According to current understanding, migraine pain is based on a neurogenic inflammatory reaction in the arteries of the meninges. Inflammatory substances are released there during the initial stage of a migraine attack. 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 head movement is painful due to allodynia and hyperpathia, intensifying the symptoms. Migraine sufferers 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. 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 halt 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).

  • Erenumab (Aimovig®), the first representative of this new class of drugs, was approved in Germany in July 2018 and has been available in pharmacies since November 2018. A legal dispute is straining the collaboration between Novartis and the US biotech company Amgen, which developed Erenumab. On April 4, 2019, the companies accused each other in court of violating a cooperation agreement regarding Aimovig. Amgen terminated the migraine cooperation agreement for Erenumab on this basis. Amgen accuses Novartis of violating this agreement because Novartis is allegedly working with a competitor on a similar drug to Aimovig. Novartis denies this.
  • The second antibody, galcanezumab (Emgality®), for migraine prophylaxis became available in German pharmacies on April 1, 2019. Galcanezumab has been approved in the EU since November 2018.
  • The third antibody, fremanezumab (Ajovy®), was also recommended for marketing authorization by the EMA's Committee for Medicinal Products for Human Use , and was approved by the European Commission in April 2019. Ajovy differs from Aimovig and Emgality, among other things, in its dosing interval: in addition to monthly administration, a quarterly application is available.

The antibodies currently available have all demonstrated their efficacy in very large-scale international studies. There are antibodies that act against the ligand CGRP (galcanezumab, fremanezumab, eptinezumab) or that block the CGRP receptor (erenumab). CGRP is thought to play a crucial role in the development of migraines. Elevated CGRP levels are found during migraine attacks, and in chronic migraine, also between attacks. Intravenous administration of CGRP can induce migraine-like headaches in migraine patients. Triptans, effective in the acute treatment of migraines, inhibit the release of CGRP. Finally, studies with gepants have shown that inhibiting the CGRP receptor can both interrupt acute migraine attacks and, with regular use, prevent them.

Fremanezumab was investigated in a total of 2,000 patients in registration trials. The Phase III Halo EM trial investigated patients with episodic migraine, and the Phase III Halo CM trial investigated patients with chronic migraine. The Halo CM trial compared the efficacy of 225 mg fremanezumab administered monthly and 675 mg fremanezumab administered quarterly to placebo in 1,130 patients. On average, patients experienced migraine on 13.2 days per month (monthly fremanezumab group), 12.8 days per month (quarterly fremanezumab group), and 13.3 migraine days per month (placebo group). In the quarterly fremanezumab group, patients received 675 mg of fremanezumab subcutaneously at baseline. Placebo doses were administered after 4 and 8 weeks. Patients receiving monthly fremanezumab were treated with a starting dose of 675 mg. They then received 225 mg of fremanezumab in both week 4 and week 8. The primary endpoint was the reduction in the average number of headache days per month. A headache day was defined as at least 4 hours of symptoms per day or the use of migraine-specific acute medication during that day.

  • The most significant reduction was observed in the monthly dosing group. In this group, patients had an average of 4.6 fewer days of migraines per month. 41% of patients achieved a halving of headache days per month with this application method.
  • When fremanezumab was administered every 3 months, an improvement in monthly migraine days of 4.3 days was observed. In this group, 38% of patients achieved a 50% reduction in headache days.
  • In comparison, the placebo group showed a reduction of 2.5 headache days per month. 18% of the placebo group experienced a halving of headache days per month.

The marketing authorization specifies the use of fremanezumab (as with erenumab and galcanezumab) in adult patients who suffer from migraine on at least four days per month. The antibodies are approved for the preventive treatment of both episodic and chronic migraine. Fremanezumab is currently the only available antibody for which significant efficacy has been demonstrated even with quarterly administration of 675 mg in three 225 mg doses (three times the monthly dose). Currently, there is no dedicated three-monthly injection available that would allow patients to administer the corresponding 675 mg dose in a single injection. Therefore, even with three-monthly treatment, patients currently require three injections, albeit all administered at a single time.

The most common undesirable side effect was pain at the injection site. These did not differ significantly between the group treated with fremanezumab or placebo.

When using monoclonal antibodies to prevent migraines, some special considerations must be taken into account:

  • Monoclonal antibodies are very expensive medications. Currently, there are no comparative studies with existing guideline-recommended preventive migraine medications. Comparing the efficacy data with existing drugs, the average values ​​do not show any particular superiority in terms of effectiveness. The significant added benefit lies in the fact that patients who did not respond to existing medications, for whom contraindications existed, or who could not tolerate them, can still achieve efficacy with monoclonal antibodies. For reasons of cost-effectiveness, the new treatment options should therefore be used for patients for whom existing guideline-recommended migraine prophylaxis was not helpful.
  • The monoclonal antibodies must be administered as an injection under the skin using an autoinjector.
  • Monoclonal antibodies have a very long duration of action with a half-life of approximately four weeks. This means that after one month, about 50% of the active ingredient is still circulating in the bloodstream and is active. Since this is a very new class of drugs, long-term effects with prolonged use cannot yet be reliably assessed.
  • Immunotherapy for the preventive treatment of migraines is not a “final cure” for migraines. Only about 30% of patients who have not responded adequately to previous preventative treatment measures can expect a reduction in migraine attacks by 50% or more. This effect is unlikely to occur in 70% of treated patients. A majority of patients who achieve this effectiveness will still experience migraine attacks that require acute medication treatment.
  • Migraine is a complex condition. It requires lifestyle adjustments to accommodate the specific genetic predisposition to migraine attacks. Knowledge, information, and behavioral modifications through regulating daily routines, breaks, relaxation, exercise, diet, and stress reduction are essential prerequisites for controlling the course of migraines.

Migraine is the third most common illness in humans, after tooth decay and tension-type headaches. Up to the age of 50, it is the most debilitating illness. It particularly impacts productive life years, including school, university, vocational training, work, starting a family, and social activities. Traditionally, migraine has been a neglected area of ​​the scientific community. Throughout human history, there has been little progress in understanding and treating migraine. This is now changing significantly for the first time in our generation. Further scientific studies with specific insights into the causes and treatment of migraine, as well as increased public awareness and research efforts, are needed. Specialized care centers that can provide interdisciplinary, multimodal, and state-of-the-art treatment for severely affected patients are essential for improved care.