CGRP monoclonal antibodies

CGRP monoclonal antibodies: Immunotherapy for migraine

Erenumab

Erenumab (Aimovig®) is a monoclonal antibody that inhibits the CGRP receptor. CGRP is thought to play a key role in the pathophysiology of migraine. 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, which are effective in the acute treatment of migraine, inhibit the release of CGRP. Finally, it has been shown that gepants, which inhibit the CGRP receptor, can both interrupt acute migraine attacks and, with regular use, prevent them.

Aimovig® was approved by the US Food and Drug Administration (FDA) in May 2018 for the preventive treatment of migraine in adults. Treatment is administered via a self-injection of the drug under the skin once a month. Aimovig is the first approved preventive migraine medication in a new class of drugs for migraine prevention. These drugs work by inhibiting the activity of calcitonin gene-related peptide (CGRP), a molecule involved in the development of migraine attacks.

effectiveness

In the registration trials, erenumab significantly reduced the number of migraine days per month compared to placebo in patients with both episodic and chronic migraine who had previously failed a maximum of two (for episodic migraine) or three (for chronic migraine) migraine prophylaxis medications. The 50% responder rate was significantly higher than with placebo, the use of acute medication was significantly lower, and a significant improvement in quality of life resulted.

In the STRIVE study (phase 3) for episodic migraine, 70 mg and 140 mg of erenumab were tested against placebo. The 50% responder rates (number of participants with a reduction in migraine days per month of at least 50%) were 43.3% with 70 mg erenumab, 50.0% with 140 mg erenumab, and 26.6% with placebo. The difference between erenumab 70 mg and 140 mg was not statistically significant. In chronic migraine (phase 2), similar 50% responder rates were achieved: 40% with 70 mg erenumab, 41% with 140 mg erenumab, and 23% with placebo.

Since no study has yet been conducted against any of the standard substances for migraine prophylaxis, the proof of additional benefit required for the reimbursement of erenumab in the statutory health insurance system is based on the LIBERTY study.

In this study, patients with episodic migraine (four to 14 migraine days per month) and a history of treatment failure with two to four standard migraine prophylaxis medications were treated with 140 mg erenumab or placebo. The response rate for 140 mg erenumab was 30%, compared to 14% for placebo; this difference was statistically significant. The number of migraine days per month decreased by 1.76 days with erenumab (baseline 9.3 days/month) and by 0.15 days with placebo. Again, the difference between erenumab and placebo was statistically significant.

In an efficacy analysis conducted at the Headache Center of the Kiel Pain Clinic between November 2018 and December 2019, a total of 193 patients were evaluated for treatment with erenumab. These patients had previously proven refractory to beta-blockers (metoprolol or propranolol), amitriptyline, topiramate, flunarizine, valproate, and, in the case of chronic migraine, onabotulinumtoxin, or for whom a contraindication precluded its use. The 50% responder rate was 38% in patients with episodic migraine (n=48). For patients with chronic migraine (n=145), a 50% responder rate of 33% was observed. Approximately three-quarters of the patients received a dose of 140 mg erenumab. The overall effectiveness rates were therefore somewhat lower than in the study patients without multiple treatment failures, but higher in episodic migraine than in the Liberty study (38% versus 30%). Experience suggests that the results of controlled studies are transferable to everyday clinical practice. Approximately one in three affected individuals who previously received inadequate prophylactic medication benefited significantly.

Use after approval and according to AMNOG procedure

Erenumab is approved for the prevention of migraine in adults with at least four migraine days per month.

The cost-effectiveness must also be considered when prescribing the medication. The drug costs approximately €495 per month (as of March 2021) and is significantly more expensive than existing preventative medications. Its cost-effectiveness is assessed through the AMNOG procedure.

AMNOG stands for "Pharmaceutical Market Reorganization Act" and aims to regulate the prices of innovative medicines in Germany. Since January 2011, this procedure has regulated the prices of new, patented drugs. The basis for this is the assessment of added benefit. This means that health insurance companies only pay the price that corresponds to the determined additional benefit of the drug. The goal is to strike a balance between innovation and affordability.

The AMNOG procedure for assessing the cost-effectiveness of a new therapy does not affect the marketing authorization status of a drug as stated in the product information. However, due to the principle of cost-effectiveness according to Section 12 of the German Social Code, Book V (SGB V), a prescription based on a decision by the Federal Joint Committee (G-BA) should only be issued if no more cost-effective alternative is available. This applies as long as no additional benefit has been demonstrated for erenumab compared to standard prophylactic medications that would justify the significantly higher treatment costs.

Due to the G-BA decision, despite broad approval, erenumab can only be prescribed at the expense of statutory health insurance under the following conditions:

Conditions for prescribing CGRP monoclonal antibodies for migraine prevention at the expense of statutory health insurance

1. Age ≥ 18 years
2. Migraine frequency ≥ four days per month
3. Treatment is initiated by doctors experienced in diagnosing and treating migraines.
4. Ineffectiveness, intolerance of metoprolol or propranolol, amitriptyline, topiramate, flunarizine and valproate, as well as onabotulinumtoxin, in cases of chronic migraine, or the substances are contraindicated for the patient

The fourth condition represents a significant restriction, which is economically justified. In return, the AMNOG procedure introduced the status of a nationwide practice exception for erenumab. If the aforementioned four conditions are met, the prescribing physician's drug guarantee volume will be adjusted by the cost of erenumab starting December 15, 2019. This will be done either as an advance deduction or retroactively, depending on the regional association of statutory health insurance physicians.

The onset of action of erenumab is usually evident within the first four weeks, but at least within three months. If there is still no response to treatment after three months, a subsequent prescription is no longer covered by the practice's special circumstances and the treatment should be discontinued. It is therefore the prescribing physician's responsibility to carefully and continuously document the patient's response quantitatively.

The AMNOG procedure does not define when a response to therapy can be assumed. A more objective approach, analogous to the efficacy parameters in the registration studies, would be to use the 50% responder rate. A response would then be considered individually documented if at least a halving of the number of migraine days per month is achieved.

In addition, the AMNOG procedure stipulated that, unlike what is prescribed in the product information, not only the initiation but also the monitoring of treatment with erenumab should be carried out by physicians who have experience in the diagnosis and treatment of migraine.

The prescribing information lists the following adverse reactions recorded in the studies: injection site reactions (5.6% with 70 mg erenumab and 4.5% with 140 mg erenumab), constipation (1.3% and 3.2%, respectively), muscle spasms (0.7% and 2.0%, respectively), and pruritus (1.0% and 1.8%, respectively). Most of these adverse reactions were of mild or moderate severity. Less than 2% of patients in the studies discontinued participation due to adverse events. The tolerability of erenumab in the patient population studied can therefore be described as very good.

According to the prescribing information (as of August 2018), the only contraindication is hypersensitivity to the active ingredient erenumab or any of the other ingredients. However, the section "Special warnings and precautions for use" states that patients with certain severe cardiovascular diseases were excluded from participation in the clinical trials. No safety data are available for these patients. At present, erenumab should be used with increased caution in patients with cardiovascular disease.

Due to the biological effects of CGRP, the use of monoclonal antibodies for migraine prophylaxis is not recommended under the following conditions:

• pregnancy
• breastfeeding
• Insufficient/missing contraception
• coronary heart disease
• stroke
• Brain hemorrhage
• peripheral arterial occlusive disease
• inflammatory bowel diseases
• COPD
• pulmonary hypertension
• M. Raynaud
• Wound healing disorders
• Transplant recipients

As a general rule, since the available studies have so far only included patients without relevant pre-existing conditions, a cautious approach should be taken with patients with chronic comorbidities.

dosage

Erenumab is currently available in Germany as an autoinjector in 70 mg and 140 mg doses. The price of both dosages is identical. Studies directly comparing the 70 mg and 140 mg doses showed no significant difference in efficacy. Only the frequency of the side effect constipation increased with the higher dose. However, the LIBERTY study tested only the 140 mg dose against placebo in patients with episodic migraine and multiple treatment failures with standard prophylactic medications. The prescribing information also indicates that patients in the study with chronic migraine who had already discontinued two or three prior therapies would have benefited more frequently from the 140 mg dose. Therefore, while the recommended dose according to the prescribing information is 70 mg erenumab every four weeks, some patients may benefit from a dose of 140 mg every four weeks. If the effect is insufficient and the tolerability is adequate, increasing the dose to 140 mg can be discussed.

Duration of treatment

According to the product information, discontinuation of treatment with erenumab should be considered after three months if no sufficient response has been observed by then.

In the majority of patients who responded to the therapy, clinical benefit was observed within three months. Maintaining a digital headache record has proven advantageous for assessing response. For clinical care, the migraine app for iOS or Android, which provides direct documentation of the course of the condition, has proven effective.

The goal of the treatment

The prescribing information does not provide an operational definition of the target parameter "response." It is also unclear when a potential dose increase from 70 to 140 mg should be considered. In the studies, a 50% reduction in monthly migraine days was chosen as a measure of efficacy. This target is also suitable for clinical practice in the treatment of episodic migraine. However, in cases of chronic migraine with otherwise treatment-resistant courses, a 30% reduction in monthly migraine days should be considered a clinically relevant response. For a patient, however, even a decrease in migraine pain intensity represents a significant improvement. If the frequency of migraines does not decrease significantly, but the use of analgesics and/or triptans decreases by 50% in episodic migraine or 30% in chronic migraine, then from a clinical perspective, a response to treatment can be assumed.

Onset of effect

A key difference between erenumab and standard oral prophylaxis medications is its rapid onset of action. Study data show a significant effect after just one month. Conversely, no further significant improvement occurs after the first two months; the achieved effect remains stable. Treatment should not be continued for more than three months in total if the stated efficacy goals are not met. This would then mean a maximum duration of erenumab use of three months in case of ineffectiveness.

Review of the necessity for long-term treatment

The prescribing information continues to recommend regularly assessing whether treatment should be continued, even after the first three months. This means that sustained efficacy, which is the sole justification for continuing treatment, must also be documented. The easiest way to do this is with the migraine app, which aggregates efficacy data over time and provides it objectively. In the erenumab studies, patients were offered continued treatment with erenumab in open-label extension phases following the double-blind study phases. The long-term data obtained over the past five years demonstrate the continued good efficacy and tolerability of erenumab. Unfortunately, however, data on the spontaneous course of migraine after discontinuation of erenumab were not collected. Therefore, it is currently unclear how long successful treatment with erenumab should be continued.

The product information does not specify a time limit for effective therapy with a monoclonal antibody for migraine prophylaxis. The same applies to the regulations regarding nationwide practice variations. According to these regulations, therapy should only be discontinued after a maximum of three months if sufficient response is not documented.

In contrast, the addendum to the guideline of the German Society for Neurology explicitly suggests: If the therapy is effective, a discontinuation attempt should be made after six to nine months to check whether the therapy is still necessary.

This goes even beyond the general recommendation for the use of migraine prophylaxis, which states that successful migraine prophylaxis should be reviewed for its continued necessity after six to twelve months by reducing the dose or discontinuing the medication. The rationale given is that in antibody studies, where efficacy was monitored after discontinuation of treatment, although a relapse occurred after five to twenty weeks, baseline values ​​were not yet reached.

According to the prescribing information/practice guidelines, interrupting effective treatment with a monoclonal antibody for migraine prophylaxis after a certain period is not formally mandatory, but merely a guideline suggestion. In addition to general economic considerations, there are also medical reasons for interrupting treatment. Beyond the question of why a potentially unnecessary treatment should be continued, it is also legitimate to ask why a potentially unnecessary treatment should be continued when its long-term health consequences are not yet foreseeable. If migraine symptoms worsen after discontinuation and a break from medication, treatment can easily be resumed. However, whether and when to attempt discontinuation – after six, nine, or twelve months – remains at the discretion of the prescribing physician at this time.

Erenumab: Practical Application

According to the product information, treatment should be initiated by physicians experienced in the diagnosis and treatment of migraines. Regular monitoring of the progress of treatment is essential (see above) to determine whether to continue treatment. The use of a migraine app is recommended for this purpose. Among other things, the app helps users adhere to individual rules for managing their headaches, avoid complications such as medication overuse headache, and provides information on non-pharmacological treatment options such as progressive muscle relaxation.

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. In contrast to their baseline condition, 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 about 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: pain relievers 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 intervals of four weeks (i.e., 28 days) 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 protein-degrading 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. Therefore, adequate contraception should be used.

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.

A slow dose increase due to potential intolerances and side effects is not necessary. If a response is observed, the onset of action can be expected quickly, initially within a few days. Side effects of previous migraine preventative medications, such as weight gain, mood changes, fatigue, reduced energy, or drowsiness, are not expected. However, the data currently available 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.

Fremanezumab

The monoclonal antibody against CGRP, Fremanezumab (Ajovy®), was also recommended for approval by the EMA's Committee for Medicinal Products for Human Use on 31 January 2019 and was approved by the European Commission in April 2019.

Ajovy® differs from Aimovig® and Emgality®, among other things, in its application interval: In addition to monthly applications, a quarterly application is also available.

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 periods of 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 four and week eight. The primary endpoint was the reduction in the average number of headache days per month. A headache day was defined as at least four hours of symptoms per day or the use of migraine-specific acute medication during the day.

• The most significant reduction was observed in the group receiving monthly doses. In this group, patients experienced an average of 4.6 fewer migraine days per month. 41% of patients achieved a halving of headache days per month with this dosage method.
• When fremanezumab was administered every three 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 in headache days per month of only 2.5 days. 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.

Fremanezumab is the only antibody currently available for which significant efficacy has been demonstrated even with quarterly administration of 675 mg in triple monthly doses of 225 mg each

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 separate monthly doses of 225 mg each. 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 adverse effect was injection site pain. This did not differ significantly between the group treated with fremanezumab and the placebo.

When using this method for migraine prevention, some fundamental aspects must be considered:

• Monoclonal antibodies are 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 antibody must be administered as an injection under the skin using an autoinjector.
• The monoclonal antibody has 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 drug, long-term effects with prolonged use cannot yet be reliably assessed.
• Immunotherapy for the preventive treatment of migraine is not a "final cure" for migraine. Only about 30% of patients who have not responded adequately to previous preventive treatments can expect a reduction in migraine attacks of 50% or more. This effect is unlikely in 70% of treated patients. Even among the majority of patients who achieve this level of effectiveness, migraine attacks will still occur, requiring treatment with acute medications.

Galcanezumab

Following erenumab (Aimovig®) on November 1, 2018, the monoclonal antibody galcanezumab (Emgality®) became available in Germany for migraine prophylaxis on April 1, 2019. Galcanezumab has been approved in the EU since November 2018. It is approved for the prevention of migraine in adults who experience migraine attacks on at least four days per month.

Galcanezumab is a humanized monoclonal antibody. Unlike erenumab, galcanezumab and fremanezumab do not work indirectly by inhibiting the CGRP receptor. They neutralize the messenger substance CGRP directly.

At the start of treatment, a so-called loading dose of 240 mg is administered. This is followed by further injections of 120 mg every month.

Similar to erenumab, galcanezumab is self-administered by patients via subcutaneous injection using an autoinjector. An initial loading dose of 240 mg is administered, followed by subsequent injections of 120 mg every month.

Galcanezumab was investigated in three large phase 3 trials: Evolve 1, Evolve 2 and Regain.

The main finding of the Evolve 1 study with 858 patients was that 62.3% of patients were able to halve their monthly headache days by at least 50%. This effect was achieved in 38.6% of patients receiving a placebo.

In the Evolve 2 trial, which included 915 patients, 59.3% of those treated with galcanezumab experienced a halving of their monthly headache days. Placebo resulted in a halving of headache days per month in 36% of patients. On average, patients receiving 120 mg of galcanezumab experienced 4.3 fewer migraine days per month, while those receiving placebo saw a reduction of 2.3 fewer days per month. Baseline migraine days per month were 9.1 in the galcanezumab group and 9.2 in the placebo group.

The Regain study examined patients with chronic migraine. Galcanezumab reduced the number of monthly headache days by 4.8 days, from a baseline of 19.4 days. Placebo treatment resulted in a reduction of 2.7 headache days per month, from a baseline of 19.6 days.

The tolerability of galcanezumab was similar to that of placebo.

Emgality® is supplied as a pre-filled pen. The pack sizes contain either two or three autoinjectors. Patients can use this autoinjector to self-administer the medication subcutaneously. The medication can be administered subcutaneously on the abdomen, thigh, upper arm, or buttocks.

The AMNOG procedure, which is important for clinical use, for the monoclonal antibodies galcanezumab (Emgality®) and fremanezumab (Ajovy®) approved during 2019, had not yet been completed at the time of writing.

Based on the positive benefit assessment, a nationwide practice exception was also agreed upon for Emgality®. This nationwide practice exception applies from April 1, 2020, but only to the patient group for whom the considerable additional benefit was determined.

On September 19, 2019, the G-BA (Federal Joint Committee) determined that Emgality® offers considerable additional benefit. This applies to patients who do not respond to, are unsuitable for, or cannot tolerate any of the following therapies or drug classes: metoprolol/propranolol, flunarizine, topiramate, amitriptyline, valproic acid, and Clostridium botulinum toxin type A (for chronic migraine).

CGRP monoclonal antibodies: possibilities and limitations

What is the added benefit compared to existing therapies?

Whether a new medication is better than existing ones is determined by comparing its efficacy, tolerability, and safety. Studies comparing the efficacy of migraine prophylaxis medications typically use the reduction in migraine days per month. However, comparing the average reduction of various active ingredients with a placebo reveals a reduction of only one to four days per month. This may sound discouraging at first – especially for patients with 15 or more migraine days per month. These are average values, however, used solely to examine the statistical superiority of a substance over a placebo. The calculation includes both patients who respond very well to the treatment and those for whom it has no effect at all. Studies on the efficacy of CGRP antibodies now show similar effectiveness to existing medications approved for migraine prevention. The reduction in migraine days per month is approximately one to three. On average, CGRP antibodies do not show any greater efficacy than the currently approved medications. Therefore, there is no proven additional benefit in terms of efficacy for patients who already respond to existing prophylactic treatments. This has also been confirmed by the Federal Joint Committee (G-BA). However, the situation is different if patients do not respond to existing medications, cannot tolerate them, or if contraindications exist. This means, for example, that the medications cannot be taken due to other illnesses.

How do CGRP antibodies work in these patients?

In this situation, CGRP antibodies can be effective in about one-third of patients. Accordingly, the G-BA (Federal Joint Committee) has determined a considerable added benefit for CGRP antibodies in adult patients with at least four migraine days per month for whom standard prophylactic medications were ineffective, not tolerated, or contraindicated. CGRP antibodies also have other advantages: Slow dose titration is not required. This allows for a rapid effect – which is important for many patients and promotes treatment adherence.

Which patients in this group, for whom the previous medications have not helped, respond to the new antibodies?

It is impossible to predict which patients will respond to treatment, especially those for whom standard prophylactic medications were previously ineffective, intolerable, or contraindicated. Each of these patients has approximately a 30% chance of experiencing a reduction in migraine days. However, this also means that the antibodies will not be effective in around 70% of patients. Therefore, close monitoring of treatment success is essential. If no significant effect is observed after three months, the therapy should be discontinued. Digital healthcare applications, such as the migraine app, can also be used to monitor treatment progress.

Is it worthwhile to switch between CGRP antibodies if the first one has not shown any effectiveness?

To date, no controlled studies have demonstrated that switching to a different antibody can be successful if another antibody has proven ineffective. The three antibodies show virtually no significant difference in their efficacy compared to placebos; direct comparisons are still lacking.

How is the tolerability in everyday clinical practice?

Common side effects include hypersensitivity reactions such as rash, swelling and edema at the injection site, itching, or muscle cramps. In contrast, side effects such as weight gain, mood changes, fatigue, cognitive deficits, or dizziness do not usually occur with the use of CGRP antibodies. Based on current knowledge, they are well tolerated.

Can patients completely get rid of migraines with the new medications?

Many patients hope that a specific treatment will end their migraines once and for all, allowing them to live as they wish. However, this is an illusion – as the figures I have described demonstrate. The treatments help to reduce some attacks. The antibodies can, at best, have an effect on the mechanisms that trigger a migraine. For those affected, it is essential to adapt their lives to their increased risk of migraine attacks. Therefore, even when using antibodies, comprehensive knowledge of the condition and specific preventative measures through a modified lifestyle are crucial.

Do CGRP antibodies also work for other types of headaches?

In the EU, CGRP antibodies are currently only approved for the preventive treatment of migraine. The antibody galcanezumab has also been shown to be effective in preventing episodic cluster headaches – it is already approved for this use in the US. The European Medicines Agency (EMA) has not indicated that it will grant approval for this indication. There is no approval for use in medication-overuse headache. Therefore, before using antibodies, this type of headache should be treated with a medication break.

Can CGRP antibodies also be used in children?

To date, no controlled study data are available for children and adolescents. Such studies are currently underway. It remains to be seen whether antibodies will also be effective for these young patients.

How long do patients have to use CGRP antibodies? For life, or can they be stopped at some point?

There are various target parameters for successful therapy, which are specified in the DGN (German Society for Neurology) guideline. According to this guideline, therapy is considered successful if the average number of monthly headache days is reduced by at least 50 percent compared to the previous treatment over a period of at least three months, or if there is a significant improvement in headache symptoms. If a patient achieves these efficacy parameters, they can attempt to discontinue the therapy after approximately nine to twelve months to determine whether it is still necessary. This approach is suggested in the DGN guidelines. However, it is not mandated by the product information, the G-BA (Federal Joint Committee) resolution, or the regulations governing nationwide practice.