from the label
is indicated for the prophylaxis of migraine in adults who have at
least 4 migraine days per month.1
related disorders are not listed among the adverse reactions listed
in the summary of product characteristics of Emgality.1
gene-related peptide has been recognized in published literature as a
neurotransmitter involved in the regulation of bone formation and
bone remodeling. Calcitonin gene-related peptide may act as a
modulator of bone metabolism through osteoblast and
osteoclast-associated mechanisms, which result in osteoblast
formation with subsequent activation of bone formation.2,3
is known that the inherited autosomal recessive disorder, familial
disautonomia, is associated with
levels of circulating CGRP
high prevalence of fractures, and
bone mineral density.4,5
association may suggest that the decrease in CGRP could be a
contributing factor to the increased fracture rate and low bone
mineral density in this population.4-6
these findings suggest that CGRP is an anabolic factor for bone
acting directly on osteoblasts. The potential risk of adverse
galcanezumab effects on bone growth and/or remodeling cannot be ruled
the galcanezumab clinical trials for migraine
prevention, calciotropic hormones were not measured, therefore
there is no information about interaction with or effect on
D, calcitonin, or
regarding fracture rates from the phase 3 migraine prevention and
bone safety findings from pre-clinical toxicology studies are
summarized separately below.
of Effects on Bone Metabolism in the Phase 3 Migraine Prevention
of the Phase 3 Migraine Studies
has been studied in phase 3 randomized, double-blind,
placebo-controlled studies in adult patients for the prevention of
migraine (EVOLVE-1 and EVOLVE-2),8,9
studies had a duration of
months for prevention of episodic migraine,8,9
months for prevention of chronic migraine, with an optional 9-month
open-label extension phase.10
were randomized at the beginning of double-blind treatment in a 2:1:1
ratio to receive monthly subcutaneous injections of
120 mg with a loading dose of 240 mg, or
Osteoporosis or Osteopenia: Phase 3 Migraine Studies
EVOLVE-1, EVOLVE-2, and REGAIN the majority (>80%) of patients
including those up to 65 years of age.4
A total of 60 patients (2.1%) reported preexisting osteopenia or
galcanezumab-treated patients, and
Rates: Phase 3 Migraine Studies
additional bone-specific biomarker or densitometry evaluations were
not assessed in galcanezumab clinical trials for migraine prevention,
adverse bone events such as bone fractures related to galcanezumab
treatment were not observed
patients with pre-existing osteoporosis or osteopenia, and
the remainder of galcanezumab-treated patients.4
adverse effects on bone growth and maintenance of bone mass were
observed in clinical trials of galcanezumab.4
EVOLVE-1, EVOLVE-2, and REGAIN, treatment-emergent fractures were
reported during double-blind treatment by
galcanezumab-treated patients (0.84%), and
placebo-treated patients (0.96%).4
difference between groups was not statistically significant.4
juvenile toxicology study in which rats were administered
galcanezumab twice weekly from Postnatal Day 21 through 90, systemic
effects were limited to reversible, minimal, nonadverse decreases in
total bone mineral content and bone mineral density at exposures
approximately 50 times the human exposure at 240 mg. 1
evaluations were done in 6-month rat and monkey toxicity studies,
examination at the time of necropsy
examination of the femur and sternum, including the bone marrow, and
pathology evaluation of calcium, inorganic phosphorus, and alkaline
addition, animals were observed for clinical signs that might suggest
effects on bone or skeletal function.4
were no effects on bone evaluations in any of the monkey studies at
exposures 156-fold greater than clinical exposures at the human dose
of 120 mg.4
morphology or growth changes were not observed in another prenatal
and postnatal development study of rats in which maternal exposures
were 34-fold higher than expected clinical exposures at 120 mg.4
potential effects of galcanezumab on growth and development,
including bone length and density was evaluated in a juvenile
toxicity study in rats.
effects suggesting a signal of potential concern regarding an effect
on bone were seen and only occurred at exposures 95-fold greater than
clinical exposures at the human dose of 120 mg.4
these findings on the bone in the juvenile toxicity rat study are not
considered to have human relevance as the non-adverse findings on
bone mineral content and bone mineral density were
in the absence of histopathology findings or clinical consequences
such as impaired use of limbs or fractures.4
there were no findings suggesting galcanezumab-related effects on
bone in the rat and monkey repeat-dose 6-month repeat-dose toxicity
Emgality [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
Naot D, Cornish J. The role of peptides and receptors of the
calcitonin family in the regulation of bone metabolism. Bone.
He H, Chai J, Zhang S, et al. CGRP may regulate bone metabolism
through stimulating osteoblast differentiation and inhibiting
osteoclast formation. Mol Med Rep. 2016;13(5):3977-3984.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Maayan C, Becker B, Gesundheit S, et al. Calcitonin gene-related
peptide in familial dysautonomia. Neuropeptides.
Maayan C, Bar-On E, Foldes AJ, et al. Bone mineral density and
metabolism in familial dysautonomia. Osteoporos Int.
Committee for Medicinal Products for Human Use (CHMP); European
Medicines Agency. CHMP assessment report: Emgality. Published
September 20, 2018. Accessed February 24, 2020.
Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of galcanezumab
for the prevention of episodic migraine: the EVOLVE-1 randomized
clinical trial. JAMA Neurol. 2018;75(9):1080-1088.
Skljarevski V, Matharu M, Millen BA, et al. Efficacy and safety of
galcanezumab for the prevention of episodic migraine: results of the
EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia.
Detke HC, Goadsby PJ, Wang S, et al. Galcanezumab in chronic
migraine: the randomized, double-blind, placebo-controlled REGAIN
study. Neurology. 2018;91(24):e2211-e2221.
Bangs ME, Kudrow D, Wang S, et al. Safety and tolerability of
monthly galcanezumab injections in patients with migraine: integrated
results from migraine studies. BMC Neurology. 2020;20(1):25.
Published correction appears in BMC Neurology. 2020;20(1):90.
= calcitonin gene-related peptide
= treatment-emergent adverse event
medicinal product is subject to additional monitoring. This will
allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.