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Emgality ® (galcanezumab)
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Does Emgality® (galcanezumab) cause weight gain or weight loss?
The percentage of galcanezumab-treated patients in phase 3 studies with treatment-emergent changes in weight was either similar to or lower than placebo, with no statistically significant or clinically meaningful differences between treatment groups.
Content overview
- What information is available about weight gain or weight loss in the summary of product characteristics (SmPC)?
- What analysis was done on treatment-emergent weight change in the migraine prevention studies?
- What were the postmarketing spontaneous reports related to weight change with galcanezumab treatment?
- Is there biological plausibility for weight change with galcanezumab treatment?
- References
- Appendix
What information is available about weight gain or weight loss in the summary of product characteristics (SmPC)?
Weight gain or weight loss is not mentioned in the list of adverse reactions in clinical studies and post-marketing reports of the SmPC of Emgality.1
What analysis was done on treatment-emergent weight change in the migraine prevention studies?
Galcanezumab has been studied in migraine prevention.2-10 Additional details on the galcanezumab migraine prevention studies are available in .
Safety results from the pivotal migraine prevention studies EVOLVE-1, EVOLVE-2, and REGAIN have been integrated, resulting in a pooled analysis of 2886 adult patients, comprising a total of 1435 patients that received monthly doses of galcanezumab (120 mg or 240 mg) administered subcutaneously.11
Treatment-emergent low and high weight was
- defined as categorical changes of ≥7.0% loss or gain, respectively, of body weight from baseline, and
- evaluated in all galcanezumab migraine prevention studies.12
Additional results are provided to supplement the primary integrated safety analysis.
Weight changes in the placebo-controlled galcanezumab migraine prevention studies
The mean changes in weight were small and not clinically meaningful in the placebo-controlled migraine prevention studies, including the
The mean weight change from baseline was
- -0.50 kg (-1.1) lb) for both galcanezumab dose groups, and -0.47 kg (-1.04 lb) for placebo in the EVOLVE-1, EVOLVE-2, and REGAIN primary integrated analysis
- 0.15 kg (0.33 lb) for galcanezumab 120 mg, and 0.21 kg (0.46 lb) for placebo in the CONQUER study, and
- 0.28 kg (0.62 lb) for both galcanezumab dose groups, and -0.13 kg (-0.13 lb) for placebo in the CGAN study.12
A similar proportion of galcanezumab- and placebo-treated patients either gained or lost ≥7.0% of their baseline weight, with no statistically significant changes observed between treatment groups. Additional information on categorical weight changes in the placebo-controlled studies can be found in .11,12
Study participation discontinuation due to weight gain in galcanezumab migraine prevention clinical trials
In the integrated safety analysis, one patient in the galcanezumab 120-mg group discontinued treatment due to increased weight at month 2 and was declared lost to follow-up.12
This patient met the treatment-emergent high weight criterion, with a baseline weight of 67.1 kg (147.6 lb) and weight at month 2 of 80.2 kg (176.4 lb).
Weight changes in the REGAIN and CONQUER open-label extensions
Patients who completed the double-blind period in both REGAIN and CONQUER were eligible to enter an optional open-label extension (OLE) of 9 months and 3 months, respectively.9,10
In the OLE phases of the REGAIN and CONQUER studies, there were no
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Weight changes in the 12-month, open-label galcanezumab migraine prevention safety studies CGAJ and CGAP
Galcanezumab has also been studied in 2 phase 3, open-label, 12-month safety studies for the prevention of episodic or chronic migraine, CGAJ and CGAP.6,7
In CGAJ, a total of 270 adult patients received monthly doses of galcanezumab (120 or 240 mg).6
In study CGAJ, the mean changes from baseline to last-observation-carried-forward endpoint in weight were
The percentage of patients in CGAJ who met the categorical criteria for treatment-emergent
- low weight was 9.8%, and
- high weight was 15.0% ().12
There were no meaningful differences between the 120-mg and 240-mg treatment groups.12 There does not appear to be any clinically meaningful impact of galcanezumab on weight given that
- weight changes may be anticipated over the course of a 12-month study
- the observed categorical weight changes occurred in both directions (weight loss and weight gain), and
- there was an observed plateau effect on weight in the 6 to 12 month period.12
In study CGAJ, no patient discontinued due to a TEAE related to weight gain or loss.12
In a 12-month open-label safety study in Japanese patients with episodic or chronic migraine (CGAP),
- no treatment-emergent clinically relevant weight changes were reported, and
- there were no discontinuations due to AEs related to weight change.7
Additional detailed information on categorical changes in weight in the CGAJ and CGAP studies are provided in .
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What were the postmarketing spontaneous reports related to weight change with galcanezumab treatment?
Through September 27, 2022, Medical Dictionary for Regulatory Activities terms related to weight change that have been reported in the Eli Lilly and Company spontaneous AE database are provided below.
Terms related to weight change that were very rarely reported (estimated rate of <0.01%) were
- abnormal weight gain
- body mass index increased
- cachexia
- fat tissue decrease
- fat tissue increase
- obesity
- overweight
- underweight
- waist circumference increase
- weight abnormal
- weight decreased
- weight fluctuation, and
- weight loss poor.12
The term weight increased was rarely reported (estimated rate of ≥0.01% and <0.1%).12
Postmarketing data do not necessarily represent the rate of occurrence of an 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.13
Spontaneous reporting has limited use due to
- lack of control population
- under-reporting or reporting bias, and
- missing or incomplete information regarding medical history or concomitant medications.13
Is there biological plausibility for weight change with galcanezumab treatment?
There is no clear biological evidence that suggests weight gain is an effect of calcitonin gene-related peptide (CGRP) inhibition.14 In fact, mice with endogenous αCGRP removed by knockout techniques
- were resistant to weight gain induced by high-fat diets compared to wild-type control animals, and
- displayed improved glucose handling and insulin sensitivity.15,16
In addition, elevated plasma levels of CGRP have been found in obese individuals.17 These findings suggest that CGRP blockade may lead to resistance in weight gain and improved metabolic health.14,15
In summary, these data do not suggest that the increase in weight seen in the galcanezumab clinical trials represent an adverse drug reaction due to the
- lack of clear biological plausibility
- bi-directionality of the effect of weight
- similar observed increase in mean change in weight (<1 kg) with shorter or longer duration of treatment, and
- observed plateau effect on weight in the 6 to 12 months period in study CGAJ.12
Additionally, it should be considered that obesity is a comorbidity in patients with migraine and therefore represents a confounding factor when assessing the increase in weight.18
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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
7Hirata K, Takeshima T, Sakai F, et al. A long-term open-label safety study of galcanezumab in Japanese patients with migraine. Expert Opin Drug Saf. 2021;20(6):721-733. https://doi.org/10.1080/14740338.2021.1866536
8Sakai F, Ozeki A, Skljarevski V. Efficacy and safety of galcanezumab for prevention of migraine headache in Japanese patients with episodic migraine: a phase 2 randomized controlled clinical trial. Cephalalgia Rep. 2020;3:251581632093257. http://dx.doi.org/10.1177/2515816320932573
9Pozo-Rosich P, Detke HC, Wang S, et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022;38(5):731-742. https://doi.org/10.1080/03007995.2022.2059975
10Reuter U, Lucas C, Dolezil D, et al. Galcanezumab in patients with multiple previous migraine preventive medication category failures: results from the open-label period of the CONQUER trial. Adv Ther. 2021;38:5465-5483. http://dx.doi.org/10.1007/s12325-021-01911-7
11Bangs ME, Kudrow D, Wang S, et al. Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies. BMC Neurol. 2020;20(1):25. https://doi.org/10.1186/s12883-020-1609-7
12Data on file, Eli Lilly and Company and/or one of its subsidiaries.
13Goldman 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
14Lima WG, Marques-Oliveira GH, da Silva TM, Chaves VE. Role of calcitonin gene-related peptide in energy metabolism. Endocrine. 2017;58(1):3-13. http://dx.doi.org/10.1007/s12020-017-1404-4
15Walker CS, Li X, Whiting L, et al. Mice lacking the neuropeptide alpha-calcitonin gene-related peptide are protected against diet-induced obesity. Endocrinology. 2010;151(9):4257-4269. http://dx.doi.org/10.1210/en.2010-0284
16Liu T, Kamiyoshi A, Sakurai T, et al. Endogenous calcitonin gene-related peptide regulates lipid metabolism and energy homeostasis in male mice. Endocrinology. 2017;158(5):1194-1206. http://dx.doi.org/10.1210/en.2016-1510
17Zelissen PM, Koppeschaar HP, Lips CJ, Hackeng WH. Calcitonin gene-related peptide in human obesity. Peptides. 1991;12(4):861-863. http://dx.doi.org/10.1016/0196-9781(91)90147-h
18Ornello R, Ripa P, Pistoia F, et al. Migraine and body mass index categories: a systematic review and meta-analysis of observational studies. J Headache Pain. 2015;16:27. http://dx.doi.org/10.1186/s10194-015-0510-z
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Glossary
αCGRP = alpha-calcitonin gene-related peptide
AE = adverse event
CGRP = calcitonin gene-related peptide
MedDRA = Medical Dictionary for Regulatory Activities
SmPC = Summary of Product Characteristics
Appendix
Migraine prevention studies
Galcanezumab has been studied in phase 2 and 3 randomized, double-blind, placebo-controlled studies in adult patients for the prevention of
|
GMB Doses Studied |
Study Duration |
120 mg monthlyc |
6 months double-blind |
|
120 mg monthlyc |
3 months double-blind, |
|
120 mg monthlyc |
3 months double-blind, |
|
120 mg monthly |
6 months double-blind |
|
120 mg monthlyc |
12 months open-label |
|
120 mg monthly |
12 months open-label |
Abbreviation: GMB = galcanezumab.
aWith the exception of study CGAJ and CGAP, all studies were randomized, double-blind, and placebo-controlled.
bDouble-blind, placebo-controlled.
cThe initial dose was administered as a 240-mg loading dose, followed by subsequent monthly doses of 120-mg.
dOpen-label study.
eAdult patients with episodic migraine who previously completed a 6-month, double-blind, placebo-controlled trial (CGAN) were newly randomized to either 120-mg or 240-mg galcanezumab from placebo, or continued their assigned galcanezumab doses. Newly enrolled patients with chronic migraine were randomized to 120-mg or 240-mg galcanezumab.
Categorical weight change tables
|
N |
Lowa |
Highb |
EVOLVE-1, EVOLVE-2, REGAIN integrated safety analysis |
|||
PBO |
1333 |
34 (2.6) |
69 (5.2) |
GMB 120 mg |
669 |
26 (3.9) |
42 (6.3) |
GMB 240 mg |
684 |
23 (3.4) |
44 (6.4) |
CONQUER |
|||
PBO |
225 |
3 (1.3) |
3 (1.3) |
GMB 120 mg |
226 |
1 (0.4) |
0 (0.0) |
CGAN |
|||
PBO |
230 |
10 (4.6) |
7 (3.0) |
GMB 120 mg |
114 |
3 (2.7) |
2 (1.8) |
GMB 240 mg |
114 |
1 (0.9) |
2 (1.8) |
Abbreviations: GMB = galcanezumab; PBO = placebo.
aDefined as a ≥7.0% decrease in body weight from baseline.
bDefined as a ≥7.0% increase in body weight from baseline.
|
GMB 120 mg |
GMB 240 mg |
GMB Pooled |
CGAJ |
N=123 |
N=131 |
N=254 |
Lowa |
13 (10.6) |
12 (9.2) |
25 (9.8) |
Highb |
17 (13.8) |
21 (16.0) |
38 (15.0) |
CGAP |
N=152 |
N=159 |
N=311 |
Lowa |
13 (8.6) |
7 (4.4) |
20 (6.4) |
Highb |
8 (5.3) |
9 (5.7) |
17 (5.5) |
Abbreviations: GMB = galcanezumab; GMB Pooled = GMB 120 mg and GMB 240 mg pooled.
aDefined as a ≥7.0% decrease in body weight from baseline.
bDefined as a ≥7.0% increase in body weight from baseline.
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Date of Last Review: 01 November 2023