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.”
Species: general tox
Chimpanzee (blinatumomab, non-terminal) and mouse (murine surrogate muS103new)
“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.”
Species: DART
Mouse EFD with murine surrogate only; no fertility studies
“In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or teratogenicity.”
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
Surrogate used in
Yes: murine surrogate muS103new for mouse repeat-dose toxicity, EFD and CNS/respiratory safety pharmacology
“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.”
Genotox: Ames
Not conducted (ICH S6)
“In vitro and in vivo genotoxicity studies were not performed in accordance with ICH S6 (R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“In vitro and in vivo genotoxicity studies were not performed in accordance with ICH S6 (R1).”
Genotox: in vivo
Not conducted (ICH S6)
“In vitro and in vivo genotoxicity studies were not performed in accordance with ICH S6 (R1).”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
Carcinogenicity timing
Not required for advanced cancer indication (ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
hERG / QT
No hERG or QT data stated; cardiovascular monitoring in 6 chimpanzees showed hypotension, possibly cytokine-related
“Cardiovascular function was monitored during the toxicity studies performed with blinatumomab in a total of 6 chimpanzees. Changes in blood pressure (hypotension) were observed in some animals and may be related to a treatment-related increase in cytokine levels.”
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 Blincyto 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: No NOAEL assigned; lymphoid tissues target organs (lymphocyte depletion, decreased cellularity); chimp hypotension dose-limiting at 0.12 ug/kg (FDA pharmacology/toxicology review, p. 12)
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).”
Anti-drug antibodies: animals
Anti-muS103new ADA in mice, mainly at low doses; did not affect kinetics or pharmacological effect in pivotal studies
“Development of ADAs in the pivotal toxicity studies did not impact on their validity since neither the kinetics nor the pharmacological effect of muS103new or blinatumomab were affected. The occurrence of ADAs was mainly reported at low dose levels”
Anti-drug antibodies: patients
Less than 2% of patients had anti-blinatumomab antibodies; 7 of 9 (78%) neutralizing
“In clinical studies, less than 2% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, 7 out of 9 (78%) had in vitro neutralizing activity.”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
- Cytokine Release Syndrome
- Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome
- Infections
- Tumor Lysis Syndrome
- Neutropenia and Febrile Neutropenia
- Effects on Ability to Drive and Use Machines
- Elevated Liver Enzymes
- Pancreatitis
- Leukoencephalopathy
- Preparation and Administration Errors
- Immunization
- Benzyl Alcohol Toxicity in Neonates
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsSecondary malignancyCytopeniasHepatotoxicityGastrointestinalEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 Blincyto 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: No NOAEL assigned; lymphoid tissues target organs (lymphocyte depletion, decreased cellularity); chimp hypotension dose-limiting at 0.12 ug/kg (FDA pharmacology/toxicology review, p. 12)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week SC mouse study with murine surrogate muS103new, 4-week recovery
“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.”
DART package
Species: DART
Mouse EFD with murine surrogate only; no fertility studies
“In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or teratogenicity.”
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.”
PPND / ePPND: when
No PPND study; reproductive toxicity limited to mouse EFD with murine surrogate (no reason given)
“Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
Carcinogenicity timing
Not required for advanced cancer indication (ICH S9)
“As it is being developed for advanced cancer indications, no carcinogenicity studies have been conducted, in accordance with ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Chimpanzee exposure (Cmax 0.9-1.36 ng/mL) higher than human Css at 9 and 28 µg/day; no NOAEL or multiple stated
“The exposure of chimpanzees in term of AUCinf was 2.9 (M) and 5.6 (F) ng.h/mL with Cmax of 0.9 (M) and 1.36 (F) ng/mL, i.e. higher than Css reached at the clinical doses of 9 µg/day (211 pg/mL) and 28 µg/day (621 pg/mL)”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Blinatumomab in NOD/SCID mouse tumor xenograft models
“Table 1. Summary of in vivo studies in NOD/SCID mice xenograft models”
Why that model
Blinatumomab binds only human and chimpanzee CD3/CD19, not mouse, rat, dog or other monkey 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.”
Reviewer's view of the efficacy data
EMA: in vitro redirected lysis of CD19+ tumor cell lines and patient tumor samples, specific to target-expressing cells
“In vitro functional assays showed blinatumomab-mediated redirected lysis of CD19 positive cell tumours (adult and paediatric cell lines) as well as patient tumour samples. This cytotoxic activity was specific since it could only be observed in the presence of target-expressing cells”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
Chimpanzee the only relevant species; limited non-terminal chimpanzee studies plus mouse studies with murine surrogate muS103new
Why: Chimpanzee is the only relevant species and its use is ethically limited; surrogate similar in binding, lysis and T-cell activation · No relevant species · Other reason
“Since there are very limited possibilities to evaluate the toxicology of blinatumomab in the only non-clinical relevant species for ethical reasons, the applicant developed a surrogate BiTE molecule specific for murine CD3 and murine CD19 from rat monoclonal antibodies.”
“A murine surrogate (muS103new) was developed and is considered as similar to blinatumomab with regard to binding to CD19 and CD3 on respective cells, efficacy of redirected target cell lysis, and ability to activate T cells in a target cell-dependent manner.”
DARTVerdict not stated
No reproductive toxicity studies with blinatumomab; mouse embryo-foetal study with murine surrogate only
“Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal developmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited extent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or teratogenicity.”
DARTVerdict not stated
No fertility studies; reproductive organs assessed in surrogate repeat-dose toxicity studies
Why: No effects on male or female reproductive organs in murine surrogate toxicity studies
“No studies have been conducted to evaluate treatment-related effects on fertility. There were no effects on male or female reproductive organs in toxicity studies with the murine surrogate (SmPC section 5.3).”
Similar precedents
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