Blincyto
blinatumomab
Species
MonkeyMouse
Longest study
13 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
Chimpanzee (only relevant species, limited non-terminal studies) plus mouse with murine surrogate
“General toxicology studies included non-terminal repeat-dose studies of intravenous administration of blinatumomab in chimpanzees and repeat-dose studies of subcutaneous and intravenous administration of a murine surrogate in mice.”
Why that species
Binds only human and chimpanzee CD3/CD19; no binding to mouse, rat, dog, cynomolgus, rhesus or other NHP PBMC
“Blinatumomab bound to B and T lymphocytes from human and chimpanzee peripheral blood mononuclear cells (PBMC) but it did not bind to PBMC from the mouse, rat, beagle dog, squirrel monkey, African Green monkey, cynomolgus monkey, rhesus monkey, and baboon.”
Surrogate molecule
Yes: murine surrogate BiTE muS103new (anti-mouse CD19 x CD3) used for most tox, repro and safety pharm
“Because blinatumomab binds only to human and chimpanzee CD3 and CD19, the Applicant generated the murine surrogate muS103new for toxicology studies in mice and compared its activity to blinatumomab.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Therefore, in the 13-week repeat-dose toxicology study in mice, BALB/c mice were administered muS103new (0, 1, or 5 mg/kg/day; 0, 2, or 10 mg/kg/day) by subcutaneous injection twice daily with an 8-hour interval between doses for 13 weeks with a 4-week recovery period.”
Pivotal GLP studies
4-week IV and 13-week SC mouse studies (surrogate muS103new); 5-weekly-dose IV infusion chimpanzee study (blinatumomab)
“For this review, the 4-week (summarized) and 13-week studies of muS103new in mice and the 5-weekly dose study of blinatumomab in chimpanzees were reviewed.”
Route in tox
IV (bolus in mice, 2-h infusion in chimpanzee); SC twice daily in 13-week mouse study
“The intended clinical route is intravenous infusion. Most animal studies were conducted with the intravenous route. The 13-week mouse study was conducted with subcutaneous administration; intravenous bolus injection was not considered feasible by the applicant for this study.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1); protein of natural amino acids)
“In vitro and in vivo genotoxicity studies were not performed in accordance with ICH S6 (R1).”
Carcinogenicity
Not conducted (ICH S9, advanced cancer indication)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
Reproductive & developmental
Mouse EFD with surrogate: placental transfer, no embryo-fetal toxicity or teratogenicity; no fertility studies
“Studies in mice using the surrogate showed no drug-related effects in male or female reproductive organs and did not reveal any embryo-fetal toxicity or teratogenicity.”
Safety pharmacology
CNS (Irwin, ICV infusion) and respiratory studies in mice with surrogate; CV in chimpanzee tox studies
“To evaluate the potential effects on the central nervous system (CNS), two CNS safety pharmacology studies were conducted with the murine surrogate muS103new in mice.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
No NOAEL assigned; lymphoid tissues target organs (lymphocyte depletion, decreased cellularity); chimp hypotension dose-limiting at 0.12 ug/kg
“Following daily administration of the surrogate for 4 or 13 weeks in mice, lymphoid tissues were the target organs of toxicity with decreased spleen weights and decreased cellularity or germinal center development observed in the lymph nodes, Peyer’s patches, and spleen.”
Risksopen answer page →
Immune & cytokine safety
IL-2, IL-6, IFN-gamma release in chimpanzees, consistent with clinical CRS; ADA to surrogate in mice
“Increases in cytokines IL-2, IL-6, and INFγ were also observed following infusion with blinatumomab in chimpanzees, a finding consistent with the cytokine release syndrome observed in the clinical trial in patients with ALL.”
Biodistribution & persistence
Short half-life (1.5-8 h), rapid elimination with renal clearance; surrogate crosses placenta
“The mean terminal half-lives in the tested species ranged from 1.5 to 8 hours, indicating rapid elimination of the drug.”
Modality-specific risk
CRS and neurotoxicity (cytokines plus VCAM-1/T-cell endothelial adhesion), B-cell depletion, infection
“It is therefore plausible that the up-regulation of both proinflammatory cytokines and VCAM-1 may at least in part contribute to neurologic adverse events seen in the blinatumomab-treated subjects (see clinical safety).”