Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Effekt på benmetabolismen

Negativa effekter på bentillväxt och underhåll av benmassa observerades inte i kliniska prövningar av galcanezumab.

Additional Information

Information from the label

Galcanezumab is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.1

Bone related disorders are not listed among the adverse reactions listed in the summary of product characteristics of Emgality.1

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.2,3

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.4,5

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.4-6

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.7

Calciotropic Hormone Measurement

During the galcanezumab clinical trials for migraine prevention, calciotropic hormones were not measured, therefore there is no information about interaction with or effect on

  • parathyroid hormone

  • vitamin D, calcitonin, or

  • calcium metabolism.4

Information regarding fracture rates from the phase 3 migraine prevention 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),8,9 and

  • chronic migraine (REGAIN).10

The studies had a duration of

  • 6 months for prevention of episodic migraine,8,9 and

  • 3 months for prevention of chronic migraine, with an optional 9-month open-label extension phase.10 

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.8-10 

Preexisting Osteoporosis or Osteopenia: Phase 3 Migraine Studies

In EVOLVE-1, EVOLVE-2, and REGAIN the majority (>80%) of patients were female,11 including those up to 65 years of age.4 A total of 60 patients (2.1%) reported preexisting osteopenia or osteoporosis including

  • 32 galcanezumab-treated patients, and

  • 28 placebo-treated patients.4

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.4

No adverse effects on bone growth and maintenance of bone mass were observed in clinical trials of galcanezumab.4

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%).4

The difference between groups was not statistically significant.4

Pre-Clinical Toxicology Studies

In a 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

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.4

In addition, animals were observed for clinical signs that might suggest effects on bone or skeletal function.4 

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.4

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.4

The potential effects of galcanezumab on growth and development, including bone length and density was evaluated in a juvenile toxicity study in rats.

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.4

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.4

Furthermore, there were no findings suggesting galcanezumab-related effects on bone in the rat and monkey repeat-dose 6-month repeat-dose toxicity studies.4

References

1. Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. 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

3. 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

4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

Glossary

CGRP = calcitonin gene-related peptide

TEAE = treatment-emergent adverse event

This 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.

Datum fӧr senaste ӧversyn 2020 M03 24


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