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.”
Species: general tox
Cynomolgus monkey only
“Therefore, cynomolgus monkey was determined to be the single relevant species for nonclinical evaluations.”
Species: DART
Cynomolgus monkey (pre/postnatal) and huCD20 transgenic mouse (dosing during organogenesis)
“The findings in cynomolgus monkey were considered secondary to an immunogenic reaction and are not considered relevant to humans. 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”
Species: carcinogenicity
Not conducted: ublituximab not active in rodents
“Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible.”
Surrogate used in
Yes: huCD20 transgenic mouse model for embryo-fetal development (clinical antibody)
“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.”
Genotox: Ames
Negative
“Genotoxicity assays are not recommended for biological therapeutics. An Ames assay was conducted, and results were negative.”
Genotox: in vitro mammalian
Not conducted (not recommended for biologics)
“Genotoxicity assays are not recommended for biological therapeutics. An Ames assay was conducted, and results were negative.”
Genotox: in vivo
Not conducted (not recommended for biologics)
“Genotoxicity assays are not recommended for biological therapeutics. An Ames assay was conducted, and results were negative.”
Carcinogenicity model
Not conducted: not feasible in monkey, inactive in rodents, 2-year bioassay poor predictor for immunosuppression
“For ublituximab, conventional carcinogenicity studies are not appropriate because carcinogenicity studies are not feasible in cynomolgus monkey, ublituximab is not pharmacologically active in rodents, and 2-year bioassay is a poor predictor of carcinogenicity risk associated with immunosuppression.”
Carcinogenicity timing
Not required (not feasible; inactive in rodents)
“Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible.”
hERG / QT
No hERG assay; no cardiac, respiratory or CNS findings in monkey general toxicology studies
“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
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: 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.”
Anti-drug antibodies: animals
Immunogenic in monkeys: ADA limited exposure and PD at lower doses; exposure maintained at 30 mg/kg for 13 and 26 weeks in most animals
“Ublituximab was shown to be immunogenic in monkeys after repeated dosing. At lower doses, anti-drug antibody (ADA) development limited plasma exposure and resulted in loss of pharmacodynamic (PD) activity. However, in spite of ADA development, exposure was maintained at the HD of 30 mg/kg for 13 and 26 weeks in most animals”
Anti-drug antibodies: patients
81% (434/534) ADA-positive; 6.4% neutralizing
“Of the 534 BRIUMVI-treated patients, 434 (81%) tested positive for ADAs at one or more timepoints, and 34 (6.4%) tested positive for neutralizing antibodies (NAbs).”
Label warnings
- Infusion Reactions
- Infections
- Fetal Risk
- Reduction in Immunoglobulins
- Liver Injury
Hypersensitivity & infusion reactionsInfectionsEmbryo-fetal toxicityHepatotoxicity
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 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
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: No NOAEL identified in the 26-week study, as only one dose level was tested (FDA pharmacology/toxicology review, p. 51)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV), single dose level, no recovery period
“In the 26-week repeat-dose study, ublituximab was tolerated at 30 mg/kg, which was the only dose evaluated. No recovery period was included.”
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.”
DART package
Species: DART
Cynomolgus monkey (pre/postnatal) and huCD20 transgenic mouse (dosing during organogenesis)
“The findings in cynomolgus monkey were considered secondary to an immunogenic reaction and are not considered relevant to humans. 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”
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.”
PPND / ePPND: when
ePPND (expanded PPND) in cynomolgus monkey: completed and submitted with the BLA
“The nonclinical studies submitted in support of the BLA include the following: • Pharmacology (in vitro, in vivo), tissue cross-reactivity (human, monkey) • Toxicology (4-, 13-, and 26-week studies in monkey) • Expanded pre- and postnatal development study (monkey)”
Carcinogenicity
Species: carcinogenicity
Not conducted: ublituximab not active in rodents
“Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible.”
Carcinogenicity model
Not conducted: not feasible in monkey, inactive in rodents, 2-year bioassay poor predictor for immunosuppression
“For ublituximab, conventional carcinogenicity studies are not appropriate because carcinogenicity studies are not feasible in cynomolgus monkey, ublituximab is not pharmacologically active in rodents, and 2-year bioassay is a poor predictor of carcinogenicity risk associated with immunosuppression.”
Carcinogenicity timing
Not required (not feasible; inactive in rodents)
“Carcinogenicity studies were not required because ublituximab is not active in rodent; therefore, standard carcinogenicity studies are not feasible.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 26-week study at only dose (30 mg/kg): Cave ~24x human at 450 mg MRHD; no NOAEL defined
“No adverse effects on male or female reproductive organs were observed at the only dose level evaluated (30 mg/kg) in a 26-week intravenous toxicity study in monkeys, which was associated with plasma exposures (C ave ) approximately 24 times that in humans at the maximum recommended human dose (450 mg).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vivo B-cell depletion in mouse models clearing patient-derived B-CLL cells
“B cell depletion by ublituximab was also observed in in vivo mouse models of the clearance of cells derived from a patient suffering from B cell chronic lymphocytic leukaemia (B-CLL).”
Why that model
No in vivo MS model run; EAE feasibility questioned because of rodent CD20 cross-reactivity and strong immunogenicity in monkeys
“However, the feasibility of such a model due to ublituximab cross-reaction with rodent CD20 and its the strong immunogenicity observed in nonhuman primate studies, is questioned.”
Reviewer's view of the efficacy data
EMA: SCID mouse B-CLL clearance studies are proof of concept for B-cell depletion, confirmed clinically
“The performed studies in immunocompromised mice models (SCID and SCID NOD) of the clearance of human B-CLL provide evidence that ublituximab can deplete tumoral B cell. This can be considered a proof of concept, also confirmed in clinical setting.”
Flexibilityopen answer page →
Flexibility accepted
RecoveryVerdict not stated
26-week monkey study tested a single dose level with no recovery period
Why: Antidrug antibodies caused loss of pharmacological activity at low and mid doses in the 13-week study · Pharmacology or kinetics
“In the 26-week study (0 or 30 mg/kg QW), only one dose level was tested, based on the development of antidrug antibodies, resulting in loss of pharmacological activity, at the low and mid doses in the 13-week study.”
DARTAcceptedBeyond the letter
Monkey ePPND confounded by immunogenicity; embryo-fetal development reassessed in huCD20 transgenic mice
Why: Monkey findings secondary to immunogenicity and not relevant to humans; transgenic mouse is a pharmacologically relevant model · No relevant species · Pharmacology or kinetics
“The findings in cynomolgus monkey were considered secondary to an immunogenic reaction and are not considered relevant to humans. 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.”
Juvenile toxAccepted with a conditionBeyond the letter
Effects on developing immune function not adequately assessed; postnatal immune function study required postmarketing
Why: Immunogenic effects in dams prevented assessment; study needed to support future paediatric development
“Potential adverse effects of ublituximab exposure during organogenesis on immune function could not be adequately assessed because of the immunogenic effects in dams.”
“To support future clinical development of ublituximab in pediatric patients, it is recommended that the sponsor conduct, as a postmarketing requirement, a GLPcompliant study to assess the potential for ublituximab to have adverse effects on immune function when administered during the postnatal period to animals of a clinically relevant age.”
SpeciesAcceptedBeyond the letter
Monkey-only programme without characterising CD20 binding in other animal species
Why: Single-species justification submitted under the IND was found acceptable
“The sponsor proposed conducting nonclinical studies of ublituximab only in monkey but did not conduct studies to characterize binding to CD20 in other animal species. Justification for this approach was submitted to the Division of Hematology and Oncology Toxicology (DHOT); DHOT found it acceptable.”
GLPAcceptedBeyond the letter
Rabbit local tolerance study and Ames assay not entirely GLP-compliant
Why: Studies not pivotal for the marketing authorisation application · Other reason
“Local tolerance study in rabbit and the bacterial reverse mutation assay, were not (entirely) performed under GLP as stated by the applicant; however, since they are not considered pivotal for the marketing authorisation application, this is considerable acceptable.”
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