Briumvi
ublituximab
Species
Monkey
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Therefore, cynomolgus monkey was determined to be the single relevant species for nonclinical evaluations.”
Why that species
High-affinity (low nM) binding to CD20 on human and cynomolgus B cells; no binding to rodent CD20
“Ublituximab binds with high affinity (low nM range) to CD20 on B cells from human and cynomolgus monkey. The product does not bind to rodent CD20.”
Surrogate molecule
Yes: human CD20 transgenic mice, used for an embryo-fetal development study with ublituximab
“In a subsequent study conducted in pregnant CD20 (huCD20) transgenic mice, a pharmacologically relevant animal model, intravenous administration of ublituximab-xiiy (0, 5, 20, or 50 mg/kg) during organogenesis (gestation day 6 and 12) resulted in no adverse effects on embryofetal development.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“General toxicology studies of up to 26 weeks’ duration were conducted in cynomolgus monkeys.”
Pivotal GLP studies
GLP 4-, 13- and 26-week intravenous toxicity studies in cynomolgus monkeys
“The sponsor conducted 4-, 13-, and 26-week GLP intravenous toxicity studies in cynomolgus monkey.”
Route in tox
Intravenous (short infusion of 3 or 15 min, or slow bolus)
“For these studies, ublituximab was administered intravenously, either by short infusion (3 or 15 min) or slow bolus.”
Skipped studiesopen answer page →
Genotoxicity
Not recommended for biologics; an Ames assay was conducted and was negative
“Genotoxicity assays are not recommended for biological therapeutics. An Ames assay was conducted, and results were negative.”
Carcinogenicity
Not conducted; not feasible because ublituximab is not active in rodents
“Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible.”
Reproductive & developmental
Monkey ePPND (0 or 30 mg/kg weekly by trimester): severe immunogenic response causing maternal morbidity, death and embryofetal loss
“Weekly intravenous administration of ublituximab-xiiy (0 or 30 mg/kg) to pregnant monkeys during the first, second, or third trimester of pregnancy produced a severe immunogenic response in dams, resulting in maternal morbidity and death and embryofetal loss.”
Safety pharmacology
Assessed in general toxicology studies; no cardiac, respiratory or CNS findings
“There were no observed clinical findings concerning cardiac, respiratory, or CNS safety pharmacology in the 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 Briumvi 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: No NOAEL identified in the 26-week study, as only one dose level was tested (FDA pharmacology/toxicology review, p. 51)
NOAEL / key findings
No NOAEL identified in the 26-week study, as only one dose level was tested
“Since only one dose level of ublituximab was administered, no NOAEL was identified.”
Risksopen answer page →
Immune & cytokine safety
No significant changes in serum IL-6, IL-8, IFN-γ or TNF-α in monkeys after repeated dosing
“Levels of four inflammatory cytokines (IL-6, IL-8, IFN-γ, and TNF-α) were evaluated after repeated dosing of ublituximab and no significant changes were observed.”
Biodistribution & persistence
Tissue cross-reactivity in human and monkey tissues: specific binding in lymphoid tissues and CD20+ areas; no off-target binding
“In addition, tissue cross reactivity studies in human and cynomolgus monkey tissue showed specific binding in lymphoid tissues and areas known to be positive for CD20+ cells, and no off-target or unexpected binding was observed.”
Modality-specific risk
Effects of in-utero exposure on immune function, not assessable in monkeys because of maternal immunogenicity
“Potential adverse effects of ublituximab exposure during organogenesis on immune function could not be adequately assessed because of the immunogenic effects in dams.”