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

Precedia/Monoclonal antibodies/Prolia/Tox package

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

denosumab · RANKL

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 Prolia 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 target organ toxicity at doses up to 50 mg/kg in 6/12-month monkey study (EMA assessment report, p. 16)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

Cynomolgus monkey SC study (study 102090), 53 weeks of dosing, with 3-month recovery

“(n=3/group, 3 months recovery n=2/group, There was no ECG evidence of cardiotoxicity after 53 weeks of treatment with denosumab. Isolated cases of slight bradycardia, fused P-T wave or slight tachycardia were observed in 102090”

✓ VerifiedEMA assessment report, p. 14Source ↗

Pivotal GLP studies

Cynomolgus monkey 1-month and 6/12-month SC studies, once monthly at 0, 1, 10, 50 mg/kg

“SC injection, 0, 1, 10 and 50 mg/kg once/month for 6 or 12 months)”

✓ VerifiedEMA assessment report, p. 15Source ↗

DART package

Species: DART

Cynomolgus monkey; RANKL knockout mice for prenatal development

“The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a "knockout mouse").”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Monkey PPND (50 mg/kg throughout pregnancy): fetal loss, stillbirths, postnatal mortality, absent lymph nodes, abnormal bone growth; fertility unaffected

“In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

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.

Carcinogenicity

Species: carcinogenicity

Not conducted, per regulatory guidance

“No carcinogenicity studies were conducted in accordance with available regulatory guidance.”

✓ VerifiedEMA assessment report, p. 16Source ↗

Carcinogenicity model

Not conducted; no preneoplastic lesions in ovariectomized monkeys treated up to 16 months

“No carcinogenicity studies were conducted in accordance with available regulatory guidance. Ovariectomized monkey treated for up to 16 months with denosumab showed no evidence of pre neoplastic lesions.”

✓ VerifiedEMA assessment report, p. 16Source ↗

Carcinogenicity timing

Not required: absence of carcinogenicity studies justified

“The absence of genotoxicity and carcinogenicity studies was sufficiently justified.”

✓ VerifiedEMA assessment report, p. 18Source ↗

Summary across all 117 monoclonal antibodies →

Prolia: 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