EMGALITY (galcanezumab-gnlm): Effect on Bone Metabolism, US

Additional Information

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

• low levels of circulating CGRP

• a high prevalence of fractures, and

• reduced bone mineral density.^3,4

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

• episodic migraine (EVOLVE-1 and EVOLVE-2),^7,8 and

• chronic migraine (REGAIN).⁹

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

• episodic cluster headache (CGAL), and

• chronic cluster headache (CGAM).^11,12

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: 61^st 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