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).”
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.”
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 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: 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.”