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The renowned European neurologist residing in Denmark, Mesud Ashina, is an active member of the Azerbaijani diaspora. As the President of the International Headache Society and a professor of neurology at the University of Copenhagen, Mesud Ashina has been awarded the medal of the Republic of Azerbaijan "For Merit in Diaspora Activities." By a decree from the head of state on December 8, 2020, Mesud Ashina was elected to the Board of Trustees of the "Yaşat" Foundation.

On the initiative of the State Committee on Work with the Diaspora and the "Yaşat" Foundation, this European neurologist provides free neurological care to veterans who fought for territorial integrity and to the families of martyrs, while also actively participating in a number of other projects. Today, the prestigious medical journal New England Journal of Medicine published an article on a new method for treating migraines. This event is significant not only due to the development of a new drug for a condition long considered incurable, but also because the author of the article and head of the study is our compatriot, Danish-Azerbaijani neurologist Professor Mesud Ashina, one of the world’s leading specialists in this field.

Currently, Professor Ashina holds the position of professor of neurology at the University of Copenhagen and senior consultant in neurology at Copenhagen University Hospital – Rigshospitalet. As of 2024, he is recognized as one of the world’s foremost experts on headache disorders, according to the Expertscape ranking. Mesud Ashina received his medical degree from Azerbaijan Medical University in 1988. He later completed his PhD and D.M.Sc. at the University of Copenhagen and completed his neurology residency at Rigshospitalet.

We interviewed Professor Ashina to discuss his discovery, research, and the future prospects for migraine treatment.

Professor, could you elaborate on migraines? They are often perceived as just severe headaches, but in reality, they are a far more serious condition. Could you dispel some myths, especially regarding the idea that they are incurable?

Migraine is not simply a severe headache, as many believe. It is one of the most common and underestimated conditions, affecting around one billion people worldwide, or roughly one in seven. Migraine is a chronic neurological disorder that, besides headache, includes symptoms such as nausea, vomiting, photophobia, and phonophobia. Attacks can last for several days, and any movement or sound can intensify the pain to an unbearable level.

It’s important to note that about 20% of those suffering from migraines experience attacks at least twice a week. This means that nearly 200 million people live with this condition regularly, losing dozens of days each year to debilitating attacks.

Migraine significantly reduces work capacity and social activity. In terms of "years lived with disability," it ranks as the leading neurological disorder. It is a serious chronic condition that requires a thorough approach to treatment.

Professor, how has the science of migraine evolved, and how do modern medications influence its treatment? What new challenges do patients and doctors face in managing this condition?

Migraine has a unique neurobiology that dictates its course. Over the past 30 years, science has made significant strides in treating it. In the early 1990s, drugs specifically designed to stop migraine attacks were introduced. These medications target migraines only, without affecting other types of pain, which was an important breakthrough.

However, a new problem emerged: frequent use of these medications can lead to a paradoxical headache. This condition is called "medication-overuse headache" — a headache caused by the overuse of medications. Therefore, these drugs are effective for people with infrequent attacks, but when migraines are frequent, improper use can worsen the condition.

Given recent advances in drug development, can we say that migraines can now be effectively prevented? What preventive methods are most effective today, and are they suitable for all patients?

Yes, migraine prevention has become possible, though in the past it wasn’t specific. Medications developed for other conditions, such as hypertension and epilepsy, were used to reduce the frequency of attacks, but they often had side effects and weren’t always effective.

With the advent of new drugs targeting the CGRP molecule, migraine prevention has become more precise. These drugs can reduce the number of migraine days for 40% of patients, cutting the frequency of attacks by 50% or more. However, they do not produce significant improvement for everyone, indicating that further development is needed to help a wider range of patients.

Thus, despite progress, migraine prevention is not effective for all, and new solutions need to be developed.

Could you please tell us about your own research on migraines? What is the focus of your work, and what prospects does it open for understanding the mechanisms of this condition?

My group has been researching migraines since 2006, focusing on molecules that play a key role in its development. We aim to identify molecules involved in triggering attacks to deepen our understanding of migraine mechanisms. Our research is conducted directly on people and examines molecules acting on nerves around the brain’s blood vessels, as well as on nerves responsible for pain conduction.

My hypothesis is that certain molecules can provoke migraine attacks in patients. This research could help develop new therapeutic approaches that block these processes, improving the quality of migraine treatment.

You mentioned that in your research, you induce migraine attacks in patients. Could you explain how this works and how this method is unique compared to other studies on neurological disorders?

Yes, the ability to induce migraine attacks in controlled conditions is a crucial part of our research. Migraine differs from other neurological disorders in that its attacks are episodic—they come and go. This allows us to study migraine in its active phase, which is not possible with chronic conditions like Parkinson's disease or dementia, where symptoms are always present.

The uniqueness of my approach lies in inducing migraine attacks in patients to observe their development and study the biological mechanisms in real time. It’s similar to a situation where a person knows that wine might trigger a migraine but decides to drink it anyway. Patients in our studies understand the possibility of an attack, but they also know they are under medical supervision and will receive help if necessary.

We use certain molecules to provoke migraine attacks. In people without migraines, these molecules may cause only a mild, short-term headache, but in those who suffer from migraines, they trigger a full-blown attack. This allows us to better understand how migraines develop at the molecular level and aids in the development of new targeted treatments.

Thus, our method offers a unique opportunity to study migraines in the active phase, opening new avenues for effective therapeutic solutions.

Could you explain the role of molecules in the development of migraines, and how your experiments have advanced understanding of their impact on the disease's pathogenesis?

One of the key molecules involved in the development of migraines is PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide). This molecule is present in structures associated with migraines, such as the perivascular nerves that innervate brain vessels and regulate their response to stimuli. During the activation of these nerves, mediators like PACAP are released, which can trigger migraine attacks.

In 2009, my lab conducted a study in which PACAP was administered intravenously to patients over a 20-minute period. The study included two sessions: one with PACAP and the other with a placebo. In more than 50% of patients, PACAP induced migraine attacks, confirming its significance in the pathogenesis of the disorder.

These findings led to the hypothesis that blocking PACAP or its receptors could become a new method of treating migraines. This study laid the groundwork for further developments in targeted therapy, aimed at blocking molecules involved in the onset of migraines, and opened up the possibility of creating more effective and precise medications.

*How do the approaches to migraine treatment using small molecules differ from those using monoclonal antibodies? What are the advantages and disadvantages of each method, and how do they influence the choice of treatment strategy?*

Small molecules and monoclonal antibodies have different approaches to treating migraines. Small molecules, such as receptor antagonists, block the receptors responsible for migraine development, providing a short-term effect (6-12 hours). They are convenient to take, as they are available in tablet form. The downside is that they need to be taken frequently.

Monoclonal antibodies block the same receptors but provide a longer-lasting effect, which can last for weeks or months. However, they require injections, as they are broken down in the gastrointestinal tract when taken orally.

The choice between small molecules and antibodies depends on the need for quick symptom relief or long-term prevention, as well as patient preferences and the ease of administration.

Could you tell us about new approaches to treating migraines with antibodies, and how your collaboration with Lundbeck contributes to the development of these methods? What stages of research have been proposed to test their effectiveness?

New approaches to treating migraines include the development of antibodies against molecules like PACAP. One of these methods involves creating monoclonal antibodies that block PACAP itself, preventing it from interacting with receptors and thus neutralizing its effect. This approach is different from traditional ones as it works at an earlier stage of the pathological process, eliminating the action of the molecule that triggers the migraine.

Lundbeck developed an antibody targeting PACAP and approached me for collaboration, knowing about my research and interest in this hypothesis. Together, we proposed conducting a study to evaluate the effectiveness of this antibody in patients with migraines. This approach to treatment could represent a significant breakthrough, as it allows for direct targeting of a key molecule involved in migraine pathogenesis.

I suggested conducting additional studies on healthy individuals before moving on to clinical trials with migraine patients. Studies on healthy volunteers (Phase 1) help to test the drug’s tolerance, identify side effects, and determine the optimal dose. My idea was to test the blocking effect of the antibody by administering PACAP intravenously to volunteers and simultaneously assessing the antibody's ability to prevent the physiological reactions caused by PACAP. This study will help better understand the effectiveness of the new method and pave the way for the next phase of clinical trials in migraine patients.

What physiological reactions were you expecting to see?

We expected reactions such as vasodilation, facial flushing, a drop in blood pressure, and an increased heart rate—typical effects of PACAP. If the drug could block these reactions in healthy individuals, it would increase the likelihood of its effectiveness against migraines.

The study showed that the antibody against PACAP successfully inhibited vasodilation, reduced heart rate, and diminished headaches. This confirmed the potential of the antibody as a treatment for migraines and other PACAP-related disorders. After this, I led Phase 2 trials, sponsored by Lundbeck, to study the preventive effect of the PACAP antibody in migraines.

How was the study with migraine patients organized, and what stages did it include?

The study included patients with both episodic and chronic migraines. We organized a multicenter study, where different centers and researchers were responsible for recruiting participants.

First, there was a screening to ensure that patients truly had migraines. After that, they were given electronic diaries to record all attacks and symptoms. This baseline phase helped confirm the patient’s suitability for the study and checked their readiness to follow the instructions.

Then, patients were blindly randomized—they didn’t know whether they would receive the active drug or a placebo. Over the next period, they continued to keep diaries so we could assess the drug's effectiveness. After the treatment ended, a follow-up period began to record any potential side effects. This is important for evaluating the drug’s safety not only during treatment but also after it is metabolized.

In the end, we compared data from before and after treatment to assess its impact on the frequency and intensity of migraines.

What was the main goal of the study, and what results did it show?

The main goal of the study was to test the efficacy of high doses of the drug (750 mg) compared to a placebo. The study showed significant improvement in patients who received 750 mg of the drug, confirming its effectiveness in preventing migraine attacks. This result validated the concept and paved the way for the next stage—Phase 3 clinical trials.

Phase 3 will include more patients and last longer to provide a final check of the drug’s efficacy and safety. If the results are positive, the drug will become available on the market, offering a new tool for migraine prevention.

The significance of the study is that over 15 years, it has progressed from examining the effect of a single molecule on migraines to the development of a potential new drug. The drug is still administered intravenously, but work is underway to create a form for self-injection under the skin, which will greatly simplify treatment for patients.

How does this new drug differ from the recently registered drug that targets another molecule?

The difference between the new drug and the recently registered one is that they target different molecules and work through different mechanisms. Imagine that each drug acts on the "doors" of a cell, but each door leads to different parts of the system, activating different processes. These drugs use different receptors to prevent migraines.

This broadens the treatment options, allowing us to choose a drug based on the individual needs of the patient. In the future, combination therapy may reduce the number of migraine days even further if one drug proves insufficiently effective.

It’s also important to understand which receptor is the key player in the pathway through which PACAP triggers migraines. This will aid in the development of new, more precise drugs. We continue to explore these mechanisms to offer more effective and specific migraine treatments in the future. At the moment, this drug is not available for clinical use, as it is still in the research stage.

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