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

Precedia/Monoclonal antibodies/Evenity/Tox package

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

romosozumab · Sclerostin

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 Evenity 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: No adverse effects at up to 100 mg/kg weekly SC for 26 weeks in rats and monkeys (37x and 90x human exposure); findings pharmacologic (bone)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week rat and 26-week monkey studies, each with 14-week recovery

“Romosozumab has been evaluated in repeat-dose toxicity studies in rats (up to 26 weeks with 14 weeks recovery) and in monkeys (up to 26 weeks with 14 weeks recovery).”

✓ VerifiedEMA assessment report, p. 35Source ↗

Pivotal GLP studies

Repeat-dose studies up to 26 weeks (14-week recovery) in rats and monkeys; rat carcinogenicity and reproductive studies

“The program includes repeat-dose studies up to 26 weeks with 14 weeks recovery in rats and monkeys; reproductive toxicity studies in rats, a carcinogenicity study in rats”

✓ VerifiedEMA assessment report, p. 35Source ↗

DART package

Species: DART

Rat only (fertility/EFD, EFD, pre- and postnatal development)

“A full reproductive and developmental toxicity package has been performed in rats, including preliminary and definitive embryo-fetal development (EFD) studies, a combined fertility and EFD study, and a pre-and post”

✓ VerifiedEMA assessment report, p. 38Source ↗

Reproductive & developmental

Rat FEED, EFD and PPND: reduced 6th cervical vertebra ventral processes at 100-300 mg/kg (17-56x)

“Findings in the definitive FEED and EFD studies included reduced ventral processes of the 6th cervical vertebrae at doses of 100 and 300 mg/kg (17-56x human exposure).”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

PPND / ePPND: when

PPND in rat completed before the marketing application (with rat FEED and EFD)

“Reproductive toxicity was evaluated in rat fertility and early embryonic development (FEED), embryofetal development (EFD) and pre- and postnatal development (PPND) studies.”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Carcinogenicity

Species: carcinogenicity

Sprague Dawley rat (98-week)

“For romosozumab, a carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week of romosozumab, equivalent to 1-19x human exposure.”

✓ VerifiedFDA multi-discipline review, p. 259Source ↗

Carcinogenicity model

Sprague-Dawley rat, SC 3, 10 or 50 mg/kg weekly from 8 to 98 weeks of age (up to 19x human AUC)

“In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg EVENITY (based on AUC comparison).”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

98-week Sprague Dawley rat carcinogenicity study completed before the marketing application

“A carcinogenicity study was conducted in Sprague Dawley rats. The rats were dosed for up to 98 weeks with 0, 3, 10, 50 mg/kg/week, equivalent to 1-19x human exposure.”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Summary across all 117 monoclonal antibodies →

Evenity: 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