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

Precedia/Monoclonal antibodies/Repatha/Tox package

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

evolocumab · PCSK9

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 Repatha 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 monoclonal antibodies

Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.

“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”

✓ VerifiedEMA 2017: Guideline on strategies to identify and mitigate risks for…, p. 11Source ↗

This product's starting point

NOAEL / key findings: Monkey 26-week study: NOAEL 300 mg/kg/week, the highest dose tested (FDA pharmacology/toxicology review, p. 59)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week cynomolgus monkey SC study (weekly) with 25-week recovery

“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection. Two monkeys/sex/group were allowed a 25-week treatment-free recovery period.”

✓ VerifiedFDA pharmacology/toxicology review, p. 59Source ↗

Pivotal GLP studies

Hamster up to 3 months and cynomolgus monkey up to 6 months, once-weekly SC

“The primary nonclinical toxicity studies of evolocumab were conducted in hamsters for up to 3 months and monkeys for up to 6 months duration with once weekly subcutaneous dosing.”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

DART package

Species: DART

Hamster (fertility, early embryonic) and cynomolgus monkey (enhanced pre/postnatal; fertility in 6-month study)

“The nonclinical reproductive and developmental safety profile of evolocumab was informed by three studies: (1) an enhanced pre-postnatal development study in cynomolgus monkeys, (2) a fertility and early embryonic development study in hamsters and (3) assessment of male and female fertility endpoints in the 6 month cynomolgus monkey study.”

✓ VerifiedEMA assessment report, p. 26Source ↗

Reproductive & developmental

Expanded monkey developmental study with infants followed 6 months: no significant drug-related effects

“In an expanded developmental study in monkeys in which offspring were followed into infancy for 6 months, no significant drug-related effects were observed.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

PPND / ePPND: when

ePPND in cynomolgus monkey: completed before the marketing application

“The Applicant performed an enhanced pre/postnatal developmental toxicity study in pregnant monkeys with administration of evolocumab at up to 50 mg/kg every other week by the subcutaneous route”

✓ VerifiedFDA pharmacology/toxicology review, p. 148Source ↗

Carcinogenicity

Species: carcinogenicity

Hamster lifetime study (up to 2 years)

“Evolocumab did not cause any drug-related tumors when administered to hamsters for up to 2 years in a lifetime carcinogenicity assay at doses administered once every other week that provide a 38-, 15- and 6.6-fold safety margin for evolocumab at the recommended human doses of 140 mg Q2W, 420 mg QM and 420 mg Q2W administered subcutaneously.”

✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Carcinogenicity model

Hamster lifetime (2-year) study, every other week dosing: no drug-related tumors at 38-, 15- and 6.6-fold human exposure

✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Carcinogenicity timing

Hamster lifetime study completed before the marketing application; not carcinogenic

“Evolocumab was not carcinogenic in hamsters with lifetime dosing at up to 38, 15 and 6.6X the human exposures at the 140 mg Q2W, 420 mg QM and 420 mg Q2W doses.”

✓ VerifiedFDA pharmacology/toxicology review, p. 152Source ↗

Summary across all 117 monoclonal antibodies →

Repatha: 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