Neues in der Migränetherapie

ZUSAMMENFASSUNG

Migränepatienten brauchen eine wirksame Akuttherapie und in schwereren Fällen auch eine medikamentöse Prophylaxe. In den letzten Jahren sind erstmals gezielt in die Pathophysiologie der Migräne eingreifende Substanzen entwickelt worden, die über die Blockade von CGRP wirken. Dies sind einerseits die Antikörper gegen CGRP und den CGRP-Rezeptor, die prophylaktisch wirken, andererseits die Gepante (CGRP-Rezeptorantagonisten), die sowohl in der Akuttherapie als auch in der Prophylaxe der Migräne eingesetzt werden können. Gemeinsam ist diesen Substanzen ihre gute Verträglichkeit. CGRP-(Rezeptor)-Antikörper haben gegenüber klassischen Prophylaktika den Vorteil eines schnellen Wirkeintritts. Für die Gepante in der Akuttherapie weisen tierexperimentelle Daten darauf hin, dass sie anders als Triptane eventuell nicht zu einem Kopfschmerz bei Medikamentenübergebrauch führen.

ABSTRACT

Migräne patients need effective acute medication and the more severe cases need preventive treatment. Recently, drugs that directly interact with migraine pathophysiology by blocking the CGRP pathway have been developed. On one hand, there are antibodies against CGRP and its receptor, used in migraine prevention. On the other hand, small molecule CGRP receptor antagonists, the gepants, are being developed for both acute therapy and prevention. The two classes of drugs have in common a favourable tolerability profile. CGRP-(receptor)-antibodies have the advantage of a fast onset of action. For the gepants, results from animal research suggest that different from triptans, they might not lead to medication overuse headache.

Schlüsselwörter

Migräne - Calcitonin-gene-related-peptide - Antikörper - Gepante

Key words

Migraine - calcitonin-gene-related-peptide - antibodies - gepants

Publication History

Article published online:
09 March 2021

• Literatur

• 1 GDB 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 2017; 16: 877-897
• 2 GDB 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18: 459-480
• 3 GDB 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018; 17: 954-976
• 4 Diener HC, May A.. Therapie der Migräneattacke und Prophylaxe der Migräne, S1-Leitlinie. Im Internet https://www.dgn.org/leitlinien/3583-ll-030-057-2018-therapie-der-migraeneattacke-und-prophylaxe-der-migraene
• 5 de Vries T, Villalón CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther 2020; 211: 107528
• 6 Eftekhari S, Salvatore CA, Calamari A. et al Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 2010; 169: 683-696
• 7 Juhasz G, Zsombok T, Modos EA. et al NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 2003; 106: 461-470
• 8 Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 183-187
• 9 Kamm K, Straube A, Ruscheweyh R. Calcitonin gene-related peptide levels in tear fluid are elevated in migraine patients compared to healthy controls. Cephalalgia 2019; 39: 1535-1543
• 10 Cernuda-Morollón E, Larrosa D, Ramón C. et al Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 2013; 81: 1191-1196
• 11 Hansen JM, Hauge AW, Olesen J. et al Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010; 30: 1179-1186
• 12 Messlinger K. The big CGRP flood – sources, sinks and signalling sites in the trigeminovascular system. J Headache Pain 2018; 19: 22
• 13 Diener HC, May A.. Prophylaxe der Migräne mit monoklonalen Antikörpern gegen CGRP oder den CGRP-Rezeptor, Ergänzung der S1-Leitlinie Therapie der Migräneattacke und Prophylaxe der Migräne, Leitlinien für Diagnostik und Therapie in der Neurologie. Leitlinien der DGN. 2019 Im Internet www.dgn.org/leitlinien
• 14 Deng H, Li GG, Nie H. et al Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine – an updated systematic review and meta-analysis. BMC Neurol 2020; 20: 57
• 15 Raffaelli B, Neeb L, Reuter U. Monoclonal antibodies for the prevention of migraine. Expert Opin Biol Ther 2019; 19: 1307-1317
• 16 Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 2019; 394: 1765-1774
• 17 Reuter U, Goadsby PJ, Lanteri-Minet M. et al Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet 2018; 392: 2280-2287
• 18 Ferrari MD, Diener HC, Ning X. et al Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet 2019; 394: 1030-1040
• 19 Detke HC, Millen BA, Zhang Q. et al Rapid Onset of Effect of Galcanezumab for the Prevention of Episodic Migraine: Analysis of the EVOLVE Studies. Headache 2020; 60: 348-359
• 20 Silberstein SD, Rapoport AM, Loupe PS. et al The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment. Headache 2019; 59: 383-393
• 21 Schwedt T, Reuter U, Tepper S. et al Early onset of efficacy with erenumab in patients with episodic and chronic migraine. J Headache Pain 2018; 19: 92
• 22 Goadsby PJ, Reuter U, Hallström Y. et al One-year sustained efficacy of erenumab in episodic migraine: Results of the STRIVE study. Neurology 2020
• 23 Tepper SJ, Ashina M, Reuter U. et al Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study. Cephalalgia 2020; 40: 543-553
• 24 Raffaelli B, Mussetto V, Israel H. et al Erenumab and galcanezumab in chronic migraine prevention: effects after treatment termination. J Headache Pain 2019; 20: 66
• 25 Stauffer VL, Wang S, Voulgaropoulos M. et al Effect of Galcanezumab Following Treatment Cessation in Patients With Migraine: Results From 2 Randomized Phase 3 Trials. Headache 2019; 59: 834-847
• 26 Rosen N, Pearlman E, Ruff D. et al 100 % Response Rate to Galcanezumab in Patients With Episodic Migraine: A Post Hoc Analysis of the Results From Phase 3, Randomized, Double-Blind, Placebo-Controlled EVOLVE-1 and EVOLVE-2 Studies. Headache 2018; 58: 1347-1357
• 27 Halker Singh RB, Aycardi E, Bigal ME. et al Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials. Cephalalgia 2019; 39: 52-60
• 28 Brandes JL, Diener HC, Dolezil D. et al The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving > = 50 %, > = 75 %, and 100 % response. Cephalalgia 2020; 40: 28-38
• 29 Szperka CL, VanderPluym J, Orr SL. et al Recommendations on the Use of Anti-CGRP Monoclonal Antibodies in Children and Adolescents. Headache 2018; 58: 1658-1669
• 30 Messlinger K, MaassenVanDenBrink A. Cardio- and cerebrovascular safety of erenumab, a monoclonal antibody targeting CGRP receptors – important studies on human isolated arteries. Cephalalgia 2019; 39: 1731-1734
• 31 Kudrow D, Pascual J, Winner PK. et al Vascular safety of erenumab for migraine prevention. Neurology 2020; 94: e497-e510
• 32 Ziegeler C, May A. Non-Responders to Treatment With Antibodies to the CGRP-Receptor May Profit From a Switch of Antibody Class. Headache 2020; 60: 469-470
• 33 Dodick DW, Goadsby PJ, Lucas C. et al Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia 2020
• 34 Goadsby PJ, Dodick DW, Leone M. et al Trial of Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med 2019; 381: 132-141
• 35 Ruscheweyh R, Broessner G, Gossrau G. et al Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts. Cephalalgia 2020
• 36 Ashina H, Iljazi A, Al-Khazali HM. et al Efficacy, tolerability, and safety of erenumab for the preventive treatment of persistent post-traumatic headache attributed to mild traumatic brain injury: an open-label study. J Headache Pain 2020; 21: 62
• 37 Voss T, Lipton RB, Dodick DW. et al A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 2016; 36: 887-898
• 38 Dodick DW, Lipton RB, Ailani J. et al Ubrogepant for the Treatment of Migraine. N Engl J Med 2019; 381: 2230-2241
• 39 Lipton RB, Dodick DW, Ailani J. et al Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA 2019; 322: 1887-1898
• 40 Ferrari MD, Goadsby PJ, Roon KI. et al Triptans (serotonin, 5-HT1B/1 D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633-658
• 41 Goadsby PJ, Tepper SJ, Watkins PB. et al Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults. Cephalalgia 2019; 39: 1753-1761
• 42 Lipton RB, Coric V, Stock EG. et al Rimegepant 75 mg, an oral calcitonin gene-related peptide antagonist, for the acute treatment of migraine: two phase 3, double-blind, randomized, placebo-controlled trials (MTIS2018-171 abstract). Cephalalgia 2018; 38: 140
• 43 Lipton RB, Croop R, Stock EG. et al Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med 2019; 381: 142-149
• 44 Croop R, Goadsby PJ, Stock DA. et al Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet 2019; 394: 737-745
• 45 Biohaven. Biohaven achieves positive topline results in pivotal phase ⅔ study of vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine [press release]. https:\\biohavenpharma.com/investors/news-events/press-releases/12-17-2019
• 46 Dodick D, Goadsby P, Lu K. et al Ubrogepant Achieves Onset of Pain Relief at 1 Hour for the Acute Treatment of Migraine (1223). Neurology 2020: 94
• 47 Marcus R, Goadsby PJ, Dodick D. et al BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 2014; 34: 114-125
• 48 Mullin K, Kudrow D, Croop R. et al Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy. Neurology 2020; 94: e2121-e2125
• 49 Berman G, Kudrow D, Halverson P. et al Oral Rimegepant 75 mg Is Well-tolerated When Used Concomitantly with Injectable Anti-CGRP Monoclonal Antibodies: Results From a Multicenter, Long-term, Open-label Safety Study. Annual Meeting American Academy of Neurology. 2020 Abstract S8.008
• 50 Rubio-Beltran E, Labastida-Ramirez A, Haanes KA. et al Characterisation of vasodilatory responses in the presence of the CGRP receptor antibody erenumab in human isolated arteries. Cephalalgia 2019; 39: 1735-1744
• 51 Rubio-Beltran E, Chan KY, Danser AJ. et al Characterisation of the calcitonin gene-related peptide receptor antagonists ubrogepant and atogepant in human isolated coronary, cerebral and middle meningeal arteries. Cephalalgia 2020; 40: 357-366
• 52 Chaitman BR, Ho AP, Behm MO. et al A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina. Clin Pharmacol Ther 2012; 91: 459-466
• 53 Berman G, Croop R, Kudrow D. et al Safety of Rimegepant, an Oral CGRP Receptor Antagonist, Plus CGRP Monoclonal Antibodies for Migraine. Headache 2020
• 54 Saengjaroentham C, Strother LC, Dripps I. et al Differential medication overuse risk of novel anti-migraine therapeutics. Brain 2020; 143: 2681-2688
• 55 Navratilova E, Behravesh S, Oyarzo J. et al Ubrogepant does not induce latent sensitization in a preclinical model of medication overuse headache. Cephalalgia 2020; 40: 892-902
• 56 Goadsby PJ, Dodick DW, Ailani J. et al Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol 2020; 19: 727-737
• 57 Biohaven. Biohaven completes enrollment in pivotal trial phase 3 migraine prevention trial [press release]. https://www.biohavenpharma.com/investors/news-events/press-releases/08-07-2019
• 58 McGinley J, L’Italien G, Thiry A. et al Results in Reductions in Monthly Migraine Days: Secondary Analysis of a Multicenter, Open Label Long-term Safety Study of Rimegepant for the Acute Treatment of Migraine. Annual Meeting American Academy of Neurology; 2020. Poster P7.011
• 59 Yiangou A. et al Calcitonin gene related peptide monoclonal antibody treats headache in patients with active idiopathic intracranial hypertension. J Headache Pain 2020; 21 (01) 116