Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial

Cephalalgia ◽  
2019 ◽  
Vol 39 (9) ◽  
pp. 1075-1085 ◽  
Author(s):  
David W Dodick ◽  
Richard B Lipton ◽  
Stephen Silberstein ◽  
Peter J Goadsby ◽  
David Biondi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Chronic Migraine ◽  
Development Program ◽  
Calcitonin Gene Related Peptide ◽  
Electronic Diary ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Double Blind ◽  
Related Peptide ◽  
Calcitonin Gene

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.

scholarly journals Assessment of immunogenicity from galcanezumab phase 3 trials in patients with episodic or chronic migraine

Cephalalgia ◽  
2020 ◽  
Vol 40 (9) ◽  
pp. 978-989 ◽  
Author(s):  
James M Martinez ◽  
Nada Hindiyeh ◽  
Greg Anglin ◽  
Kavita Kalidas ◽  
Michael E Hodsdon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Migraine ◽  
Antibody Titer ◽  
Episodic Migraine ◽  
Calcitonin Gene Related Peptide ◽  
Phase 3 ◽  
Related Peptide ◽  
Antidrug Antibody ◽  
Calcitonin Gene ◽  
Antidrug Antibodies

Background This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials. Methods Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites. Findings Across studies, 5.9–11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6–12.4% in the galcanezumab group and 0.5–1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3–6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies. Interpretation These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

Calcitonin gene-related peptide levels in tear fluid are elevated in migraine patients compared to healthy controls

Cephalalgia ◽  
2019 ◽  
Vol 39 (12) ◽  
pp. 1535-1543 ◽  
Author(s):  
Katharina Kamm ◽  
Andreas Straube ◽  
Ruth Ruscheweyh
Keyword(s):  
Chronic Migraine ◽  
Trigeminal Nerve ◽  
Plasma Concentrations ◽  
Calcitonin Gene Related Peptide ◽  
Tear Fluid ◽  
Direct Access ◽  
Healthy Controls ◽  
Significant Group ◽  
Related Peptide ◽  
Calcitonin Gene

Background Calcitonin gene-related peptide (CGRP) released from trigeminal nerve fibres indicates trigeminal activation and has a key role in migraine pathophysiology. The trigeminal nerve directly innervates the eye. Therefore, in this study, we compared Calcitonin gene-related peptide in tear fluid of migraine patients and healthy controls. Methods Calcitonin gene-related peptide concentrations in tear fluid and plasma of 48 episodic and 45 chronic migraine patients and 48 controls were assessed using ELISA. Results Calcitonin gene-related peptide levels in tear fluid (0.94 ± 1.11 ng/ml) were ∼140 times higher than plasma concentrations (6.81 ± 4.12 pg/ml). Tear fluid CGRP concentrations were elevated in interictal migraine patients (1.10 ± 1.27 ng/ml, n = 49) compared to controls (0.75 ± 0.80 ng/ml, p = 0.022). There was no difference in tear fluid CGRP levels between interictal episodic and chronic migraine patients (episodic: 1.09 ± 1.47 ng/ml, n = 30 and chronic: 1.10 ± 0.89 ng/ml, n = 19) and no correlation of tear fluid CGRP levels with headache frequency in interictal patients (rho = 0.062, p = 0.674). Unmedicated ictal migraine patients had even more elevated tear fluid CGRP levels than interictal migraine patients (1.92 ± 1.84 ng/ml, n = 13, p = 0.102), while medicated ictal migraine patients had lower levels (0.56 ± 0.47 ng/ml, n = 25, p = 0.011 compared to interictal patients), which were undistinguishable from controls ( p = 0.609). In contrast to tear fluid, no significant group differences were found in plasma CGRP levels. Conclusion To the best of our knowledge, this study shows, for the first time, increased CGRP tear fluid levels in migraine patients compared to healthy subjects. Detection of calcitonin gene-related peptide in tear fluid is non-invasive, and likely allows a more direct access to CGRP released from the trigeminal nerve than plasma sampling.

Haemodynamic effects of intravenous human calcitonin-gene-related peptide in man

1988 ◽  
Vol 74 (4) ◽  
pp. 413-418 ◽  
Author(s):  
C. W. Howden ◽  
Catherine Logue ◽  
Karen Gavin ◽  
Lizbeth Collie ◽  
P. C. Rubin
Keyword(s):  
Blood Pressure ◽  
Standing Position ◽  
Calcitonin Gene Related Peptide ◽  
Double Blind Study ◽  
Human Calcitonin ◽  
Facial Flushing ◽  
Double Blind ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Higher Doses

1. The effects of intravenous bolus doses of human calcitonin-gene-related peptide (hCGRP) were studied in ten healthy male volunteers. 2.5, 10 and 25 μg of hCGRP and placebo were administered to each subject in a randomized double-blind study. 2. hCGRP had no effect on systolic or diastolic blood pressure in the supine or standing position. 3. hCGRP increased supine and standing heart rate. Both the extent and duration of the tachycardia were dose related. 4. Plasma noradrenaline levels were transiently increased after 10 and 25 μg of hCGRP. 5. All subjects displayed marked facial flushing after the two higher doses of hCGRP. 6. We conclude that systemic administration of hCGRP produces tachycardia and stimulation of the sympathetic nervous system in the absence of any change in blood pressure.

scholarly journals Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy–2) study

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Stephen Silberstein ◽  
Merle Diamond ◽  
Nada A. Hindiyeh ◽  
David M. Biondi ◽  
Roger Cady ◽  
...  
Keyword(s):  
Chronic Migraine ◽  
Patient Reported Outcomes ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Patient Global Impression ◽  
Calcitonin Gene ◽  
Patient Reported ◽  
Global Impression Of Change

Abstract Background PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide–targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment. Methods Patients received up to two 30-min IV administrations of eptinezumab 100 mg, 300 mg, or placebo separated by 12 weeks. Patients recorded migraine and headache endpoints in a daily eDiary. Additional assessments, including patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 32-week study period (screening, day 0, and weeks 2, 4, 8, 12, 16, 20, 24, and 32). Results A total of 1072 adults received treatment: eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366. The reduction in mean monthly migraine days observed during the first dosing interval (100 mg, − 7.7 days; 300 mg, − 8.2 days; placebo, − 5.6 days) was further decreased after an additional dose (100 mg, − 8.2 days; 300 mg, − 8.8 days; placebo, − 6.2 days), with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥ 75% migraine responder rates (MRRs) increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% MRRs weeks 13–24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥ 75% MRRs weeks 13–24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%). The percentages of patients who improved on patient-reported outcomes, including the Headache Impact Test and Patient Global Impression of Change, increased following the second dose administration at week 12, and were greater with eptinezumab than with placebo at all time points. No new safety concerns were identified with the second dose regarding the incidence, nature, and severity of treatment-emergent adverse events. Conclusion Eptinezumab 100 mg or 300 mg administered IV at day 0 and repeated at week 12 provided sustained migraine preventive benefit over a full 24 weeks and demonstrated an acceptable safety profile in patients with chronic migraine. Trial registration ClinicalTrials.gov (Identifier: NCT02974153). Registered November 23, 2016.

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