenous doses, up to 30 mg/kg. There was no indication of toxicity in these evaluations.”
Genotox: Ames
Not conducted (not applicable to a therapeutic protein)
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Genotox: in vitro mammalian
Not conducted (not applicable to a therapeutic protein)
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Genotox: in vivo
Not conducted (not applicable to a therapeutic protein)
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Carcinogenicity model
Not conducted; no binding to murine IL-5Rα makes a 2-year rodent bioassay inappropriate
“Since benralizumab does not bind to murine IL-5Rα, direct assessment of carcinogenic risk of benralizumab in a classic 2-year rodent bioassay was not appropriate.”
Carcinogenicity timing
Not required (agreed by CDER Executive Carcinogenicity Assessment Committee)
“AstraZeneca submitted a carcinogenicity risk assessment that was evaluated by the CDER Executive Carcinogenicity Assessment Committee. The Committee agreed that a carcinogenicity study was not required.”
hERG / QT
No hERG assay; no abnormal ECG findings in monkey toxicity study
“There were no abnormal ECG findings in any animals on study.”
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 Fasenra 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 10 mg/kg IV and 30 mg/kg SC; post-dose reaction (bruising, low platelets, abnormal erythrocytes) in one 25 mg/kg IV female (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
NOAEL 10 mg/kg IV and 30 mg/kg SC; post-dose reaction (bruising, low platelets, abnormal erythrocytes) in one 25 mg/kg IV female
“NOAELs of 10 mg/kg IV and 30 mg/kg SC were identified. The primary finding at a dose of 25 mg/kg IV was a post-dose reaction in one high-dose female that included bruising in the areas of the eyes, face, chest and lower abdomen, a decrease in platelet counts, and abnormal erythrocytes after the fourth dose.”
Risksopen answer page →
Immune & cytokine safety
ADA in 8.3%, 25% and 5.5% of monkeys in the 9-, 15- and 39-week studies
“Testing for development of anti-benralizumab antibodies was also completed and this was seen in 2 of 24 (8.3%), 9 of 36 (25%) and 2 of 36 (5.5%) of monkeys given benralizumab in the 9-, 15- and 39-week studies, respectively.”
Biodistribution & persistence
Placental and/or milk transfer in monkeys: infants had detectable benralizumab
“In pregnant monkeys, there was evidence of placental and/or milk transfer as infants showed detectable benralizumab concentrations despite not being dosed directly.”
Modality-specific risk
Eosinophil and basophil depletion via enhanced ADCC from afucosylated Fc
“The absence of fucose in the Fc domain of benralizumab results in higher affinity for FcγRIIIa receptors (approximately 6-fold compared to the fucosylated parental antibody) on immune effector cells, leading to apoptosis of eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC).”
Anti-drug antibodies: animals
Anti-benralizumab antibodies in 8.3%, 25% and 5.5% of monkeys in 9-, 15- and 39-week studies
“Testing for development of anti-benralizumab antibodies was also completed and this was seen in 2 of 24 (8.3%), 9 of 36 (25%) and 2 of 36 (5.5%) of monkeys given benralizumab in the 9-, 15- and 39-week studies, respectively.”
Anti-drug antibodies: patients
ADA 13% in adults and adolescents (12-17) with asthma over 48-56 weeks; 12% neutralizing
“In adult and pediatric patients aged 12 to 17 years with asthma, the incidence of ADA to benralizumab in patients treated with FASENRA at the recommended dosing regimen during the 48 to 56-week treatment period was 13%. A total of 12% of patients treated with FASENRA developed neutralizing antibodies.”
Label warnings
- Hypersensitivity Reactions
- Acute Asthma Symptoms or Deteriorating Disease
- Reduction of Corticosteroid Dosage
- Parasitic (Helminth) Infection
Hypersensitivity & infusion reactionsInfections
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 Fasenra 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 10 mg/kg IV and 30 mg/kg SC; post-dose reaction (bruising, low platelets, abnormal erythrocytes) in one 25 mg/kg IV female (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (IV/SC) study with 12-week recovery
“partially reversibility of the reduction in eosinophils was noted in the 39-week study (the recovery period was 12 weeks)”
Pivotal GLP studies
39-week cynomolgus study: 10 or 25 mg/kg IV, or 30 mg/kg SC, every 2 weeks (20 doses)
“In the pivotal 39-week toxicity study, cynomolgus monkeys (6/sex/group) received 0 (IV/SC), 10 (IV), 25 (IV), or 30 (SC) mg/kg benralizumab once every 2 weeks for a total of 20 doses.”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development; fertility in 39-week study)
“An enhanced pre- and post-natal development studies were conducted with cynomolgus monkeys to evaluate benralizumab’s effects on development.”
Reproductive & developmental
Monkey ePPND: not teratogenic; NOAEL for maternal toxicity and teratogenicity 30 mg/kg
“Benralizumab was not teratogenic in cynomolgus monkeys. The NOAEL for maternal toxicity and teratogenicity was identified at 30 mg/kg.”
PPND / ePPND: when
ePPND in cynomolgus monkey completed before the marketing application
“To evaluate the effects of benralizumab in development, an enhanced pre- and post-natal development (ePPND) study was conducted in cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted (rodents not pharmacologically relevant)
“Carcinogenicity studies were not conducted since rodents are not pharmacologically relevant species.”
Carcinogenicity model
Not conducted; no binding to murine IL-5Rα makes a 2-year rodent bioassay inappropriate
“Since benralizumab does not bind to murine IL-5Rα, direct assessment of carcinogenic risk of benralizumab in a classic 2-year rodent bioassay was not appropriate.”
Carcinogenicity timing
Not required (agreed by CDER Executive Carcinogenicity Assessment Committee)
“AstraZeneca submitted a carcinogenicity risk assessment that was evaluated by the CDER Executive Carcinogenicity Assessment Committee. The Committee agreed that a carcinogenicity study was not required.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL AUC 153- to 271-fold the exposure at the recommended clinical dose
“The NOAEL doses were associated with systemic exposures (AUC) that provided 153- to 271-fold exposure margins compared to the recommended clinical dose.”
NOAEL / key findings
NOAEL 10 mg/kg IV and 30 mg/kg SC; post-dose reaction (bruising, low platelets, abnormal erythrocytes) in one 25 mg/kg IV female
“NOAELs of 10 mg/kg IV and 30 mg/kg SC were identified. The primary finding at a dose of 25 mg/kg IV was a post-dose reaction in one high-dose female that included bruising in the areas of the eyes, face, chest and lower abdomen, a decrease in platelet counts, and abnormal erythrocytes after the fourth dose.”
Efficacy evidenceopen answer page →
Efficacy evidence
Naive and allergen-challenged cynomolgus monkeys: eosinophil depletion in blood, bone marrow and BAL fluid
“In in vivo pharmacology studies, benralizumab, when given to naive or allergen-challenged cynomolgus monkeys, demonstrated rapid and pronounced reduction of eosinophils in blood, bone marrow and bronchoalveolar lavage fluid, demonstrating its pharmacological activity in vivo in this species.”
Why that model
Binds human and cynomolgus IL-5Rα (KD 11 and 42 pM) but not murine IL-5Rα
“Benralizumab binds to human and cynomolgus monkey IL-5Rα with KD values of 11 and 42 pM, respectively (as measured by BIAcore). Benralizumab did not cross-react with murine IL-5Rα.”
Reviewer's view of the efficacy data
EMA: monkey data sufficiently supported the eosinophil-reduction hypothesis for clinical testing; some non-responding individuals unexplained
“The reasons for these instances of difference are not understood. However, the results suggest that the hypothesis, that reducing eosinophilic cell infiltration in the lungs could improve lung function in an asthma challenge, was supported sufficiently to support clinical testing in patients with asthma.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies or mouse surrogate for chronic asthma therapy; carcinogenicity risk assessment instead
Why: Rodents not pharmacologically relevant; Executive Carcinogenicity Assessment Committee agreed rodent studies and a mouse surrogate were not required · No relevant species · Weight of evidence
“Carcinogenicity studies were not conducted since rodents are not pharmacologically relevant species.”
“The ECAC agreed that rodent carcinogenicity studies are not required for benralizumab. Further, the ECAC agreed that development of a mouse surrogate was not required.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal toxicity studies
Why: Adult indication; no nonclinical studies in the agreed paediatric investigation plan; enhanced pre- and postnatal study results · Weight of evidence · Other reason
“The lack of studies with dosing of juvenile animals is also accepted, considering that the medicine is intended for adults, the lack of non-clinical studies in the agreed paediatric investigation plan, and the results from the enhanced pre- and post-natal development study.”
GLPCriticised but acceptedBeyond the letter
Single-dose toxicity limited to a non-GLP study in three monkeys without control group or terminal necropsy
Why: Repeat-dose GLP-compliant studies available · Weight of evidence
“Single dose toxicity studies were limited to a non-GLP study in three monkeys only with no control group or terminal necropsy: the primary objective was to evaluate toxicokinetics and immunogenicity of benralizumab.”
“The study has some insufficiencies which hinder interpretation of observed findings of haematuria and proteinuria, in addition to reduction of eosinophil counts, but as there are data from repeat dose GLP compliant studies, this is accepted.”
DARTVerdict not stated
No dedicated fertility studies; fertility endpoints assessed in the 39-week monkey study in sexually mature animals
“No dedicated fertility studies have been conducted however assessment of specific fertility endpoints (menstrual cycle lengths, testicular volume/size, sperm analysis for sperm count, morphology and motility and analysis of reproductive hormones), in addition to the reproductive organ weights and histopathology analysis at necropsy, were carried out in the 39-week repeat dose toxicity study, in which all monkeys were sexually mature.”
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