Nemluvio
nemolizumab
Species
Monkey
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 only
“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”
Why that species
No binding to mouse, rat or rabbit IL-31RA; binds human and monkey IL-31RA with similar tissue staining
“No interactions were detected between nemolizumab and IL-31RA from mice, rats, or rabbits.”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkeys (mouse anti-IL-31RA BM095 used only in an AD mouse pharmacology model)
“In addition, by using a mouse surrogate anti-IL31RA monoclonal antibody (BM095) the effect of blocking IL-31RA in a mite antigen-induced AD mouse model was evaluated.”
Species: general tox
Cynomolgus monkey only (3- and 6-month studies)
“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”
Species: DART
Cynomolgus monkey: fertility endpoints in 6-month toxicity study; EFD, pre/postnatal and juvenile in ePPND study
“Safety pharmacology endpoints and fertility assessment were incorporated into the 6-month repeat-dose toxicity study. Embryofetal development, pre- and postnatal development, and juvenile toxicity were evaluated in the ePPND study.”
Species: carcinogenicity
Not conducted; ECAC concurred that carcinogenicity studies are not needed
“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”
Surrogate used in
Yes: mouse IL-31RA neutralizing antibody BM095 in a mite antigen-induced AD mouse model
“The Applicant created BM095, a mouse IL-31RA neutralizing antibody. The effects of BM095 on a mite antigen-induced mouse AD model were investigated.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Dose and frequency of dosing: 0 (vehicle), 1, 5, and 25 mg/kg, once every two weeks for 26 weeks (14 doses in total)”
Pivotal GLP studies
GLP cynomolgus monkey SC repeat-dose studies of 3 and 6 months, biweekly dosing
“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genetic toxicology studies are not needed to support the development of nemolizumab, per the International Council for Harmonisation (ICH) S6(R1) guidance”
Carcinogenicity
Not conducted; weight-of-evidence assessment; no proliferative lesions or immunosuppression in 6-month monkey study
“There was no evidence of tissue proliferation (i.e., hyperplasia, preneoplastic lesions) or immunosuppression in the 6-month repeat-dose subcutaneous toxicity study in monkeys.”
Reproductive & developmental
Monkey ePPND: no maternal or embryofetal toxicity up to 25 mg/kg; increased early postnatal death at 25 mg/kg (3 vs 1 control)
“Early postnatal death occurred in the offspring of one control monkey and 3 monkeys at 25 mg/kg (36 times the MRHD for PN and 50 times for AD, based on AUC comparison).”
Safety pharmacology
Incorporated into repeat-dose monkey studies: no effects on ECG, blood pressure, respiration or neurobehavior
“Safety pharmacology parameters were studied in GLP toxicity studies in cynomolgus monkeys, which is in line with ICH S6(R1). No significant effects on the cardiovascular system (ECG and/or blood pressure) were observed in the 3- and/or 6-month toxicity studies”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genetic toxicology studies are not needed to support the development of nemolizumab, per the International Council for Harmonisation (ICH) S6(R1) guidance”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genetic toxicology studies are not needed to support the development of nemolizumab, per the International Council for Harmonisation (ICH) S6(R1) guidance”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genetic toxicology studies are not needed to support the development of nemolizumab, per the International Council for Harmonisation (ICH) S6(R1) guidance”
Carcinogenicity model
Not conducted; carcinogenicity risk assessment reviewed by ECAC instead
“Carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of nemolizumab. The Applicant submitted a carcinogenicity risk assessment to the corresponding IND, and it was reviewed by the Executive Carcinogenicity Assessment Committee of Center for Drug Evaluation and Research.”
Carcinogenicity timing
Not required (ECAC concurrence)
“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”
hERG / QT
No significant ECG or blood pressure effects in 3- and 6-month monkey studies
“No significant effects on the cardiovascular system (ECG and/or blood pressure) were observed in the 3- and/or 6-month toxicity studies”
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 Nemluvio 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 25 mg/kg every two weeks (high dose) in 26-week monkey study; no significant toxicity (FDA integrated review, p. 105)
NOAEL / key findings
NOAEL 25 mg/kg every two weeks (high dose) in 26-week monkey study; no significant toxicity
“No significant toxicity was noted in this study. The NOAEL was identified as the high dose, 25 mg/kg once every two weeks.”
Risksopen answer page →
Immune & cytokine safety
In vitro whole-blood cytokine release far below alemtuzumab/TGN1412 controls; no effects on monkey TDAR, lymphocyte subsets or serum cytokines; ADA in some monkeys
“An increase in TNF or IL-6 concentration was observed in 2 samples after nemolizumab exposure (1 sample for each of the cytokines), but the levels were considerably lower than the levels reached with the positive controls”
Biodistribution & persistence
Crossed placenta in monkeys: offspring plasma on PND 7 comparable to dams
“Concentrations of nemolizumab in offspring plasma on postnatal day (PND) 7 were comparable to those in dams, suggesting that nemolizumab crossed the placenta.”
Modality-specific risk
Higher postnatal loss in high-dose monkey ePPND; otherwise no unexpected or off-target toxicity
“In vitro and in vivo toxicity studies conducted with nemolizumab identified no unexpected toxicities or off-target findings, with the exception of higher postnatal loss in ePPND study in dams treated with high dose of 25 kg/mg/q2w.”
Anti-drug antibodies: animals
ADA in both monkey repeat-dose studies, neutralizing in some animals; ADA correlated with loss of exposure
“ADA were detected in both RTD studies, and in some animals neutralizing effects were evident. As expected, there was a good correlation between the development of ADA and loss of exposure to nemolizumab.”
Anti-drug antibodies: patients
PN: 7% treatment-emergent ADA, 3% neutralizing (24 weeks); AD: 6.1% (67/1092) up to 16 weeks
“Prurigo Nodularis: In the Phase 3 trials (OLYMPIA 1, OLYMPIA 2) up to 24 weeks, the incidence of treatment-emergent ADAs was 7%; neutralizing antibodies were seen in 3% of subjects. Atopic Dermatitis: In the phase 3 trials (ARCADIA 1, ARCADIA 2) up to 16 weeks, the incidence of treatment-emergent ADAs was 6.1% (67/1092).”
Label warnings
- Hypersensitivity
- Vaccinations
Hypersensitivity & infusion reactions
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 Nemluvio 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 25 mg/kg every two weeks (high dose) in 26-week monkey study; no significant toxicity (FDA integrated review, p. 105)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey SC study with 17-week recovery
“26 weeks of nemolizumab treatment (with a 17-week recovery period) using SC dosing was well tolerated in Cynomolgus monkey, and no mortalities or adverse toxicities were noted.”
Pivotal GLP studies
GLP cynomolgus monkey SC repeat-dose studies of 3 and 6 months, biweekly dosing
“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”
DART package
Species: DART
Cynomolgus monkey: fertility endpoints in 6-month toxicity study; EFD, pre/postnatal and juvenile in ePPND study
“Safety pharmacology endpoints and fertility assessment were incorporated into the 6-month repeat-dose toxicity study. Embryofetal development, pre- and postnatal development, and juvenile toxicity were evaluated in the ePPND study.”
Reproductive & developmental
Monkey ePPND: no maternal or embryofetal toxicity up to 25 mg/kg; increased early postnatal death at 25 mg/kg (3 vs 1 control)
“Early postnatal death occurred in the offspring of one control monkey and 3 monkeys at 25 mg/kg (36 times the MRHD for PN and 50 times for AD, based on AUC comparison).”
PPND / ePPND: when
ePPND in cynomolgus monkey completed before the marketing application
“The toxicity profile of nemolizumab has been adequately evaluated in repeat-dose subcutaneous toxicity studies with treatment durations up to 6 months and an enhanced pre- and postnatal development (ePPND) study in cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted; ECAC concurred that carcinogenicity studies are not needed
“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”
Carcinogenicity model
Not conducted; carcinogenicity risk assessment reviewed by ECAC instead
“Carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of nemolizumab. The Applicant submitted a carcinogenicity risk assessment to the corresponding IND, and it was reviewed by the Executive Carcinogenicity Assessment Committee of Center for Drug Evaluation and Research.”
Carcinogenicity timing
Not required (ECAC concurrence)
“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 25 mg/kg Q2W (6 months) 53x MRHD for PN and 72x for AD (AUC)
“No effects on fertility parameters as reproductive organ morphology, menstrual cycle length, or sperm/testicular analysis were observed in male or female sexually mature cynomolgus monkeys that were administered nemolizumab-ilto at subcutaneous doses up to 25 mg/kg once every two weeks for 6 months (53 times the MRHD for PN and 72 times for AD, based on AUC comparison).”
NOAEL / key findings
NOAEL 25 mg/kg every two weeks (high dose) in 26-week monkey study; no significant toxicity
“No significant toxicity was noted in this study. The NOAEL was identified as the high dose, 25 mg/kg once every two weeks.”
Efficacy evidenceopen answer page →
Efficacy evidence
Clinical antibody in IL-31-induced itch model in cynomolgus monkeys; mouse surrogate BM095 in mite antigen-induced AD mouse model
“In vivo pharmacology studies investigating the itch-inhibiting effect of nemolizumab in a cynomolgus monkey model and effects of an anti-mouse IL-31RA surrogate antibody in a mite antigeninduced AD mouse model were also provided.”
Why that model
Nemolizumab cross-reacts only with monkey IL-31RA, and no monkey AD model exists
“Based on presented data nemolizumab appears to cross react only to IL-31RA in cynomolgus monkeys. No monkey AD model exists, however, in vivo studies were conducted to assess the effect of nemolizumab in the cynomolgus monkey in an IL-31-induced itch model.”
Reviewer's view of the efficacy data
EMA: monkey itch data support effect on IL-31-induced itch; surrogate mouse AD data further support IL-31RA blockade
“Furthermore, in vivo data from a cynomolgus monkey itch model provide support for effect of nemolizumab on IL-31-induced itching. Reduction of scratching and exacerbation of dermatitis symptoms by a mouse surrogate anti-IL31RA antibody in a mite antigen-induced mouse AD model provides further support for that blocking of IL-31RA could ameliorate itching and inflammation.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for chronic prurigo nodularis and atopic dermatitis use; literature weight-of-evidence instead
Why: Literature on IL-31 inhibition raises no significant carcinogenicity concern · Weight of evidence
“A weight-of-evidence analysis does not raise significant safety concerns for carcinogenicity based on the evaluation of available literature related to IL31 inhibition.”
“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”
DARTAccepted
Monkey enhanced pre- and postnatal development study in place of a separate embryo-fetal development study
Why: ePPND may replace an EFD study in accordance with ICH S5 · Within the guideline
“While the ePPND study, where Non-Human Primates (NHPs) are generally selected by ultrasound scanning at GD 18–20 to start on study, gives no information regarding effects of exposure during implantation and earliest stages of embryogenesis, an ePPND study can be conducted instead of an EFD study in accordance with ICH S5.”
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