ISSN 0017-8748 doi: 10.1111/head.12479 Published by Wiley Periodicals, Inc.
Headache © 2014 American Headache Society
Clinical Trials Update Clinical Trials Update 2014: Year in Review Stephen J. Peroutka, MD, PhD
This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that were ongoing at the end of 2014, according to data obtained from both the “ClinicalTrials.Gov” website and from corporate press releases and presentations. Key words: clinical trial, review, headache (Headache 2015;55:149-157)
2014: THE YEAR IN REVIEW The year 2014 was a year of unique and potentially significant progress in the field of migraine research. First of all, there were major advances in the clinical development of a group of antibodies targeting calcitonin gene-related peptide (CGRP). Indeed, there were initial reports of efficacy from 2 of the 4 known agents in development. In addition, 3 different medical therapeutic devices obtained US Food and Drug Administration (FDA) approval within the past 12 months for the treatment of migraine. These therapeutic products represent the first medical devices ever approved for the management of migraine. Finally, the FDA released new guidance for the clinical evaluation of acute migraine therapeutics. Overall, 2014 was a busy and, potentially, a paradigm shifting year for migraine research due to the
advancement of both biological CGRP antagonists and medical devices in the treatment of migraine. Indeed, the number of active major clinical trials has more than doubled within the past year. However, for the fifth year in a row, no new pharmacological therapeutic agents were approved by the FDA for the acute and/or prophylactic treatment of migraine. In addition, negative clinical data were published on 2 novel therapeutic agents in migraine: selurampanel and filorexant.1,2 FDA Approvals in 2014.—Three new prescription medical devices were approved by the FDA for migraine headaches within the past year. Since these devices are not ingested or metabolized like pharmacological agents, they tend to have few, if any, systemic side effects. CerenaTMS Device.—In December, 2013, the FDA approved the marketing of the Cerena Transcranial Magnetic Stimulator (TMS) device (eNeura Therapeutics; formerly Neuralieve, Baltimore, MD, USA) for the relief of pain caused by migraine with aura. The recommended daily usage of the device is not to exceed 1 treatment in 24 hours. However, this specific device was never marketed, as the company had developed a
From Semnur Pharmaceuticals, Inc., Los Altos, CA, USA. Address all correspondence to S.J. Peroutka, Chief Medical Officer, Semnur Pharmaceuticals, Inc., 4970 El Camino Real, Los Altos, CA 94022, USA. Email: [email protected] Accepted for publication November 6, 2014.
149
Single-ascending dose study of AMG 333 in healthy subjects and subjects with migraines TI-001 (intranasal oxytocin) for treatment of chronic migraine Study to determine the efficacy and safety of ELS-M11 in acute migraine A noninvasive neuromodulation device for treatment of migraine headache Phase I, double-blind, placebo, MAD Study to evaluate the safety, tolerability, PK, and PD of AMG 333 in healthy subjects and migraine subjects A study of LY2951742 in healthy Japanese and Caucasian participants A multicenter assessment of LBR-101 in highfrequency episodic migraine Chordate system S020 acute migraine clinical investigation Assessment of LBR-101 in chronic migraine
Title
AMG 333
TI-001
ELS-M11 Dermafen (5% Ketoprofen gel)
Neuromodulation for episodic migraine headache AMG 333
LY2951742
LBR-101
Chordate system S020
LBR-101
Chronic migraine
Migraine headaches
Migraine headache, episodic
Migraine
Migraine disorders
Episodic migraine Headache
Acute migraine
Chronic migraine
Interventions
Migraine
Conditions
Phase 2
Phase 2
Phase 2
Phase 1
Phase 1
Phase 2
Phase 1| Phase 2
Phase 2
Phase 1
Phases
225
100
270
44
48
76
50
240
80
Planned Enrollment
Table 1.—2015 Ongoing Clinical Trials in Migraine
Jan 14
Jul 14
Jan 14
Jun 14
May 14
Aug 13
Mar 14
May 13
Oct 13
Start Date
Mar 15
Jan 15
Jan 15
Jan 15
Dec 14
Oct 14
Sep 14
Aug 14
Aug 14
Expected Completion Date
NCT02021773
NCT02185703
NCT02025556
NCT02104765
NCT02132429
NCT01899040
NCT02057315
NCT01839149
NCT01953341
NCT Number
150 January 2015
A study to assess the longterm safety and efficacy of AMG 334 in chronic migraine prevention A phase 2 study to evaluate the efficacy and safety of AMG 334 in migraine prevention
A study of LY2951742 in participants with migraine headache Chordate system prophylactic migraine clinical investigation Occipital nerve stimulation (ONS) for migraine: OPTIMISE A study to evaluate the efficacy and safety of AMG 334 in chronic migraine prevention A multicenter, randomized, double-blind, placebocontrolled trial to assess the efficacy and safety of subcutaneous histamine dihydrochloride for migraine prophylaxis A multicenter assessment of ALD403 in chronic migraine Occipital nerve stimulator AMG 334
Histamine dihydrochloride
ALD403
Migraine disorders
Treatment for prevention of chronic migraine Migraine prophylaxis
Prevention of migraine headache in chronic migraineurs Treatment for prevention of chronic migraine Migraine prophylaxis
Chordate system S020
Migraine
AMG 334
AMG 334
LY2951742
Migraine headache
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
483
490
600
130
490
180
80
402
Aug 13
Jun 14
Oct 14
Sep 14
Feb 14
Jan 13
Sep 14
Jul 14
Mar 20
Dec 16
Jul 16
Sep 15
Aug 16
Jun 16
Jun 15
Jun 15
NCT01952574
NCT02174861
NCT02275117
NCT02021474
NCT02066415
NCT01775735
NCT02243865
NCT02163993
Headache 151
152 smaller version of the device that was available shortly after the initial FDA approval. The Cerena TMS device was found to be significantly more effective than a placebo control in treating migraine with aura based on a randomized, double-blind, parallel-group clinical trial involving 164 subjects who treated at least one attack with the active (n = 82) or sham device (n = 82).3 Pain-free response rates after 2 hours were significantly higher with the active (39%) than with sham stimulation (22%). Sustained pain-free response rates significantly favored treatment at 24 hours and 48 hours posttreatment. No device-related serious adverse events were recorded. The authors concluded that the therapeutic effect with the TMS device was similar to existing treatments for migraine but with markedly reduced adverse events and side effects.3 However, treatment was not associated with relief of other associated symptoms of migraine, including sensitivity to light or sound and nausea. The FDA also noted that the device should not be used in patients who have metals in the head, neck, or upper body; who have an implanted medical device such as a deep brain stimulator or pacemaker, or those who have suspected or diagnosed epilepsy or a personal or family history of seizures. SpringTMS Device.—The SpringTMS is a secondgeneration TMS device from the same manufacturer as the CerenaTMS device (ie, eNeura). It provides the same therapy as the Cerena device but with improved portability. It was approved for clinical use by the FDA in May, 2014. There are no published studies with the SpringTMS device. The initial US availability of the SpringTMS was expected to be launched at a select number of US specialist headache centers in late 2014. Cefaly Transcutaneous Electrical Nerve Stimulation Device.—The Cefaly device is a battery-powered headband with a transcutaneous electrical nerve stimulator (TENS) that is centered above the eyes. It delivers a steady current at 14 mA to the supraorbital transcutaneous nerves (ie, branches of the trigeminal nerve) through a set of reusable (and replaceable) electrodes. The electrodes are suggested to be used 7 to 10 times before replacement. The device is
January 2015 intended to be worn for 20 minutes (at which time point it stops automatically) each day and is intended to reduce the frequency of migraine headaches. It was FDA approved as a preventative treatment for migraine in March 2014 and represents the first medical device ever approved for migraine prevention. The marketing approval was based on a review of safety and effectiveness data from a clinical study conducted in Belgium involving 67 subjects who experienced more than 2 migraine attacks per month, as well as a patient satisfaction study of 2313 Cefaly users in France and Belgium. The clinical study was a double-blinded, randomized, and sham-controlled trial conducted in Belgian headache clinics.4 After a 1-month run-in, subjects were randomized to active or sham stimulation, applying the device daily for 20 minutes each day for 3 months. The mean number of migraine days decreased significantly in the active, but not in the sham, subgroup, as did the number of monthly migraine attacks, monthly headache days, and monthly acute anti-migraine drug intake. The 50% responder rate was significantly greater in the active (38%) than in the sham group (12%). The patient satisfaction study showed that ∼53% of patients were satisfied using the Cefaly treatment and were willing to purchase the device for continued use.5 The most commonly reported adverse events were dislike of the electrostimulation sensations (and therefore not wanting to continue using the device), sleepiness during the treatment session, and headache after the treatment session. There were no serious adverse events reported during either study.
ACUTE TREATMENT OF MIGRAINE Possible FDA Approvals in Late 2014 and 2015.—The year 2015 should prove to be another lean year for new migraine products, as the only likely FDA approvals would be for a novel intranasal formulation of sumatriptan and inhaled dihydroergotamine. Sumatriptan Intranasal (AVP-825, Formerly Called Optinose).—Avanir Pharmaceuticals, Inc. announced in January 2014 that it had submitted a New Drug Application (NDA) to the FDA for approval of
Headache AVP-825, its Breath Powered investigational drug device combination product for the acute treatment of migraine. If approved, AVP-825 would be the first fast-acting,dry-powder intranasal form of sumatriptan for the treatment of migraine. The FDA was expected to complete its review by November 26, 2014. Dihydroergotamine Inhaled (Semprana, Formerly Referred to as MAP0004 and Levadex).—In April 2013,Allergan announced that the US FDA had issued a complete response letter to its NDA for dihydroergotamine inhalation aerosol for the acute treatment of migraine in adults.The company announced that it had met with the FDA, agreed to new requirements, and submitted an amended file in December 2013. However, in June 2014, the FDA notified the company of its third rejection of the inhalable migraine therapy. The company announced that FDA approval will likely be delayed until the second quarter of 2015. Products in the Pipeline.—BMS-927711 (Small Molecule CGRP Receptor Antagonist).—Bristol– Myers Squibb evaluated a small molecule CGRP antagonist (designated BMS-927711) in a large (n = 825) phase 2 study entitled “Dose Ranging Study of a Drug for the Treatment of Acute Migraine” (NCT00216736), the results from which were published in 2014.6 The company has not announced any future development plans for BMS-927711, and the drug no longer appears as a pipeline product on the corporate website, as of late 2014. Lasmiditan (Formerly Referred to as COL-144). —CoLucid Pharmaceuticals, Inc. (Durham, NC, USA) reported in May 2014 that it reached agreement with the FDA for a planned trial to evaluate the safety and efficacy of 2 doses of lasmiditan in comparison to placebo for the treatment of acute migraine. This agent is believed to penetrate the central nervous system and acts at 5-HT1F receptors. Patients with risk factors for cardiovascular disease will be included in the study. The agreement included 2 novel endpoints for the approval of acute migraine therapies: a primary endpoint of the proportion of patients who are free of headache pain at 2 hours and a key secondary endpoint of the proportion of patients who no longer suffer from their most both-
153 ersome associated symptom of migraine (ie, nausea, photophobia, phonophobia) at 2 hours. However, as of late 2014, this study has not yet been initiated. Selurampanel (Formerly Referred to as BGG492; AMPA/Kainate Antagonist).—Selurampanel is an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist and putative anticonvulsant being developed by Novartis. A randomized, doubleblind, phase 2 study assessed the efficacy of selurampanel (250 mg) vs sumatriptan (100 mg) and placebo and in 75 subjects with acute migraine attacks.1 Clinical improvement from severe/moderate to mild/no headache pain was reported in 58%, 58%, and 54% of the selurampanel treated subjects at 2, 3, and 4 hours post-dose, respectively, compared with 68%, 84%, and 92% of the sumatriptan-treated subjects, and 40%, 48%, and 44% in the placebo group. Adverse events were reported by 80%, 56%, and 60% of selurampanel, sumatriptan, and placebo subjects, respectively.The authors concluded that selurampanel failed to meet their predetermined efficacy criterion of a ≥25% therapeutic benefit vs placebo.1 AMG 333.—AMG 333 is an oral agent being studied in the acute treatment of migraine. A phase 1 study entitled “Single-Ascending Dose Study of AMG 333 in Healthy Subjects and Subjects With Migraines” (NCT01953341) was initiated by Amgen in late 2013, with a planned enrollment of 80 subjects. A second study entitled “Phase I, Double-Blind, Placebo, MAD Study to Evaluate the Safety, Tolerability, PK, and PD of AMG 333 in Healthy Subjects and Migraine Subjects” (NCT02132429) was initiated in mid-2014. However, no further information (eg, its mechanism of action, initial study results) has been provided by the company. Intranasal Kinetic Oscillation Stimulation.— Chordate Medical is a medical device company based in Stockholm, Sweden. The company is developing a new neuromodulation technology for the treatment of both acute and chronic migraine. The company initiated a phase 2 clinical trial in 2014 entitled “A Randomized, Placebo-Controlled, Double-Blind, Multi-Center Pilot Study to Evaluate the Prophylactic Effect and Tolerability of Intranasal Kinetic Oscillation Stimulation (KOS) Using the Chordate System
154 S200 in Patients (NCT01899040).
January 2015 Diagnosed
With
Migraine”
MIGRAINE PROPHYLAXIS AND CHRONIC MIGRAINE Filorexant (Formerly MK-6096) (Antagonist of OX(1)R and OX(2)R).—A randomized, doubleblind, placebo-controlled, phase 2 trial with 235 subjects experiencing 4 to 14 days with migraine during a 1-month baseline period were randomized to the orexin receptor antagonist filorexant (10 mg nightly) or placebo for 3 months.2 There was no statistically significant difference between the treatment groups for change from baseline in mean monthly migraine days or headache days. The authors concluded that these data failed to provide evidence that antagonism of orexin receptors with filorexant, when administered each evening, is effective for migraine prophylaxis.2 Cyclobenzaprine.—A small phase 3 study entitled “Efficacy and Safety of Cyclobenzaprine Hydrochloride Extended Release for the Treatment of Chronic Migraine” (NCT01151787) began in 2010. The study drug (cyclobenzaprine) is an extended release formulation of the marketed product Flexeril. Although the plan was to enroll 70 subjects, the study was terminated after enrolling 31 subjects. The principle outcome variable will be the mean total number of migraine/migrainous headache days which will be calculated for the month prior to enrollment in the study (pretreatment) and then calculated for the third month after study treatment after taking 15 mg of cyclobenzaprine or placebo. Cyclobenzaprine hydrochloride extended release at daily doses of 15 mg daily for 12 weeks did not result in statistically significant reductions in mean monthly migraine/migrainous days compared to placebo. TI-001 (Intranasal Oxytocin).—Trigemina Inc. (Mountain View, CA, USA) is developing TI-001, an intranasal formulation of the hormone oxytocin. A phase 2 study entitled “TI-001 (Intranasal Oxytocin) for Treatment of Chronic Migraine” (NCT01839149) was initiated by Trigemina Inc. in 2013. The planned 240 subjects are being enrolled over the course of a year with investigators in Chile and Australia. The study results can therefore be expected in early 2015.
ELS-M11 (Topical Ketoprofen).—ELS-M11 is a topical cream formulation of ketoprofen being developed by Achelios Therapeutics. A phase IB, 12-week, randomized, double-blind, cross-over, placebo-controlled clinical trial entitled “Study to Determine the Efficacy and Safety of ELS-M11 in Acute Migraine” (NCT02057315) was expected to complete in late 2014. The study results can therefore be expected in early 2015. Histamine Dihydrochloride.—BioHealthonomics Inc. (Santa Monica, CA, USA) filed its first investigational new drug (IND) application for migraine prophylaxis in December 2013. A phase 2 trial entitled “A Multicenter, Randomized, Double-Blind, PlaceboControlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis” (NCT02021474) was scheduled to begin in late 2014, with a planned enrollment of 130 subjects. Occipital Nerve Stimulation.—A study entitled “Occipital Nerve Stimulation (ONS) for Migraine: OPTIMISE” was initiated by the Boston Scientific Corporation in 2013 (NCT01775735). The primary objective of this study is to evaluate the safety and efficacy of ONS using the Precision System in the management of intractable chronic migraine, when used in conjunction with anti-migraine medications. The study plans to enroll 180 subjects, and final data collection was expected in December 2014. Intranasal Kinetic Oscillation Stimulation.— Chordate Medical (Stockholm, Sweden) is developing a new neuromodulation technology for the prophylactic treatment of chronic migraine. The company initiated a phase 2 clinical trial in 2014 entitled “A Randomized, Placebo-Controlled, Double-Blind, Multi-Center Pilot Study to Evaluate the Prophylactic Effect and Tolerability of Intranasal Kinetic Oscillation Stimulation (KOS) Using the Chordate System S200 in Patients Diagnosed With Migraine” (NCT02243865). Neuromodulation System.—Scion NeuroStim (Raleigh, NC, USA) is developing a noninvasive neuromodulation system for the treatment of migraine. A study entitled “A Non-Invasive Neuromodulation Device for Treatment of Migraine Headache” (NCT01899040) was scheduled to com-
Headache plete in late 2014. In this study, a standardized active neuromodulation waveform was used for all active device subjects. The device was to be used twice daily. The results can be expected sometime in 2015. LY2951742 (Humanized CGRP Antibody).— Arteaus Therapeutics, LLC (Cambridge, MA, USA) licensed worldwide development rights in 2011 from Eli Lilly and Co. to a humanized monoclonal antibody that potently and selectively binds to CGRP (ie, LY2951742). Lilly reacquired the commercial rights to the product in 2014. The results from a randomized, double-blind, placebo-controlled phase 2 study entitled “A Study of LY2951742 in Patients With Migraine” (NCT01625988) were reported in late 2014.7 Subjects with a history of 4-14 migraine headache days per month received subcutaneous doses of LY2951742 150 mg (n = 107) every 2 weeks or placebo (n = 110) for a total of 12 weeks. The primary endpoint (ie, mean change in migraine headache days per month) at 12 weeks when compared to baseline was −4.2 (63% decrease) for LY2951742 vs −3.0 (42% decrease) for placebo. LY2951742 was also superior to placebo for all secondary endpoints including “Headache days” −4.9 vs −3.7 (P < .0117), “Migraine attacks” −3.1 vs −2.3 (P < .0051), and “Responder rate” 70% vs 45%. Adverse events occurred more frequently with LY2951742 than with placebo and included injection site pain, upper respiratory tract infections, and abdominal pain. The authors concluded that treatment with LY2951742 in subjects with a history of frequent migraine days was efficacious and well tolerated.7 These data therefore represent the first available efficacy data from the use of CGRP antibodies in the treatment of migraine. A clinical trial entitled “A Single and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY2951742 Administered Subcutaneously to Japanese and Caucasian Healthy Subjects” (NCT02104765) was initiated in 2014 with a planned enrolled of 44 subjects. A phase 2b, randomized, double-blind, placebocontrolled study of LY2951742 in patients with episodic migraine (NCT02163993) was also initiated in mid-2014, with a planned enrollment of 402 subjects.
155 ALD403 (CGRP Antibody).—ALD403 is a genetically engineered humanized anti-CGRP antibody being developed for the treatment of migraine by Alder Biopharmaceuticals Inc. (Bothell, WA, USA). A double-blind, placebo-controlled, randomized study entitled “Safety, Efficacy and Pharmacokinetics of ALD403” (NCT01772524) evaluated the safety and efficacy of ALD403 administered monthly.8 Subjects (n = 163) with 5-14 migraine days per 28-day period were randomly assigned to receive a single intravenous dose of ALD403 1000 mg or placebo. The mean change in migraine days between baseline and weeks 5-8 was −5.6 for the ALD403 group compared with −4.6 for the placebo group (difference −1.0, one sided P = 0.031). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. No safety concerns were noted with an intravenous dose of ALD403 1000 mg. The authors concluded that this study provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days.8 A phase 2 study entitled “A Parallel Group, Double-Blind, Randomized, Placebo Controlled, Dose-Ranging Phase 2 Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of ALD403 Administered Intravenously in Patients With Chronic Migraine” (NCT02275117) was initiated in late 2014. The study plans to enroll 600 subjects and to complete in 2016. The company has also stated that it intends to initiate another migraine study in 2015. LBR-101 (Formerly PF-04427429 and RN-307) (Humanized CGRP Antibody).—Teva Pharmaceuticals (North Wales, PA, USA) acquired Labrys Biologics Inc. in June 2014 and thereby obtained the rights to develop LBR-101 for the prevention of chronic migraine and other disorders. LBR-101 (formerly called PF-04427429 and RN-307) is a humanized monoclonal antihuman antibody that binds to CGRP itself, thereby blocking its ability to interact with the CGRP receptor. Two clinical trials with LB-101 were initiated in early 2014. A study entitled “A Multicenter, Randomized, Double-Blind, Double-Dummy, PlaceboControlled, Parallel Group, Multi-Dose Study
156 Comparing the Efficacy and Safety of Subcutaneous LBR-101 With Placebo for the Preventive Treatment of Chronic Migraine” (NCT02021773) planned to enroll 225 subjects and to complete in 2015. Another study entitled “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, ParallelGroup, Study Comparing the Efficacy and Safety of Two Doses of Subcutaneous LBR-101 With Placebo for the Preventive Treatment of High Frequency Episodic Migraine” (NCT02025556) planned to enroll 270 subjects and to complete in 2015. AMG 334 (Fully Human CGRP Receptor Antibody).—AMG 334 (from Amgen) is a fully human monoclonal antibody that is selective for the CGRP receptor complex (as opposed to the 3 other antibodies being developed that target CGRP itself). In theory, the ability to block the CGRP receptor (as opposed to CGRP) might be advantageous since binding to the CGRP receptor might prevent receptor activation, independent of CGRP release. A phase 1 study of 68 subjects entitled “Ascending Single Doses of AMG 334 in Healthy Subjects and Migraine Patients” (NCT01688739) was completed in mid-2013, and a second phase 1 study of 40 subjects entitled “Ascending Multiple-Doses of AMG 334 in Healthy Subjects and in Migraine Patients” (NCT01723514) was scheduled to complete in late 2013, but the results are not yet available. In addition, the company has 3 different phase 2 studies in progress. The first, “A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention” (NCT01952574), was initiated in late 2013 with a planned enrollment of 483 subjects. The second, “A Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention” (NCT02066415), was initiated in early 2014 with a planned enrollment of 490 subjects. The third, “A Study to Assess the Long-Term Safety and Efficacy of AMG 334 in Chronic Migraine Prevention” (NCT02174861), was initiated in mid-2014 with a planned enrollment of 490 subjects. The company has announced that results from a phase 2 episodic migraine study are expected by the end of 2014, followed by results from a phase 2 chronic migraine study in 2016.
January 2015
COMING ATTRACTIONS: KEY DATA EXPECTED IN 2015 AND BEYOND The multiple ongoing trials of CGRP antibodies should provide a definitive answer as to whether this therapeutic approach will lead to a new class of antimigraine agents. Perhaps more importantly, these data will provide a clear assessment of whether chronic modulation of CGRP can alter the frequency and/or severity of migraine.The data should provide a definitive test of the hypothesis that was first developed over 25 years ago, that CGRP plays a key role in the pathophysiology of migraine. The increasing interest in the use of medical devices to treat migraine may also represent a paradigm shift in treatment options. There remains a clear need for improved therapeutic agents for migraine and other headache disorders. The reported successes of the past year offer hope that additional clinical and scientific insights will allow the treatment of migraine and other types of headache to progress significantly. REFERENCES 1. Gomez-Mancilla B, Brand R, Jürgens TP, et al. Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks. Cephalalgia. 2014;34:103-113. 2. Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia. 2014;[Epub ahead of print]; pii: 0333102414544979. 3. Lipton RB, Dodick DW, Silberstein SD, et al. Singlepulse transcranial magnetic stimulation for acute treatment of migraine with aura: A randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9:373-380. 4. Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. Neurology. 2013;80:697-704. 5. Magis D, Sava S, d’Elia TS, Baschi R, Schoenen J. Safety and patients’ satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: A survey of 2313 headache sufferers in the general population. J Headache Pain. 2013;14:95-102.
Headache 6. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: A double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34:114125. 7. Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of
157 migraine: A phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885892. 8. Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: A randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13:1100-1107.
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Clinical Trials Update Clinical Trials Update 2014: Year in Review Stephen J. Peroutka, MD, PhD
This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that were ongoing at the end of 2014, according to data obtained from both the “ClinicalTrials.Gov” website and from corporate press releases and presentations. Key words: clinical trial, review, headache (Headache 2015;55:149-157)
2014: THE YEAR IN REVIEW The year 2014 was a year of unique and potentially significant progress in the field of migraine research. First of all, there were major advances in the clinical development of a group of antibodies targeting calcitonin gene-related peptide (CGRP). Indeed, there were initial reports of efficacy from 2 of the 4 known agents in development. In addition, 3 different medical therapeutic devices obtained US Food and Drug Administration (FDA) approval within the past 12 months for the treatment of migraine. These therapeutic products represent the first medical devices ever approved for the management of migraine. Finally, the FDA released new guidance for the clinical evaluation of acute migraine therapeutics. Overall, 2014 was a busy and, potentially, a paradigm shifting year for migraine research due to the
advancement of both biological CGRP antagonists and medical devices in the treatment of migraine. Indeed, the number of active major clinical trials has more than doubled within the past year. However, for the fifth year in a row, no new pharmacological therapeutic agents were approved by the FDA for the acute and/or prophylactic treatment of migraine. In addition, negative clinical data were published on 2 novel therapeutic agents in migraine: selurampanel and filorexant.1,2 FDA Approvals in 2014.—Three new prescription medical devices were approved by the FDA for migraine headaches within the past year. Since these devices are not ingested or metabolized like pharmacological agents, they tend to have few, if any, systemic side effects. CerenaTMS Device.—In December, 2013, the FDA approved the marketing of the Cerena Transcranial Magnetic Stimulator (TMS) device (eNeura Therapeutics; formerly Neuralieve, Baltimore, MD, USA) for the relief of pain caused by migraine with aura. The recommended daily usage of the device is not to exceed 1 treatment in 24 hours. However, this specific device was never marketed, as the company had developed a
From Semnur Pharmaceuticals, Inc., Los Altos, CA, USA. Address all correspondence to S.J. Peroutka, Chief Medical Officer, Semnur Pharmaceuticals, Inc., 4970 El Camino Real, Los Altos, CA 94022, USA. Email: [email protected] Accepted for publication November 6, 2014.
149
Single-ascending dose study of AMG 333 in healthy subjects and subjects with migraines TI-001 (intranasal oxytocin) for treatment of chronic migraine Study to determine the efficacy and safety of ELS-M11 in acute migraine A noninvasive neuromodulation device for treatment of migraine headache Phase I, double-blind, placebo, MAD Study to evaluate the safety, tolerability, PK, and PD of AMG 333 in healthy subjects and migraine subjects A study of LY2951742 in healthy Japanese and Caucasian participants A multicenter assessment of LBR-101 in highfrequency episodic migraine Chordate system S020 acute migraine clinical investigation Assessment of LBR-101 in chronic migraine
Title
AMG 333
TI-001
ELS-M11 Dermafen (5% Ketoprofen gel)
Neuromodulation for episodic migraine headache AMG 333
LY2951742
LBR-101
Chordate system S020
LBR-101
Chronic migraine
Migraine headaches
Migraine headache, episodic
Migraine
Migraine disorders
Episodic migraine Headache
Acute migraine
Chronic migraine
Interventions
Migraine
Conditions
Phase 2
Phase 2
Phase 2
Phase 1
Phase 1
Phase 2
Phase 1| Phase 2
Phase 2
Phase 1
Phases
225
100
270
44
48
76
50
240
80
Planned Enrollment
Table 1.—2015 Ongoing Clinical Trials in Migraine
Jan 14
Jul 14
Jan 14
Jun 14
May 14
Aug 13
Mar 14
May 13
Oct 13
Start Date
Mar 15
Jan 15
Jan 15
Jan 15
Dec 14
Oct 14
Sep 14
Aug 14
Aug 14
Expected Completion Date
NCT02021773
NCT02185703
NCT02025556
NCT02104765
NCT02132429
NCT01899040
NCT02057315
NCT01839149
NCT01953341
NCT Number
150 January 2015
A study to assess the longterm safety and efficacy of AMG 334 in chronic migraine prevention A phase 2 study to evaluate the efficacy and safety of AMG 334 in migraine prevention
A study of LY2951742 in participants with migraine headache Chordate system prophylactic migraine clinical investigation Occipital nerve stimulation (ONS) for migraine: OPTIMISE A study to evaluate the efficacy and safety of AMG 334 in chronic migraine prevention A multicenter, randomized, double-blind, placebocontrolled trial to assess the efficacy and safety of subcutaneous histamine dihydrochloride for migraine prophylaxis A multicenter assessment of ALD403 in chronic migraine Occipital nerve stimulator AMG 334
Histamine dihydrochloride
ALD403
Migraine disorders
Treatment for prevention of chronic migraine Migraine prophylaxis
Prevention of migraine headache in chronic migraineurs Treatment for prevention of chronic migraine Migraine prophylaxis
Chordate system S020
Migraine
AMG 334
AMG 334
LY2951742
Migraine headache
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
Phase 2
483
490
600
130
490
180
80
402
Aug 13
Jun 14
Oct 14
Sep 14
Feb 14
Jan 13
Sep 14
Jul 14
Mar 20
Dec 16
Jul 16
Sep 15
Aug 16
Jun 16
Jun 15
Jun 15
NCT01952574
NCT02174861
NCT02275117
NCT02021474
NCT02066415
NCT01775735
NCT02243865
NCT02163993
Headache 151
152 smaller version of the device that was available shortly after the initial FDA approval. The Cerena TMS device was found to be significantly more effective than a placebo control in treating migraine with aura based on a randomized, double-blind, parallel-group clinical trial involving 164 subjects who treated at least one attack with the active (n = 82) or sham device (n = 82).3 Pain-free response rates after 2 hours were significantly higher with the active (39%) than with sham stimulation (22%). Sustained pain-free response rates significantly favored treatment at 24 hours and 48 hours posttreatment. No device-related serious adverse events were recorded. The authors concluded that the therapeutic effect with the TMS device was similar to existing treatments for migraine but with markedly reduced adverse events and side effects.3 However, treatment was not associated with relief of other associated symptoms of migraine, including sensitivity to light or sound and nausea. The FDA also noted that the device should not be used in patients who have metals in the head, neck, or upper body; who have an implanted medical device such as a deep brain stimulator or pacemaker, or those who have suspected or diagnosed epilepsy or a personal or family history of seizures. SpringTMS Device.—The SpringTMS is a secondgeneration TMS device from the same manufacturer as the CerenaTMS device (ie, eNeura). It provides the same therapy as the Cerena device but with improved portability. It was approved for clinical use by the FDA in May, 2014. There are no published studies with the SpringTMS device. The initial US availability of the SpringTMS was expected to be launched at a select number of US specialist headache centers in late 2014. Cefaly Transcutaneous Electrical Nerve Stimulation Device.—The Cefaly device is a battery-powered headband with a transcutaneous electrical nerve stimulator (TENS) that is centered above the eyes. It delivers a steady current at 14 mA to the supraorbital transcutaneous nerves (ie, branches of the trigeminal nerve) through a set of reusable (and replaceable) electrodes. The electrodes are suggested to be used 7 to 10 times before replacement. The device is
January 2015 intended to be worn for 20 minutes (at which time point it stops automatically) each day and is intended to reduce the frequency of migraine headaches. It was FDA approved as a preventative treatment for migraine in March 2014 and represents the first medical device ever approved for migraine prevention. The marketing approval was based on a review of safety and effectiveness data from a clinical study conducted in Belgium involving 67 subjects who experienced more than 2 migraine attacks per month, as well as a patient satisfaction study of 2313 Cefaly users in France and Belgium. The clinical study was a double-blinded, randomized, and sham-controlled trial conducted in Belgian headache clinics.4 After a 1-month run-in, subjects were randomized to active or sham stimulation, applying the device daily for 20 minutes each day for 3 months. The mean number of migraine days decreased significantly in the active, but not in the sham, subgroup, as did the number of monthly migraine attacks, monthly headache days, and monthly acute anti-migraine drug intake. The 50% responder rate was significantly greater in the active (38%) than in the sham group (12%). The patient satisfaction study showed that ∼53% of patients were satisfied using the Cefaly treatment and were willing to purchase the device for continued use.5 The most commonly reported adverse events were dislike of the electrostimulation sensations (and therefore not wanting to continue using the device), sleepiness during the treatment session, and headache after the treatment session. There were no serious adverse events reported during either study.
ACUTE TREATMENT OF MIGRAINE Possible FDA Approvals in Late 2014 and 2015.—The year 2015 should prove to be another lean year for new migraine products, as the only likely FDA approvals would be for a novel intranasal formulation of sumatriptan and inhaled dihydroergotamine. Sumatriptan Intranasal (AVP-825, Formerly Called Optinose).—Avanir Pharmaceuticals, Inc. announced in January 2014 that it had submitted a New Drug Application (NDA) to the FDA for approval of
Headache AVP-825, its Breath Powered investigational drug device combination product for the acute treatment of migraine. If approved, AVP-825 would be the first fast-acting,dry-powder intranasal form of sumatriptan for the treatment of migraine. The FDA was expected to complete its review by November 26, 2014. Dihydroergotamine Inhaled (Semprana, Formerly Referred to as MAP0004 and Levadex).—In April 2013,Allergan announced that the US FDA had issued a complete response letter to its NDA for dihydroergotamine inhalation aerosol for the acute treatment of migraine in adults.The company announced that it had met with the FDA, agreed to new requirements, and submitted an amended file in December 2013. However, in June 2014, the FDA notified the company of its third rejection of the inhalable migraine therapy. The company announced that FDA approval will likely be delayed until the second quarter of 2015. Products in the Pipeline.—BMS-927711 (Small Molecule CGRP Receptor Antagonist).—Bristol– Myers Squibb evaluated a small molecule CGRP antagonist (designated BMS-927711) in a large (n = 825) phase 2 study entitled “Dose Ranging Study of a Drug for the Treatment of Acute Migraine” (NCT00216736), the results from which were published in 2014.6 The company has not announced any future development plans for BMS-927711, and the drug no longer appears as a pipeline product on the corporate website, as of late 2014. Lasmiditan (Formerly Referred to as COL-144). —CoLucid Pharmaceuticals, Inc. (Durham, NC, USA) reported in May 2014 that it reached agreement with the FDA for a planned trial to evaluate the safety and efficacy of 2 doses of lasmiditan in comparison to placebo for the treatment of acute migraine. This agent is believed to penetrate the central nervous system and acts at 5-HT1F receptors. Patients with risk factors for cardiovascular disease will be included in the study. The agreement included 2 novel endpoints for the approval of acute migraine therapies: a primary endpoint of the proportion of patients who are free of headache pain at 2 hours and a key secondary endpoint of the proportion of patients who no longer suffer from their most both-
153 ersome associated symptom of migraine (ie, nausea, photophobia, phonophobia) at 2 hours. However, as of late 2014, this study has not yet been initiated. Selurampanel (Formerly Referred to as BGG492; AMPA/Kainate Antagonist).—Selurampanel is an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist and putative anticonvulsant being developed by Novartis. A randomized, doubleblind, phase 2 study assessed the efficacy of selurampanel (250 mg) vs sumatriptan (100 mg) and placebo and in 75 subjects with acute migraine attacks.1 Clinical improvement from severe/moderate to mild/no headache pain was reported in 58%, 58%, and 54% of the selurampanel treated subjects at 2, 3, and 4 hours post-dose, respectively, compared with 68%, 84%, and 92% of the sumatriptan-treated subjects, and 40%, 48%, and 44% in the placebo group. Adverse events were reported by 80%, 56%, and 60% of selurampanel, sumatriptan, and placebo subjects, respectively.The authors concluded that selurampanel failed to meet their predetermined efficacy criterion of a ≥25% therapeutic benefit vs placebo.1 AMG 333.—AMG 333 is an oral agent being studied in the acute treatment of migraine. A phase 1 study entitled “Single-Ascending Dose Study of AMG 333 in Healthy Subjects and Subjects With Migraines” (NCT01953341) was initiated by Amgen in late 2013, with a planned enrollment of 80 subjects. A second study entitled “Phase I, Double-Blind, Placebo, MAD Study to Evaluate the Safety, Tolerability, PK, and PD of AMG 333 in Healthy Subjects and Migraine Subjects” (NCT02132429) was initiated in mid-2014. However, no further information (eg, its mechanism of action, initial study results) has been provided by the company. Intranasal Kinetic Oscillation Stimulation.— Chordate Medical is a medical device company based in Stockholm, Sweden. The company is developing a new neuromodulation technology for the treatment of both acute and chronic migraine. The company initiated a phase 2 clinical trial in 2014 entitled “A Randomized, Placebo-Controlled, Double-Blind, Multi-Center Pilot Study to Evaluate the Prophylactic Effect and Tolerability of Intranasal Kinetic Oscillation Stimulation (KOS) Using the Chordate System
154 S200 in Patients (NCT01899040).
January 2015 Diagnosed
With
Migraine”
MIGRAINE PROPHYLAXIS AND CHRONIC MIGRAINE Filorexant (Formerly MK-6096) (Antagonist of OX(1)R and OX(2)R).—A randomized, doubleblind, placebo-controlled, phase 2 trial with 235 subjects experiencing 4 to 14 days with migraine during a 1-month baseline period were randomized to the orexin receptor antagonist filorexant (10 mg nightly) or placebo for 3 months.2 There was no statistically significant difference between the treatment groups for change from baseline in mean monthly migraine days or headache days. The authors concluded that these data failed to provide evidence that antagonism of orexin receptors with filorexant, when administered each evening, is effective for migraine prophylaxis.2 Cyclobenzaprine.—A small phase 3 study entitled “Efficacy and Safety of Cyclobenzaprine Hydrochloride Extended Release for the Treatment of Chronic Migraine” (NCT01151787) began in 2010. The study drug (cyclobenzaprine) is an extended release formulation of the marketed product Flexeril. Although the plan was to enroll 70 subjects, the study was terminated after enrolling 31 subjects. The principle outcome variable will be the mean total number of migraine/migrainous headache days which will be calculated for the month prior to enrollment in the study (pretreatment) and then calculated for the third month after study treatment after taking 15 mg of cyclobenzaprine or placebo. Cyclobenzaprine hydrochloride extended release at daily doses of 15 mg daily for 12 weeks did not result in statistically significant reductions in mean monthly migraine/migrainous days compared to placebo. TI-001 (Intranasal Oxytocin).—Trigemina Inc. (Mountain View, CA, USA) is developing TI-001, an intranasal formulation of the hormone oxytocin. A phase 2 study entitled “TI-001 (Intranasal Oxytocin) for Treatment of Chronic Migraine” (NCT01839149) was initiated by Trigemina Inc. in 2013. The planned 240 subjects are being enrolled over the course of a year with investigators in Chile and Australia. The study results can therefore be expected in early 2015.
ELS-M11 (Topical Ketoprofen).—ELS-M11 is a topical cream formulation of ketoprofen being developed by Achelios Therapeutics. A phase IB, 12-week, randomized, double-blind, cross-over, placebo-controlled clinical trial entitled “Study to Determine the Efficacy and Safety of ELS-M11 in Acute Migraine” (NCT02057315) was expected to complete in late 2014. The study results can therefore be expected in early 2015. Histamine Dihydrochloride.—BioHealthonomics Inc. (Santa Monica, CA, USA) filed its first investigational new drug (IND) application for migraine prophylaxis in December 2013. A phase 2 trial entitled “A Multicenter, Randomized, Double-Blind, PlaceboControlled Trial to Assess the Efficacy and Safety of Subcutaneous Histamine Dihydrochloride for Migraine Prophylaxis” (NCT02021474) was scheduled to begin in late 2014, with a planned enrollment of 130 subjects. Occipital Nerve Stimulation.—A study entitled “Occipital Nerve Stimulation (ONS) for Migraine: OPTIMISE” was initiated by the Boston Scientific Corporation in 2013 (NCT01775735). The primary objective of this study is to evaluate the safety and efficacy of ONS using the Precision System in the management of intractable chronic migraine, when used in conjunction with anti-migraine medications. The study plans to enroll 180 subjects, and final data collection was expected in December 2014. Intranasal Kinetic Oscillation Stimulation.— Chordate Medical (Stockholm, Sweden) is developing a new neuromodulation technology for the prophylactic treatment of chronic migraine. The company initiated a phase 2 clinical trial in 2014 entitled “A Randomized, Placebo-Controlled, Double-Blind, Multi-Center Pilot Study to Evaluate the Prophylactic Effect and Tolerability of Intranasal Kinetic Oscillation Stimulation (KOS) Using the Chordate System S200 in Patients Diagnosed With Migraine” (NCT02243865). Neuromodulation System.—Scion NeuroStim (Raleigh, NC, USA) is developing a noninvasive neuromodulation system for the treatment of migraine. A study entitled “A Non-Invasive Neuromodulation Device for Treatment of Migraine Headache” (NCT01899040) was scheduled to com-
Headache plete in late 2014. In this study, a standardized active neuromodulation waveform was used for all active device subjects. The device was to be used twice daily. The results can be expected sometime in 2015. LY2951742 (Humanized CGRP Antibody).— Arteaus Therapeutics, LLC (Cambridge, MA, USA) licensed worldwide development rights in 2011 from Eli Lilly and Co. to a humanized monoclonal antibody that potently and selectively binds to CGRP (ie, LY2951742). Lilly reacquired the commercial rights to the product in 2014. The results from a randomized, double-blind, placebo-controlled phase 2 study entitled “A Study of LY2951742 in Patients With Migraine” (NCT01625988) were reported in late 2014.7 Subjects with a history of 4-14 migraine headache days per month received subcutaneous doses of LY2951742 150 mg (n = 107) every 2 weeks or placebo (n = 110) for a total of 12 weeks. The primary endpoint (ie, mean change in migraine headache days per month) at 12 weeks when compared to baseline was −4.2 (63% decrease) for LY2951742 vs −3.0 (42% decrease) for placebo. LY2951742 was also superior to placebo for all secondary endpoints including “Headache days” −4.9 vs −3.7 (P < .0117), “Migraine attacks” −3.1 vs −2.3 (P < .0051), and “Responder rate” 70% vs 45%. Adverse events occurred more frequently with LY2951742 than with placebo and included injection site pain, upper respiratory tract infections, and abdominal pain. The authors concluded that treatment with LY2951742 in subjects with a history of frequent migraine days was efficacious and well tolerated.7 These data therefore represent the first available efficacy data from the use of CGRP antibodies in the treatment of migraine. A clinical trial entitled “A Single and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY2951742 Administered Subcutaneously to Japanese and Caucasian Healthy Subjects” (NCT02104765) was initiated in 2014 with a planned enrolled of 44 subjects. A phase 2b, randomized, double-blind, placebocontrolled study of LY2951742 in patients with episodic migraine (NCT02163993) was also initiated in mid-2014, with a planned enrollment of 402 subjects.
155 ALD403 (CGRP Antibody).—ALD403 is a genetically engineered humanized anti-CGRP antibody being developed for the treatment of migraine by Alder Biopharmaceuticals Inc. (Bothell, WA, USA). A double-blind, placebo-controlled, randomized study entitled “Safety, Efficacy and Pharmacokinetics of ALD403” (NCT01772524) evaluated the safety and efficacy of ALD403 administered monthly.8 Subjects (n = 163) with 5-14 migraine days per 28-day period were randomly assigned to receive a single intravenous dose of ALD403 1000 mg or placebo. The mean change in migraine days between baseline and weeks 5-8 was −5.6 for the ALD403 group compared with −4.6 for the placebo group (difference −1.0, one sided P = 0.031). Adverse events were experienced by 46 (57%) of 81 patients in the ALD403 group and 43 (52%) of 82 in the placebo group. No safety concerns were noted with an intravenous dose of ALD403 1000 mg. The authors concluded that this study provides preliminary evidence for the efficacy of ALD403 in the preventive treatment of migraine in patients with a high monthly frequency of migraine days.8 A phase 2 study entitled “A Parallel Group, Double-Blind, Randomized, Placebo Controlled, Dose-Ranging Phase 2 Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of ALD403 Administered Intravenously in Patients With Chronic Migraine” (NCT02275117) was initiated in late 2014. The study plans to enroll 600 subjects and to complete in 2016. The company has also stated that it intends to initiate another migraine study in 2015. LBR-101 (Formerly PF-04427429 and RN-307) (Humanized CGRP Antibody).—Teva Pharmaceuticals (North Wales, PA, USA) acquired Labrys Biologics Inc. in June 2014 and thereby obtained the rights to develop LBR-101 for the prevention of chronic migraine and other disorders. LBR-101 (formerly called PF-04427429 and RN-307) is a humanized monoclonal antihuman antibody that binds to CGRP itself, thereby blocking its ability to interact with the CGRP receptor. Two clinical trials with LB-101 were initiated in early 2014. A study entitled “A Multicenter, Randomized, Double-Blind, Double-Dummy, PlaceboControlled, Parallel Group, Multi-Dose Study
156 Comparing the Efficacy and Safety of Subcutaneous LBR-101 With Placebo for the Preventive Treatment of Chronic Migraine” (NCT02021773) planned to enroll 225 subjects and to complete in 2015. Another study entitled “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, ParallelGroup, Study Comparing the Efficacy and Safety of Two Doses of Subcutaneous LBR-101 With Placebo for the Preventive Treatment of High Frequency Episodic Migraine” (NCT02025556) planned to enroll 270 subjects and to complete in 2015. AMG 334 (Fully Human CGRP Receptor Antibody).—AMG 334 (from Amgen) is a fully human monoclonal antibody that is selective for the CGRP receptor complex (as opposed to the 3 other antibodies being developed that target CGRP itself). In theory, the ability to block the CGRP receptor (as opposed to CGRP) might be advantageous since binding to the CGRP receptor might prevent receptor activation, independent of CGRP release. A phase 1 study of 68 subjects entitled “Ascending Single Doses of AMG 334 in Healthy Subjects and Migraine Patients” (NCT01688739) was completed in mid-2013, and a second phase 1 study of 40 subjects entitled “Ascending Multiple-Doses of AMG 334 in Healthy Subjects and in Migraine Patients” (NCT01723514) was scheduled to complete in late 2013, but the results are not yet available. In addition, the company has 3 different phase 2 studies in progress. The first, “A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention” (NCT01952574), was initiated in late 2013 with a planned enrollment of 483 subjects. The second, “A Study to Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine Prevention” (NCT02066415), was initiated in early 2014 with a planned enrollment of 490 subjects. The third, “A Study to Assess the Long-Term Safety and Efficacy of AMG 334 in Chronic Migraine Prevention” (NCT02174861), was initiated in mid-2014 with a planned enrollment of 490 subjects. The company has announced that results from a phase 2 episodic migraine study are expected by the end of 2014, followed by results from a phase 2 chronic migraine study in 2016.
January 2015
COMING ATTRACTIONS: KEY DATA EXPECTED IN 2015 AND BEYOND The multiple ongoing trials of CGRP antibodies should provide a definitive answer as to whether this therapeutic approach will lead to a new class of antimigraine agents. Perhaps more importantly, these data will provide a clear assessment of whether chronic modulation of CGRP can alter the frequency and/or severity of migraine.The data should provide a definitive test of the hypothesis that was first developed over 25 years ago, that CGRP plays a key role in the pathophysiology of migraine. The increasing interest in the use of medical devices to treat migraine may also represent a paradigm shift in treatment options. There remains a clear need for improved therapeutic agents for migraine and other headache disorders. The reported successes of the past year offer hope that additional clinical and scientific insights will allow the treatment of migraine and other types of headache to progress significantly. REFERENCES 1. Gomez-Mancilla B, Brand R, Jürgens TP, et al. Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks. Cephalalgia. 2014;34:103-113. 2. Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia. 2014;[Epub ahead of print]; pii: 0333102414544979. 3. Lipton RB, Dodick DW, Silberstein SD, et al. Singlepulse transcranial magnetic stimulation for acute treatment of migraine with aura: A randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9:373-380. 4. Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. Neurology. 2013;80:697-704. 5. Magis D, Sava S, d’Elia TS, Baschi R, Schoenen J. Safety and patients’ satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: A survey of 2313 headache sufferers in the general population. J Headache Pain. 2013;14:95-102.
Headache 6. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: A double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34:114125. 7. Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of
157 migraine: A phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885892. 8. Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: A randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13:1100-1107.
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