Arzerra
ofatumumab
Species
Monkey
Longest study
30 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
Cynomolgus monkey only
“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”
Why that species
Cross-reactivity studies and cDNA analysis showed monkey (not mouse, rat or dog) is a suitable species
“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”
Species: general tox
Cynomolgus monkey only (not mouse, rat or dog)
“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”
Species: DART
Cynomolgus monkey (EFD) for the original CLL approval
“The reproductive toxicology assessment supporting the original BLA consisted of an embryofetal development study in cynomolgus monkey.”
Species: carcinogenicity
Not conducted
“No carcinogenicity or mutagenicity studies of ofatumumab have been conducted.”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkeys
“Based on cross-reactivity studies and cDNA analysis it was determined that cynomolgus monkey was suitable as test species in the nonclinical safety studies, but not mouse, rat or dog.”
Study lengthopen answer page →
Longest pivotal study
30 (7 months)
“populations of NK cells, which are central to immune surveillance, did not change during pivotal repeat dose studies of up to 7 months duration.”
Pivotal GLP studies
Pivotal monkey IV infusion studies of 4 weeks and 7 months; a cycled IV study and a short SC study also run
“some safety pharmacology end points, such as cardiovascular and renal parameters and body temperature, were evaluated as part of the pivotal 4 week and 7 month repeat dose toxicity studies in cynomolgus monkeys.”
Route in tox
IV infusion (pivotal); SC in a single study
“The majority of studies were performed by the IV route (infusion over 30 minutes) as this is the clinical route of administration; however, the SC route of administration was also examined in a single study.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“The lack of genotoxicity studies is considered justified according to ICH S6”
Carcinogenicity
Not conducted; rodents not pharmacologically responsive and no evidence anti-CD20 B-cell depletion causes cancer
“2) ofatumumab is not pharmacologically active in rodents and so the standard carcinogenicity bioassays are unsuitable, 3) there is no scientific evidence to suggest that depletion of B cells by any other anti-CD20 therapeutics leads to cancer”
Reproductive & developmental
Monkey EFD: no malformations, fetal B-cell depletion. Fertility: no adverse effects. ePPND: high-dose infant deaths and impaired immune function
“While the high dose was a no-effect dose for adverse developmental effects, a no-effect dose for mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose.”
Safety pharmacology
Incorporated into pivotal 4-week and 7-month monkey studies (cardiovascular, renal, body temperature endpoints); no heart rate or QT changes
“some safety pharmacology end points, such as cardiovascular and renal parameters and body temperature, were evaluated as part of the pivotal 4 week and 7 month repeat dose toxicity studies in cynomolgus monkeys.”
Genotox: Ames
Not conducted (ICH S6)
“The lack of genotoxicity studies is considered justified according to ICH S6”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“The lack of genotoxicity studies is considered justified according to ICH S6”
Genotox: in vivo
Not conducted (ICH S6)
“The lack of genotoxicity studies is considered justified according to ICH S6”
Carcinogenicity model
Not conducted; ofatumumab not pharmacologically active in rodents
“The Division agreed with the sponsor that a standard assessment of carcinogenic risk was not required because ofatumumab is not pharmacologically active in rodent species.”
Carcinogenicity timing
Not required (no rodent pharmacological activity)
“The Division agreed with the sponsor that a standard assessment of carcinogenic risk was not required because ofatumumab is not pharmacologically active in rodent species.”
hERG / QT
No hERG assay; no heart rate or QT changes in monkey repeat-dose studies up to 100 mg/kg
“There were no treatment-related changes in heart rate or QT interval in either investigation at doses up to 100 mg/kg.”
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 Arzerra 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Haemolytic anaemia (possibly ADA/immune-complex mediated) with unscheduled deaths; lymphoid germinal centre atrophy; infections (EMA assessment report, p. 20)
NOAEL / key findings
Haemolytic anaemia (possibly ADA/immune-complex mediated) with unscheduled deaths; lymphoid germinal centre atrophy; infections
“In repeat-dose toxicity studies, haemolytic anaemia developed in cynomolgus monkeys, leading to unscheduled deaths.”
Risksopen answer page →
Immune & cytokine safety
Monkey complement activation and IL-6 rise suggesting mild cytokine release; ADA in all studies; reduced KLH antibody response
“These results suggest that administration of ofatumumab may be associated with cytokine release syndrome. However, the severity of this syndrome in the monkeys was limited and clinical manifestations were not observed.”
Biodistribution & persistence
Placental transfer (detected in 17 of 20 fetal cord blood samples); no off-target binding in human TCR
“Ofatumumab was present in maternal plasma up to Gestation Day 100 and was also detectable in 17 of 20 umbilical cord blood samples from the foetuses, confirming exposure to ofatumumab during late pregnancy (GD100).”
Modality-specific risk
Infections from B-cell depletion and haemolytic anaemia led to monkey deaths; fetal B-cell depletion
“The reasons for animal withdrawal can be categorised into those which had a probable Campylobacter jejuni (C. jejuni) infection and those which showed signs of haemolytic anaemia.”
Anti-drug antibodies: animals
Monkey ADAs reduced plasma exposure at the low dose but not notably at the high dose (fertility study)
“Anti-drug antibodies reduced plasma exposures at the low dose (LD) but not notably at the high dose (HD).”
Anti-drug antibodies: patients
Anti-ofatumumab antibodies in less than 1% of CLL patients
“Formation of anti-ofatumumab antibodies was observed in less than 1% of patients with CLL after treatment with ofatumumab.”
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 Arzerra 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Haemolytic anaemia (possibly ADA/immune-complex mediated) with unscheduled deaths; lymphoid germinal centre atrophy; infections (EMA assessment report, p. 20)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
7-month cynomolgus monkey IV infusion study (GLP) with 6-month recovery
“GLP 7-months + 6 months recovery Cynomolgus monkey/ 3-4/sex/group 20, 100 mg/kg IV (infusion)”
Pivotal GLP studies
Pivotal monkey IV infusion studies of 4 weeks and 7 months; a cycled IV study and a short SC study also run
“some safety pharmacology end points, such as cardiovascular and renal parameters and body temperature, were evaluated as part of the pivotal 4 week and 7 month repeat dose toxicity studies in cynomolgus monkeys.”
DART package
Species: DART
Cynomolgus monkey (EFD) for the original CLL approval
“The reproductive toxicology assessment supporting the original BLA consisted of an embryofetal development study in cynomolgus monkey.”
Reproductive & developmental
Monkey EFD: no malformations, fetal B-cell depletion. Fertility: no adverse effects. ePPND: high-dose infant deaths and impaired immune function
“While the high dose was a no-effect dose for adverse developmental effects, a no-effect dose for mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose.”
PPND / ePPND: when
ePPND in cynomolgus monkey: not in the original oncology BLA (EFD only); submitted later for the new MS indication
“The nonclinical toxicology package for the original BLA for ofatumumab included an embryofetal development study in monkeys. To support approval for the new indication, the applicant submitted an enhanced preand post-natal development study also in monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity or mutagenicity studies of ofatumumab have been conducted.”
Carcinogenicity model
Not conducted; ofatumumab not pharmacologically active in rodents
“The Division agreed with the sponsor that a standard assessment of carcinogenic risk was not required because ofatumumab is not pharmacologically active in rodent species.”
Carcinogenicity timing
Not required (no rodent pharmacological activity)
“The Division agreed with the sponsor that a standard assessment of carcinogenic risk was not required because ofatumumab is not pharmacologically active in rodent species.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey EFD maternal exposure at no-effect dose ~2.4x clinical exposure at 2 g
“The mean maternal plasma exposure corresponds to 2.4-fold the clinical exposure following administration of 2 gram ofatumumab.”
NOAEL / key findings
Haemolytic anaemia (possibly ADA/immune-complex mediated) with unscheduled deaths; lymphoid germinal centre atrophy; infections
“In repeat-dose toxicity studies, haemolytic anaemia developed in cynomolgus monkeys, leading to unscheduled deaths.”
Efficacy evidenceopen answer page →
Efficacy evidence
SCID mouse xenografts of human B-cell tumour lines treated with ofatumumab
“The potential therapeutic effects of ofatumumab in vivo were examined in severe combined immunodeficiency (SCID) mouse tumour xenograft models.”
Why that model
Ofatumumab binds human and cynomolgus but not mouse, rat, rabbit, pig or dog tissue, so rodent efficacy needs human tumour cells
“In contrast, ofatumumab did not bind to spleen sections obtained from mouse, rat, rabbit, pig and dog.”
Reviewer's view of the efficacy data
EMA accepted that ofatumumab protected SCID mice from implanted B-cell tumours, with CDC and ADCC as mechanisms in vitro
“In vivo, ofatumumab was able to protect SCID mice from implanted B-cell line tumours.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No fertility or pre-/postnatal development studies; embryo-fetal study in monkey only
Why: No off-target binding and no CD20 expression in reproductive tissues · Pharmacology or kinetics
“However, it was considered acceptable that fertility and pre- and post natal development studies were not submitted due to 1) the lack of ofatumumab off-target binding, 2) the lack of CD20 expression in reproductive tissues”
OtherQuestioned
Anti-drug antibody assays inadequately validated; drug interference with ADA detection unresolved
“For both assays several concerns were raised regarding the design and the validation of the methods, especially since the presence of ofatumumab seems to interfere with the detection of anti-ofatumumab antibodies even at low concentrations. The applicant did not provide adequate answers to these concerns.”
“The results of the immunogenicity analyses should be interpreted with caution due to limitations in the detection methods (ELISA assays).”
OtherAccepted
No single-dose toxicity studies
Why: In line with the EMA concept paper on single dose/acute toxicity · Within the guideline
“The lack of single-dose toxicity studies is acceptable in accordance with the concept paper on single dose/acute toxicity (EMEA/CHMP/SWP/302413/2008).”
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