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Emgality ® (galcanezumab-gnlm) injection
100 mg/mL, 120 mg/mL
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EMGALITY (galcanezumab-gnlm): Effect on Bone Metabolism, US
Biological Plausibility
Calcitonin 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.1,2
It is known that the inherited autosomal recessive disorder, familial disautonomia, is associated with
This 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.3-5
Collectively, 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 out.6
Calciotropic Hormone Measurement
During the galcanezumab clinical trials for migraine prevention and cluster headache, calciotropic hormones were not measured, therefore there is no information about interaction with or effect on
parathyroid hormone
vitamin D, calcitonin, or
calcium metabolism.3
Information regarding fracture rates from the phase 3 migraine prevention and cluster headache populations, a phase 2 osteoarthritis study, and bone safety findings from pre-clinical toxicology studies are summarized separately below.
Summary of Effects on Bone Metabolism in the Phase 3 Migraine Prevention Studies
Overview of the Phase 3 Migraine Studies
Galcanezumab has been studied in phase 3 randomized, double-blind, placebo-controlled studies in adult patients for the prevention of
The studies had a duration of
6 months for prevention of episodic migraine,7,8 and
3 months for prevention of chronic migraine, with an optional 9-month open-label extension phase.9
Patients were randomized at the beginning of double-blind treatment in a 2:1:1 ratio to receive monthly subcutaneous injections of
placebo
galcanezumab 120 mg with a loading dose of 240 mg, or
galcanezumab 240 mg.7-9
Preexisting Osteoporosis or Osteopenia: Phase 3 Migraine Studies
In EVOLVE-1, EVOLVE-2, and REGAIN the majority (>80%) of patients were female,10 including those up to 65 years of age.3 A total of 60 patients (2.1%) reported preexisting osteopenia or osteoporosis including
32 galcanezumab-treated patients, and
28 placebo-treated patients.3
Fracture Rates: Phase 3 Migraine Studies
Although 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
in patients with pre-existing osteoporosis or osteopenia, and
in the remainder of galcanezumab-treated patients.3
No adverse effects on bone growth and maintenance of bone mass were observed in clinical trials of galcanezumab.3
In EVOLVE-1, EVOLVE-2, and REGAIN, treatment-emergent fractures were reported during double-blind treatment by
12 galcanezumab-treated patients (0.84%), and
14 placebo-treated patients (0.96%).3
The difference between groups was not statistically significant.3
Summary of Effects on Bone Metabolism in the Phase 3 Cluster Headache Studies
Overview of the Phase 3 Cluster Headache Studies
Galcanezumab was studied in 2 phase 3 randomized, double-blind, placebo-controlled studies in adults with
The studies had a double-blind treatment duration of
2 months for episodic cluster headache, and
3 months for chronic cluster headache, with an optional 12-month open-label extension phase.11,12
Patients were randomized at the beginning of double-blind treatment in a 1:1 ratio to receive monthly subcutaneous doses of
placebo, or
galcanezumab 300 mg.11
The CGAM study in chronic cluster headache did not meet its primary endpoint.12 However, safety results from the 2 placebo-controlled cluster headache trials were integrated and are the primary analysis set used for evaluation of galcanezumab safety in cluster headache.3
Preexisting Osteoporosis or Osteopenia and Fracture Rates: Phase 3 Cluster Headache Studies
In CGAL and CGAM, the majority of patients were male (>75%). There were 83 females across treatment groups in these studies.3
Two galcanezumab-treated patients (1.2%) in CGAL and CGAM reported the preexisting condition of osteoporosis. No patients reported the preexisting condition of osteopenia.3
No patients reported a treatment-emergent fracture during double-blind treatment.3
Phase 2 Study: Osteoarthritis of the Knee
The efficacy and safety of galcanezumab was evaluated in a phase 2 randomized, double-blind, placebo and active-controlled study in patients with mild to moderate osteoarthritis pain of the knee.13
In this study
patients were required to be between 40 to 75 years of age at the time of visit 1 inclusive, and
mean age at enrollment was 58 ± 9 years.13
This was the only study of galcanezumab that included patients above the age of 65.3
The study was terminated early at a planned interim analysis (treatment week 8) due to inadequate analgesic efficacy of galcanezumab. No safety events influenced this decision.3,13
Analyses by age subgroup were not conducted.3
The TEAE of fracture was not reported.3
Pre-Clinical Toxicology Studies
Bone evaluations were done in 6-month rat and monkey toxicity studies, consisting of
gross examination at the time of necropsy
microscopic examination of the femur and sternum, including the bone marrow, and
clinical pathology evaluation of calcium, inorganic phosphorus, and alkaline phosphatase.3
In addition, animals were observed for clinical signs that might suggest effects on bone or skeletal function.3
There 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.3
Bone 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.3
The potential effects of galcanezumab on growth and development, including bone length and density was evaluated in a juvenile toxicity study in rats.3
Galcanezumab-related 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.3
Overall, 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
minimal
reversible, and
occurred in the absence of histopathology findings or clinical consequences such as impaired use of limbs or fractures.3
Furthermore, there were no findings suggesting galcanezumab-related effects on bone in the rat and monkey repeat-dose 6-month repeat-dose toxicity studies.3
Enclosed Prescribing Information
EMGALITY® (galcanezumab-gnlm) injection, for subcutaneous use, Lilly
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1. Naot D, Cornish J. The role of peptides and receptors of the calcitonin family in the regulation of bone metabolism. Bone. 2008;43(5):813-818. http://dx.doi.org/10.1016/j.bone.2008.07.003
2. 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. http://dx.doi.org/10.3892/mmr.2016.5023
3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
4. Maayan C, Becker B, Gesundheit S, et al. Calcitonin gene-related peptide in familial dysautonomia. Neuropeptides. 2001;35(3&4):189-195. http://dx.doi.org/10.1054/npep.2001.0863
5. Maayan C, Bar-On E, Foldes AJ, et al. Bone mineral density and metabolism in familial dysautonomia. Osteoporos Int. 2002;13(5):429-433. http://dx.doi.org/10.1007/s001980200050
6. Committee for Medicinal Products for Human Use (CHMP); European Medicines Agency. CHMP assessment report: Emgality. Published September 20, 2018. Accessed February 24, 2020. https://www.ema.europa.eu/en/documents/assessment-report/emgality-epar-public-assessment-report_en.pdf
7. 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. http://dx.doi.org/10.1001/jamaneurol.2018.1212
8. 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. 2018;38(8):1442-1454. http://dx.doi.org/10.1177/0333102418779543
9. 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. http://dx.doi.org/10.1212/WNL.0000000000006640
10. 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. http://dx.doi.org/10.1186/s12883-020-1609-7. Published correction appears in BMC Neurology. 2020;20(1):90. http://dx.doi.org/10.1186/s12883-020-01675-7
11. Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141. http://dx.doi.org/10.1056/NEJMoa1813440
12. Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Presented as an oral presentation at: 61st Annual Meeting of the American Headache Society; July 11-14, 2019; Philadelphia, PA. https://doi.org/10.1111/head.13549
13. Jin Y, Smith C, et al. CGRP blockade by galcanezumab was not associated with reductions in signs and symptoms of knee osteoarthritis in a randomized clinical trial. Osteoarthritis Cartilage. 2018;26(12):1609-1618. https://doi.org/10.1016/j.joca.2018.08.019
Glossary
CGRP = calcitonin gene-related peptide
TEAE = treatment-emergent adverse event
Date of Last Review: May 10, 2024