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.”
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.”
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 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: 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).”