Monoclonal antibodies for migraine: an update

Monoclonal antibodies for migraine: an update Journal of Neurology (2018) 265:1491–1492 https://doi.org/10.1007/s00415-018-8886-8 JOURNAL CLUB 1 1 Daniel Castle  · Neil P. Robertson Published online: 14 May 2018 © The Author(s) 2018 Introduction This month’s journal club will review clinical trial results for a series of novel monoclonal antibodies that target CGRP Migraine is an episodic neurological disorder resulting in in patients with migraine. The first paper examines the use attacks of headache associated with neurological symptoms. of erenumab in the STRIVE study for episodic migraine; the Whilst episodes of migraine are debilitating for the patient, second paper updates our understanding of fremanezumab they also result in a significant burden for society as a whole. for chronic migraine and finally galcanezumab in episodic The World Health Organisation now ranks migraine as the migraine. third most prevalent medical condition in the world, and the second most disabling neurological condition. The economic cost of migraine is also considerable and has an estimated A controlled trial of erenumab for episodic worldwide annual cost of $20 billion, relating to healthcare, migraine procedures and loss of productivity. A number of therapeutic avenues have been explored to In this well publicised international multicentre, ran- combat migraines over the decades, with perhaps the most domised, double-blind, placebo-controlled, parallel-group significant milestone occurring in the 1990s with the intro- phase three trial, Goadsby et al. investigated the efficacy of duction of serotonin 5-HT1B/1D receptor agonists which the drug erenumab in treating episodic migraine. Erenumab led to improvement in the management of acute migraine, is a monoclonal antibody directed against the canonical albeit with some continuing concerns regarding cardiovas- CGRP receptor. In this study, 955 patients were randomly cular side effects. However, despite the widespread use of allocated to receive a subcutaneous injection of erenumab these medications, only a third of patients have sustained 70 mg, erenumab 140 mg or placebo once a month for 6 freedom from pain. months. Participants were assessed over a 4-week period The relevance of calcitonin gene-related peptides (CGRP) to ensure they met trial inclusion criteria as well as estab- in the pathophysiology of migraine was first identified in lishing a baseline data set. This included data on migraine 1990 by Goadsby et al. who established that CGRP levels frequency, medication use and functional impact of migraine were increased in the cranial venous outflow during acute as measured through a daily electronic diary of migraine and genuine migraine attacks. Further studies demonstrated that headache symptoms. those treated successfully with triptans during a migraine The study demonstrated a statistically significant fall in attack had a drop in their level of CGRP. Furthermore, migraine days from baseline assessment, when adjusted peripheral infusion of CGRP induced an attack in those for placebo, of 1.4 days in the 70 mg group and 1.9 in the known to suffer with migraine but appeared to have little 140 mg group. There was also a 50% reduction in migraine effect on healthy volunteers. As a result, a range of monoclo- days when adjusted for placebo seen in 23.4% of patients in nal antibodies have been produced which target the peptide the 140 mg cohort and 16.7% in the 70 mg. Secondary out- itself or its corresponding receptor. comes included statistically significant reductions compared to placebo in use of acute migraine-specific medications and patient functional abilities as assessed with migraine physi- cal function impact diary. Similar rates of adverse incidents * Neil P. Robertson were observed across all 3 cohorts with mild to moderate robertsonnp@cardiff.ac.uk needle site injection reactions being most common. No car- Department of Neurology, Institute of Psychological diac or liver abnormalities were observed but 35 out of 628 Medicine and Clinical Neurosciences, Cardiff University, post baseline antibody tests were positive to anti-erenumab Cardiff CF14 4XW, UK Vol.:(0123456789) 1 3 1492 Journal of Neurology (2018) 265:1491–1492 antibodies with one patient in the 70 mg group developing indication. However, the study does suggest that freman- neutralising antibodies. ezumab is effective and also offers a unique and attractive Comments: This well-powered and designed study has treatment regimen of four times per year administration. demonstrated the potential benefits of erenumab in episodic Silberstein et al (2017) New England Journal of Medicine migraine management. However, as noted by the authors, a 30;377(22):2113–2122 limitation of this study was the exclusion of patients who had had a lack of therapeutic response to more than two classes of migraine preventative drugs as well as women of childbear- Eec ff t of different doses of galcanezumab ing potential. Inclusion of these patient groups clearly offers vs placebo for episodic migraine prevention challenges, but since refractory females of childbearing age a randomised clinical trial may be a highly relevant target group for this drug, the addi- tional complexities may have been worth it. The final paper is a phase 2b placebo controlled, dose- Goadsby et al. (2017) New England Journal of Medicine ranging study of galcanezumab (which selectively binds 30;377(22):2123–2132 CRGP) in episodic migraine. 936 patients were reviewed over a screening and baseline period and 410 patients enrolled. Patients were randomised to monthly; placebo, Fremanezumab for the preventive treatment 5, 50, 120 and 300 mg intervention groups in a 2:1:1:1:1 of chronic migraine order, respectively. Patients received a subcutaneous injec- tion once a month for 3 months with drug or placebo. Func- This paper by Silberstein et  al. examines treatment of tional outcomes were assessed by reporting to an automated chronic migraine with fremanezumab, an antibody that binds phone line and completion of the headache impact test to CGRP itself. This double-blind, randomised, placebo- questionnaire. controlled phase 3 trial assessed 3148 participants over a The primary objective was to assess whether at least one 4-week baseline period, recruiting 1130 eligible patients. dose of galcanezumab was superior to placebo in the preven- Participants were divided into a placebo, monthly and quar- tion of migraine, by reduction in migraine headache days terly group. Each group received a subcutaneous injection (MHDs). MHD was defined as any calendar day in which a once a month, with the monthly group receiving freman- migraine headache lasted ≥ 30 min, the use of acute migraine ezumab every month and the quarterly group receiving treatment was not automatically counted as an MHD. After fremanezumab on the first injection and placebo thereaf- placebo adjustment, the 120 mg monthly cohort demonstrated ter. Functional outcomes were assessed with an electronic the only statistically significant response, with a reduction in diary and headache impact test questionnaire. The primary MHD of 1.1. Safety profiling demonstrated relatively good outcome was reduction of headache days compared with outcomes. Mild or moderate injection site reactions were com- baseline. A headache day was defined as any day in which mon. One participant was diagnosed with Crohn’s disease, head pain lasted ≥ 4 consecutive hours with a peak severity another treated for appendicitis and one developed suicidal ide- of at least moderate, or the use of acute migraine medica- ation, which the investigators felt were unrelated to the drug. tions. Secondary outcomes included drug safety profiling, Comments: The level of MHD reduction observed, and reduction in migraine days and percentage reduction by 50%. proportion with 50% reduction of migraine days is compara- Fremanezumab demonstrated statistically significant ble if not inferior to some current therapies including topira- improvement when adjusted for placebo and reduced head- mate, propranolol and acupuncture. As a result, an analysis ache days by 1.8 days in the quarterly group and 2.1 days in of cost effectiveness is likely to be relevant and trials which the monthly group. Reduction in migraine days was also sig- consider these drugs against an active comparator would be nificant, with 1.7 in the quarterly and 1.8 days reduction in enlightening. Although the safety profile was generally good, the monthly group, when adjusted for placebo. Mild to mod- the participants in this and the previous study who developed erate needle site reactions were once again the most com- suicidal ideation may be a feature to monitor going forward. mon adverse event. There was some evidence of transient Skljaarevski et al (2018) JAMA Neurology 75(2):187–193 liver function test derangement, but may have been related to Open Access This article is distributed under the terms of the Crea- concurrent medications. One participant on fremanezumab tive Commons Attribution 4.0 International License (http://creat iveco developed suicidal ideation leading to trial discontinuation. mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Comments: The statistically significant treatment effect tion, and reproduction in any medium, provided you give appropriate for headaches lasting over 4 h and to a lesser extent migraine credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. is promising. However, the primary objective in this trial was reasonably vague and covered treatment of migraine and non-migrainous head pain, potentially complicating its 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurology Springer Journals

Monoclonal antibodies for migraine: an update

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Medicine & Public Health; Neurology; Neurosciences; Neuroradiology
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Abstract

Journal of Neurology (2018) 265:1491–1492 https://doi.org/10.1007/s00415-018-8886-8 JOURNAL CLUB 1 1 Daniel Castle  · Neil P. Robertson Published online: 14 May 2018 © The Author(s) 2018 Introduction This month’s journal club will review clinical trial results for a series of novel monoclonal antibodies that target CGRP Migraine is an episodic neurological disorder resulting in in patients with migraine. The first paper examines the use attacks of headache associated with neurological symptoms. of erenumab in the STRIVE study for episodic migraine; the Whilst episodes of migraine are debilitating for the patient, second paper updates our understanding of fremanezumab they also result in a significant burden for society as a whole. for chronic migraine and finally galcanezumab in episodic The World Health Organisation now ranks migraine as the migraine. third most prevalent medical condition in the world, and the second most disabling neurological condition. The economic cost of migraine is also considerable and has an estimated A controlled trial of erenumab for episodic worldwide annual cost of $20 billion, relating to healthcare, migraine procedures and loss of productivity. A number of therapeutic avenues have been explored to In this well publicised international multicentre, ran- combat migraines over the decades, with perhaps the most domised, double-blind, placebo-controlled, parallel-group significant milestone occurring in the 1990s with the intro- phase three trial, Goadsby et al. investigated the efficacy of duction of serotonin 5-HT1B/1D receptor agonists which the drug erenumab in treating episodic migraine. Erenumab led to improvement in the management of acute migraine, is a monoclonal antibody directed against the canonical albeit with some continuing concerns regarding cardiovas- CGRP receptor. In this study, 955 patients were randomly cular side effects. However, despite the widespread use of allocated to receive a subcutaneous injection of erenumab these medications, only a third of patients have sustained 70 mg, erenumab 140 mg or placebo once a month for 6 freedom from pain. months. Participants were assessed over a 4-week period The relevance of calcitonin gene-related peptides (CGRP) to ensure they met trial inclusion criteria as well as estab- in the pathophysiology of migraine was first identified in lishing a baseline data set. This included data on migraine 1990 by Goadsby et al. who established that CGRP levels frequency, medication use and functional impact of migraine were increased in the cranial venous outflow during acute as measured through a daily electronic diary of migraine and genuine migraine attacks. Further studies demonstrated that headache symptoms. those treated successfully with triptans during a migraine The study demonstrated a statistically significant fall in attack had a drop in their level of CGRP. Furthermore, migraine days from baseline assessment, when adjusted peripheral infusion of CGRP induced an attack in those for placebo, of 1.4 days in the 70 mg group and 1.9 in the known to suffer with migraine but appeared to have little 140 mg group. There was also a 50% reduction in migraine effect on healthy volunteers. As a result, a range of monoclo- days when adjusted for placebo seen in 23.4% of patients in nal antibodies have been produced which target the peptide the 140 mg cohort and 16.7% in the 70 mg. Secondary out- itself or its corresponding receptor. comes included statistically significant reductions compared to placebo in use of acute migraine-specific medications and patient functional abilities as assessed with migraine physi- cal function impact diary. Similar rates of adverse incidents * Neil P. Robertson were observed across all 3 cohorts with mild to moderate robertsonnp@cardiff.ac.uk needle site injection reactions being most common. No car- Department of Neurology, Institute of Psychological diac or liver abnormalities were observed but 35 out of 628 Medicine and Clinical Neurosciences, Cardiff University, post baseline antibody tests were positive to anti-erenumab Cardiff CF14 4XW, UK Vol.:(0123456789) 1 3 1492 Journal of Neurology (2018) 265:1491–1492 antibodies with one patient in the 70 mg group developing indication. However, the study does suggest that freman- neutralising antibodies. ezumab is effective and also offers a unique and attractive Comments: This well-powered and designed study has treatment regimen of four times per year administration. demonstrated the potential benefits of erenumab in episodic Silberstein et al (2017) New England Journal of Medicine migraine management. However, as noted by the authors, a 30;377(22):2113–2122 limitation of this study was the exclusion of patients who had had a lack of therapeutic response to more than two classes of migraine preventative drugs as well as women of childbear- Eec ff t of different doses of galcanezumab ing potential. Inclusion of these patient groups clearly offers vs placebo for episodic migraine prevention challenges, but since refractory females of childbearing age a randomised clinical trial may be a highly relevant target group for this drug, the addi- tional complexities may have been worth it. The final paper is a phase 2b placebo controlled, dose- Goadsby et al. (2017) New England Journal of Medicine ranging study of galcanezumab (which selectively binds 30;377(22):2123–2132 CRGP) in episodic migraine. 936 patients were reviewed over a screening and baseline period and 410 patients enrolled. Patients were randomised to monthly; placebo, Fremanezumab for the preventive treatment 5, 50, 120 and 300 mg intervention groups in a 2:1:1:1:1 of chronic migraine order, respectively. Patients received a subcutaneous injec- tion once a month for 3 months with drug or placebo. Func- This paper by Silberstein et  al. examines treatment of tional outcomes were assessed by reporting to an automated chronic migraine with fremanezumab, an antibody that binds phone line and completion of the headache impact test to CGRP itself. This double-blind, randomised, placebo- questionnaire. controlled phase 3 trial assessed 3148 participants over a The primary objective was to assess whether at least one 4-week baseline period, recruiting 1130 eligible patients. dose of galcanezumab was superior to placebo in the preven- Participants were divided into a placebo, monthly and quar- tion of migraine, by reduction in migraine headache days terly group. Each group received a subcutaneous injection (MHDs). MHD was defined as any calendar day in which a once a month, with the monthly group receiving freman- migraine headache lasted ≥ 30 min, the use of acute migraine ezumab every month and the quarterly group receiving treatment was not automatically counted as an MHD. After fremanezumab on the first injection and placebo thereaf- placebo adjustment, the 120 mg monthly cohort demonstrated ter. Functional outcomes were assessed with an electronic the only statistically significant response, with a reduction in diary and headache impact test questionnaire. The primary MHD of 1.1. Safety profiling demonstrated relatively good outcome was reduction of headache days compared with outcomes. Mild or moderate injection site reactions were com- baseline. A headache day was defined as any day in which mon. One participant was diagnosed with Crohn’s disease, head pain lasted ≥ 4 consecutive hours with a peak severity another treated for appendicitis and one developed suicidal ide- of at least moderate, or the use of acute migraine medica- ation, which the investigators felt were unrelated to the drug. tions. Secondary outcomes included drug safety profiling, Comments: The level of MHD reduction observed, and reduction in migraine days and percentage reduction by 50%. proportion with 50% reduction of migraine days is compara- Fremanezumab demonstrated statistically significant ble if not inferior to some current therapies including topira- improvement when adjusted for placebo and reduced head- mate, propranolol and acupuncture. As a result, an analysis ache days by 1.8 days in the quarterly group and 2.1 days in of cost effectiveness is likely to be relevant and trials which the monthly group. Reduction in migraine days was also sig- consider these drugs against an active comparator would be nificant, with 1.7 in the quarterly and 1.8 days reduction in enlightening. Although the safety profile was generally good, the monthly group, when adjusted for placebo. Mild to mod- the participants in this and the previous study who developed erate needle site reactions were once again the most com- suicidal ideation may be a feature to monitor going forward. mon adverse event. There was some evidence of transient Skljaarevski et al (2018) JAMA Neurology 75(2):187–193 liver function test derangement, but may have been related to Open Access This article is distributed under the terms of the Crea- concurrent medications. One participant on fremanezumab tive Commons Attribution 4.0 International License (http://creat iveco developed suicidal ideation leading to trial discontinuation. mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Comments: The statistically significant treatment effect tion, and reproduction in any medium, provided you give appropriate for headaches lasting over 4 h and to a lesser extent migraine credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. is promising. However, the primary objective in this trial was reasonably vague and covered treatment of migraine and non-migrainous head pain, potentially complicating its 1 3

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Published: May 14, 2018

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