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.”
Species: general tox
Sprague-Dawley rat and cynomolgus monkey (SC, up to 6 months)
“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.”
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.”
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.”
Surrogate used in
No surrogate used; galcanezumab itself is active in rat, rabbit and human
“Galcanezumab is pharmacologically active in rat, rabbit, and human, as characterized in a series of binding and functional in vitro assays.”
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.”
Genotox: Ames
Not conducted (not applicable to biologics)
“Genetic toxicology studies are typically considered not applicable to biologic products and were not required.”
Genotox: in vitro mammalian
Not conducted (not applicable to biologics)
“Genetic toxicology studies are typically considered not applicable to biologic products and were not required.”
Genotox: in vivo
Not conducted (not applicable to biologics)
“Genetic toxicology studies are typically considered not applicable to biologic products and were not required.”
Carcinogenicity model
Not conducted: CGRP biology, target specificity, no structural alerts and tox/clinical data indicate 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, and submitted toxicity and clinical studies, which indicated that galcanezumab has a low potential for carcinogenicity.”
Carcinogenicity timing
Not required (weight-of-evidence: CGRP biology, specificity, no structural alerts, tox and clinical data)
“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.”
hERG / QT
No QTc, heart rate, RR or ECG changes in 6-month monkey study (telemetry)
“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
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.”
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.”
Anti-drug antibodies: animals
Suspected ADA reduced exposure in 1 high-dose female (6-week) and several 2 mg/kg females (6-month) monkeys
“The reduced galcanezumab serum concentrations due to suspected ADAs observed in 1 female exposed to the highest dose level (100 mg/Kg) in the 6-week study, and in a number of female monkeys in the 6-month study in the lowest dose level (2 mg/kg), were recorded after Days 36 and 176, respectively, outside the cardiovascular/neurovascular timepoints assessment.”
Anti-drug antibodies: patients
ADA 4.8% (33/688) in controlled studies up to 6 months; 32 of 33 neutralizing
“In controlled studies with EMGALITY up to 6 months (Study 1, Study 2, and Study 3), the incidence of anti-galcanezumab-gnlm antibody development was 4.8% (33/688) in patients receiving EMGALITY once monthly (32 out of 33 of whom had in vitro neutralizing activity).”
Label warnings
- Hypersensitivity Reactions
- Constipation with Serious Complications
- Hypertension
- Raynaud's Phenomenon
Hypersensitivity & infusion reactionsGastrointestinalCardiovascular
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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.”
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)
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.”
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.”
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.”
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.”
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.”
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.”
Carcinogenicity model
Not conducted: CGRP biology, target specificity, no structural alerts and tox/clinical data indicate 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, and submitted toxicity and clinical studies, which indicated that galcanezumab has a low potential for carcinogenicity.”
Carcinogenicity timing
Not required (weight-of-evidence: CGRP biology, specificity, no structural alerts, tox and clinical data)
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
General tox NOAELs: rat 20 mg/kg ~1x human AUC (7x Cmax); monkey 100 mg/kg 21x AUC (143x Cmax)
“Rat 0, 20, 250 20 213 7x 29900 1x Unexplained death in 2 HD males General Toxicology Monkey 0, 2, 100 100 4490 143x 579500 21x”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Capsaicin-induced dermal blood flow increase in normal rats and cynomolgus monkeys
“In vivo activity was demonstrated in male rat and in female cynomolgus models of capsaicin-induced increase of dermal blood flow (DBF).”
Why that model
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.
Reviewer's view of the efficacy data
FDA: galcanezumab shown to bind CGRP with high affinity and effectively antagonize CGRP activity
“Galcanezumab was shown to have high affinity for CGRP, relative to other family members, and effectively antagonizes CGRP activity.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic migraine indication; weight-of-evidence assessment instead
Why: CGRP biology, target specificity, no structural alerts, and toxicity and clinical data indicate low carcinogenic potential · Weight of evidence · Pharmacology or kinetics · Human data
“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.”
Safety pharmacologyAcceptedBeyond the letter
No dedicated nonclinical study of the theoretical cardiovascular risk of CGRP inhibition, before or after approval
Why: Nonclinical studies unlikely to provide useful information given limited understanding of CGRP's role · Other reason
“Without a better understanding of the role of CGRP, it is unlikely that nonclinical studies of galcanezumab could be designed and conducted that would provide useful information; therefore, no post-marketing study to further assess the cardiovascular safety of galcanezumab is recommended.”
Similar precedents
AjovyAntibodies · fremanezumab · CGRPMonkey + rodent · 26 wkVyeptiAntibodies · eptinezumab · CGRPMonkey + rodent · 26 wkAimovigAntibodies · erenumab · CGRP receptorMonkey only · 26 wkNurtec ODTSmall molecules · rimegepant · CGRP receptorMonkey + rodent · 39 wkQuliptaSmall molecules · atogepant · CGRP receptorMonkey + rodent · 39 wkUbrelvySmall molecules · ubrogepant · CGRP receptorMonkey + rodent · 39 wk