Campath
alemtuzumab
Species
MonkeyMouse
Longest study
4 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 (general toxicity); huCD52 transgenic mouse (reproductive toxicity)
“Single and repeated dose toxicity studies were investigated in cynomolgus monkeys.”
Why that species
Pharmacologically active in monkey but of limited relevance due to CD52 amino acid sequence differences
“With respect to cynomolgus monkeys, the CHMP considered that although alemtuzumab was pharmacologically active in the species, the relevance of this species was limited due to species differences in the amino acid sequence for the CD52 antigen.”
Surrogate molecule
Yes: human CD52 transgenic mouse model, used for fertility, embryo-fetal and pre/postnatal studies
“Reproductive and developmental toxicity studies were conducted in the huCD52 transgenic mouse model. This model was characterised in a series of pharmacodynamic studies.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“In a previous CHMP scientific advice, the 30-day toxicity testing was considered sufficient to cover the clinical schedule for alemtuzumab treatment, i.e. administration on 5 consecutive days followed by administration on 3 consecutive days after one year.”
Pivotal GLP studies
Two cynomolgus monkey repeat-dose studies: daily dose escalation over a month and a dose-ranging tolerability pilot
“Two repeat dose studies were conducted in cynomolgus monkeys.”
Route in tox
IV and SC
“Alemtuzumab was investigated in 3 single dose toxicity studies in cynomolgus monkeys, using both i.v. and s.c. administrations of alemtuzumab at dose levels ranging from 0.1 to 30 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“The lack of genotoxicity testing was considered acceptable, as in accordance with the ICH S6 guideline, the range and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed.”
Carcinogenicity
Not conducted: no appropriate animal model; established indirect tumorigenicity risk from prolonged immunosuppression
“The CHMP also considered acceptable that no carcinogenicity testing was performed, taking into account the lack of an appropriate animal model, the well-established risk of indirect tumorigenicity caused by prolonged immunosuppression”
Reproductive & developmental
huCD52 mice: no teratogenic effects; embryolethality with dosing in organogenesis
“When alemtuzumab was administered to pregnant huCD52 transgenic mice during organogenesis (gestation days [GD] 6–10 or GD 11–15) at intravenous doses of 3 or 10 mg/kg, no teratogenic effects were observed. However, there was an increase in embryolethality”
Safety pharmacology
No dedicated studies; CV and respiratory effects assessed in monkey toxicity studies; not clinically relevant
“No dedicated safety pharmacology studies were conducted by the applicant.”
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 Campath 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: No NOAEL defined; dose-limiting infections or hypersensitivity causing deaths; reduced CD52 affinity in monkey limits model (EMA assessment report, p. 26)
NOAEL / key findings
No NOAEL defined; dose-limiting infections or hypersensitivity causing deaths; reduced CD52 affinity in monkey limits model
“dose-limiting toxicity (increased susceptibility to infections or hypersensitivity leading to lethality/early sacrifice) and limitation of the animal model (decreased affinity of alemtuzumab for CD52 in the cynomolgus monkey).”
Risksopen answer page →
Immune & cytokine safety
IL-6, IL-10, MCP-1 and TNF-α elevated 2-4 hours after dosing in huCD52 transgenic mice
“The levels of the cytokines IL-6, IL-10, MCP-1 and TNF-α were significantly elevated especially at 2-4 hours post-dosing.”
Biodistribution & persistence
Placental transfer to fetuses in huCD52 transgenic mice
“Alemtuzumab was detected in foetuses of dams treated with alemtuzumab during gestation which confirmed transfer across the placental barrier.”
Modality-specific risk
Immunosuppression and severe infections from lymphocyte depletion limited achievable exposure margins
“evaluating doses corresponding to a 10-fold exposure margin when compared to the exposure in the MS patients would not be feasible due to immunosuppression and severe infections.”