Nucala
mepolizumab
Species
MonkeyMouse
Longest study
26 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 (clinical antibody); mouse with surrogate antibody for fertility/EFD
“The nonclinical program with mepolizumab was conducted in Cynomolgus monkeys, which were determined to be the only pharmacologically relevant nonclinical test species.”
Why that species
Binds human and nonhuman primate IL-5 only; no binding to mouse or rat IL-5
“The species specificity of mepolizumab was restricted to human and nonhuman primate IL-5 only. Mepolizumab did not bind to mouse or rat IL-5.”
Surrogate molecule
Yes: SB264091, rat anti-human IL-5 IgG2b cross-reacting with murine IL-5, used for mouse fertility and embryofetal development study
“Fertility and embryofetal development were evaluated with male and female CD-1 mice treated with SB264091, a rat anti-human IL-5 surrogate monoclonal antibody (lgG2b), which cross reacts with human and murine IL-5.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In toxicology studies up to 6 months duration, no target organs of toxicity were identified at a SC dose of 10 mg/kg or intravenous (IV) doses of 10-100 mg/kg administered once every 4 weeks for a total of 7 doses.”
Pivotal GLP studies
Cynomolgus monkey 6-month study: 10 mg/kg SC or 10/100 mg/kg IV once every 4 weeks, 7 doses
“In a 6-month toxicology study, Cynomolgus monkeys received mepolizumab (SB240563) at a subcutaneous dose of 10 mg/kg or an intravenous dose of 10 or 100 mg/kg once every 4 weeks for a total of 7 doses”
Route in tox
IV and SC
“In a 6-month toxicology study, Cynomolgus monkeys received mepolizumab (SB240563) at a subcutaneous dose of 10 mg/kg or an intravenous dose of 10 or 100 mg/kg once every 4 weeks for a total of 7 doses”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not applicable to a therapeutic biologic protein
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Carcinogenicity
Not conducted; waived given no related findings in 6-month monkey study and infeasible rodent study
“The need for a carcinogenicity study was discussed with the Executive Carcinogenicity Assessment Committee and it was concluded that a carcinogenicity study was not required given the lack of related findings in the 6-month toxicology study in monkeys and since conduct of a study in rodents did not appear to be technically feasible.”
Reproductive & developmental
Monkey fertility (histopathology) and PPND: no effects up to 100 mg/kg IV (~70- and 30-fold margins); mouse surrogate FEED/EFD: no effects
“No effects on fertility or development parameters were identified in monkeys at doses up to 100 mg/kg IV; exposure margins of approximately 70-fold and 30-fold were available for fertility and developmental parameters, respectively. Similarly, no effects on fertility or embryofetal development parameters were identified in mice treated with the surrogate antibody.”
Safety pharmacology
Dedicated single-dose IV monkey study: no effects on arterial pressure, heart rate, respiratory rate or renal parameters up to 100 mg/kg
“Mepolizumab at single intravenous doses up to 100 mg/kg had no effects on mean arterial pressure, heart rate, respiratory rate, urinary pH and water, osmolality, sodium, potassium, chloride, and creatinine excretion rates.”
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 Nucala 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: Monkey NOAEL 100 mg/kg IV or 10 mg/kg SC q4 weeks; ~70-fold exposure margin (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
Monkey NOAEL 100 mg/kg IV or 10 mg/kg SC q4 weeks; ~70-fold exposure margin
“The NOAEL was the high IV dose of 100 mg/kg q4 weeks or the SC dose of 10 mg/kg q4 weeks; the NOAEL for IV dosing provided a safety margin of approximately 70-fold compared to the maximum recommended clinical dose based on systemic exposure comparisons.”
Risksopen answer page →
Immune & cytokine safety
No effect on infant vaccine (Tripedia) titers in monkey PPND; ADA in one mother and its infant at 10 mg/kg
“Following immunization with Tripedia®, there were no treatment-related effects on development of specific titers to the vaccine components. Anti-mepolizumab antibodies were detected in one mother and its infant from the 10 mg/kg group.”
Biodistribution & persistence
Transplacental exposure in monkeys: infant levels ~2.4x maternal, quantifiable through day 178 postpartum
“Concentrations of mepolizumab were approximately 2.4 times higher in infants than in mothers for several months post-partum. Mepolizumab was quantifiable in infant plasma samples continuing through day 178 postpartum.”
Modality-specific risk
Eosinophil depletion and host defense, including a possible role of eosinophils in antiviral responses
“The published scientific literature provides evidence that eosinophils can play a role in the antiviral host response.”