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.”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”