Migraine ranks third among the most common human diseases worldwide, after dental caries and tension-type headaches [28]. The one-year prevalence in Europe for all forms of migraine is 43.6% in women and 26.9% in men [29]. Every day, approximately 900,000 people in Germany alone are affected by migraine attacks. 100,000 people are unable to work and are bedridden due to migraine attacks each day. On average, three million Germans take a headache tablet daily via self-medication. Around 59,000 single doses of triptans are used every day in Germany to treat migraine attacks [19].

According to current understanding, migraine pain is based on a neurogenic inflammatory reaction in the arteries of the meninges. Inflammatory substances are released there in the initial stage of a migraine attack [5, 10, 16, 25]. These lead to increased pain sensitivity of the meninges with swelling and dilation of the vessel walls. Every heartbeat results in a throbbing, pounding migraine pain; every movement of the head is painful and intensifies the pain. Migraine patients therefore try to maintain as much rest and avoid stimuli as possible during an attack, as well as physical activity and jarring movements.

In recent years, it has been possible to develop specific antibodies against messenger substances that trigger inflammation during a migraine attack. The focus here is on calcitonin gene-related peptide, or CGRP for short [1, 13, 14, 20, 23, 24]. It is a neuropeptide consisting of 37 amino acids and is encoded by the same gene as the hormone calcitonin. CGRP is one of the most potent vasodilators and plays a key role in the development of migraines. Administering so-called monoclonal antibodies can block the effects of these inflammatory substances for several weeks and reduce the likelihood of migraine attacks. Four antibodies have been developed and tested in numerous studies: erenumab (AMG 334), galcanezumab (LY2951742), fremanezumab (TEV-48125), and eptinezumab (ALD403) [4, 8, 12, 14, 15, 21, 22, 32, 33]. Erenumab was the first representative of this new class of drugs to be approved in Germany in July 2018 and has been available in pharmacies since November 2018. All of the now available antibodies have demonstrated efficacy in very large-scale international studies. Some antibodies target the ligand CGRP (galcanezumab, fremanezumab, eptinezumab), while others block the CGRP receptor (erenumab) [31].

For erenumab, study data are available for episodic migraine (up to 14 migraine days per month) and chronic migraine (more than 15 headache days per month) [2, 3, 6, 7, 9, 11, 17, 26, 27, 30]. It has also been investigated whether patients who have not responded to previously approved preventive medications can still experience an effect [26]. Comparative studies with existing preventive medications are not yet available. The reduction in migraine days per month compared to placebo is approximately one to three migraine days, similar to the reduction achieved with existing prophylactic medications approved for this indication. Therefore, cost-effectiveness plays a particularly important role in prescribing erenumab: the price for a monthly dose of 70 mg erenumab (Aimovig®) is €688.36. This equates to annual therapy costs of €8,260.32, which could potentially accrue over years or even decades. For treatment with 140 mg, the annual therapy costs amount to €16,520.64. It is not yet definitively determined for which forms of migraine and for which patients reimbursement by statutory health insurance companies. Due to the high costs, and in order to comply with the principle of cost-effectiveness, the new immunotherapy will only be considered if the currently available specific behavioral measures and preventive migraine medications are ineffective, not tolerated, or contraindicated.

Against this background, the manufacturer is seeking time-limited reimbursement for severely affected migraine patients for whom four (for episodic migraine, i.e., fewer than 15 headache days per month) to five (for chronic migraine, i.e., 15 or more headache days per month) approved prior therapies have been unsuccessful. Which prior therapies these should be is not yet definitively defined. According to the guidelines, amitriptyline, beta-blockers (metoprolol, propranolol, bisoprolol), flunarizine, topiramate, and valproate are relevant for the treatment of episodic migraine. For the preventive treatment of chronic migraine, onabotulinumtoxin, currently the only specifically approved drug for this purpose, should also be considered. Prescribing rights should be restricted for patients for whom these prior therapies have not been adequately exhausted.

However, direct evidence of added benefit for the treatment of the targeted patient group cannot be immediately discerned from the data. While the LIBERTY study [26] investigated the efficacy and safety of 140 mg erenumab in patients with episodic migraine experiencing four to 14 migraine days per month, in whom two to four prior preventive therapies had failed due to lack of efficacy or intolerable side effects, only 30.3% of patients receiving erenumab 140 mg, compared to 13.7% receiving placebo, showed a reduction in monthly headache days of at least 50%. Clinically, however, this translated to an absolute reduction of only 1.76 headache days per month with 140 mg erenumab and 0.15 headache days per month with placebo. The number of days per month requiring specific acute migraine medication decreased by 1.3 days with erenumab 140 mg compared to 0.5 days with placebo.

Given the study's parameters, no significant effect can be expected in approximately 70% of treated patients. It should be noted that this, the only study to date addressing efficacy in cases of other treatment failure, was not conducted with the standard dose of 70 mg, but rather with 140 mg of erenumab for episodic migraine. Furthermore, the previous unsuccessful therapies did not explicitly include the four active ingredients now targeted for the proposed reimbursement restriction in Germany. These included amitriptyline, candesartan, flunarizine, lisinopril, metoprolol, propranolol, topiramate, valproate, venlafaxine, and others. In fact, 39% of the study participants had previously only tried two prophylactic medications without success. Therefore, the added benefit of 70 mg of erenumab compared to existing treatment options is currently not supported by study data for either episodic or chronic migraine. For the severely affected patient group with chronic migraine and complete failure of first-line migraine prophylaxis drugs, the effect of both 70 mg and 140 mg of erenumab is completely unknown.

Erenumab is approved for migraine prophylaxis in adults with at least four migraine days per month. Treatment should be initiated by physicians experienced in the diagnosis and treatment of migraine. The recommended dose is 70 mg erenumab every four weeks. Some patients may benefit from a dose of 140 mg every four weeks, administered as two subcutaneous injections of 70 mg each. In clinical trials, the 140 mg dose resulted in a numerically higher response rate, although this was not statistically significant [2, 11, 17, 26, 30]. A response to therapy may be evident within the first two weeks of treatment. Treatment should be discontinued in patients who do not show a response after three months. Treatment should be continuously evaluated. The migraine app (available free for iOS and Android) is suitable for monitoring progress and treatment success.

Approximately 50% of patients with more than 15 headache days per month for at least three months have medication overuse headache (MOH) as an additional underlying cause for the increasing frequency of headache days, in addition to their original primary headache disorder [18, 19]. In contrast to their baseline status, most affected individuals experience a reduction in headache days per month and a renewed response to preventive and acute medication after a medication break. Therefore, counseling, knowledge of the connection, and the consequences of medication overuse headache (MOH) are essential. Patients with medication overuse headache (MOH) should undergo an adequate medication break before initiating treatment with erenumab and be encouraged to adhere to the 10-20 rule: analgesics and specific migraine medications should be used on fewer than 10 days per month, and at least 20 days per month should be completely free of their use.

The injections are administered using an autoinjector at four-week intervals. Many migraine patients are familiar with this autoinjector, as a nearly identical pen is also used for the subcutaneous administration of sumatriptan. In contrast, the pen is not used during an attack as needed. Instead, it is administered at fixed four-week intervals for prevention, according to a defined treatment plan. This immunotherapy is a form of passive immunization. The antibodies are not produced by the human body itself, but are manufactured in the laboratory as a fully human monoclonal IgG2 antibody in Chinese hamster (CHO) ovarian cells using recombinant DNA technology. For this reason, the administration must be repeated regularly. Immunotherapy, or passive "vaccination," does not mean that the disease will no longer occur. It reduces the risk of future attacks. During the dosing period, erenumab is primarily eliminated via a non-specific proteolytic pathway and has an elimination half-life of approximately 28 days.

Erenumab is self-administered subcutaneously. The injection can be given in the abdomen, thigh, or outer upper arm. A different injection site should be used for each subsequent injection. Injections should not be given into sensitive, broken, reddened, or hardened areas of skin. The autoinjector is for single use only. As a precaution, the use of erenumab during pregnancy should be avoided. Adequate contraception should therefore be used.

Side effects reported with 70 mg and 140 mg of erenumab include injection site reactions, constipation, muscle spasms, and pruritus. Most of these side effects are mild or moderate. However, long-term effects and long-term side effects are currently unknown.

The medication should be stored in a refrigerator at 2-8 degrees Celsius and should not be frozen. The autoinjector should be kept in its outer carton, protected from light. If the medication is stored at room temperature up to 25 degrees Celsius, it must be used within 14 days or discarded. The solution should be visually inspected before use. If it contains cloudiness, flakes, particles, or a yellow discoloration, it must not be used. To avoid discomfort at the injection site, the autoinjector should be removed from the refrigerator before injection and stored at room temperature for at least 30 minutes, avoiding shaking and direct sunlight or other heat sources.

Unlike all other currently available preventative medications, this new immunotherapy has been specifically developed for migraine prevention. A slow dose titration due to potential intolerances and side effects is not necessary. If a patient responds, the onset of action is expected quickly, initially within a few days. Side effects of previous migraine preventatives, such as weight gain, mood swings, fatigue, reduced energy, or drowsiness, are not expected. However, the data available so far indicate that one should not assume that the new mechanism of action will eliminate migraines and allow one to live as one pleases. Approximately 70% of patients with episodic migraine who have previously failed other therapies will likely not respond to the new mechanism of action either. It is not yet possible to predict who will be among the 30% who respond. However, the efficacy of the treatment in patients with chronic migraine who have not responded to any standard prophylaxis, including onabotulinumtoxin, and who are hoping most for an improvement in their condition, is currently unknown. They were excluded from the study program.

literature

  1. Ashina H, Schytz HW, Ashina M (2018) CGRP in Human Models of Migraine. Handb Exp Pharmacol
  2. Ashina M, Dodick D, Goadsby PJ, Reuter U, Silberstein S, Zhang F, Gage JR, Cheng S, Mikol DD, Lenz RA (2017) Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study. Neurology 89:1237-1243
  3. Ashina M, Tepper S, Brandes JL, Reuter U, Boudreau G, Dolezil D, Cheng S, Zhang F, Lenz R, Klatt J, Mikol DD (2018) Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study. Cephalalgia 38:1611-1621
  4. Cauchi M, Robertson NP (2016) CGRP and migraine. J Neurol 263:192–194
  5. Charles A (2018) The pathophysiology of migraine: implications for clinical management. Lancet Neurol 17:174-182
  6. de Hoon J, Van Hecken A, Vandermeulen C, Herbots M, Kubo Y, Lee E, Eisele O, Vargas G, Gabriel K (2018) Phase 1, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers. Cephalalgia:333102418776017
  7. de Hoon J, Van Hecken A, Vandermeulen C, Yan L, Smith B, Chen JS, Bautista E, Hamilton L, Waksman J, Vu T, Vargas G (2018) Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple-dose Studies of Erenumab in Healthy Subjects and Patients With Migraine. Clin Pharmacol Ther 103:815–825
  8. Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, Vigneri S, Edvinsson L, Maassen Van Den Brink A, European Headache Federation School of Advanced S (2017) Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain 18:96
  9. Depre C, Antalik L, Starling A, Koren M, Eisele O, Lenz RA, Mikol DD (2018) A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients With Stable Angina. Headache 58:715–723
  10. Dodick DW (2018) A Phase-by-Phase Review of Migraine Pathophysiology. Headache 58 Suppl 1:4-16
  11. Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard H, Mikol DD, Lenz RA (2018) ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 38:1026–1037
  12. Edvinsson L (2015) The Journey to Establish CGRP as a Migraine Target: A Retrospective View. Headache 55:1249–1255
  13. Edvinsson L (2018) The CGRP Pathway in Migraine as a Viable Target for Therapies. Headache 58 Suppl 1:33-47
  14. Edvinsson L, Haanes KA, Warfvinge K, Krause DN (2018) CGRP as the target of new migraine therapies – successful translation from bench to clinic. Nat Rev Neurol 14:338–350
  15. Fiala JL, Lowery D (2016) Patent watch: Migraine therapies targeting the CGRP pathway: intellectual property landscape. Nat Rev Drug Discov 15:8-9
  16. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S (2017) Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev 97:553–622
  17. Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA (2017) A controlled trial of erenumab for episodic migraine. N Engl J Med 377:2123–2132
  18. Göbel H, Heinze A (2011) Chronic migraine and headache by medication overuse. Evolution and revision of classification. Pain 25:493-500
  19. Göbel H (2012) Headaches. Springer, Berlin, Heidelberg, New York, London, Paris, Tokyo, Hong Kong, Barcelona, ​​Budapest
  20. Holland PR (2018) Foreword: The CGRP Pathway and Migraine Prevention: Reducing the Burden of Disease. Headache 58 Suppl 1:1-3
  21. Karsan N, Goadsby PJ (2015) CGRP mechanism antagonists and migraine management. Curr Neurol Neurosci Rep 15:25
  22. Khan S, Olesen A, Ashina M (2017) CGRP, a target for preventive therapy in migraine and cluster headache: Systematic review of clinical data. Cephalalgia:333102417741297
  23. Maasumi K, Michael RL, Rapoport AM (2018) CGRP and Migraine: The Role of Blocking Calcitonin Gene-Related Peptide Ligand and Receptor in the Management of Migraine. Drugs 78:913–928
  24. Messina R, Goadsby PJ (2018) CGRP – a target for acute therapy in migraine: Clinical data. Cephalalgia:333102418768095
  25. Ong JJY, Wei DY, Goadsby PJ (2018) Recent Advances in Pharmacotherapy for Migraine Prevention: From Pathophysiology to New Drugs. Drugs 78:411–437
  26. Reuter U, Goadsby PJ, Lanteri-Minet M, Wen S, Hours-Zesiger P, Ferrari MD, Klatt J (2018) Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomized, double-blind, placebo-controlled, phase 3b study. Lancet
  27. Schwedt T, Reuter U, Tepper S, Ashina M, Kudrow D, Broessner G, Boudreau GP, McAllister P, Vu T, Zhang F, Cheng S, Picard H, Wen S, Kahn J, Klatt J, Mikol D (2018) Early onset of efficacy with erenumab in patients with episodic and chronic migraine. J Headache Pain 19:92
  28. Steiner TJ, Stovner LJ, Birbeck GL (2013) Migraine: the seventh disabler. Cephalalgia 33:289–290
  29. Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lanteri-Minet M, Rastenyte D, Ruiz de la Torre E, Tassorelli C, Barre J, Andree C (2014) The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain 15:31
  30. Tepper S, Ashina M, Reuter U, Brandes JL, Dolezil D, Silberstein S, Winner P, Leonardi D, Mikol D, Lenz R (2017) Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomized, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 16:425-434
  31. Tepper SJ (2018) History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment. Headache 58 Suppl 3:238-275
  32. Wrobel Goldberg S, Silberstein SD (2015) Targeting CGRP: A New Era for Migraine Treatment. CNS Drugs 29:443–452
  33. Yuan H, Lauritsen CG, Kaiser EA, Silberstein SD (2017) CGRP Monoclonal Antibodies for Migraine: Rationale and Progress. BioDrugs 31:487–501