Emgality ® (galkanezumab)

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Emgality® ▼ (galcanezumab): Förstoppning i migränförebyggande studier

Förstoppning rapporterades hos ≤2% av patienterna som behandlades med galcanezumab i kliniska fas 3-studier. De flesta händelser var milda eller måttliga i svårighetsgrad och inga patienter avbröt behandlingen på grund av förstoppning.

Information from the Summary of Product Characteristics

Constipation is a common adverse reaction of galcanezumab. Constipation was reported by 1.0 % and 1.5 % of patients with 120 mg and 240 mg galcanezumab, respectively.1

Summary of Constipation in the Phase 3 Migraine Prevention Studies

Galcanezumab has been studied in migraine prevention.2-6 Constipation events for each population are summarized separately below.

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)2,3

  • chronic migraine (REGAIN),4 and

  • episodic or chronic migraine that has not benefited from 2 to 4 previous migraine prevention medication categories (CONQUER).5

The EVOLVE-1, EVOLVE-2, and REGAIN studies were the pivotal studies and safety results have been integrated resulting in a pooled analysis of 2886 adult patients, comprised of a total of 1435 patients that received monthly doses of galcanezumab (120 mg or 240 mg) administered subcutaneously.7

Results from CONQUER and the phase 3 open-label safety study are provided to supplement the primary integrated safety analysis. In the CONQUER study, there was a total of 462 adult patients enrolled, with 232 patients that received monthly doses of galcanezumab 120 mg.5 In the 12-month open-label safety study, a total of 270 adult patients received monthly doses of galcanezumab (120 or 240 mg).6

Note: 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 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.

Incidence and Characterization of Constipation Events: Migraine Prevention Studies

The incidence and severity of constipation during the double-blind treatment phase of the galcanezumab studies for migraine prevention are summarized in Table 1.

The constipation reports

  • did not have a pattern of occurrence with regard to timing of injection, and

  • were mild or moderate in severity, with no severe events reported.8

No patients discontinued due to constipation.8 However, in the CONQUER study, 1 patient in the galcanezuamb group did report an event of constipation of moderate severity after completing the double-blind phase and opted to not continue in the optional open-label phase of the study as a result of that event.

Table 1. Summary of Treatment-Emergent Constipation Events in the EVOLVE-1, EVOLVE-2, and REGAIN Studies: Double-Blind Treatment Phase7,8

 

PBO
N=1451
n (%)

GMB 120 mg
N=705
n (%)

GMB 240 mg
N=730
n (%)

Incidence

8 (0.6)

7 (1.0)

11 (1.5)a

Severity

Mild

4 (0.3)

2 (0.3)

5 (0.7)

Moderate

4 (0.3)

5 (0.7)

6 (0.8)

Severe

0 (0.0)

0 (0.0)

0 (0.0)

Abbreviations: GMB = galcanezumab; PBO = placebo.

a p<.05 vs placebo.

In the CONQUER study, constipation events were reported by

  • 5 patients in the placebo group (2.17%), and

  • 5 patients in the galcanezumab 120 mg group (2.16%).5

The majority of cases were of mild severity (4 out of 5 cases in each treatment group). No cases were reported as severe.8

In the 12-month open-label safety study, there were 2 events of constipation reported in the galcanezumab 120 mg group (1.55%) with 1 case each reported as mild and moderate severity.8

Duration of Treatment-Emergent Constipation Events: Migraine Prevention Studies

The duration of constipation events by treatment group is summarized in  .

Persistent constipation was defined as resolution in >30 days.8 More patients treated with galcanezumab reported persistent constipation (n=6) than placebo (n=2). Three patients in the galcanezumab 120-mg dose group reported mild to moderate constipation that persisted for >90 days. These cases are summarized in Table 3.

Table 2. Durationa of Treatment-Emergent Constipation Events in the EVOLVE-1, EVOLVE-2, and REGAIN Studies: Double-Blind Treatment Phase8

TEAE duration

N

PBO
(n)

GMB 120 mg
(n)

GMB 240 mg
(n)

7 days

10

4

0

6

>7 to ≤30 days

2

1

1

0

>30 to ≤60 days

4

2

1

1

>60 to ≤90 days

1

0

1

0

>90 days

3

0

3

0

Abbreviation: GMB = galcanezumab; PBO = placebo; TEAE = treatment-emergent adverse event.

a Duration for treatment-emergent constipation events were calculated only for those events with a documented start and end date.

Table 3. Reports of Constipation That Persisted for >90 Days in the EVOLVE-1, EVOLVE-2, and REGAIN Studies8

Duration of Constipation

Reported Term for AE

Severity

Details

95 days

Intermittent Constipation

mild

  • Considered not potentially related by investigator

  • Reported no other AEs

  • Treated with Miralax and was on diphenhydramine PRN

138 days

Constipation

mild

  • Considered potentially related by investigator

  • Also reported diarrhea and gastroenteritis around same timeframe

  • Taking citalopram since 2010

183 days

Obstipation

moderate

  • Considered potentially related by investigator

  • Reported no other AEs

  • Treated with bisacodyl PRN for constipation.

Abbreviation: AE = adverse event; PRN = as needed.

In the CONQUER study, 5 of the events did not have a documented end date, thus duration are available for only 5 of the 10 events reported.8 Those events with a documented end date had a duration of

  • 14 and 43 days in the galcanezumab group, and

  • between 3 and 14 days in the placebo group.8

In the 12-month open-label safety study, the 2 cases of constipation had a duration of ≤7 days.8

Postmarketing Spontaneous Reports

Through 27 March 2020, the MedDRA term of constipation has been rarely reported in the Eli Lilly and Company spontaneous AE database. Rarely reported is defined as an AE that has been reported at an estimated rate of ≥.01% and <0.1% according to the reporting system information.8

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.9

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.9

Biological Plausibility

Calcitonin gene-related peptide is

  • widely expressed throughout the central and peripheral nervous system,10 and

  • primarily localized to C and A-delta sensory fibers and has a dual role in sensory (nociceptive) and efferent (effector) function.11

Calcitonin gene-related peptide and its receptors are also widely expressed in the enteric system and animal studies have suggested a role for CGRP in modulating intestinal neurotransmission, mobility, and secretion.12,13 Rodent studies have demonstrated alteration of GI tract motility and secretions when given agents that antagonize CGRP or its receptors.13,14

A mouse study evaluating the effect of CGRP inhibition on GI transit time found that the

  • CGRP receptor antibody and small molecule CGRP receptor antagonist significantly inhibited GI transit time in the large intestine, and

  • CGRP ligand antibody did not have a significant effect.14

Thus, it is plausible that modulating CGRP function may have potential impact on the human GI tract.

References

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

2. 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

3. 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

4. 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

5. Mulleners WM, Kim B-K, 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

6. 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(1):188. http://dx.doi.org/10.1186/s12883-018-1193-2

7. 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 Neurol. 2020;20(1):25. http://dx.doi.org/10.1186/s12883-020-1609-7. Published correction appears in BMC Neurol. 2020;20(1):90. http://dx.doi.org/10.1186/s12883-020-01675-7

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

9. Goldman 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

10. Goadsby PJ, Holland PR, Martins-Oliveira M, et al. Pathophysiology of migraine: A disorder of sensory processing. Physiol Rev. 2017;97(2):553-622. http://dx.doi.org/10.1152/physrev.00034.2015

11. Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099-1142. http://dx.doi.org/10.1152/physrev.00034.2013

12. Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158(4):543-559. http://dx.doi.org/10.1097/j.pain.0000000000000831

13. Cottrell GS, Alemi F, Kirkland JG, et al. Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract. Peptides. 2012;35(2):202-211. http://dx.doi.org/10.1016/j.peptides.2012.03.020

14. Johnson K, Li X, Baolin L. Characterization of transit times in the large intestine of mice following treatment with a CGRP antibody, CGRP receptor antibody and a small molecule CGRP receptor antagonist. Neurology. 2020;94(15 suppl):1791. https://n.neurology.org/content/94/15_Supplement/1791

Glossary

CGRP = calcitonin gene-related peptide

GI = gastrointestinal

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 2019 M04 04


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