Correspondence
(CGRP). Mean decrease from baseline in migraine days in 4 weeks was higher in patients given LY2951742 (4·2) than in those given placebo (3·0; p=0·003).1 Results of other trials that use antibodies against CGRP will probably be published soon.2 Apart from the clinical questions such as benefit and tolerability, this new prophylactic treatment raises questions about the pathophysiology of migraine. Most available prophylactic drugs for migraine exert their various effects in the CNS, seemingly supporting the neuronal theory of migraine. In discussing the possible site of action of LY2951742, Dodick and colleagues state that “the site and mechanism of action of CGRP monoclonal antibodies is unclear”, but suggest that blocking neurogenic vasodilation induced by CGRP or inhibition of central trigeminal nociceptive transmission could each be possible mechanisms of action.1 The authors acknowledge that monoclonal antibodies do not readily penetrate the blood–brain barrier, and the results of study, along with other results with CGRP receptor antagonists, seem to suggest a peripheral site of action.1 The authors then argue that the blood–brain barrier might be more permeable during migraines, giving sufficient access to central sites of action. The authors thus suggest that during migraines there is a temporary window, in which opening of the blood–brain barrier allows access of LY2951742 to the CNS and thus inhibiting nociceptive transmission of the central trigeminal nerve, resulting in a prophylactic effect in migraine. In the trial, 32% of patients with migraine were complete responders (no migraine days) in the 3 months versus 17% in the placebo group. If the above hypothesis was correct, then complete responders would not benefit from further treatment with LY2951742 because there is no access to CNS without migraine attacks. Without this 32
access for LY2951742, the migraine attacks would be expected to recur and, after this, a new period with effect of LY2951742 could result. However, this hypothetical sequence of effect alternating with no effect is incompatible with long-term complete response. In addition, it would be a serious drawback for the clinical use of a monoclonal antibody to CGRP in migraine prophylaxis. In conclusion, monoclonal antibodies do not readily cross the blood–brain barrier under normal physiological conditions.3 In 2008, a review of the blood–brain barrier in migraine treatment concluded that no clear proof has been shown of breakdown or leakage of the bloodbrain barrier during migraines.4 In an MRI study of seven patients with migraine with aura and in 14 patients with migraine without aura during migraine attacks, there was no gadolinium enhancement during attacks, compatible with an intact blood-brain barrier.4,5 On the basis of these MRI results and the above argument against a temporary window, a CNS effect of LY2951742 in migraine prophylaxis is, in my view, most unlikely. I declare no competing interests.
Peer Tfelt-Hansen [email protected] Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Glostrup 2600, Denmark. 1
2
3
4
5
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 885–92. Yu YJ, Watts RJ. Developing therapeutic antibodies for neurodegenerative disease. Neurotheraeutics 2013; 10: 459–72. Reuter U. Anti-CGRP antibodies: a new approach to migraine treatment. Lancet Neurol 2014; 13: 857–59. Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia 2008; 28: 1245–58. Sanchez del Rio M, Bakker D, et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19: 701–07.
Authors’ reply We thank Peer Tfelt-Hansen for his interest in our study1 and his important questions about mechanism of action for monoclonal antibodies against CGRP, particularly LY2951742. Tfelt-Hansen argues that since monoclonal antibodies do not cross the blood–brain barrier, their site of action cannot be central because there is no clear proof to suggest that the blood–brain barrier is breeched in patients with migraine, either during or between attacks. He further argues that even if the blood–brain barrier were opened during attacks, then that would not explain the complete resolution of attacks in a significant proportion of subjects after the first dose of study drug. As we noted, the principle site of action of monoclonal CGRP antibodies is not known; a peripheral site of action seems likely, but a central site of action cannot be ruled out. Although antibodies are generally considered not to cross the blood– brain barrier or to reach intracellular targets in sufficient quantity to have a physiological or therapeutic effect, the ability of large protein molecules to cross the blood–brain barrier is well known. For example, insulin and transferrin are believed to enter the brain by receptor-mediated transcytosis through binding to receptors expressed by capillary endothelial cells.2,3 Dual-specific monoclonal antibodies that bind to the transferrin receptor have been used to allow therapeutic monoclonal antibodies to traverse the blood–brain barrier in animal models, including primates.4 Other drugs cross the blood–brain barrier by mimicking an endogenous substrate of a transporter receptor. For example, gabapentin, a water-soluble drug, is active in the CNS because the drug crosses the blood–brain barrier on the large neutral amino-acid transporter.5 Whether monoclonal CGRP antibodies specifically cross the blood–brain barrier is unknown, although the www.thelancet.com/neurology Vol 14 January 2015
Correspondence
classic work of Felgenhauer showing that IgG does enter the CSF in normal circumstances suggests CGRP monoclonal antibodies might also do so.6 Whether the concentration is sufficient for target engagement should be assessed. Until then, we think it is prudent not to draw a firm conclusion that these therapeutic antibodies work exclusively through a peripheral mechanism of action. DWD has served on advisory boards or consulted for Allergan, Amgen, Alder, Arteaus Therapeutics, Pfizer, Boston Scientific, Medtronic, St Jude, BristolMyers Squibb, Lundbeck, Impax, MAP, Electrocore, Colucid, Merck, ENeura, NuPathe, Eli Lilly, Autonomic Technologies, Ethicon Johnson and Johnson, Zogenix, Supernus, and Labrys; has received funding for travel, speaking, or editorial activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, West Virginia University Foundation, Canadian Headache Society, Healthlogix, Wiley, Universal Meeting Management, WebMD, UptoDate, Oregon Health Science Center, Starr Clinical, Decision Resources, and Synergy. PJG is on advisory boards for Allergan,
www.thelancet.com/neurology Vol 14 January 2015
Colucid, MAP pharmaceuticals, MSD, eNeura, Autonomic Technologies, Boston Scientific, Electrocore, Eli Lilly, Medtronic, Linde Gases, Arteaus Therapeutics, AlderBio, and Bristol-Myers Squibb; has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax, Zosano, and Dr Reddy’s Laboratories; has been compensated for expert legal testimony in a patent matter unrelated to CGRP mechanisms; has received grant support from Allergan, Amgen, MAP, and MSD; and has received honoraria for editorial work from Journal Watch Neurology and for developing educational materials and teaching for the American Headache Society. ELHS has served as a consultant to Arteaus Therapeutics and received a research grant from Arteaus Therapeutics as an investigator in the present study. JCS was an employee of Eli Lilly, but has since retired. SPS is an employee of Arteaus Therapeutics. DSG is an employee of Arteaus Therapeutics and owns stock or stock options in Arteaus.
*David W Dodick, Peter J Goadsby, Egilius L H Spierings, Joel C Scherer, Steven P Sweeney, David S Grayzel [email protected] Department of Neurology, Mayo Clinic, Phoenix, AZ, USA (DWD); NIHR Wellcome Trust Clinical Research Facility, King’s College London, London, UK (PJG);
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA (ELHS); Eli Lilly and Company, Indianapolis, IN, USA (JCS); and Arteaus Therapeutics, Cambridge, MA, USA (SPS, DSG) 1
2
3
4
5
6
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 885–92. Ardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem 1985; 44: 1771–78. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism 1987; 36: 892–95 Yu YJ, Atwal JK, Zhang Y, et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Transl Med 2014; 6: 261ra154. Wang Y, Welty DF. The simultaneous estimation of the influx and efflux bloodbrain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res 1996; 13: 398–403. Felgenhauer K. Protein size and cerebrospinal fluid composition. Klinische Wochenschrift 1974; 52: 1158–64.
33
(CGRP). Mean decrease from baseline in migraine days in 4 weeks was higher in patients given LY2951742 (4·2) than in those given placebo (3·0; p=0·003).1 Results of other trials that use antibodies against CGRP will probably be published soon.2 Apart from the clinical questions such as benefit and tolerability, this new prophylactic treatment raises questions about the pathophysiology of migraine. Most available prophylactic drugs for migraine exert their various effects in the CNS, seemingly supporting the neuronal theory of migraine. In discussing the possible site of action of LY2951742, Dodick and colleagues state that “the site and mechanism of action of CGRP monoclonal antibodies is unclear”, but suggest that blocking neurogenic vasodilation induced by CGRP or inhibition of central trigeminal nociceptive transmission could each be possible mechanisms of action.1 The authors acknowledge that monoclonal antibodies do not readily penetrate the blood–brain barrier, and the results of study, along with other results with CGRP receptor antagonists, seem to suggest a peripheral site of action.1 The authors then argue that the blood–brain barrier might be more permeable during migraines, giving sufficient access to central sites of action. The authors thus suggest that during migraines there is a temporary window, in which opening of the blood–brain barrier allows access of LY2951742 to the CNS and thus inhibiting nociceptive transmission of the central trigeminal nerve, resulting in a prophylactic effect in migraine. In the trial, 32% of patients with migraine were complete responders (no migraine days) in the 3 months versus 17% in the placebo group. If the above hypothesis was correct, then complete responders would not benefit from further treatment with LY2951742 because there is no access to CNS without migraine attacks. Without this 32
access for LY2951742, the migraine attacks would be expected to recur and, after this, a new period with effect of LY2951742 could result. However, this hypothetical sequence of effect alternating with no effect is incompatible with long-term complete response. In addition, it would be a serious drawback for the clinical use of a monoclonal antibody to CGRP in migraine prophylaxis. In conclusion, monoclonal antibodies do not readily cross the blood–brain barrier under normal physiological conditions.3 In 2008, a review of the blood–brain barrier in migraine treatment concluded that no clear proof has been shown of breakdown or leakage of the bloodbrain barrier during migraines.4 In an MRI study of seven patients with migraine with aura and in 14 patients with migraine without aura during migraine attacks, there was no gadolinium enhancement during attacks, compatible with an intact blood-brain barrier.4,5 On the basis of these MRI results and the above argument against a temporary window, a CNS effect of LY2951742 in migraine prophylaxis is, in my view, most unlikely. I declare no competing interests.
Peer Tfelt-Hansen [email protected] Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Glostrup 2600, Denmark. 1
2
3
4
5
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 885–92. Yu YJ, Watts RJ. Developing therapeutic antibodies for neurodegenerative disease. Neurotheraeutics 2013; 10: 459–72. Reuter U. Anti-CGRP antibodies: a new approach to migraine treatment. Lancet Neurol 2014; 13: 857–59. Edvinsson L, Tfelt-Hansen P. The blood-brain barrier in migraine treatment. Cephalalgia 2008; 28: 1245–58. Sanchez del Rio M, Bakker D, et al. Perfusion weighted imaging during migraine: spontaneous visual aura and headache. Cephalalgia 1999; 19: 701–07.
Authors’ reply We thank Peer Tfelt-Hansen for his interest in our study1 and his important questions about mechanism of action for monoclonal antibodies against CGRP, particularly LY2951742. Tfelt-Hansen argues that since monoclonal antibodies do not cross the blood–brain barrier, their site of action cannot be central because there is no clear proof to suggest that the blood–brain barrier is breeched in patients with migraine, either during or between attacks. He further argues that even if the blood–brain barrier were opened during attacks, then that would not explain the complete resolution of attacks in a significant proportion of subjects after the first dose of study drug. As we noted, the principle site of action of monoclonal CGRP antibodies is not known; a peripheral site of action seems likely, but a central site of action cannot be ruled out. Although antibodies are generally considered not to cross the blood– brain barrier or to reach intracellular targets in sufficient quantity to have a physiological or therapeutic effect, the ability of large protein molecules to cross the blood–brain barrier is well known. For example, insulin and transferrin are believed to enter the brain by receptor-mediated transcytosis through binding to receptors expressed by capillary endothelial cells.2,3 Dual-specific monoclonal antibodies that bind to the transferrin receptor have been used to allow therapeutic monoclonal antibodies to traverse the blood–brain barrier in animal models, including primates.4 Other drugs cross the blood–brain barrier by mimicking an endogenous substrate of a transporter receptor. For example, gabapentin, a water-soluble drug, is active in the CNS because the drug crosses the blood–brain barrier on the large neutral amino-acid transporter.5 Whether monoclonal CGRP antibodies specifically cross the blood–brain barrier is unknown, although the www.thelancet.com/neurology Vol 14 January 2015
Correspondence
classic work of Felgenhauer showing that IgG does enter the CSF in normal circumstances suggests CGRP monoclonal antibodies might also do so.6 Whether the concentration is sufficient for target engagement should be assessed. Until then, we think it is prudent not to draw a firm conclusion that these therapeutic antibodies work exclusively through a peripheral mechanism of action. DWD has served on advisory boards or consulted for Allergan, Amgen, Alder, Arteaus Therapeutics, Pfizer, Boston Scientific, Medtronic, St Jude, BristolMyers Squibb, Lundbeck, Impax, MAP, Electrocore, Colucid, Merck, ENeura, NuPathe, Eli Lilly, Autonomic Technologies, Ethicon Johnson and Johnson, Zogenix, Supernus, and Labrys; has received funding for travel, speaking, or editorial activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, West Virginia University Foundation, Canadian Headache Society, Healthlogix, Wiley, Universal Meeting Management, WebMD, UptoDate, Oregon Health Science Center, Starr Clinical, Decision Resources, and Synergy. PJG is on advisory boards for Allergan,
www.thelancet.com/neurology Vol 14 January 2015
Colucid, MAP pharmaceuticals, MSD, eNeura, Autonomic Technologies, Boston Scientific, Electrocore, Eli Lilly, Medtronic, Linde Gases, Arteaus Therapeutics, AlderBio, and Bristol-Myers Squibb; has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax, Zosano, and Dr Reddy’s Laboratories; has been compensated for expert legal testimony in a patent matter unrelated to CGRP mechanisms; has received grant support from Allergan, Amgen, MAP, and MSD; and has received honoraria for editorial work from Journal Watch Neurology and for developing educational materials and teaching for the American Headache Society. ELHS has served as a consultant to Arteaus Therapeutics and received a research grant from Arteaus Therapeutics as an investigator in the present study. JCS was an employee of Eli Lilly, but has since retired. SPS is an employee of Arteaus Therapeutics. DSG is an employee of Arteaus Therapeutics and owns stock or stock options in Arteaus.
*David W Dodick, Peter J Goadsby, Egilius L H Spierings, Joel C Scherer, Steven P Sweeney, David S Grayzel [email protected] Department of Neurology, Mayo Clinic, Phoenix, AZ, USA (DWD); NIHR Wellcome Trust Clinical Research Facility, King’s College London, London, UK (PJG);
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA (ELHS); Eli Lilly and Company, Indianapolis, IN, USA (JCS); and Arteaus Therapeutics, Cambridge, MA, USA (SPS, DSG) 1
2
3
4
5
6
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 885–92. Ardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem 1985; 44: 1771–78. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism 1987; 36: 892–95 Yu YJ, Atwal JK, Zhang Y, et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Transl Med 2014; 6: 261ra154. Wang Y, Welty DF. The simultaneous estimation of the influx and efflux bloodbrain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res 1996; 13: 398–403. Felgenhauer K. Protein size and cerebrospinal fluid composition. Klinische Wochenschrift 1974; 52: 1158–64.
33
