ISSN 0017-8748 doi: 10.1111/head.12267 Published by Wiley Periodicals, Inc.
Headache © 2013 American Headache Society
Feature Article Clinical Trials Update. 2013: 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 are ongoing at the present time, according to data obtained from both the “ClinicalTrials.Gov” website and from corporate press releases and presentations. (Headache 2014;54:189-194)
2013: THE YEAR IN REVIEW 2013 was a year of limited progress in the clinical development of new antimigraine products. Indeed, there were more discontinuations than initiations of clinical development for new chemical entities within the field of migraine. For the fourth year in a row, no new therapeutic agents were approved by the Food and Drug Administration (FDA) for the acute and/or prophylactic treatment of migraine, although a novel patch formulation of sumatriptan did obtain FDA approval (as noted below). Data from only one major clinical efficacy trial of a new chemical entity (ie, BMS-927711) were reported in 2013. Nonetheless, 2013 was a year in which early stage clinical development progress was made with a group of antibodies targeting calcitonin gene-related peptide (CGRP). The clinical evaluation of CGRP antagonists remains the most active area within migraine drug research with at least 6 novel CGRP-related agents in clinical development in 2013.
FDA APPROVALS IN 2013 Sumatriptan Ionotophoretic Transdermal System (Zecuity, Formerly Called Zelrix and NP101).— NuPathe Inc. announced on January 17, 2013 that the U.S. FDA had approved Zecuity (sumatriptan iontophoretic transdermal system) for the acute treatment of migraine with or without aura in adults. The product is a single-use, battery-powered patch that actively delivers sumatriptan through the skin, providing relief of both migraine headache pain and migraine-related nausea. It is the first transdermal patch approved for the treatment of migraine. The company has also announced that it is planning for the market launch of the product by the end of 2013. ACUTE TREATMENT OF MIGRAINE Possible FDA Approvals in 2014.—2014 should prove to be another lean year for new migraine products, as the only possible FDA approval would be for inhaled dihydroergotamine. Dihydroergotamine Inhaled (Levadex®, Formerly Referred to as MAP0004).—In January 2013, MAP Pharmaceuticals, Inc., the developer of dihydroergotamine inhalation aerosol (Levadex), was acquired by Allergan, Inc.
From the Scientific Affairs, PRA International, Carmel, CA, USA.
189
190 In April 2013, Allergan announced that the U.S. FDA had issued a Complete Response Letter to its New Drug Application for dihydroergotamine inhalation aerosol for the acute treatment of migraine in adults. The company announced that it had met with the FDA to clarify their specific requirements for approval of the product. The company stated that it has agreed to these new requirements and that it planned to submit an amended file by the end of 2013. Based on these assumptions, possible FDA approval is expected in mid-2014.
PRODUCTS IN THE PIPELINE MK-1602 (CGRP Antagonist).—Merck initiated a large Phase 2 trial of MK-1602 entitled “A DoseFinding Study of MK-1602 in the Treatment of Acute Migraine” (NCT01613248) in 2012. The study compared a 100-fold range of MK-1602 doses (ie, 1 to 100 mg) vs placebo. The planned 834 subject study was reportedly completed in late 2012. However, no results from this study have been disclosed, as of late 2013. No further clinical development plans for MK-1602 have been announced by the company, and the drug no longer appears on the corporate listing of its products in development, as of late 2013. BMS-927711 (Small Molecule CGRP Receptor Antagonist).—Bristol-Myers Squibb evaluated a small molecule CGRP antagonist (designated BMS927711) in a large (n = 825) Phase 2 study entitled “Dose Ranging Study of a Drug for the Treatment of Acute Migraine” (NCT00216736). The objective of the study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine. In this randomized, double-blind, placebo-controlled, dose-ranging study, the subjects were randomized using an adaptive design to one of the following dose groups: BMS927711 (10, 25, 75, 150, 300, or 600 mg), sumatriptan 100 mg (active comparator), or placebo. All subjects were treated for a single migraine attack. Pain freedom at 2 hours postdose, the primary end point, was significantly higher after doses of 75 mg (31%, P = .002), 150 mg (33%, P < .001), and 300 mg (30%, P = .002) BMS-927711, and after
January 2014 100 mg (35%, P < .001) sumatriptan compared with placebo (15%). In terms of the secondary end point of sustained pain freedom from 2 to 24 hours postdose, BMS927711 doses of 25-600 mg were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no subjects discontinued because of AEs. The authors concluded that BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile. 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 2013. LY2951742 (Humanized CGRP Antibody).— Arteaus Therapeutics, LLC, licensed worldwide development rights in 2011 from Eli Lilly and Co. to a humanized monoclonal antibody that potently and selectively binds to CGRP. LY2951742 has completed Phase 1 clinical testing in 56 subjects (NCT01337596). Although the preliminary results reportedly demonstrated that the antibody appeared to be well tolerated, the final results from the study are not expected to be presented until early in 2014. A Phase 2 study entitled “A Study of LY2951742 in Patients With Migraine” (NCT01625988) was initiated at 21 sites in the United States in June 2012. The planned enrollment for the study was 190 subjects, and the study had completed enrollment of subjects as of late 2013. The objective of the study was to assess the efficacy and safety of LY2951742 in the prevention of migraine headache during 3 months of treatment in subjects with a “moderate frequency of migraine headaches.” The antibody was administered as a subcutaneous injection once every other week. Results from this study are expected to be available early in 2014. These data should therefore represent the first available efficacy data from the use of CGRP antibodies in the treatment of migraine. 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.
Headache In theory, the ability to block the CGRP receptor (as opposed to CGRP itself) might be advantageous because binding to the CGRP receptor might prevent receptor activation, independent of CGRP release. An initial 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, but the results have yet to be reported. A second Phase 1 study of 40 subjects entitled “Ascending Multiple-Doses of AMG 334 in Healthy Subjects and in Migraine Patients” (NCT01723514) was started in late 2012 and is scheduled to complete in late 2013. “A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention” (NCT01952574) was initiated in late 2013. It has a planned enrollment of 468 subjects at 39 study sites. It is likely that some of these data would be available in late 2014. In addition, AMG 334 is also being studied in a Phase 1 trial in women with hot flashes associated with menopause (NCT01890109). AMG 333.—A Phase 1 Study entitled “SingleAscending 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. AMG 333 is an oral agent being studied in the acute treatment of migraine. However, no further information (eg, its mechanism of action) has been provided by the company. ALD403 (CGRP Antibody).—In March 2013, Alder Biopharmaceuticals Inc. announced the dosing of the first patients in a proof-of-concept Phase 1B clinical study of ALD403, an antibody targeting CGRP for the treatment of migraine. The doubleblind, placebo-controlled, randomized study entitled “Safety, Efficacy and Pharmacokinetics of ALD403” (NCT01772524) will evaluate the safety and efficacy of ALD403 administered monthly. Enrollment of a planned 160 subjects with frequent, episodic migraine was completed in mid-2013 at 26 study locations in the United States. Subjects in the study were to have experienced between 4 and 14 migraines per month in
191 at least 3 months prior to enrollment and take acute migraine medication. Since Alder completed this Phase 1B study in frequent episodic migraine in late 2013, results are expected to be available sometime in 2014. LBR-101 (Formerly PF-04427429 and RN-307) (Humanized CGRP Antibody).—Labrys Biologics Inc. is developing LBR-101 for the prevention of chronic migraine. LBR-101 (formerly called PF-04427429 and RN-307) is a humanized monoclonal antihuman CGRP antibody of the immunoglobulin G2 isotype. The antibody binds to CGRP itself, thereby blocking its ability to bind to the CGRP receptor. The company presented its Phase 1 data at the 2013 International Headache Conference, demonstrating the pharmacokinetic and safety profile of LBR-101. Based upon pooled data from 5 separate Phase 1 studies from a total of 94 healthy volunteer subjects who received active drug, both single doses of LBR-101 (ranging from 0.2 mg to 2000 mg intravenous [IV]) and 2 doses of LBR-101 (up to 300 mg IV administered once every 14 days) were well tolerated. LBR-101 exhibited a long terminal half-life ranging from 39 to 48 days. The most common AEs were reported to be headache, nasopharyngitis, gastroenteritis, and back pain. Most treatment-related AEs were reported to be mild, transient, and resolve spontaneously. Of potential interest is the fact that AEs did not increase in frequency as a function of dose, despite the 10,000fold dose range studied. Therefore, a maximum tolerated dose was not identified. The company has indicated that it plans to conduct a Phase 2b clinical trial in chronic migraine utilizing monthly subcutaneous dosing with LB-101. Nasal Carbon Dioxide.—A Phase 2 study (NCT01253915) of carbon dioxide infused into the nasal cavity for the acute treatment of migraine was initiated by Capnia, Inc., in January 2012 but was terminated in April 2013. The company has not announced any future development plans for the product related to migraine. Lasmiditan (Formerly Known as COL144).—CoLucid Pharmaceuticals, Inc.’s development
192 of lasmiditan, a 5-HT1F receptor agonist, appears to have been suspended as there are no known ongoing clinical trials with the drug.
MIGRAINE PROPHYLAXIS Filorexant (Formerly MK-6096) (Antagonist of OX(1)R and OX(2)R).—Merck was developing filorexant, an orally bioavailable potent and selective reversible antagonist of OX(1)R and OX(2)R. MK-6096 for insomnia, painful diabetic neuropathy, depression, and migraine. A Phase 2 study entitled “A Study of the Safety and Efficacy of MK-6096 for Migraine Prophylaxis in Participants With Episodic Migraine” (NCT01513291) was initiated in early 2012, with an expected enrollment of 450 subjects. The results from this proof of concept study were expected in 2013 but have not been announced. However, a company drug development pipeline update in April 2013 indicated that filorexant was now being developed for only insomnia, suggesting a discontinuation of its development for migraine prevention. BGG492 (AMPA/kainate Antagonist).—BGG is an AMPA antagonist and putative anticonvulsant being developed by Novartis. A Phase 2 acute migraine study using single doses of the drug was completed in late 2010 but the data were never published. In addition, another Phase 2 study entitled “A Randomized, Double Blind, Placebo Controlled Study to Assess Efficacy, Safety and Tolerability of BGG492 in Migraine Prevention” (NCT01617941) was initially planned to begin in 2012. However, enrollment into this planned 90 subject study was suspended in January 2013. BGG492 is also in clinical development for epilepsy and tinnitus. CHRONIC MIGRAINE Cyclobenzaprine (Amrixl®).—A small (n = 70 subjects) 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®.
January 2014 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 (posttest) after taking 15 mg of cyclobenzaprine or placebo. The study is being conducted at a single site in the United States (ie, The Headache Center at Kennedy Health Alliance in New Jersey). The study is scheduled to complete in 2014. TI-001 (Intranasal Oxytocin).—Trigemina, Inc., is developing TI-001, an intranasal formulation of the hormone oxytocin. The results of a single-dose, placebo-controlled, double-blind study found that TI-001was safe and effective in the acute treatment of chronic migraine. The data from this study included 40 subjects with chronic migraine who received 32 units of nasally applied oxytocin dose of the agent and were asked to rate their pain, nausea, photophobia, and phonophobia on a 4-point scale (indicating severe, moderate, mild, or none) after dosing with TI-001. At 2 hours after dosing, nasal OT reduced pain by 2 categories in 42% of subjects compared with 11% for placebo. Photophobia and phonophobia were also decreased compared to placebo. The authors concluded that nasal oxytocin may be a viable alternative for the treatment of chronic migraine headache. 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 late 2014 or early 2015.
COMING ATTRACTIONS: KEY DATA EXPECTED IN 2014 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. Phase 2 efficacy data for anti-CGRP antibodies can be expected in 2014 from Arteaus, Alder, and Amgen. Perhaps more importantly, these data should provide a significant
ALD403 (CGRP antibody) AMG 334 (CGRP receptor antibody) TI-001 (Intranasal Oxytocin) cyclobenzaprine
AMG 333 (mechanism of action not reported) AMG 334 (CGRP receptor antibody)
Migraine prophylaxis Migraine prophylaxis
Chronic migraine Chronic migraine
Migraine prophylaxis
Migraine prophylaxis
Interventions
LY2951742 (CGRP antibody)
Conditions
Migraine prophylaxis
CGRP = calcitonin gene-related peptide.
A Study of LY2951742 in Patients With Migraine Safety, Efficacy and Pharmacokinetics of ALD403 Ascending Multiple-Doses of AMG 334 in Healthy Subjects and in Migraine Patients TI-001 (Intranasal Oxytocin) for Treatment of Chronic Migraine Efficacy and Safety of Cyclobenzaprine Hydrochloride Extended Release for the Treatment of Chronic Migraine Single-Ascending Dose Study of AMG 333 in Healthy Subjects and Subjects With Migraines A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
Title
Phase 2
Phase 1
Phase 3
Phase 2
Phase 1
Phase 2
Phase 2
Phases
468
80
70
240
40
160
190
Planned Enrollment
Table 1.—2014 Ongoing Clinical Trials in Migraine
August 2013
October 2013
July 2010
May 2013
November 2012
January 2013
June 2012
Start Date
July 2015
August 2014
June 2014
June 2014
December 2013
November 2013
October 2013
Expected Completion Date
NCT01952574
NCT01953341
NCT01151787
NCT01839149
NCT01723514
NCT01772524
NCT01625988
NCT Number
Headache 193
194 assessment of whether chronic modulation of CGRP will lead to a viable treatment for migraine after 25 years of research supporting its role in the disorder.
MIGRAINE CLINICAL RESEARCH IN 2014 AND BEYOND At this point in time, it is sobering to note that clinical research in the field of migraine has been decreasing steadily over the past few years, with the exception of a recent increase in the clinical evaluation of CGRP antagonists in migraine. Particularly striking is the fact that all but one of the ongoing clinical trials (Table 1) involve migraine prevention or the treatment of chronic migraine. This may be the first time in many decades that so few new agents are being evaluated in the acute treatment of migraine. The reasons for this significant decrease in clinical development are numerous. First and foremost, a number of new pharmaceutical agents that modulate novel therapeutic targets (eg, glutamate and orexin receptors) have failed to demonstrate efficacy in clinical trials. Second, a few agents have demonstrated efficacy, yet have safety profiles that appear to limit their further development. However, there also appears to be a third reason for the slower development of novel therapies in migraine. This reason for decreased clinical development might be termed “pharmaceutical limbo,” defined as the discontinuation of development for agents that do demonstrate clinical efficacy with an acceptable safety profile, but whose degree of efficacy is not deemed sufficient by the sponsor to warrant further clinical development. Within the past few years, a number of potentially novel migraine therapies appear to have fallen into this category, most prominently of which are the small
January 2014 molecule CGRP antagonists. There have now been at least 5 different small molecule CGRP antagonists that have demonstrated statistical proof of efficacy in the acute treatment of migraine. At least 2 of these agents are orally available with no known major safety concerns. However, future development of these agents (eg, BMS-927711 and BI 44370) appears to have been discontinued or suspended. Lasmiditan, an 5-HT1F receptor agonist, is another example of this situation. Although 6 clinical studies with lasmiditan have been completed successfully, including a Phase 2B double-blind, placebocontrolled oral dose ranging study treating a single migraine attack, the drug has been unable to progress to Phase 3. It is interesting to speculate that the failure of these novel drugs to continue through the development pipeline (and ultimately onto the market) relates to the fact that they tend to display a similar efficacy to existing available antimigraine products. Although these novel agents may indeed be advantageous to subgroups of migraineurs who may not tolerate or gain adequate relief from existing agents, there remain no data to suggest that the financial expense needed to complete the development of these agents can be justified from an purely business perspective. Hence, these effective antimigraine products have entered a “pharmaceutical limbo,” with no apparent way to exit because of the current cost of late-stage drug development. Nonetheless, there remains a clear need for improved therapeutic agents for migraine and other headache disorders. Additional clinical and scientific, as well as possible business model, insights are now needed if the treatment of migraine and other types of headache is to progress significantly.
Headache © 2013 American Headache Society
Feature Article Clinical Trials Update. 2013: 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 are ongoing at the present time, according to data obtained from both the “ClinicalTrials.Gov” website and from corporate press releases and presentations. (Headache 2014;54:189-194)
2013: THE YEAR IN REVIEW 2013 was a year of limited progress in the clinical development of new antimigraine products. Indeed, there were more discontinuations than initiations of clinical development for new chemical entities within the field of migraine. For the fourth year in a row, no new therapeutic agents were approved by the Food and Drug Administration (FDA) for the acute and/or prophylactic treatment of migraine, although a novel patch formulation of sumatriptan did obtain FDA approval (as noted below). Data from only one major clinical efficacy trial of a new chemical entity (ie, BMS-927711) were reported in 2013. Nonetheless, 2013 was a year in which early stage clinical development progress was made with a group of antibodies targeting calcitonin gene-related peptide (CGRP). The clinical evaluation of CGRP antagonists remains the most active area within migraine drug research with at least 6 novel CGRP-related agents in clinical development in 2013.
FDA APPROVALS IN 2013 Sumatriptan Ionotophoretic Transdermal System (Zecuity, Formerly Called Zelrix and NP101).— NuPathe Inc. announced on January 17, 2013 that the U.S. FDA had approved Zecuity (sumatriptan iontophoretic transdermal system) for the acute treatment of migraine with or without aura in adults. The product is a single-use, battery-powered patch that actively delivers sumatriptan through the skin, providing relief of both migraine headache pain and migraine-related nausea. It is the first transdermal patch approved for the treatment of migraine. The company has also announced that it is planning for the market launch of the product by the end of 2013. ACUTE TREATMENT OF MIGRAINE Possible FDA Approvals in 2014.—2014 should prove to be another lean year for new migraine products, as the only possible FDA approval would be for inhaled dihydroergotamine. Dihydroergotamine Inhaled (Levadex®, Formerly Referred to as MAP0004).—In January 2013, MAP Pharmaceuticals, Inc., the developer of dihydroergotamine inhalation aerosol (Levadex), was acquired by Allergan, Inc.
From the Scientific Affairs, PRA International, Carmel, CA, USA.
189
190 In April 2013, Allergan announced that the U.S. FDA had issued a Complete Response Letter to its New Drug Application for dihydroergotamine inhalation aerosol for the acute treatment of migraine in adults. The company announced that it had met with the FDA to clarify their specific requirements for approval of the product. The company stated that it has agreed to these new requirements and that it planned to submit an amended file by the end of 2013. Based on these assumptions, possible FDA approval is expected in mid-2014.
PRODUCTS IN THE PIPELINE MK-1602 (CGRP Antagonist).—Merck initiated a large Phase 2 trial of MK-1602 entitled “A DoseFinding Study of MK-1602 in the Treatment of Acute Migraine” (NCT01613248) in 2012. The study compared a 100-fold range of MK-1602 doses (ie, 1 to 100 mg) vs placebo. The planned 834 subject study was reportedly completed in late 2012. However, no results from this study have been disclosed, as of late 2013. No further clinical development plans for MK-1602 have been announced by the company, and the drug no longer appears on the corporate listing of its products in development, as of late 2013. BMS-927711 (Small Molecule CGRP Receptor Antagonist).—Bristol-Myers Squibb evaluated a small molecule CGRP antagonist (designated BMS927711) in a large (n = 825) Phase 2 study entitled “Dose Ranging Study of a Drug for the Treatment of Acute Migraine” (NCT00216736). The objective of the study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine. In this randomized, double-blind, placebo-controlled, dose-ranging study, the subjects were randomized using an adaptive design to one of the following dose groups: BMS927711 (10, 25, 75, 150, 300, or 600 mg), sumatriptan 100 mg (active comparator), or placebo. All subjects were treated for a single migraine attack. Pain freedom at 2 hours postdose, the primary end point, was significantly higher after doses of 75 mg (31%, P = .002), 150 mg (33%, P < .001), and 300 mg (30%, P = .002) BMS-927711, and after
January 2014 100 mg (35%, P < .001) sumatriptan compared with placebo (15%). In terms of the secondary end point of sustained pain freedom from 2 to 24 hours postdose, BMS927711 doses of 25-600 mg were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no subjects discontinued because of AEs. The authors concluded that BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile. 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 2013. LY2951742 (Humanized CGRP Antibody).— Arteaus Therapeutics, LLC, licensed worldwide development rights in 2011 from Eli Lilly and Co. to a humanized monoclonal antibody that potently and selectively binds to CGRP. LY2951742 has completed Phase 1 clinical testing in 56 subjects (NCT01337596). Although the preliminary results reportedly demonstrated that the antibody appeared to be well tolerated, the final results from the study are not expected to be presented until early in 2014. A Phase 2 study entitled “A Study of LY2951742 in Patients With Migraine” (NCT01625988) was initiated at 21 sites in the United States in June 2012. The planned enrollment for the study was 190 subjects, and the study had completed enrollment of subjects as of late 2013. The objective of the study was to assess the efficacy and safety of LY2951742 in the prevention of migraine headache during 3 months of treatment in subjects with a “moderate frequency of migraine headaches.” The antibody was administered as a subcutaneous injection once every other week. Results from this study are expected to be available early in 2014. These data should therefore represent the first available efficacy data from the use of CGRP antibodies in the treatment of migraine. 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.
Headache In theory, the ability to block the CGRP receptor (as opposed to CGRP itself) might be advantageous because binding to the CGRP receptor might prevent receptor activation, independent of CGRP release. An initial 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, but the results have yet to be reported. A second Phase 1 study of 40 subjects entitled “Ascending Multiple-Doses of AMG 334 in Healthy Subjects and in Migraine Patients” (NCT01723514) was started in late 2012 and is scheduled to complete in late 2013. “A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention” (NCT01952574) was initiated in late 2013. It has a planned enrollment of 468 subjects at 39 study sites. It is likely that some of these data would be available in late 2014. In addition, AMG 334 is also being studied in a Phase 1 trial in women with hot flashes associated with menopause (NCT01890109). AMG 333.—A Phase 1 Study entitled “SingleAscending 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. AMG 333 is an oral agent being studied in the acute treatment of migraine. However, no further information (eg, its mechanism of action) has been provided by the company. ALD403 (CGRP Antibody).—In March 2013, Alder Biopharmaceuticals Inc. announced the dosing of the first patients in a proof-of-concept Phase 1B clinical study of ALD403, an antibody targeting CGRP for the treatment of migraine. The doubleblind, placebo-controlled, randomized study entitled “Safety, Efficacy and Pharmacokinetics of ALD403” (NCT01772524) will evaluate the safety and efficacy of ALD403 administered monthly. Enrollment of a planned 160 subjects with frequent, episodic migraine was completed in mid-2013 at 26 study locations in the United States. Subjects in the study were to have experienced between 4 and 14 migraines per month in
191 at least 3 months prior to enrollment and take acute migraine medication. Since Alder completed this Phase 1B study in frequent episodic migraine in late 2013, results are expected to be available sometime in 2014. LBR-101 (Formerly PF-04427429 and RN-307) (Humanized CGRP Antibody).—Labrys Biologics Inc. is developing LBR-101 for the prevention of chronic migraine. LBR-101 (formerly called PF-04427429 and RN-307) is a humanized monoclonal antihuman CGRP antibody of the immunoglobulin G2 isotype. The antibody binds to CGRP itself, thereby blocking its ability to bind to the CGRP receptor. The company presented its Phase 1 data at the 2013 International Headache Conference, demonstrating the pharmacokinetic and safety profile of LBR-101. Based upon pooled data from 5 separate Phase 1 studies from a total of 94 healthy volunteer subjects who received active drug, both single doses of LBR-101 (ranging from 0.2 mg to 2000 mg intravenous [IV]) and 2 doses of LBR-101 (up to 300 mg IV administered once every 14 days) were well tolerated. LBR-101 exhibited a long terminal half-life ranging from 39 to 48 days. The most common AEs were reported to be headache, nasopharyngitis, gastroenteritis, and back pain. Most treatment-related AEs were reported to be mild, transient, and resolve spontaneously. Of potential interest is the fact that AEs did not increase in frequency as a function of dose, despite the 10,000fold dose range studied. Therefore, a maximum tolerated dose was not identified. The company has indicated that it plans to conduct a Phase 2b clinical trial in chronic migraine utilizing monthly subcutaneous dosing with LB-101. Nasal Carbon Dioxide.—A Phase 2 study (NCT01253915) of carbon dioxide infused into the nasal cavity for the acute treatment of migraine was initiated by Capnia, Inc., in January 2012 but was terminated in April 2013. The company has not announced any future development plans for the product related to migraine. Lasmiditan (Formerly Known as COL144).—CoLucid Pharmaceuticals, Inc.’s development
192 of lasmiditan, a 5-HT1F receptor agonist, appears to have been suspended as there are no known ongoing clinical trials with the drug.
MIGRAINE PROPHYLAXIS Filorexant (Formerly MK-6096) (Antagonist of OX(1)R and OX(2)R).—Merck was developing filorexant, an orally bioavailable potent and selective reversible antagonist of OX(1)R and OX(2)R. MK-6096 for insomnia, painful diabetic neuropathy, depression, and migraine. A Phase 2 study entitled “A Study of the Safety and Efficacy of MK-6096 for Migraine Prophylaxis in Participants With Episodic Migraine” (NCT01513291) was initiated in early 2012, with an expected enrollment of 450 subjects. The results from this proof of concept study were expected in 2013 but have not been announced. However, a company drug development pipeline update in April 2013 indicated that filorexant was now being developed for only insomnia, suggesting a discontinuation of its development for migraine prevention. BGG492 (AMPA/kainate Antagonist).—BGG is an AMPA antagonist and putative anticonvulsant being developed by Novartis. A Phase 2 acute migraine study using single doses of the drug was completed in late 2010 but the data were never published. In addition, another Phase 2 study entitled “A Randomized, Double Blind, Placebo Controlled Study to Assess Efficacy, Safety and Tolerability of BGG492 in Migraine Prevention” (NCT01617941) was initially planned to begin in 2012. However, enrollment into this planned 90 subject study was suspended in January 2013. BGG492 is also in clinical development for epilepsy and tinnitus. CHRONIC MIGRAINE Cyclobenzaprine (Amrixl®).—A small (n = 70 subjects) 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®.
January 2014 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 (posttest) after taking 15 mg of cyclobenzaprine or placebo. The study is being conducted at a single site in the United States (ie, The Headache Center at Kennedy Health Alliance in New Jersey). The study is scheduled to complete in 2014. TI-001 (Intranasal Oxytocin).—Trigemina, Inc., is developing TI-001, an intranasal formulation of the hormone oxytocin. The results of a single-dose, placebo-controlled, double-blind study found that TI-001was safe and effective in the acute treatment of chronic migraine. The data from this study included 40 subjects with chronic migraine who received 32 units of nasally applied oxytocin dose of the agent and were asked to rate their pain, nausea, photophobia, and phonophobia on a 4-point scale (indicating severe, moderate, mild, or none) after dosing with TI-001. At 2 hours after dosing, nasal OT reduced pain by 2 categories in 42% of subjects compared with 11% for placebo. Photophobia and phonophobia were also decreased compared to placebo. The authors concluded that nasal oxytocin may be a viable alternative for the treatment of chronic migraine headache. 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 late 2014 or early 2015.
COMING ATTRACTIONS: KEY DATA EXPECTED IN 2014 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. Phase 2 efficacy data for anti-CGRP antibodies can be expected in 2014 from Arteaus, Alder, and Amgen. Perhaps more importantly, these data should provide a significant
ALD403 (CGRP antibody) AMG 334 (CGRP receptor antibody) TI-001 (Intranasal Oxytocin) cyclobenzaprine
AMG 333 (mechanism of action not reported) AMG 334 (CGRP receptor antibody)
Migraine prophylaxis Migraine prophylaxis
Chronic migraine Chronic migraine
Migraine prophylaxis
Migraine prophylaxis
Interventions
LY2951742 (CGRP antibody)
Conditions
Migraine prophylaxis
CGRP = calcitonin gene-related peptide.
A Study of LY2951742 in Patients With Migraine Safety, Efficacy and Pharmacokinetics of ALD403 Ascending Multiple-Doses of AMG 334 in Healthy Subjects and in Migraine Patients TI-001 (Intranasal Oxytocin) for Treatment of Chronic Migraine Efficacy and Safety of Cyclobenzaprine Hydrochloride Extended Release for the Treatment of Chronic Migraine Single-Ascending Dose Study of AMG 333 in Healthy Subjects and Subjects With Migraines A Phase 2 Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
Title
Phase 2
Phase 1
Phase 3
Phase 2
Phase 1
Phase 2
Phase 2
Phases
468
80
70
240
40
160
190
Planned Enrollment
Table 1.—2014 Ongoing Clinical Trials in Migraine
August 2013
October 2013
July 2010
May 2013
November 2012
January 2013
June 2012
Start Date
July 2015
August 2014
June 2014
June 2014
December 2013
November 2013
October 2013
Expected Completion Date
NCT01952574
NCT01953341
NCT01151787
NCT01839149
NCT01723514
NCT01772524
NCT01625988
NCT Number
Headache 193
194 assessment of whether chronic modulation of CGRP will lead to a viable treatment for migraine after 25 years of research supporting its role in the disorder.
MIGRAINE CLINICAL RESEARCH IN 2014 AND BEYOND At this point in time, it is sobering to note that clinical research in the field of migraine has been decreasing steadily over the past few years, with the exception of a recent increase in the clinical evaluation of CGRP antagonists in migraine. Particularly striking is the fact that all but one of the ongoing clinical trials (Table 1) involve migraine prevention or the treatment of chronic migraine. This may be the first time in many decades that so few new agents are being evaluated in the acute treatment of migraine. The reasons for this significant decrease in clinical development are numerous. First and foremost, a number of new pharmaceutical agents that modulate novel therapeutic targets (eg, glutamate and orexin receptors) have failed to demonstrate efficacy in clinical trials. Second, a few agents have demonstrated efficacy, yet have safety profiles that appear to limit their further development. However, there also appears to be a third reason for the slower development of novel therapies in migraine. This reason for decreased clinical development might be termed “pharmaceutical limbo,” defined as the discontinuation of development for agents that do demonstrate clinical efficacy with an acceptable safety profile, but whose degree of efficacy is not deemed sufficient by the sponsor to warrant further clinical development. Within the past few years, a number of potentially novel migraine therapies appear to have fallen into this category, most prominently of which are the small
January 2014 molecule CGRP antagonists. There have now been at least 5 different small molecule CGRP antagonists that have demonstrated statistical proof of efficacy in the acute treatment of migraine. At least 2 of these agents are orally available with no known major safety concerns. However, future development of these agents (eg, BMS-927711 and BI 44370) appears to have been discontinued or suspended. Lasmiditan, an 5-HT1F receptor agonist, is another example of this situation. Although 6 clinical studies with lasmiditan have been completed successfully, including a Phase 2B double-blind, placebocontrolled oral dose ranging study treating a single migraine attack, the drug has been unable to progress to Phase 3. It is interesting to speculate that the failure of these novel drugs to continue through the development pipeline (and ultimately onto the market) relates to the fact that they tend to display a similar efficacy to existing available antimigraine products. Although these novel agents may indeed be advantageous to subgroups of migraineurs who may not tolerate or gain adequate relief from existing agents, there remain no data to suggest that the financial expense needed to complete the development of these agents can be justified from an purely business perspective. Hence, these effective antimigraine products have entered a “pharmaceutical limbo,” with no apparent way to exit because of the current cost of late-stage drug development. Nonetheless, there remains a clear need for improved therapeutic agents for migraine and other headache disorders. Additional clinical and scientific, as well as possible business model, insights are now needed if the treatment of migraine and other types of headache is to progress significantly.
