Campath (alemtuzumab): what was done before first-in-human, and what came after?

Precedia/Monoclonal antibodies/Campath/Tox package

Campath: what was done before first-in-human, and what came after?

alemtuzumab · CD52

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.”

✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗

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)

Full method, every step sourced →

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.”

✓ VerifiedEMA assessment report, p. 21Source ↗

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.”

✓ VerifiedEMA assessment report, p. 21Source ↗

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.”

✓ VerifiedEMA assessment report, p. 27Source ↗

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”

✓ VerifiedUS prescribing informationSource ↗

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.”

✓ VerifiedEMA assessment report, p. 27Source ↗

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.”

✓ VerifiedEMA assessment report, p. 26Source ↗

Carcinogenicity model

Not conducted: no appropriate animal model; known indirect tumorigenicity risk from prolonged immunosuppression

Campath: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other monoclonal antibodies