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.”
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”
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 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 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.”