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

Precedia/Monoclonal antibodies/Emgality/Tox package

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

galcanezumab · CGRP

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 Emgality 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: Rat 6-month NOAEL low dose (2 high-dose male deaths, drug relation not ruled out); monkey 6-month NOAEL high dose (injection-site irritation non-adverse) (FDA pharmacology/toxicology review, p. 60)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

6-month SC studies in rat and cynomolgus monkey; no recovery listed for them (shorter studies had 9- and 6-week recovery)

“The pivotal (GLP) subcutaneous (SC) toxicity studies (6-week + 9-week recovery, 3-month + 6- week recovery, and 6-month) were conducted in Sprague-Dawley rat and cynomolgus monkey.”

✓ VerifiedFDA pharmacology/toxicology review, p. 5Source ↗

Pivotal GLP studies

Rat and cynomolgus monkey SC: 6-week (+9-week recovery), 3-month (+6-week recovery) and 6-month studies

“The pivotal (GLP) subcutaneous (SC) toxicity studies (6-week + 9-week recovery, 3-month + 6-week recovery, and 6-month) were conducted in Sprague-Dawley rat and cynomolgus monkey.”

✓ VerifiedFDA pharmacology/toxicology review, p. 5Source ↗

DART package

Species: DART

Rat (male and female fertility, EFD, pre/postnatal) and rabbit (EFD)

“Studies in rats were conducted to assess the potential effects of galcanezumab on male and female fertility, embryo-fetal development (also in rabbits), and prenatal and postnatal development.”

✓ VerifiedEMA assessment report, p. 20Source ↗

Reproductive & developmental

Rat and rabbit studies: no drug-related fetal/offspring effects; an unexplained high-dose dam death in the rat pre- and postnatal study

“No drug-related effects were observed in the fetuses/offspring of either species. The only maternal finding of note was a death (Lactation Day 15) at the high dose in the pre- and postnatal study; the cause of death was not identified.”

✓ VerifiedFDA pharmacology/toxicology review, p. 6Source ↗

PPND / ePPND: when

PPND in rat completed before the marketing application

“The toxicology package consisted of general toxicology studies up to 6 months in rat and monkey, which included a safety pharmacology assessment in monkeys; fertility and embryofetal development studies in rat and rabbit; a pre- and postnatal development study in rat; and a juvenile animal toxicology study in rat.”

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (weight-of-evidence; not required)

“Carcinogenicity studies were not required, based on the potential for galcanezumab to counter CGRP associated angiogenesis and immunosuppression, specificity of galcanezumab for CGRP, lack of structural alerts on galcanezumab, and submitted toxicity and clinical studies, which indicated that galcanezumab has a low potential for carcinogenicity.”

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Carcinogenicity model

Not conducted: CGRP biology, target specificity, no structural alerts and tox/clinical data indicate low potential

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Carcinogenicity timing

Not required (weight-of-evidence: CGRP biology, specificity, no structural alerts, tox and clinical data)

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Summary across all 117 monoclonal antibodies →

Emgality: 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