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.”
Species: general tox
Cynomolgus monkey
“Single and repeated dose toxicity studies were investigated in cynomolgus monkeys.”
Species: DART
huCD52 transgenic mouse (all reproductive and developmental studies)
“Reproductive and developmental toxicity studies were conducted in the huCD52 transgenic mouse model. This model was characterised in a series of pharmacodynamic studies.”
Species: carcinogenicity
Not conducted (no appropriate animal model)
“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 and the previous scientific advice provided by the CHMP.”
Surrogate used in
Yes: huCD52 transgenic mouse model (with alemtuzumab) for pharmacology and reproductive/developmental toxicity
“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.”
Genotox: Ames
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.”
Genotox: in vitro mammalian
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.”
Genotox: in vivo
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 model
Not conducted: no appropriate animal model; known 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 and the previous scientific advice provided by the CHMP.”
Carcinogenicity timing
Not required (accepted by CHMP)
“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 and the previous scientific advice provided by the CHMP.”
hERG / QT
No hERG assay; monkey cardiovascular effects only at 30 mg/kg in single animals; ventricular premature complexes considered a normal variant
“Cardiovascular effects were observed in both studies at doses of 30 mg/kg, but the effects were only seen in a single animal per study. With respect to the ventricular premature complexes seen in one animal in the repeat-dose study, the CHMP acknowledged that this observation could be a normal variant in cynomolgus monkeys and therefore not treatment-related.”
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)
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: 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.”
Anti-drug antibodies: animals
ADA in the majority of animals tested; no significant influence on pharmacokinetics
“Anti-alemtuzumab antibodies were detected in the majority of the animals tested. However, the presence of anti-alemtuzumab antibodies was not considered by the CHMP to have any significant influence on the alemtuzumab pharmacokinetics in the studies conducted.”
Anti-drug antibodies: patients
8.3% (11/133) of previously untreated patients had anti-human antibodies; two weakly neutralizing
“Using an ELISA assay, anti-human antibodies (HAHA) were detected in 11 of 133 (8.3%) previously untreated patients. In addition, two patients were weakly positive for neutralizing activity.”
Label warnings
Boxed warning: Cytopenias, infusion-related reactions, and infections
- Cytopenias
- Infusion-Related Reactions
- Immunosuppression/Infections
- Immunization
CytopeniasInfectionsHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and 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 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)
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: No NOAEL defined; dose-limiting infections or hypersensitivity causing deaths; reduced CD52 affinity in monkey limits model (EMA assessment report, p. 26)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
One-month (30-day) daily dose-escalation study in cynomolgus monkeys; recovery phase not stated
“The first study was a one-month daily dose escalation study in which monkeys were administered 1, 1.5, 2 and 3 mg/kg on days 1 – 7, 8 – 10, 11 – 14 and 15 – 30, respectively.”
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.”
DART package
Species: DART
huCD52 transgenic mouse (all reproductive and developmental studies)
“Reproductive and developmental toxicity studies were conducted in the huCD52 transgenic mouse model. This model was characterised in a series of pharmacodynamic studies.”
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”
PPND / ePPND: when
Pre- and postnatal studies in huCD52 transgenic mice: completed and included in the EU marketing application
“Reproductive and developmental toxicity studies were conducted in the huCD52 transgenic mouse model.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no appropriate animal model)
“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 and the previous scientific advice provided by the CHMP.”
Carcinogenicity model
Not conducted: no appropriate animal model; known 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 and the previous scientific advice provided by the CHMP.”
Carcinogenicity timing
Not required (accepted by CHMP)
“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 and the previous scientific advice provided by the CHMP.”
Safety marginopen answer page →
Safety margin at NOAEL
huCD52 mouse developmental NOAEL: below clinical exposure by Cmax; 0.6- to 4.4-fold by AUC
“Based on Cmax values, the exposures were significantly below those observed in the clinical setting, following administration of the recommended therapeutic dose. Higher exposure margins were established by the applicant based on AUC values obtained in a PK study. The use of these AUC data yielded exposure margins of 0.6- to 4.4-fold.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Lymphocyte depletion in huCD52 transgenic mice and cynomolgus monkeys
“The primary pharmacodynamic effect evaluated in the in vivo pharmacology studies was lymphocyte cell depletion. The studies were conducted in the human CD52 (huCD52) transgenic mouse model and in the cynomolgus monkey.”
Why that model
No MS animal model studies: clinical MS efficacy data already existed when huCD52 mice were developed
“Efficacy studies in animal models of MS were not conducted with alemtuzumab, because clinical efficacy data were already available from clinical experience with alemtuzumab for MS at the time huCD52 transgenic mice were developed and characterised.”
Reviewer's view of the efficacy data
CHMP: lack of EAE proof-of-concept studies acceptable given existing clinical MS experience
“No proof-of-concept studies in this model were conducted by the applicant. However, as clinical experience with alemtuzumab in the treatment of MS was already available at the time huCD52 transgenic mice were developed and characterised, the lack of these studies was considered acceptable by the CHMP.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
No long-term repeat-dose toxicity study in cynomolgus monkey
Why: 10-fold exposure margin not feasible due to immunosuppression and severe infections requiring antibiotics · Pharmacology or kinetics
“In their advice, the CHMP had acknowledged that 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.”
“Overall, the CHMP had concluded that no further long-term repeat dose testing in cynomolgus monkey was warranted.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity testing for a repeated-course immunosuppressive therapy
Why: No appropriate animal model; indirect tumorigenicity risk from prolonged immunosuppression already well established; prior CHMP scientific advice · No relevant species · Weight of evidence
“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 and the previous scientific advice provided by the CHMP.”
SpeciesAcceptedBeyond the letter
Reproductive and developmental toxicity studied in huCD52 transgenic mice instead of monkeys
Why: Neutralising anti-drug antibodies in a proportion of monkeys · No relevant species
“Cynomolgus monkey was not considered an appropriate species for reasons of anti-alemtuzumab antibodies developing in proportion of monkeys, which in some cases could exert a neutralizing activity. The CHMP also considered that the studies were conducted in compliance with the CHMP scientific advice.”
Safety marginVerdict not stated
Developmental toxicity NOAEL in transgenic mice below clinical exposure by Cmax; 0.6- to 4.4-fold by AUC
“Based on Cmax values, the exposures were significantly below those observed in the clinical setting, following administration of the recommended therapeutic dose. Higher exposure margins were established by the applicant based on AUC values obtained in a PK study. The use of these AUC data yielded exposure margins of 0.6- to 4.4-fold.”
Efficacy modelAcceptedBeyond the letter
No proof-of-concept studies in the EAE model of multiple sclerosis
Why: Clinical experience with alemtuzumab in MS already available · Human data
“No proof-of-concept studies in this model were conducted by the applicant. However, as clinical experience with alemtuzumab in the treatment of MS was already available at the time huCD52 transgenic mice were developed and characterised, the lack of these studies was considered acceptable by the CHMP.”
Similar precedents
ErbituxAntibodies · cetuximab · EGFRMonkey + rodent · 39 wkTecentriqAntibodies · atezolizumab · PD-L1Monkey + rodent · 26 wkUnituxinAntibodies · dinutuximab · GD2Monkey + rodent · 4 wkVyloyAntibodies · zolbetuximab · Claudin 18.2Monkey + rodent · 13 wkBavencioAntibodies · avelumab · PD-L1Monkey only · 13 wkCyramzaAntibodies · ramucirumab · VEGFR2Monkey only · 39 wk