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.”
Species: general tox
Cynomolgus monkey only
“The nonclinical program with mepolizumab was conducted in Cynomolgus monkeys, which were determined to be the only pharmacologically relevant nonclinical test species.”
Species: DART
Cynomolgus monkey (fertility histopathology in 6-month study; pre/postnatal development); mouse with surrogate antibody
“Development and reproductive endpoints were evaluated as part of the 6-month chronic toxicology study of mepolizumab in monkeys (fertility based on histopathology of male and female reproductive organs), a pre- and postnatal development study of mepolizumab in pregnant female cynomolgus monkeys, and a study in mice that were treated with a surrogate monoclonal antibody (IgG2b).”
Species: carcinogenicity
Not conducted (waived by ECAC; rodent study not technically feasible)
“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.”
Surrogate used in
Yes: rat anti-IL-5 surrogate SB264091 (IgG2b) 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.”
Genotox: Ames
Not conducted (not applicable to a biologic protein)
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Genotox: in vitro mammalian
Not conducted (not applicable to a biologic protein)
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Genotox: in vivo
Not conducted (not applicable to a biologic protein)
“Genetic toxicity studies were not applicable for this therapeutic biologic protein.”
Carcinogenicity model
Not conducted; no related findings in 6-month monkey study and rodent study not technically feasible
“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.”
Carcinogenicity timing
Not required (ECAC)
“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.”
hERG / QT
No treatment-related effects on heart rate or ECG in chronic monkey toxicity study
“There were no treatment-related effects on heart rate or ECG parameters.”
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
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: 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.”
Anti-drug antibodies: animals
Weakly immunogenic in monkeys: ADA in 3% of animals (IV studies), enhancing clearance without adverse reactions
“In the intravenous studies, only 3% of the animals generated anti-drug antibodies, which resulted in an enhanced systemic clearance of mepolizumab and in no adverse reactions.”
Anti-drug antibodies: patients
Severe asthma, 100 mg: 6% (15/260) ADA; neutralizing antibodies in 1 patient; ~20% higher clearance
“In adult and adolescent patients with severe asthma receiving NUCALA 100 mg, 15/260 (6%) had detectable anti-mepolizumab antibodies. Neutralizing antibodies were detected in 1 patient with asthma receiving NUCALA 100 mg. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab.”
Label warnings
- Hypersensitivity Reactions
- Acute Symptoms of Asthma or Chronic Obstructive Pulmonary Disease or Acute Deteriorating Disease
- Opportunistic Infections: Herpes Zoster
- Reduction of Corticosteroid Dosage
- Parasitic (Helminth) Infection
Hypersensitivity & infusion reactionsPulmonary toxicityInfections
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 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
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: Monkey NOAEL 100 mg/kg IV or 10 mg/kg SC q4 weeks; ~70-fold exposure margin (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey study: SC 10 mg/kg or IV 10/100 mg/kg 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”
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”
DART package
Species: DART
Cynomolgus monkey (fertility histopathology in 6-month study; pre/postnatal development); mouse with surrogate antibody
“Development and reproductive endpoints were evaluated as part of the 6-month chronic toxicology study of mepolizumab in monkeys (fertility based on histopathology of male and female reproductive organs), a pre- and postnatal development study of mepolizumab in pregnant female cynomolgus monkeys, and a study in mice that were treated with a surrogate monoclonal antibody (IgG2b).”
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.”
PPND / ePPND: when
PPND in cynomolgus monkey (IV up to 100 mg/kg every 4 weeks) completed before the marketing application
“In reproductive toxicity studies, there were no adverse findings in a pre- and post-natal development study with monkeys that were treated with mepolizumab at IV doses up to 100 mg/kg q4 weeks”
Carcinogenicity
Species: carcinogenicity
Not conducted (waived by ECAC; rodent study not technically feasible)
“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.”
Carcinogenicity model
Not conducted; no related findings in 6-month monkey study and rodent study not technically feasible
“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.”
Carcinogenicity timing
Not required (ECAC)
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 100 mg/kg q4 weeks >90x human AUC at 100 mg SC q4 weeks
“The NOAEL of 100 mg/kg q4 weeks provides adequate safety margin (greater than 90-fold on an AUC basis) for the proposed clinical dose of 100 mg SC q4 weeks.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Acute Ascaris suum challenge asthma model in cynomolgus monkeys; reduced pulmonary eosinophilia
“In vivo, mepolizumab decreased peripheral eosinophil counts in Cynomolgus monkeys and reduced pulmonary eosinophilia in response to A. suum challenge in an acute model of asthma.”
Why that model
Mepolizumab binds only human and nonhuman primate IL-5, not 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.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo PD showed IL-5 inhibition; pharmacology programme satisfactory, no further studies required
“The in vitro and in vivo pharmacodynamic studies indicated that mepolizumab had an inhibitory effect on IL-5. The applicant conducted a satisfactory programme of pharmacology studies and the CHMP considered that further studies were not required.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
Carcinogenicity study waived for a chronic asthma indication
Why: No related findings in 6-month monkey study; rodent study not technically feasible · Weight of evidence · No relevant species
“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.”
“I agree that the decision to waive the carcinogenicity study is reasonable and the EPC for mepolizumab is appropriate.”
DARTAcceptedBeyond the letter
Embryo-fetal development studied in mice with a surrogate antibody, not in monkeys; teratogenicity not assessed in monkey PPND study
Why: Masking of embryo-foetal toxicity by insufficient drug exposure considered unlikely · Other reason
“However, mepolizumab crosses the placental barrier and the teratogenic potential of mepolizumab was not studied in the monkey pre and post-natal study. An embryofoetal development study was conducted in mice and not in monkeys.”
“The potential for masking of embryo-foetal toxicity due to insufficient drug exposure was considered unlikely. This was considered acceptable by the CHMP.”
DARTCriticised but acceptedBeyond the letter
Small monkey PPND study (8-9 infants per group) without skeletal or visceral malformation examinations
“Infants were not examined for skeletal or visceral malformations and variations. The results of this study should be judged with caution given the limitations in study design and resources.”
“The present study is considered adequate; however, it should be noted that this study was small with only 8 or 9 infant monkeys per group for assessment.”
OtherAcceptedBeyond the letter
Abbreviated toxicity programme: one species and two dose levels in pivotal studies
Why: Other standard laboratory species not suitable; chosen doses adequate · No relevant species
“The applicant conducted an abbreviated toxicity programme with mepolizumab, in only one species, the cynomolgus monkey, and at two doses in the pivotal studies.”
“The CHMP accepted that other standard laboratory species would not have been suitable and that the doses chosen for the pivotal toxicity studies were adequate.”
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