AUTHOR COMMENTARIES - 2008 - From Special Topics

Dr. Olesen is a professor at the University of Copenhagen as well as the chief of the Danish Headache Center, headquartered in the Department of Neurology at Glostrup University Hospital in Copenhagen. He is also a member (and past president) of the International Headache Society, the European Federation of Neurological Sciences, and the European Brain Council, as well as a fellow of the Royal College of Physicians.

In the interview below, Dr. Olesen talks with ScienceWatch.com correspondent Gary Taubes about his migraine research.

What prompted the line of research on calcitonin gene-related peptide that led to your highly cited 2004 New England Journal of Medicine article (Olesen J, et al., "Calcitonin gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine," 350[11]: 1104-10, 11 March 2004)?

We had done a lot of work on a particular signaling molecule, called CGRP, which stands for calcitonin gene-related peptide. It’s found in nerves that surround the brain blood vessels—the arteries of the brain—and it is a very strong opener of the arteries; it widens the arteries in the brain. We had shown that when you actually give this substance to migraine patients, you can induce a migraine attack. That work was published in the late 1990s, originally in Cephalalgia. That result suggested that CGRP plays a very important role in migraine, and if we could somehow block the effect of that molecule, we might have a new kind of treatment for the disorder.

This particular New England Journal of Medicine article was reporting on a clinical trial studying a compound that had been developed by Bohringer Ingleheim in Germany. The compound proved to work and so was a proof of principle: here was a potentially whole new class of drugs that could now be developed, because blocking this particular receptor works in migraine. After the trial, Merck developed a better compound that is now in phase III trials.

Can you quantify for us how well the Bohringer Ingleheim compound did in the trial?

This was a phase II study, a proof-of-concept study, which means we had relatively small numbers. So we were able to say it works, that it looks pretty good, but we couldn’t say, for instance, how it worked compared with other treatments. Roughly, it looked about the same as the common drugs for migraines, called triptans. There are a lot of additional issues that have to be worked out in further trials. This particular compound was never going to go anywhere because you have to give it by intravenous injection. That’s unsuitable for a drug but suitable for a trial to prove the principle. The Merck compound can be given orally, as a tablet, and so that’s what we’re now studying.

What have you been working on since that 2004 paper?

Our main focus is on repeating the success we had with CGRP. That means looking at other messenger or signaling molecules, seeing whether they can induce a headache in normal volunteers and a migraine in migraine sufferers, and then finding out whether these compounds work in animal experiments, with the hope of generating more targets for migraine drugs.

Have you found any?

Yes. We have found some, and they are going to be published. I think this is the way to find new drugs for migraine.

Is that the exclusive focus of your lab at the moment?

There’s one other molecule we’ve been working on, which we haven’t discussed—nitric oxide. It can also induce a migraine attack. If you inhibit the production of this molecule in the human body you have a treatment for migraine attacks. We showed that quite a few years ago and since then we’ve been studying how this molecule can possibly be involved in migraine.

Do you know what it does to bring on the migraine?

That’s not completely clear, which means the explanation is a complicated one. What nitric oxide certainly does is open up blood vessels, the arteries of the brain. It may also have some interaction with CGRP. These two seem to be interrelated in a number of ways. It’s also involved in central pain mechanisms—in our sensitivity to pain, how we perceive pain.

The papers you list as significant on your website have very little overlap with ESI’s assessment of your most-cited papers. You seem more concerned with genetic determinants of migraine types. Why is that?

We have done a lot in genetics, but we’ve not had a great success finding new genes. That’s a common phenomenon in this field. Genetic research on migraines seems to be on the down slope. People were enthusiastic about genetics a number of years ago but now it doesn’t look like it’s going to tell us much about migraine or headache, apparently because these are very complex disorders.

What’s the most difficult or challenging aspect of migraine research?

The most challenging aspect of this work is that we don’t have any clear biological markers. We cannot take a blood test and make a migraine diagnosis from it, or score the severity of the migraine, and so on. Migraine is a subjective phenomenon and that makes it extremely difficult to study.

What do you see the next five years bringing in migraine research and therapy?

Much more knowledge about the molecular mechanisms of migraine; several new drug targets and one or two new drugs on the market that work by a totally new mechanism.

If you had an unlimited source of funding—if this were an ideal world—what experiment would you do that you couldn’t do now?

Actually, I would just do a lot more of the research that we are doing right now. I’d also make sure that all our discoveries would be translated into drug development, which is not happening at the moment. Companies don’t seem to appreciate the importance of what we do.

Why not?

Because it’s new. Companies always like to do more of the same.

Is there one message you would give to the lay public about your research?

The final message is that investing both from a public and a private perspective in migraine research is probably one of most profitable and yet under-resourced areas you can find. We have data showing that. We have a recent publication showing that migraine has the poorest resource support of any major brain disorder.

Why do you think that’s the case?

Because there is no biomarker; there are no structural lesions. And it’s mostly a female disorder—80 or 90 percent of the burden of migraine is on women.

Does that funding situation cross national boundaries?

If anything, it’s even worse in the United States than it is in Europe.

Jes Olesen, M.D.
Danish Headache Center
and
University of Copenhagen
Copenhagen, Denmark