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Emgality ® (galcanezumab)
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Was vertigo reported in Emgality® (galcanezumab) clinical trials?
Most vertigo events in the phase 3 studies were mild or moderate in severity and resolved. 1 galcanezumab-treated patient in the phase 3 migraine prevention studies discontinued due to vertigo.
Content Overview
Summary of Vertigo in the Phase 3 Migraine Prevention Studies
Treatment-Emergent Vertigo Events in the Phase 3 Migraine Prevention Studies
- Migraine Prevention: Incidence and Characterization of Vertigo
- Migraine Prevention: Duration of Treatment-Emergent Vertigo Events
Summary of Vertigo in the Phase 3 Migraine Prevention Studies
The reported adverse drug reaction for 120 mg and 240 mg in migraine clinical trials was
- vertigo (0.7 %/1.2 %).1
General information on vertigo and biological plausibility can be found in the Appendix.
Treatment-Emergent Vertigo Events in the Phase 3 Migraine Prevention Studies
Migraine Prevention: Incidence and Characterization of Vertigo
The incidence and severity of vertigo during the EVOLVE-1, EVOLVE-2, REGAIN, CONQUER, and CGAJ studies are summarized in Summary of Treatment-Emergent Vertigo Events: Phase 3 Migraine Headache Studies.
In a majority of reports, galcanezumab-treated patients in the EVOLVE-1, EVOLVE-2, REGAIN, CONQUER, and CGAJ studies reported their vertigo severity as mild or moderate.7
A total of 20 galcanezumab-treated patients in the migraine prevention studies reported 26 events of vertigo. Of those, 16 patients reported a single event of vertigo, with 9 of 16 events reported following the first dose. Of the 4 patients reporting multiple vertigo events
- 1 patient from the EVOLVE-1 study reported 3 events of vertigo, each occurring after the first, second, and third doses, respectively
- 1 patient from the EVOLVE-2 study reported 2 events of vertigo, each occurring the day after the first and second doses, respectively
- 1 patient from the open-label safety study reported 3 events of vertigo, each occurring after the first, fourth, and fifth doses, respectively, and
- another patient from the open-label safety study reported 2 events of vertigo, each occurring after the ninth dose.7
The two patients from the EVOLVE-1 and EVOLVE-2 studies completed the rest of their dosing visits without recurrence. In the open-label safety study, the patient with 2 vertigo events completed the study and the patient with three events of vertigo discontinued after their fifth dose.7
The onset of vertigo in the 26 events was
- within 7 days in 14 events, of which 9 were reported the day of or the day after a dose, and
- between 8 and 32 days after a dose in the remaining 12 cases.7
Two patients discontinued due to vertigo,
- one placebo-treated patient in the EVOLVE-2 study discontinued due to severe vertigo 2 days after receiving the third injection, and
- one patient treated with galcanezumab 240 mg from the open-label safety study.7
|
PBO |
GMB 120 mg |
GMB 240 mg |
PBO |
GMB 120 mg |
GMB 120 mg |
GMB 240 mg |
|
EVOLVE-1, EVOLVE-2, REGAIN |
CONQUER |
CGAJ |
||||
Incidence |
3 (0.2) |
5 (0.7) |
9 (1.2) |
4 (1.7) |
1 (0.4) |
3 (2.3) |
2 (1.4) |
Severity |
|||||||
Mild |
0 (0.0) |
2 (0.3) |
7 (1.0) |
3 (1.3) |
0 (0.0) |
3 (2.3) |
1 (0.7) |
Moderate |
2 (0.1) |
1 (0.1) |
2 (0.3) |
1 (0.4) |
1 (0.4) |
0 (0.0) |
1 (0.7) |
Severe |
1 (0.1) |
2 (0.3) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
Abbreviations: GMB = galcanezumab; PBO = placebo.
The recommended dose of galcanezumab is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1 The results of a maintenance dose of galcanezumab 240 mg once monthly are also described here. Even though this dose has been tested in pivotal studies, it has not been approved and therefore is not recommended.
Migraine Prevention: Duration of Treatment-Emergent Vertigo Events
The duration of vertigo events during the EVOLVE-1, EVOLVE-2, and REGAIN studies is summarized in Duration of Treatment-Emergent Vertigo Events: EVOLVE-1, EVOLVE-2, and REGAIN Studies.
TEAE Duration |
N |
PBO |
GMB 120 mg |
GMB 240 mg |
≤7 days |
13 |
1 |
5 |
7 |
>7 to ≤30 days |
1 |
0 |
0 |
1 |
>30 to ≤60 days |
2 |
0 |
1b |
1c |
Not resolved |
1 |
1d |
0 |
0 |
Abbreviations: GMB = galcanezumab; PBO = placebo; TEAE = treatment-emergent adverse event.
aDuration for treatment-emergent vertigo events was calculated only for those events with a documented start and end date.
bPatient received all planned study doses. Event occurred on day of the first dose with a duration of 32 days; 5 additional monthly doses received with no recurrence.
cPatient received all planned study doses. Event occurred 8 days after the second dose with a duration of 35 days; 4 additional monthly doses received with no recurrence.
dPatient received all planned study doses. Event occurred 8 days after the fifth dose and was not resolved by the end of study follow-up.
The recommended dose of galcanezumab is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1 The results of a maintenance dose of galcanezumab 240 mg once monthly are also described here. Even though this dose has been tested in pivotal studies, it has not been approved and therefore is not recommended.
During double-blind treatment in the CONQUER study, the duration of vertigo was reported as
- 123 days in the galcanezumab-treated patient
- 7 days or less in 3 placebo-treated patients, and
- not resolved in 1 placebo-treated patient who reported 2 events of vertigo.7
Of the 5 patients in the open-label safety study that reported vertigo,
- 2 patients treated with galcanezumab 120 mg reported their vertigo as resolving
- 2 galcanezumab-treated patients reported their vertigo duration as <7 days, and
- 1 patient treated with galcanezumab 240 mg reported a vertigo duration of 82 days.7
Postmarketing Spontaneous Reports
Based on postmarketing spontaneous reports through September 27, 2021 vertigo was rarely reported (≥0.01% and <0.1%).7
Postmarketing data do not necessarily represent the rate of occurrence of an adverse event (AE) in a treated population, but they represent a reporting rate of a particular AE to the company. Spontaneous reporting of AEs can be highly variable and is not appropriately controlled clinical information on which to base an assessment of whether a particular drug product is the causal agent of an event.8
Spontaneous reporting has limited use due to
- lack of control population
- underreporting or reporting bias, and
- missing or incomplete information regarding medical history or concomitant medications.8
Therapeutic Indication
Galcanezumab is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month.1
The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1
References
1Emgality [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Stauffer 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
3Skljarevski 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
4Detke 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
5Mulleners WM, Kim BK, Láinez MJA, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19(10):814-825. http://dx.doi.org/10.1016/S1474-4422(20)30279-9
6Camporeale 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(1):188. http://dx.doi.org/10.1186/s12883-018-1193-2
7Data on file, Eli Lilly and Company and/or one of its subsidiaries.
8Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-C44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6
9Reilly BM. Dizziness. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Butterworths; 1990:chap 212.
10Lempert T, Neuhauser H. Epidemiology of vertigo, migraine and vestibular migraine. J Neurol. 2009;256(3):333-338. http://dx.doi.org/10.1007/s00415-009-0149-2
11Dash AK, Panda N, Khandelwal G, et al. Migraine and audiovestibular dysfunction: is there a correlation? Am J Otolaryngol. 2008;29(5):295-299. http://dx.doi.org/10.1016/j.amjoto.2007.09.004
12Kong 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(3):487-497. https://doi.org/10.1046/j.0953-816x.2001.01880.x
13Schrott-Fischer A, Kammen-Jolly K, Scholtz A, et al. Efferent neurotransmitters in the human cochlea and vestibule. Acta Otolaryngol. 2007;127(1):13-19. http://dx.doi.org/10.1080/00016480600652123
Appendix
Vertigo General Information
Dizziness is a non-specific term that is also sometimes used to describe vertigo.9 The 4 recognized types of dizziness are
- vertigo
- disequilibrium
- presyncope, or
- lightheadedness.
Vertigo refers to the illusion of environmental motion (typically with a rotational component) or a disorientation in space.9 Vertigo reflects some level of dysfunction of the vestibular system. It is classically described as
- spinning
- whirling
- like getting off a merry-go-round, or
- the ground tilts up and down, like being on a boat at sea.
Biological Plausibility
Vertigo has been identified by Eli Lilly and Company as an adverse drug reaction.7 An adverse drug reaction is a clinical event that is considered related to exposure to a drug. Adverse drug reaction determination is based on the review of
- all the planned summaries or analyses
- any additional ad hoc displays, and
- case reviews needed to assist Lilly Medical in such determination.
In addition to the data presented here, results of human ex-vivo studies in both cochlear and vestibular efferent systems provide evidence of the role of calcitonin gene-related peptide in the neurotransmission and neuroregulation of these systems, supporting the biological plausibility of an association between the inhibition of calcitonin gene-related peptide and interference with vestibular function.12,13
Overview of Phase 3 Migraine Prevention Studies
Galcanezumab has been studied in phase 3, randomized, double-blind, placebo-controlled studies in adult patients for the prevention of
Galcanezumab has also been studied in a phase 3, open-label, 12-month safety study for the prevention of episodic or chronic migraine (CGAJ).6
The galcanezumab doses used and duration of the migraine prevention studies are summarized in Summary of Study Design in the Migraine Prevention Studies.
|
Treatments |
Study Duration |
PBO, GMB 120 mg,b |
6-month double-blind |
|
REGAIN4 |
PBO, GMB 120 mg,b |
3-month double-blind, |
CONQUER5 |
PBO or GMB 120 mg SQ monthlyb |
3-month double-blind, |
CGAJ6 |
GMB 120 mgb |
12-month open-label |
Abbreviations: GMB = galcanezumab; PBO = placebo; SQ = subcutaneous.
aWith the exception of study CGAJ, all studies were randomized, double-blind, and placebo-controlled.
bThe initial dose was administered as a 240-mg loading dose, followed by subsequent monthly doses of 120 mg.
The recommended dose is 120 mg galcanezumab injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose.1 The results of a maintenance dose of 240 mg galcanezumab once monthly are also described here. Even though this dose has been tested in pivotal studies, it has not been approved and therefore is not recommended.
Date of Last Review: 13 January 2022