Top

Published in:

Open Access 01-12-2020 | Migraine | Research article

Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies

Authors: Mark E. Bangs, David Kudrow, Shufang Wang, Tina M. Oakes, Gisela M. Terwindt, Delphine Magis, Laura Yunes-Medina, Virginia L. Stauffer

Published in: BMC Neurology | Issue 1/2020

Abstract

Background

Galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days in phase 2 and 3 trials. In these analyses, we aimed to evaluate the safety and tolerability of galcanezumab compared with placebo for prevention of episodic or chronic migraine.

Methods

Data were integrated from three double-blind clinical studies for the up to 6-month galcanezumab exposure group (N = 1435), and from five clinical studies for the up to 1-year all-galcanezumab exposure group (N = 2276). Patients received a monthly 120 mg subcutaneous injection of galcanezumab (with a 240 mg loading dose in month 1), 240 mg galcanezumab, or placebo. Outcomes measured were treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and discontinuation due to AEs (DCAEs). Laboratory results, vital signs, electrocardiogram (ECG), suicidal ideation and behavior results were evaluated.

Results

TEAEs that occurred more frequently in galcanezumab-treated patients included injection site pain, injection site reactions excluding pain, constipation, vertigo, and pruritus. The proportion of DCAEs among galcanezumab-treated patients ranged between 1.8 and 3.0%, and differed from placebo group for galcanezumab 240 mg (P < 0.05). Fewer than 2.0% of patients in either galcanezumab dose-group compared with 1.0% of placebo-treated patients reported a SAE. There were no clinically meaningful differences between galcanezumab and placebo in laboratory measures, vital signs including blood pressure, ECGs, cardiovascular-related AEs, or suicidal ideation and behavior.

Conclusions

Galcanezumab demonstrated a favorable safety and tolerability profile for up to 1 year of treatment for the prevention of migraine.

Trial registration

Clinical Trials CGAB = NCT02163993, EVOLVE-1 = NCT02614183, EVOLVE-2 = NCT02614196, REGAIN = NCT02614261, and CGAJ = NCT02614287. All were first posted on 25 November 2015, except CGAB posted on 16 June 2014, and before enrolling the first patient.

Eftekhari S, Salvatore CA, Calamari A, et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169:683–96. https://doi.org/10.1016/j.neuroscience.2010.05.016.CrossRefPubMed

Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 1994;14:320–7. https://doi.org/10.1046/j.1468-2982.1994.1405320.x.CrossRefPubMed

Bigal ME, Walter S, Rapoport AM. Calcitonin gene-related peptide (CGRP) and migraine current understanding and state of development. Headache. 2013;53:1230–44. https://doi.org/10.1111/head.12179.CrossRefPubMed

Edvinsson L, Haanes KA, Warfvinge K, et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14:338–50. https://doi.org/10.1038/s41582-018-0003-1.CrossRefPubMed

Cady RJ, Glenn JR, Smith KM, et al. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain. 2017;7:94–105. https://doi.org/10.1186/1744-8069-7-94.CrossRef

Hirsch S, Corradini L, Just S, et al. The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats. Pain. 2013;154:700–7. https://doi.org/10.1016/j.pain.2013.01.002.CrossRefPubMed

Russell FA, King R, Smillie S-J, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94:1099–142. https://doi.org/10.1152/physrev.00034.2013.CrossRefPubMedPubMedCentral

MaassenVanDenBrink A, Meijer J, Villalόn CM, et al. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37:779–89. https://doi.org/10.1016/j.tips.2016.06.002.CrossRefPubMed

Kurth T, Gaziano J, Cook NR, et al. Migraine and risk of cardiovascular disease in women. JAMA. 2006;296:283–91. https://doi.org/10.1001/jama.296.3.283.CrossRefPubMed

10.

Becker C, Brobert G, Almqvist PM, et al. Migraine and the risk of stroke, TIA, or death in the UK. Headache. 2007;47:1374–84. https://doi.org/10.1111/j.1526-4610.2007.00937.x.CrossRefPubMed

11.

Le H, Tfelt-Hansen P, Russell MB, et al. Co-morbidity of migraine with somatic disease in a large population-based study. Cephalalgia. 2011;31:43–64. https://doi.org/10.1177/0333102410373159.CrossRefPubMed

12.

Chen YC, Tang CH, Ng K, et al. Comorbidity profiles of chronic migraine sufferers in a national database in Taiwan. J Headache Pain. 2012;13:311–9. https://doi.org/10.1007/s10194-012-0447-4.CrossRefPubMedPubMedCentral

13.

Sacco S, Ornello R, Ripa P, et al. Migraine and risk of ischaemic heart disease: a systematic review and meta-analysis of observational studies. Eur J Neurol. 2015;22:1001–11. https://doi.org/10.1111/ene.12701.CrossRefPubMed

14.

Peng KP, Chen YT, Fuh JL, et al. Migraine and incidence of ischemic stroke: a nationwide population-based study. Cephalalgia. 2017;37:327–35. https://doi.org/10.1177/0333102416642602.CrossRefPubMed

15.

Benschop RJ, Collins EC, Darling RJ, et al. Development of a novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. Osteoarthr Cartil. 2014;22:578–85. https://doi.org/10.1016/j.joca.2014.01.009.CrossRefPubMed

16.

Oakes TM, Skljarevski V, Zhang Q, et al. Safety of galcanezumab in patients with episodic migraine: a randomized placebo-controlled dose-ranging phase 2b study. Cephalalgia. 2018;38:1015–25. https://doi.org/10.1177/0333102417747230.CrossRefPubMed

17.

Dodick DW, Goadsby PJ, Spierings ELH, et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885–92. https://doi.org/10.1016/S1474-4422(14)70128-0.CrossRefPubMed

18.

Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2018;75:187–93. https://doi.org/10.1001/jamaneurol.2017.3859.CrossRefPubMed

19.

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;75:1080–8. https://doi.org/10.1001/jamaneurol.2018.1212.CrossRefPubMedPubMedCentral

20.

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;38:1442–54. https://doi.org/10.1177/0333102418779543.CrossRefPubMed

21.

Detke HC, Goadsby PJ, Wang S, et al. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91:e2211–21. https://doi.org/10.1212/WNL.0000000000006640.CrossRefPubMedPubMedCentral

22.

Camporeale A, Kudrow D, Sides R, et al. A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine. BMC Neurol. 2018;18:188–99. https://doi.org/10.1186/s12883-018-1193-2.CrossRefPubMedPubMedCentral

23.

Förderreuther S, Zhang Q, Stauffer VL, et al. Preventive effects of galcanezumab in adult patients with episodic or chronic migraine are persistent: data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2, and REGAIN studies. J Headache Pain. 2018;19:121. https://doi.org/10.1186/s10194-018-0951-2.CrossRefPubMedPubMedCentral

24.

Silberstein SD, Stauffer VL, Day KA, et al. Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2). J Headache Pain. 2019;20:75. https://doi.org/10.1186/s10194-019-1024-x.CrossRefPubMedPubMedCentral

25.

Xu D, Chen D, Zhu LN, et al. Safety and tolerability of calcitonin-gene-related peptide binding monoclonal antibodies for the prevention of episodic migraine - a meta-analysis of randomized controlled trials. Cephalalgia. 2019;39:1164–79. https://doi.org/10.1177/0333102419829007.CrossRefPubMed

26.

Posner K, Brown GK, Stanley B, et al. The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–77. https://doi.org/10.1176/appi.ajp.2011.10111704.CrossRefPubMedPubMedCentral

27.

Buse DC, Rupnow MFT, Lipton RB. Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidities, and quality of life. Mayo Clin Proc. 2009;84:422–35. https://doi.org/10.1016/S0025-6196(11)60561-2.CrossRefPubMedPubMedCentral

28.

Dodick DW, Ashina M, Brandes JL, et al. ARISE: a phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38:1026–37. https://doi.org/10.1177/0333102418759786.CrossRefPubMed

29.

Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–32. https://doi.org/10.1056/NEJMoa1705848.CrossRefPubMed

30.

Tepper SJ, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425–34. https://doi.org/10.1016/S1474-4422(17)30083-2.CrossRefPubMed

31.

Aimovig™ (Erenumab-aooe) injection. Amgen Inc. and Novartis Pharmaceuticals Corporation. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761077s003lbl.pdf. Accessed 4 Aug 2019.

32.

Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319:1999–2008. https://doi.org/10.1001/jama.2018.4853.CrossRefPubMed

33.

Silberstein SD, Aycardi E, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–22. https://doi.org/10.1056/NEJMoa1709038.CrossRefPubMed

34.

Ajovy™ (fremanezumab-vfrm) injection. Teva Pharmaceuticals USA, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf. Accessed 10 Jan 2018.

35.

Silberstein SD, McAllister P, Ning X, et al. Safety and tolerability of fremanezumab for the prevention of migraine: a pooled analysis of phases 2b and 3 clinical trials. Headache. 2019;59:880–90. https://doi.org/10.1111/head.13534.CrossRefPubMed

36.

Sacco S, Bendtsen L, Ashina M, et al. European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. J Headache Pain. 2019;20(6). https://doi.org/10.1186/s10194-018-0955-y Erratum in: J Headache Pain. 2019;20:58.

37.

Kaiser EA, Rea BL, Kuburas A, et al. Anti-CGRP antibodies block CGRP-induced diarrhea in mice. Neuropeptides. 2017;64:95–9.CrossRef

38.

Lempert T, Neuhauser H. Epidemiology of vertigo, migraine and vestibular migraine. J Neurol. 2009;256:333–8. https://doi.org/10.1007/s00415-009-0149-2.CrossRefPubMed

39.

Dash AK, Panda N, Khandelwal G, et al. Migraine and audiovestibular dysfunction: is there a correlation? Otolaryngol Head Neck Surg. 2008;29:295–9. https://doi.org/10.1016/j.amjoto.2007.09.004.CrossRef

40.

Kong WJ, Scholtz AW, Kammen-Jolly K, et al. Ultrastructural evaluation of calcitonin gene-related peptide immunoreactivity in the human cochlea and vestibular endorgans. Eur J Neurosci. 2002;15:487–97. https://doi.org/10.1046/j.0953-816x.2001.01880.x.CrossRefPubMed

41.

Schrott-Fischer A, Kammen-Jolly K, Scholtz A, et al. Efferent neurotransmitters in the human cochlea and vestibule. Acta Otolaryngol. 2007;127:13–9. https://doi.org/10.1080/00016480600652123.CrossRefPubMed

42.

Regev A, Camporeale A, Skljarevski V, et al. Hepatic safety of galcanezumab in patients with migraine: results of three phase 2 double-blind placebo-controlled trials. Neurology. 2017;88(Suppl):164–8.

43.

Hepp Z, Dodick D, Varon SF, et al. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35:478–88. https://doi.org/10.1177/0333102414547138.CrossRefPubMed

44.

Loder EW, Rizzoli P. Tolerance and loss of beneficial effect during migraine prophylaxis: clinical considerations. Headache. 2011;51:1336–45. https://doi.org/10.1111/j.1526-4610.2011.01986.x.CrossRefPubMed

Title: Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies
Authors: Mark E. Bangs
David Kudrow
Shufang Wang
Tina M. Oakes
Gisela M. Terwindt
Delphine Magis
Laura Yunes-Medina
Virginia L. Stauffer
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Migraine
Galcanezumab
Published in: BMC Neurology / Issue 1/2020
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-020-1609-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies

Abstract

Background

Methods

Results

Conclusions

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2020

Cost-effectiveness of the PDSAFE personalised physiotherapy intervention for fall prevention in Parkinson’s: an economic evaluation alongside a randomised controlled trial

Additional factors to corelate with a more than 30% NIHSS score improvement in patients 7 days after fibrinolytic and/or endovascular treatment for ischemic stroke

Genetic analysis of spinal dysraphism with a hamartomatous growth (appendix) of the spinal cord: a case series

Protocols of a diagnostic study and a randomized controlled non-inferiority trial comparing televisits vs standard in-person outpatient visits for narcolepsy diagnosis and care: TElemedicine for NARcolepsy (TENAR)

Paroxysmal extreme pain disorder in family with c.3892G > T (p.Val1298Phe) in the SCN9A gene mutation – case report

The development of a return to work intervention programme for stroke survivor (SReTWIP): a Delphi survey