Emgality
galcanezumab
Species
MonkeyRat
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“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.”
Why that species
Monkey CGRP sequence identical to human, so binding affinity assumed similar (not assessed)
“Binding to monkey CGRP was not assessed because its sequence is identical to that of human CGRP; therefore, binding affinity was assumed to be similar in both species.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rat and cynomolgus monkey
“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.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“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.”
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.”
Route in tox
SC (weekly)
“In monkey, the high dose tested in the 6-week (0, 1.5, 15, or 100 mg/kg QW), 3-month (0, 15, or 100 mg/kg QW), and 6-month (0, 2, or 100 mg/kg QW) studies was the NOAEL in all studies.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Consistently with ICH S6(R1) guidance, genotoxicity studies were not conducted because galcanezumab is a monoclonal antibody.”
Carcinogenicity
Not conducted; weight-of-evidence: counters CGRP-associated angiogenesis and immunosuppression, specific, no structural alerts; low potential
“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”
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.”
Safety pharmacology
No cardiovascular effects (ECG, heart rate, RR, QTc) in the 6-month SC monkey study
“No galcanezumab-related effects on cardiovascular parameters measured were identified in the 6-month monkey study: i.e. no rhythm abnormalities or qualitative ECG changes and no effect on heart rate, RR or QTc interval were observed following galcanezumab SC administration at any dose group.”
First doseopen answer page →
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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
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)
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)
“The NOAEL in the 6-month rat study was the LD, because a drug-related cause of death could not be ruled out in the 2 HDM. In the 6-month monkey study, the NOAEL was the HD, because the injection site irritation was not considered adverse.”
Risksopen answer page →
Immune & cytokine safety
Decreased plasma drug levels after repeat dosing attributed to ADA formation
“The sponsor attributed the decreases in plasma drug levels following repeat dosing to ADA formation (no individual animal ADA data were provided).”
Biodistribution & persistence
TCR: staining of neurons and innervated tissues in human, monkey and rat, plus unexpected kidney tubular epithelium binding
“A tissue cross-reactivity study assessing galcanezumab binding positively stained select human, monkey, and rat tissues that were consistent with the association of CGRP with neurons and innervated tissues; however, specific binding was also observed in tissues not expected to express CGRP (i.e., tubular epithelium of the kidney).”
Modality-specific risk
Cardiovascular risk of long-term CGRP antagonism (loss of vasodilation), especially with cardiovascular risk factors
“Because of the potent vasodilatory properties of CGRP, concerns were raised regarding long-term antagonism of the CGRP in humans, particularly in patients with cardiovascular risk factors.”
Similar precedents
Ajovyfremanezumab · CGRPMonkey + rodent · 26 wkVyeptieptinezumab · CGRPMonkey + rodent · 26 wkAimovigerenumab · CGRP receptorMonkey only · 26 wkAduhelmaducanumab · Aggregated amyloid-βMonkey + rodent · 26 wkKisunladonanemab · Amyloid-β (N3pG)Monkey + rodent · 22 wkBriumviublituximab · CD20Monkey only · 26 wk