Clinical analysis of triptans for the relief of migraine attacks

In May 2021, the US Food and Drug Administration (FDA) approved Aimovig (international nonproprietary name: erenumab), the first fully human antibody for the treatment of migraine. This medicine, developed jointly by the pharmaceutical companies Novartis and Amgen, has a fundamentally different mechanism of action than the drugs traditionally used to treat migraine. Will Aimovig be able to significantly reduce symptoms and improve the quality of life of migraine sufferers? Let's try to figure it out.

Modern medicines

A special project about modern medicines, the history of their creation, development methods and development trends.

The special project partner, Cytiva, was formed as a result of the sale of the GE Healthcare Biopharma division to Danaher Corporation. Cytiva is a global provider of technologies and services that advance and accelerate the development and manufacturing of therapeutics. The company has a rich heritage dating back hundreds of years. Cytiva's clients conduct life-saving activities ranging from basic biological research to the development of innovative vaccines, biologics and novel cell and gene therapies. The company's mission is to provide the tools and services they need to do things better, faster and safer, leading to better outcomes for patients.

The first two articles of our special project “Modern Medicines” were devoted to general issues of how the drug industry developed [1] and how scientists search for new drug targets [2]. This article opens a number of news materials about interesting modern medicines.

How big is the problem?

Migraine, a neurological disease characterized primarily by severe attacks of headache, has been known for more than 3000 years [3]. However, despite the well-studied symptoms and manifestations, the causes of migraine have not yet been fully established. It was previously believed that migraine is caused by changes in cerebral circulation, but many researchers now suggest that this is not the main cause [4].

Current understanding of the pathogenesis of migraine involves the involvement of certain neural pathways and neuropeptides, particularly the trigeminal nerve and CGRP, a calcitonin gene-related peptide. Research has shown that excited nerve cells can activate the trigeminal nerve, leading to the release of CGRP and other neuropeptides. CGRP greatly dilates blood vessels, causing local swelling, and this attracts cells involved in the process of inflammation. With inflammation of the vessels of the skull and dura mater, proinflammatory molecules stimulate pain endings in the meninges, which leads to migraine (Fig. 1) [5–8].

This excitation of nerve cells, which triggers migraine, is associated with heredity and physiology, but today its causes are far from precisely determined [3]. It is only known that this process can be provoked by a variety of factors: from banal stress, fatigue and insufficient sleep to current hormonal levels, depressive states and medication use [9].

Figure 1. Pathogenesis of migraine
What happens during a migraine attack?

At the same time, migraine manifests itself not only as a headache: the symptoms of this serious illness are much more diverse, and often more painful. Debilitating migraine attacks can be painful and unbearable and sometimes last from several hours to several days, accompanied by nausea, vomiting and increased sensitivity to light, sound and smell [3], [10]. Such attacks deprive millions of people around the world of the ability to think, live and work normally. It is believed that every seventh inhabitant of the planet suffers from migraine today, and in the ranking of causes limiting the ability to work, this disease took second place in the world (according to 2021 data) [11], [12].

It is not surprising that migraine was included by the World Health Organization in the list of diseases that most disrupt the social adaptation of patients [3].

Migrepam

The main active ingredient of Migrepam is zolmitriptan. This anti-migraine drug targets exactly the cause of the headache, so it helps to cope with even long-term migraines and severe episodes of headaches. In addition to headaches, Migrepam also relieves symptoms such as fear of light and sensitivity to sounds, nausea and sweating. Improvement occurs approximately an hour after taking the tablet. But not everyone can use this drug due to side effects. Therefore, be sure to consult your doctor before purchasing Migrepam.

Migrepam

Migrepam® effectively relieves headaches and other symptoms of migraine (nausea, photophobia, phonophobia).
Equally effective against migraine with aura, without aura and migraine associated with menstruation. from 166

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Migraine treatment today

Unfortunately, today there is no medicine that can get rid of migraines once and for all. The drugs used can mainly reduce the intensity and number of attacks or reduce symptoms and relieve pain. In this regard, therapy with such drugs is divided into two groups:

• Abortive (acute) therapy - to relieve or reduce symptoms of migraine that has already appeared.
• Preventative treatment – ​​to reduce the intensity, duration or frequency of attacks.

In this article we talk about drug treatment and prevention, but leave behind the scenes a variety of non-pharmacological treatments for migraine: from relaxation techniques to cognitive behavioral psychotherapy and transcranial electrical stimulation. Meanwhile, these methods in some cases can be an effective alternative to medications in case of resistance or contraindications to drug therapy, and sometimes effectively complement it in the combined treatment of migraines [13].

Abortion therapy

In the treatment of mild to moderate migraines, various analgesics and NSAIDs (non-steroidal anti-inflammatory drugs) are prescribed, including the well-known paracetamol, acetylsalicylic acid and ibuprofen, sometimes in combination with caffeine, codeine or psychotropic substances in combination medications [14], [15]. ]. A significant drawback is the possible reverse effect of uncontrolled use of analgesics: worsening headaches, which in such conditions can become daily [8], [15].

When it comes to dealing with more severe and prolonged attacks of migraine pain, the “heavy artillery” comes into play, namely ergot alkaloids and triptans. Triptans were the first drugs created specifically for the treatment of migraine; They began to be developed back in 1972. Even then it was known that the ergot alkaloid ergotamine can reduce migraine attacks, which was associated with its vasoconstrictor effect [16]. This drug remained the only specific treatment for migraine until, in 1991, rational research finally led to the emergence of sumatriptan, the first drug of a new class that acts in a similar way to ergotamine, but is more effective and safe (Fig. 2) [16].

Unlike its famous derivative, LSD, ergotamine itself does not have hallucinogenic properties.

Figure 2. Triptans, medications used to relieve migraines, are selective serotonin receptor agonists. They bind to and activate specific subtypes of these receptors (5HT1B, 5HT1D and 5HT1F). This leads to inhibition of the release of neurotransmitters from the presynaptic membrane of the trigeminal nerve endings (shown in yellow), located in the vessels of the head. At the same time, the release of the already mentioned CGRP, a key neurotransmitter that causes migraines, is also inhibited. This “neural” mechanism of action is believed to block the main pathological link in the development of migraine. It is also known that taking triptans selectively constricts the vessels of the dura mater, reduces the permeability of the vascular wall and reduces edema. Either way, these medications are effective—they reduce inflammation and pain, as well as the intensity of accompanying migraine symptoms [17]. The ergot alkaloids ergotamine and dihydroergotamine act in a similar way, although they are less selective - they can bind to dopamine and adrenergic receptors, which is why their effectiveness and safety are lower.

[18]

However, despite their good efficacy and safety profile, triptans may theoretically be dangerous for patients with coronary artery disease due to their vasoconstrictor effects, which limits their widespread use as therapy for migraine [16].

Preventive therapy

Drug prevention is indicated when migraines are regular (more than 2-3 times a month), and it must be said that today such therapy is not entirely safe and effective: it is associated with significant side effects and the development of rapid tolerance to treatment (tachyphylaxis) [14]. In this case, several classes of drugs are used, originally developed for other indications, and so far with a largely unclear mechanism of action for migraine. These medications include: tricyclic antidepressants, antiepileptic drugs, beta blockers, calcium channel blockers, ACE inhibitors and some others [14], [19].

By the way, you can read about many of the listed drugs, their direct indications, history of appearance and mechanism of action in the first article of our series “Three generations of drugs” [1].

Sumamigren

This drug contains the substance sumatriptan, which has serotin-generating and anti-migraine effects. The headache is relieved quickly because vasoconstriction occurs selectively. Sumatriptan is a truly effective substance that helps quickly get rid of a migraine attack. “Sumamigren” contains only 50 mg of sumatriptan, so during an intense migraine attack you can take two tablets at once. Moreover, the headache will go away in about 15-20 minutes. But Sumamigren has serious contraindications and side effects, so it must be prescribed by a doctor.

Sumamigren

Polfa, Poland

Relief of migraine attacks with or without aura.
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Targeted therapy for migraine: a solution to the problem?

Since migraine is a chronic disease and the effectiveness and safety of the drugs used for prevention is poor, there is clearly an unmet need in this area; however, there are few new drugs specifically developed for this indication [14].

Amgen and Novartis can boast of a breakthrough today, having received approval in May 2021 for the use of the targeted drug Aimovig erenumab antibodies ) for the prevention of migraine in adult patients [20]. This is the first fully human antibody to be commercialized whose preventive effect is due to binding and blocking the CGRP receptor, which is considered critically important in the development of migraine (Fig. 3).

Figure 3. Aimovig specifically binds to the CGRP receptor, preventing CGRP from binding to it. The binding of CGRP to its receptor in a molecular complex (shown on the left) results in the transmission of pain signals associated with migraine. In people with migraine, CGRP levels are elevated during a painful attack and return to normal levels when the migraine pain subsides.

About Aimovig® (erenumab) in migraine prevention

Aimovig was approved after three series of clinical trials, the results of which, although slightly different, were similar in one thing: the drug showed a significant reduction in the number of days with attacks and the total duration of migraine pain. Moreover, in phase III trials, in 50% of patients taking 140 mg of Aimovig, the number of painful days decreased by half compared to placebo, and the safety and tolerability of the drug turned out to be quite similar to placebo [21], [22]. . These results are very encouraging, and it is clear that although Aimovig is not a panacea, its use will definitely change the lives of patients suffering from frequent and severe migraines for the better.

Antibody purification using continuous countercurrent chromatography

Biotechnologically derived antibodies can be purified using the chromatography equipment of this material's partner, Cytiva. This is done in continuous counter-current chromatography (PCC) mode on an ÄKTA pcc . In combination with the minimal dimensions of the system, continuous chromatography technology ensures the most efficient use of the chromatographic sorbent (resin). This method is particularly suitable for the purification of unstable molecules, as the rapid process ensures the stability of the target product. The ÄKTA pcc system is based on the well-established and widely used ÄKTA chromatography system platform by scientists around the world. Key features of the ÄKTA pcc system:

• Flow rate: 0.5–75 ml/min.
• Maximum operating pressure: 20 bar.
• Supports three and four column PCC configuration (3C and 4C PCC).
• Integrated UV detectors: one tunable wavelength (three values) and three fixed wavelength (280 nm).
• Monitors for tracking pH and conductivity readings.
• Interactive visualization that continuously shows column status and process progress.
• Trend lines that allow you to immediately begin analyzing the information received about the process.

ÄKTA chromatography systems can be used in conjunction with AxiChrom columns, although they are also suitable for larger scale protein purifications. A wide range of column sizes of the same type (Figure 4) allows protein purification to be scaled up with minimal parameter changes.

Figure 4. AxiChrom is a family of pilot-scale to industrial-scale protein purification columns with i.d. diameters of 50–1600 mm. AxiChrom columns successfully combine standardization and customization and are compatible with a variety of advanced media, such as MabSelect SuRe™ antibody purification resin.

Cytiva's research has confirmed the similarity between the protein purified in the laboratory and in production. In this case, the volume of the drug was scaled by 294 times (Fig. 5).

Figure 5. Comparison of chromatograms obtained using ÄKTA pcc on HiTrap columns (a) and AxiChrom 50 columns (b)

Material provided by our partner - Cytiva

Mode of application

The tablets should be taken orally. The triptan dosage is 2.5 mg. If the pain returns, you can repeat taking the drug, but not earlier than 2 hours after taking the previous tablet. The spray is sprayed into the nasal cavity, which ensures better absorption.

The use of triptans is completely contraindicated in the presence of the following diseases:

• Hypertension;
• Arrhythmia;
• Ischemic disease;
• Angiospastic angina;
• Cerebrovascular accident;
• High sensitivity to the components included in triptans;
• Adolescence.

The drug should be used with extreme caution during lactation, pregnancy, as well as severe liver or kidney failure.

"Aimovig" and competitors

It must be said that Novartis and Amgen already have serious competitors in the field of targeted anti-migraine therapy: Eli Lilly released Emgality, and Teva Pharmaceutical released Ajovy. These drugs are humanized monoclonal antibodies that target the ligand rather than the CGRP receptor, and in this way they differ from Aimovig, being inferior to the latter at least in tolerability. When using Ajovy, 43–45% of patients experienced pain, redness and itching at the injection site, when using Emgality, 18% of patients experienced such symptoms, and Aimovig caused such reactions only in 5–6% of cases. At the same time, Aimovig is also more convenient to use, since of the three listed drugs, only it comes in the form of an auto-injector - a device that resembles an insulin syringe pen - which needs to be used only once a month. The listed advantages, coupled with the fact that Aimovig became the first targeted drug for the treatment of migraine and immediately filled an empty niche in the market, will most likely provide it with a bright financial future: according to experts, its market share in 2024 will be $2 billion, while the predicted shares of competitors are approximately half as much [20].

The success of Aimovig, apparently, cannot be hampered even by the extremely high price ($575 per month according to the Amgen price list - however, in the United States, the drug is covered by insurance for many patients), which, by the way, some experts consider unreasonable [11]. The company is conducting research on Aimovig in Russia, but when the drug will appear on the market, how much it will cost and who will pay for it is still unknown.

Literature

1. Three generations of drugs;
2. Search for drug targets;
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4. How a migraine happens. Johns Hopkins Medicine;
5. Migraine headaches. (2018). WebMD;
6. Paul L. Durham. (2006). Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache
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7. What to know about the new anti CGRP migraine treatment options. (2018). American Migraine Foundation;
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9. Migraine triggers: your personal checklist. (2019). WebMD;
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21. Aimovig (erenumab) for the treatment of episodic migraine. Clinical Trials Arena;
22. Khoruzhaya A. (2018). A new anti-migraine drug goes on sale. "Neuronews";
23. Targeted therapy is a targeted strike against the disease.