Uplizna
inebilizumab
Species
Mouse
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
Human CD19 transgenic mouse only
“Therefore, toxicology studies were conducted using a transgenic mouse model expressing human CD19 (huCD19 Tg).”
Why that species
Binds human CD19 only; no cross-reactivity with nonhuman primate, rodent or rabbit CD19
“Inebilizumab binds specifically to human CD19 and shows no cross-reactivity for CD19 in nonhuman primate, rodents, or rabbits. Therefore, the species selected for nonclinical testing was the human CD19 transgenic mouse model (huCD19 Tg), which was considered the only relevant species.”
Surrogate molecule
Yes: human CD19 transgenic (huCD19 Tg) mouse model, used for all general, fertility/EFD and PPND toxicology studies
“The pivotal nonclinical studies were conducted in a transgenic mouse (hCD19Tg) model that expresses human CD19 because inebilizumab is not pharmacologically active in rodent (mouse, rat) or nonrodent (rabbit, monkey).”
Species: general tox
huCD19 transgenic mouse only (4-week, 3-month and 6-month studies)
“General toxicity studies of 4 weeks, 3 months, and 6 months’ duration were conducted using the huCD19Tg mouse model.”
Species: DART
huCD19 transgenic mouse (combined fertility/EFD and pre- and postnatal development)
“Two reproductive toxicology studies were conducted in the huCD19Tg mouse model: combined male and female fertility and embryofetal development study and a pre-and postnatal development study.”
Species: carcinogenicity
Not conducted; carcinogenicity studies not required
“Carcinogenicity studies were not required, as agreed to by the Division (IND 117295, May 4, 2016).”
Surrogate used in
Yes: human CD19 transgenic mouse model for all pivotal studies (drug inactive in standard species)
“The pivotal nonclinical studies were conducted in a transgenic mouse (hCD19Tg) model that expresses human CD19 because inebilizumab is not pharmacologically active in rodent (mouse, rat) or nonrodent (rabbit, monkey).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Inebilizumab was administered to huCD19Tg mice (24/sex/group) by IV injection weekly for 26 weeks at dose levels of 0, 3, or 30 mg/kg.”
Pivotal GLP studies
huCD19 Tg mouse 1-, 3- and 6-month weekly IV studies up to 30 mg/kg; additional 3-month SC study
“General toxicology studies were conducted in huCD19Tg mouse with durations of 1, 3, and 6 months in which inebilizumab was administered weekly by IV injection at doses up to 30 mg/kg. (A second 3-month study was conducted using SC administration.)”
Route in tox
Intravenous (plus one 3-month SC study)
“General toxicology studies were conducted in huCD19Tg mouse with durations of 1, 3, and 6 months in which inebilizumab was administered weekly by IV injection at doses up to 30 mg/kg. (A second 3-month study was conducted using SC administration.)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“No genotoxicity studies were conducted, which is acceptable in accordance with ICH S6.”
Carcinogenicity
Not conducted; waived based on ICH S6(R1) weight-of-evidence argumentation
“In accordance with the weight of evidence approach outlined in ICH S6 (R1), the applicant has presented argumentation for waiving of carcinogenicity studies.”
Reproductive & developmental
huCD19 Tg mouse: reduced fertility index at both 3 and 30 mg/kg doses given weekly from 15 days before mating to GD15
“Animals that received IV doses (0, 3, or 30 mg/kg) inebilizumab weekly beginning 15 days prior to mating and through GD15 showed reduced fertility index at both dose levels.”
Safety pharmacology
No stand-alone studies; endpoints incorporated into repeat-dose toxicology studies
“Stand-alone safety pharmacology studies were not conducted for inebilizumab. Safety pharmacology endpoints were evaluated as part of the repeat-dose general toxicology studies.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted, which is acceptable in accordance with ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted, which is acceptable in accordance with ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted, which is acceptable in accordance with ICH S6.”
Carcinogenicity model
Not conducted; waived on ICH S6(R1) weight-of-evidence argumentation
“In accordance with the weight of evidence approach outlined in ICH S6 (R1), the applicant has presented argumentation for waiving of carcinogenicity studies.”
Carcinogenicity timing
Not required, as agreed with the FDA Division under the IND
“Carcinogenicity studies were not required, as agreed to by the Division (IND 117295, May 4, 2016).”
hERG / QT
No dedicated safety pharmacology; no neurological, cardiovascular or respiratory effects in repeat-dose studies
“Dedicated safety pharmacology studies were not performed. The potential for exaggerated pharmacology on the neurological, cardiovascular, and respiratory systems was assessed through cage side observations and detailed physical examinations conducted during the repeat-dose toxicology 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 Uplizna 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: IV NOAEL 30 mg/kg/week in huCD19 Tg mice; HED safety margin 6.9-fold and exposure margin 55-fold (EMA assessment report, p. 34)
NOAEL / key findings
IV NOAEL 30 mg/kg/week in huCD19 Tg mice; HED safety margin 6.9-fold and exposure margin 55-fold
“A HED-based safety margin of 6.9-fold and an exposure-based safety margin of 55-fold was calculated by comparing doses and exposures at the NOAEL of 30 mg/kg/week over a 6-month treatment period in huCD19 Tg mice in the 09-2153 study and human patients.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies mainly at lowest doses, correlated with B-cell depletion/recovery kinetics
“It appeared like ADA were primarily formed in the lowest dose groups (at 0.675 mg/kg and 0.5 mg/kg in the 1- and 3-months study respectively).”
Biodistribution & persistence
Crosses placenta and depletes B cells in the fetus
“These results demonstrate that inebilizumab-cdon crosses the placenta and depletes B cells in the fetus.”
Modality-specific risk
B-cell depletion causing immunosuppression (dose-related skin ulceration and early deaths in transgenic mice)
“In the longer duration studies (3 and 6 months) a dose-related increase in skin ulceration was observed and was the reason for multiple early deaths. This finding was considered related to the immunosuppression resulting from the B-cell depletion induced by inebilizumab.”
Anti-drug antibodies: animals
Mouse ADA mainly in lowest-dose groups (0.675 and 0.5 mg/kg in 1- and 3-month studies), tracking B-cell depletion/recovery
“It appeared like ADA were primarily formed in the lowest dose groups (at 0.675 mg/kg and 0.5 mg/kg in the 1- and 3-months study respectively). As stated by the applicant, the ADA formation correlated with depletion and recovery kinetics of B lymphocytes in the inebilizumab treated groups”
Anti-drug antibodies: patients
Treatment-emergent ADA in 5.6% of patients (Study 1)
“In Study 1, treatment-emergent antibodies (those that appeared or significantly increased from baseline after administration of UPLIZNA), were detected in 5.6% patients receiving UPLIZNA.”
Label warnings
- Infusion Reactions
- Infections
- Reduction in Immunoglobulins
- Fetal Risk
Hypersensitivity & infusion reactionsInfectionsEmbryo-fetal toxicity
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 Uplizna 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: IV NOAEL 30 mg/kg/week in huCD19 Tg mice; HED safety margin 6.9-fold and exposure margin 55-fold (EMA assessment report, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week huCD19 transgenic mouse (weekly IV) with 36-week recovery
“Inebilizumab was administered to huCD19Tg mice (24/sex/group) by IV injection weekly for 26 weeks at dose levels of 0, 3, or 30 mg/kg. (Satellite groups of 18/sex were dosed at 3 and 30 mg/kg for TK and immunogenicity and as potential replacement animals.) The dosing period was followed by a 36-week recovery period.”
Pivotal GLP studies
huCD19 Tg mouse 1-, 3- and 6-month weekly IV studies up to 30 mg/kg; additional 3-month SC study
“General toxicology studies were conducted in huCD19Tg mouse with durations of 1, 3, and 6 months in which inebilizumab was administered weekly by IV injection at doses up to 30 mg/kg. (A second 3-month study was conducted using SC administration.)”
DART package
Species: DART
huCD19 transgenic mouse (combined fertility/EFD and pre- and postnatal development)
“Two reproductive toxicology studies were conducted in the huCD19Tg mouse model: combined male and female fertility and embryofetal development study and a pre-and postnatal development study.”
Reproductive & developmental
huCD19 Tg mouse: reduced fertility index at both 3 and 30 mg/kg doses given weekly from 15 days before mating to GD15
“Animals that received IV doses (0, 3, or 30 mg/kg) inebilizumab weekly beginning 15 days prior to mating and through GD15 showed reduced fertility index at both dose levels.”
PPND / ePPND: when
PPND in huCD19 transgenic mouse completed before the marketing application
“In a pre-and postnatal development study, huCD19Tg mice received IV doses of inebilizumab every 3 days throughout gestation (beginning on GD6) and continuing through lactation.”
Carcinogenicity
Species: carcinogenicity
Not conducted; carcinogenicity studies not required
“Carcinogenicity studies were not required, as agreed to by the Division (IND 117295, May 4, 2016).”
Carcinogenicity model
Not conducted; waived on ICH S6(R1) weight-of-evidence argumentation
“In accordance with the weight of evidence approach outlined in ICH S6 (R1), the applicant has presented argumentation for waiving of carcinogenicity studies.”
Carcinogenicity timing
Not required, as agreed with the FDA Division under the IND
“Carcinogenicity studies were not required, as agreed to by the Division (IND 117295, May 4, 2016).”
Safety marginopen answer page →
Safety margin at NOAEL
huCD19 Tg mouse 6-month NOAEL 30 mg/kg/week: 55-fold exposure margin (6.9-fold HED-based)
“A HED-based safety margin of 6.9-fold and an exposure-based safety margin of 55-fold was calculated by comparing doses and exposures at the NOAEL of 30 mg/kg/week over a 6-month treatment period in huCD19 Tg mice in the 09-2153 study and human patients.”
NOAEL / key findings
IV NOAEL 30 mg/kg/week in huCD19 Tg mice; HED safety margin 6.9-fold and exposure margin 55-fold
“A HED-based safety margin of 6.9-fold and an exposure-based safety margin of 55-fold was calculated by comparing doses and exposures at the NOAEL of 30 mg/kg/week over a 6-month treatment period in huCD19 Tg mice in the 09-2153 study and human patients.”
Efficacy evidenceopen answer page →
Efficacy evidence
EAE and Sle1 autoimmune models in huCD19 transgenic mice: B-cell depletion, reduced autoantibodies and disease scores
“Treatment with inebilizumab effectively depleted CD19+ B cells and plasma cells in EAE huCD19 Tg mice. This led to a global reduction of autoantibodies in blood and in the CNS and to significantly reduced disease scores (Chen et al, 2014 and Chen et al, 2016).”
Why that model
Human-CD19-specific antibody with poor cross-reactivity in rat, rabbit and monkeys, so huCD19 Tg mice were the relevant species
“The in vivo pharmacological activity of inebilizumab was evaluated in huCD19 Tg mice as the relevant species since this mAb was specific for human CD19 and had poor cross-reactivity with CD19 on the surface of B cells from rat, rabbit, baboon, rhesus monkey, African green monkey, or cynomolgus monkey.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo studies comprehensive and relevant; proof of concept and mode of action established
“In general, the in vitro and in vivo studies were comprehensive and relevant. Proof of concept and mode of action were established and are supported.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
No cross-reactive animal species; all toxicology in human CD19 transgenic mice
Why: huCD19 transgenic mouse the only relevant species; use supported by ICH S6(R1) · No relevant species · Within the guideline
“Therefore, the species selected for nonclinical testing was the human CD19 transgenic mouse model (huCD19 Tg), which was considered the only relevant species.”
“Toxicology The use of the transgenic huCD19 mouse model for the toxicology programme of inebilizumab, is supported in accordance with ICH S6(R1).”
CarcinogenicityAccepted
No carcinogenicity studies for chronic NMOSD use; weight-of-evidence waiver
Why: Two-year study in huCD19 transgenic mice would add little given limited interpretability and no historical data · Weight of evidence · Within the guideline
“Carcinogenicity In accordance with the weight of evidence approach outlined in ICH S6 (R1), the applicant has presented argumentation for waiving of carcinogenicity studies.”
“It is agreed, that data from a 2-year carcinogenicity study in human transgenic CD19 mice do not seem to provide much additional clinically relevance, due to the limited interpretability of study results, as a lack of historical reference data.”
DARTAccepted with a conditionBeyond the letter
Neurobehavioral testing in the transgenic mouse PPND study inadequate (too few animals, maze test done improperly)
Why: Concerns manageable with labeling · Other reason
“The neurobehavioral testing conducted as part of the pre- and postnatal development study was not considered adequate for the following 2 reasons: 1) Insufficient number of animals per group was tested, 2) the learning and memory assessment with the Biel maze was not conducted appropriately.”
“These concerns can be managed with labeling.”
Safety marginVerdict not stated
No no-effect dose identified for adverse effects on fertility in transgenic mice
“A no-effect dose for adverse effects on fertility was not identified.”
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