Migraine: New Therapy, False Promises?

16. January 2018

Neurologists have developed antibodies for migraine treatment. These antibodies are intended for use primarily as prophylaxes. Although studies prove their effectiveness, whether they are more suitable than existing medications is nonetheless controversial.

An estimated eight million people in Germany have to endure migraine. Behind this number one finds not only a lot of suffering, but also a huge market – something which arouses the desires of research-based manufacturers. In recent times, little has happened. The guidelines mention in particular nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans for use in acute therapy. The beta blockers propranolol and metoprolol, the calcium channel antagonist flunarizine as well as the anticonvulsants valproic acid and topiramate are the highest ranked prophylactic substances. Now however scientists are reporting new options using monoclonal antibodies. If everything goes according to plan, we will see several approvals in the coming months.

New target structure CGRP

Scientists are through their new active agents targeting calcitonin gene related peptides (CGRP). The neuropeptide together with its receptor is to be found in central and peripheral nerve cells. During a migraine attack, CGRP is released from fibres of the trigeminal nerve. CGRP is one of the strongest blood vessel relaxants in the body, which explains its effect on migraine. Following binding to receptors, the enzyme adenylate cyclase gets activated and smooth muscle relaxes. At the same time the release of nitric oxide (NO) from the endothelium occurs. Both factors dilate the blood vessels in the brain. According to the vascular hypothesis, stretch receptors on dilated blood vessels of the head produce signals that our cerebral cortex interprets as pain.

For researchers, this opens up two conceivable strategies. New pharmaceutical agents might block the binding sites by functioning as CGRP receptor antagonists. Another option is to capture the CGRP protein. The newly developed substances are aimed for use in acute therapy as well as for use as a migraine prophylaxis.

Turning off the receptor

Migräne-01

Telcagepant © Wikipedia, CC0

A new drug class carrying the name ending “-gepant” has emerged in the pharmaceutical world. Telcagepant, a small, organic molecule produced by Merck & Co, at first proved to be an interesting candidate.

Sooner or later, however, questions would always have arisen about the added value of comparison therapies: telcagepant showed the same efficacy as rizatriptan and zolmitriptan in two phase III clinical trials treating acute migraine. This can be placed together with data derived from a migraine prevention clinical trial. Under verum, patients had 1.4 fewer migraine days per month than under placebo. However, in 2.5 percent of all study participants alanine transaminase levels climbed. Elevated levels indicate liver damage. Shortly thereafter, the pharmaceutical manufacturer withdrew from the research project.

Following this course of events there is still some hope for the “gepants”. The pharmaceutical company Allergan is currently recruiting patients for a phase III trial of ubrogepant. Data from a phase IIb study is already available. It not only provides proof about safety and effectiveness for its use in acute therapy, but also give clues about the possible dosage of ubrogepant.

Catch the protein

The strategy of using monoclonal antibodies to attack CGRP or its receptor reached the goal much faster. At present four researching manufacturers have human-based monoclonal antibodies in the pipeline. All carry the typical name ending “-mab” which stands for “monoclonal antibody”.

In the case of fremanezumab and erenumab there are sets of data from manufacturer-funded phase III studies suggesting approval could happen soon. Stephen D. Silberstein of the Jefferson Headache Center has studied fremanezumab. Both the treatment and the prevention of chronic migraine are the focus of treatment. Those affected by this condition suffer from headaches of various kinds for at least 15 days per month. By definition migraines occur on at least eight of these days. For his study, Silberstein randomised 1,130 patients into three study arms. 376 of them received fremanezumab in a single dose, followed by placebo. Another 379 people got fremanezumab every month, and 375 only received placebo. The study ran for three months. Initially, patients reported having 13.2, 12.8, and 13.3 headache days per month, respectively. In the three groups, this measure decreased by 4.3 versus 4.6 versus 2.5 days. The number of migraine days in the observation period were cut back by 38 to 41 percent (placebo: 18 percent).

Episodic migraine was the focus of a phase III study done by dr. Peter J. Goadsby. Researcher at King’s College Hospital, London. Patients suffer from typical headache in phases and have no symptoms for months afterwards. On average, this occurs on fewer than 15 days per month. Goadsby randomised 955 patients. 317 received 70 mg erenumab monthly, another 319 received 140 mg monthly and 319 placebo only. The average number of migraine days per month was 8.3 at the beginning. It decreased by 3.2 versus 3.7 versus 1.8 days. One in two participants halved their number of migraine days per month (placebo: 26.6 per cent). In both studies there were often mild reactions at the injection site. Thus, effectiveness and safety are beyond question. Yet do antibodies really provide added value?

More expensive, but also better?

Andrew D. Hershey from the University of Cincinnati College of Medicine explores the matter in more depth in an editorial. He assesses therapies that are based on a specific mechanism of action as “important progress”. For the first time, a known, well-characterised target structure is the focus of attention. At the same time, Hershey points to a lack of long-term data and to the question of which patients actually benefit.

A significant, but minor benefit is countered by expected high costs. Employing a methodically correct manner, Silberstein, Goadsby and colleagues compare their molecules with placebo. But how strong is the effect? Should the new drugs be competing not with placebo but rather with already approved first-line therapies?

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