Emgality® ▼ (galcanezumab): Immunogenicity

Information from the Label

In the clinical studies, the incidence of anti-drug antibody development during the double-blind treatment phase was 4.8 % in patients receiving galcanezumab once monthly (all but one of whom had in vitro neutralizing activity). With 12 months of treatment, up to 12.5 % of galcanezumab-treated patients developed anti-drug antibodies, most of which were of low titre and tested positive for neutralising activity in vitro. However, the presence of anti-drug antibodies did not affect the pharmacokinetics, efficacy, or safety of galcanezumab.¹

Galcanezumab is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients (L-histidine, L-histidine hydrochloride monohydrate, Polysorbate 80, Sodium chloride, Water for injections).¹

Immunogenicity in Phase 3 Studies Migraine Prevention Studies

Galcanezumab is a humanized monoclonal IgG4 antibody. Because the possibility for an immunogenic response exists with any monoclonal antibody, subjects in all galcanezumab clinical studies were tested for the presence of ADA. An integrated assessment of immunogenicity was completed to evaluate any potential clinically relevant correlations with immunogenicity.²

This integrated assessment³ included the

• baseline and double-blind, placebo-controlled phases of the EVOLVE-1, EVOLVE-2, and REGAIN studies,^4-6 and

• baseline and open-label phases of the open-label safety study CGAJ.⁷

See Overview of Phase 3 Migraine Prevention Programfor an overview of these studies.

Migraine Prevention: Incidence of ADA at Baseline, TE ADA, and NAb

Patients were considered to have developed TE ADA if

• ADA was not present at baseline and they have at least one postbaseline sample with ADA detected at titer ≥1:20, or

• ADA present at baseline and they have at least one postbaseline sample with ADA detected at titer ≥4-fold greater than baseline titer.²

In double-blind placebo-controlled studies, EVOLVE-1, EVOLVE-2, and REGAIN, up to 9.4% of patients treated with galcanezumab developed TE ADA. In the 12-month open-label study CGAJ, up to 12.4% of patients treated with galcanezumab developed TE ADA during the treatment phase.²

The majority of patients who developed TE ADA with galcanezumab treatment did not have pre-existing ADA.²

For details, see Table 1.

Table 1. Anti-Drug and Neutralizing Antibody Findings Across the Phase 3 Galcanezumab Studies²

Abbreviations: ADA = anti-drug antibody; BL = baseline; GMB = galcanezumab; NAb = neutralizing antibody; PBO = placebo; TE = treatment-emergent.

^a During the 3-month, double-blind treatment phase.

^b Defined as patients without ADA present at baseline and at least one postbaseline sample with ADA detected at titer ≥1:20, or patients with ADA present at baseline and at least one postbaseline sample with ADA titer ≥4-fold greater than baseline titer.

^c In the treatment period, NAb present refers to patients who were TE ADA+ and had NAb detected at least once. Analyses were conducted on TE ADA evaluable patients in the safety population using modal dose.

^d p<.05 vs placebo.

^e During the 6-month, double-blind treatment phase.

^f p<.001 vs placebo.

^g During the 12-month, open-label treatment phase.

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.

Migraine Prevention: ADA Titer Over Time

Across all the studies, the majority of patients who developed TE ADA with galcanezumab treatment

• had a TE ADA+ titer detected at only one assessment during the treatment phase, and

• had maximum postbaseline titers ≤1:160 that decreased over time (many no longer had TE ADA titers by their last assessment of the treatment period).²

Within the 6-month treatment period in EVOLVE-1and EVOLVE-2, 20.5% of patients who were TE ADA+ earlier in the study no longer had TE ADA titers at the final assessment.³

In the 12-month open-label study CGAJ, a greater proportion of TE ADA+ patients, 46.2%, had titers that decreased over time and 38.5% no longer had TE ADA titers at the final assessment.³

Migraine Prevention: Effect of ADA on Galcanezumab PK and Target Engagement

ADA had no notable effect on

• galcanezumab PK, nor

• binding of the CGRP ligand to galcanezumab.²

Migraine Prevention: Impact of TE ADA on Efficacy

The range of mean monthly MHD changes in patients who developed TE ADA was similar to that observed for all galcanezumab-treated patients, regardless of TE ADA status.² These findings support a lack of clinically meaningful impact of the observed immunogenicity on galcanezumab efficacy.

Migraine Prevention: Impact of TE ADA on Safety

No PTs were reported exclusively by TE ADA+ patients for

• hypersensitivity events, or

• injection site-related AEs.²

Criteria for case level review was based on OR and p-value from the Cochran-Mantel-Haenszel test that compared the proportions of patients with ≥1 hypersensitivity event preferred term or ≥1 preferred term related to injection sites between TE ADA+ and TE ADA- patients, stratified by study.² Events with an OR >2.0 or p≤.05 met flagging criteria for further review.

For hypersensitivity events or injection site-related AEs that met criteria for case level review, no consistent temporal relationship, or titer response relationship were observed between the presence of TE ADA and the events. As with any therapeutic antibody, treatment with galcanezumab can elicit an ADA response in some patients.³

These analyses from the phase 3 migraine program characterize the immunogenicity of galcanezumab treatment in patients with episodic and chronic migraine, and reveal that immunogenicity did not impact

• hypersensitivity events

• injection site-related AEs

• galcanezumab concentrations

• CGRP concentrations, or

• the efficacy profile of galcanezumab.²

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

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

2. Martinez JM, Garces S, Anglin G, et al. Immunogenicity findings from phase 3 galcanezumab trials in patients with episodic or chronic migraine. Poster presented at: 12th European Headache Federation Congress; September 28-30, 2018; Florence, Italy.

3. Martinez JM, Hindiyeh N, Anglin G, et al. Assessment of immunogenicity from galcanezumab phase 3 trials in patients with episodic or chronic migraine. Cephalalgia. 2020;40(9):978-989. https://doi.org/10.1177/0333102420920642

4. 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

5. 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

6. 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

7. 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

Glossary

ADA = anti-drug antibody

AE = adverse event

CGRP = calcitonin gene-related peptide

IgG4 = immunoglobulin G (subclass) 4

MHD = migraine headache day

NAb = neutralizing antibody

OR = odds ratio

PK = pharmacokinetics

PT = preferred term

TE ADA = treatment-emergent anti-drug antibodies

▼ 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.

Appendix

Overview of Phase 3 Migraine Prevention Program

EVOLVE-1, EVOLVE-2, and REGAIN 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),^4,5 and

• chronic migraine (REGAIN).⁶

The studies had a duration of

• 6 months for prevention of episodic migraine,^4,5 and

• 3 months for prevention of chronic migraine, with an optional 9-month open-label extension phase.⁶ 

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.^4-6 

12 Month Open-Label Safety Study

Galcanezumab has also been studied in a phase 3, open-label, 12-month safety study for the prevention of episodic or chronic migraine.⁷

In this study, patients were randomized to receive 12 monthly subcutaneous injections of 

• galcanezumab 120 mg with a loading dose of 240 mg, or

• galcanezumab 240 mg.⁷