The medical revolution has reached migraine: new treatments based on medical nutrition and antibodies

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On the International Day of Action against Migraine we present the latest advances arising within the therapy field of this neurological condition so widespread and with severe disabling effects. A medical revolution is brewing around this pathology, emerging the foundations of a medicine through food, and not focused only on the use of drugs. 

Medical nutrition represents a new therapeutic approach with high security profiles, effectiveness and that is emerging through a large body of clinical trials.

Affecting between a 15 to a 20 per cent of the world’s population (a total of 1050 million people), being doubly widespread among women than men, a 17% and 8% respectively, its effects are characterized by acute pain or throbbing headaches that can last between 4 to 72 hours, and that extend along between 4 to 15 days during each month.

These headaches must be distinguished from headaches, as the tension headache, which is much more than usual, a cluster headache and the secondary headaches that may be caused by a multitude of causes, such as the flu, meningitis, brain trauma and brain tumors. For its part, migraines are often accompanied by symptoms of diverse nature as nausea or vomiting, sensitivity to light or sounds and dizziness.

It is for this reason that the correct diagnosis of migraine has reduced rates of around 50% for cases of episodic migraine and 40% for cases of chronic migraine. This is why many researchers and leading centers for the study and management of migraines have indicated that in general medicine there is a confusion in the diagnosis of this disease, associating their symptoms to comon headeaches, being the treatments and preventive measures radically different for each one.

In the trio “diagnosis, disease and treatment”, the boundaries between the different possibilities are not always clearly defined. In fact the economic conditions and policies of the countries that affect public health, coupled with the prevailing opinions of the medical fields and the efforts that may be able to develop the biomedical industry by becoming a gap between its major customers, those factors are some which define the types of resources and approaches to deal with, diagnose and conceive diseases. 

In addition, the treatments developed up to the present, based according to their order of appearance in: ergots, followed by beta-blockers, and crowned by the use of triptans, have reduced efficiencies. In addition them give rise to adverse effects and cannot be prescribed for any type of patient, as they present incompatibilities with different diseases and physical conditions, such as cardiometabolic alterations in the case of the triptans. This makes it no possible to offer treatment to a large number of patients.

For this reason, to understand the association between migraine and these terms of contraindication of the different treatments is vital for the correct handling of migraines.

In this way, the migraine occupies the 19th place on the list of diseases that produce greater disability, according to the WHO. In fact, patients tend to retire to a space in darkness and quiet, needing to remain inactive until symptoms disappear. Finally, the first attacks usually appear before the age of 30 years in the 80% of migraine`s patients .

 

Recent advances in the treatment of migraine

8 new drugs are currently in the throes of clinical trials in Phase IIb and III, and it is expected that begin to be marketed before 2026. All of them have new mechanisms of action that respond to some of the most pressing needs in the treatment of migraine. On the other hand they can be classified into three new classes: monoclonal anti-CGRP antibodies (mAbs), ditans and gepants.

Lasmiditan (Ditano) and ubrogepant (gepant), are designed specifically for the treatment of patients with cardiovascular disorders or with risk to suffer them and who do not respond to treatment based on triptans.

Both types of active principles are the most promising for the treatment of acute episodes of migraine, and in addition are in the final stages of development, being able to be launched on the market in about eight years.

At present, the treatment of acute episodes of migraine is dominated by generic drugs based on triptans, since the drugs of reference have been losing their patents, both being ineffective and pose adverse effects. However, the therapeutic possibilities are dividing between the segments of drugs designed for the treatment of acute phases (abortive) and indicated for the prevention of the emergence of migraines (prophylactic).

It is in this last segment in which there are devoting increased efforts in research for the development of preventive treatments of marked specificity and effectiveness. Among them four variants are anti-CGRP mAbs: erenumab, galcanezumab, fremanezumab and eptinezumab, developed by Amgen, Eli Lilly, Teva, and Alder, respectively.

Between the active principles with the greatest commercial potential and better clinical outcomes are Erenumab and Galcanezumab, followed by Fremanezumab, Atogepant, Ubrogepant and Lasmiditan. Data extracted from PharmaPoint: Migraine Global Drug Forecast and Market Analysis to 2026 by GlobalData.

These anti-CGRP MAbs are expected to revolutionize the treatment of migraine, because clinical trials are leading to results which show that their profiles of efficacy and safety are superior to any other drug for this indication.

 

The new era of the treatments of migraine with antibodies

The Danish Headache Center (DHC) in Copenhagen, Denmark, has more than 30 years of being a world leader in the research on the mechanisms of migraine. Its experimental line is based on the human model of migraine, in which the mechanisms of the disease are elucidated through studies in which are induced migraine attacks in humans, so the results are directly applicable to pharmacological and medical level.

These studies have established that two types of neurotransmitters, among which are the peptide calcitonin gene-related peptide (CGRP) and the pituitary adenylate cyclase activation polipeptide (PACAP), can trigger migraine attacks associated with the dilation of blood vessels in the brain.

In this context, PACAP38 has emerged as a signaling molecule involved in a key manner in the development of migraine, and possibly also in the cluster headache. In addition, the results of brain imaging studies have shown neural and vascular changes in patients with migraine after the infusion of PACAP38.

PACAP38 is a potent vasodilator that triggers migraine attacks. It belongs to the superfamily of secretin peptides/glucagon, also constituted by the vasoactive intestinal polypeptide (VIP). All of these peptides activate VPAC1 and VPAC2, but only PACAP38 activates the PAC1.

Representation of an antibody molecule (in the center), joining the receptor on the surface of a cell (on the left). Specifically, the anti-CRGRP and anti-PACP, bind to these peptides of activation and inhibit their effects, among which cause migraines by induction of vasodilation of the blood vessels in the brain through different mechanisms. In these mechanisms are directly involved the peptide calcitonin gene-related peptide (CGRP) and the pituitary adenylate cyclase activation polipeptide (PACAP).

Continuing with the previous relations between the activation of receptors in the brain, VIP induces vasodilation but does not produce migraine attacks in humans. Therefore, it is likely that the migraine caused by the activity of PACAP38 is caused by the receptor of activation PAC1, as it is the only one which can join and activate this receptor.

In this way, there are strong indications that a selective antagonist (drug designed to join PAC1, inhibiting its activity) that blocks the receptor PAC1 can be effective in treating migraine.

With regard to the data from clinical trials phase II and III of four monoclonal antibodies with lock function (MAbs) of the CGRP – which are identical to the antibodies of the immune cells – collectively show a positive effect in the preventive treatment of chronic and episodic migraine, with favorable profiles of side effects.

In view of these results, the aim is to investigate the effects of mAbs designed to block the receptor PAC1 in patients with migraine. In this way, also will check if them have greater therapeutic potential that the antibodies anti-CGRP, as the PAC1 target for the PACAP8 can be more specific for migraine that the target of the anti-CGRPs.

At present, from the Danish Headache Center are awaiting the results of a randomized clinical trial of proof of concept that reveal this therapeutic potential of the anti-PAC1 in the prevention of migraine headache.

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Only time will tell us whether this will represent a paradigm shift in the treatment of this neurological disorder.

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However, it should be borne in mind that the administration of these drugs continues to be invasive and difficult, by the fact that they must be administered intravenously. This may pose negative effects, causing minor treatment adherence on the part of the patients, in addition to the inconvenience of having to go to the hospital centers to be administered.

 

The real change of paradigm in the treatment of migraine

Greater efficiency, ease of treatment, diagnostic accuracy and… a new approach with a guarantee of safety… these are some of the properties of the treatment based on the DAO intestinal enzime. All of them backed by more than two decades of research both in the scientific and clinical spheres, and presented at all levels: in Congresses, medical associations, research centers and the pharmaceutical industry.

The Diamine Oxidase (DAO) is a natural enzyme that is produced in our intestines, and that being administered as a functional food is able to effectively combat the onset and severity of migraines, of which 90% are due to a dysfunction in this enzyme.

This disorder has received the name of histamine intolerance and its biochemical diagnosis has been established at all health centers throughout Spain, this being of high precision.

In addition, attached to this advance and its ease of use, as it is in the form of tablets to be taken shortly before meals or dusting in powder format on this, does not cause adverse effects and includes some dietary recommendations that are customizable for each patient. These nutrition standards are based on avoiding those foods rich in histamine, highly inflammatory molecule found in certain foods and that represents one of the causes of migraine.

The histamine at not being able to be metabolized and eliminated in the intestine of patients with a dysfunctional DAO, passes to the bloodstream and causes inflammatory effects throughout the body, causing among other symptoms migraine, neurological, epidermal and musculoskeletal disorders.

deficitDao
Points of the metabolization of histamine in which acts DAO. Since this is the first enzyme that acts on the degradation of the same, the metabolic pathway does not develop without their presence, leaving unchanged the histamine and being able to accumulate in tissues or pass into the bloodstream and cause inflammatory effects throughout the body.

The Clinical Institute of the Deficit of DAO of the Hospital General de Catalunya, is the first unit in Spain specific for the treatment of patients who have this deficiency.

More than 2.000 patients has been treated at the Institute and a large part of them have presented a significant improvement of both the headache and other symptoms related to the migraines due to the DAO deficiency.

This pioneering institute is led by Dr. Joan Izquierdo, researcher and neurologist. This research center was born with the goal of preventing and diagnosing the deficit of DAO, coming to consolidate itself today as a center of reference in this pathology at the global level, but not without great effort and perseverance.

The barriers encountered the approach of preventive treatment through DAO have been numerous, and in many moments have been able to seem insurmountable. This is due to the fact that it is within the scope of the “medical nutrition”, or medicine through nutrition, and even today there is no European regulation nor anywhere else in the world that controls and manages the development of clinical trials with food, intended for the treatment of diseases. However, it is through the development of these clinical trials the only way to obtain scientific evidence for the effectiveness of this new approach.

If we focus on the legal framework “studies with medications to treat diseases are directed to patients; while the studies with food is made for the treatment of “symptoms” and should be directed to healthy people. We had to alter that equation, doing studies with food to treat diseases and aimed at patients.” told us Juajo Duelo, CEO and founder of the innovative biomedical company Dr. Healthcare, which has been the first to develop a treatment for migraine based on DAO. “Therefore the only way forward is now adapt the models of research protocol of drugs in foods,[…] This deficiency is subsequently moved to scientific journals which continue to struggle to publish evidence on food for the aforementioned deregulation, entering into an endless loop”, also shared Juanjo with us in an exclusive interview that you can access through here, concluding that “there is a widespread tendency to go admitting the role of many nutrients in the prophylaxis of migraine, although progress is slow. In fact, it notes that it is a widespread trend in many diseases including cancer, attributing a more important role to what Americans christened as “medical nutrition,” or medicine through nutrition.”

With regard to the clinical results of the DAO enzyme, Dr. Joan Izquierdo presented in 2013 at the World Congress of Neurology in Vienna the results of a research project that the same led and which shows that the 87% of migraine patients had a deficit in the enzyme diamine oxidase, and that in the 90% of cases can be treated from the prevention with a dietetic food of enzyme DAO.

In March 2015, in the framework of Infarma Barcelona, the pharmaceutical congress of reference in Europe, were presented the results of a clinical study that reaffirms the conclusions of the project led by Dr. Izquierdo. The study, conducted on patients with deficit of DAO, notes that a diet low in histamine food and supplemented with enzyme diamine oxidase significantly improves the symptoms associated with migraine.

Research on this syndrome have been happening, creating a large body of publications of scientific results and the development of new clinical research projects. Among them, in September 2016 the start of the Project of Clinical Research based on the treatment with DAO in patients with chronic rhinitis allergic reaction, and between June and October 2017 were published the results of ” The effects of folic acid and pyridoxine supplementation on characteristics of migraine attacks in migraine patients with aura: A double-blind, placebo-controlled, randomized clinical trial” and the results of the study “diamine oxidase activity in patients with migraine and effect of the enzyme supplementation as a preventive treatment of the episodic migraine”. 

Between 2016 and 2017 also was developed the project Obtaining probiotic microorganisms with endogenous DAO activity”, co-sponsored by DR Healthcare, included in the Ris3Cat Food Community (Ris3Cat is an organization of the Catalan Government designed to promote R&D projects) and co-funded by the European Union through the European Regional Development Fund.

2018 has also been a prolific year in the publication of clinical outcomes, among which we can highlight:

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  • Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO Deficiency: A randomized double-blind trial, January 2018
  • Histamine-reduced diet and increase of serum diamine oxidase correlating to diet compliance in histamine intolerance
  • And the low-histamine diet supplemented with exogenous diamine oxidase enzyme is useful for treating migraine in patients with DAO Deficiency

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In reference to the latest publications of scientific studies, citing some of the most relevant:

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  • In December 2016, the risk assessment of histamine in the consumption of sausage (UB),  
  • In July 2017 was published “Low serum diamine oxidase (DAO) activity levels in patients with migraine”, in August of this year the study”Serum diamine oxidase in Pseudoallergy in the Pediatric Population”, in October, the public is study of basic molecular biology “Mapping of the binding sites of human diamine oxidase (DAO) monoclonal antibodies”
  • In 2018 has been published the study “What about legumes as a plant source of the DAO enzyme?”

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Pressing Needs in the management and treatment of migraine

The greatest needs that today are neglected diseases are:

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  • Treatments for patients who do not respond to TRIPTANS, or who have cardiovascular problems or are at risk.
  • Improving the education of physicians in the diagnosis and abortive and prophylactic treatments of migraines in patients that suffer frequently
  • The improvement of the training of doctors and health personnel in the management of migraines

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For this reason, it is of vital importance that governments and the big pharmaceutical companies allocate more funds and efforts to respond to these needs burning issues.

 

The future of the world market of migraines

The world market of migraine wa in 2016 3.3 billion dollars, divided between the 7 main markets (US, France, Germany, Italy, Spain, UK and Japan).

In 8 years (until 2026), it is expected that this market to grow to reach 8.7 billion dollars at a rate of 10.3% CAGR.

With regard to the leaders in the industry, the United States will continue dominating with 77% of the total sales, followed by Germany (5.6%) and Italy (5.2%).

If we focus on the market for anti-CGRP mAbs, they are expected to reach the sales volumes of 4 billion jointly in 2026.

Among the companies that have entered into this sector are some of the major pharmaceutical companies in the world. Among them we can highlight:

Pfizer, Amgen, Eli Lilly, Teva, Alder Biopharmaceuticals, Merck & Co, Allergan, Zogenix, RedHill BioPharma, OptiNose, Supernus Pharmaceuticals, GlaxoSmithKline, sweats, Eisai, Kyorin, Pozen, Par Pharmaceuticals, Pernix Therapeutics, Endo Pharmaceuticals, Desitin, IntelGenx, Grupe JUSTE, Grünenthal, Almirall, Aspen Japan KK, Elan Pharmaceuticals, Menarini, Vernalis, AZ MedPointe, Impax Laboratories, PHARMACIA COPORATION, Mallinckrodt, Janssen, AbbVie, CoLuicd, Rinat, Labrys Biologics, Arteaus Therapeutics, Novartis, NeurAxon Pharma, Curtis AG, Achelios Promius Pharma, Therapeutics, TrioxBio, Trigmina Biohaven, Pharmaceutical, Biofrontera, Ionis Pharmaceuticals and Dr. Healthcare.

 

Image credits: Panchenko Vladimir, scanrail1,,,ustas belu23eu piick Tone Balaguer / shutterstock.com

References:

PharmaPoint: Migraine Global Drug Forecast and Market Analysis to 2026

http://blogs.biomedcentral.com/on-medicine/2018/03/09/breakthroughs-migraine-treatment/

 

Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial.

Comas-Baste Izquierdo-Casas J, OR, Latorre-Moratalla ML, Lorente-Gascon M, Bereavement, Soler-Singla Vidal-Carou L, MC.

Clin Nutr. 2018 Feb 15. Pii: S0261-5614(18)30014-1. doi: 10.1016/j.clnu.2018.01.013.

 

Low serum diamine oxidase (DAO) activity levels in patients with migraine.

Comas-Baste Izquierdo-Casas J, OR, Latorre-Moratalla ML, Lorente-Gascon M, Bereavement, Vidal-Carou MC, Soler-Singla l.

J Physiol Biochem. 2018 Feb;74(1):93-99. doi: 10.1007/s13105-017-0571-3. Epub 2017 Jun 17.

 

Association of diamine oxidase and histamine N-methyltransferase polymorphisms with presence of migraine in a group of Mexican mothers of children with allergies.

Meza-Velazquez R, López-Márquez F, Rivera-Guillen Espinosa-Padilla S, M, Avila-Hernández J, Rosales-GonzÁlez m.

Neurology. Oct 2017;32(8):500-507. doi: 10.1016/j.nrl.2016.02.025. Epub 2016 Apr 26. English, Spanish

 

Diamine oxidase rs10156191 and rs2052129 variants are associated with the risk for migraine.

García-Martin E, Martinez C, Serrador M, Alonso-Navarro H, Ayuso P, Navacerrada F, Agundez JA, JIMENEZ-JIMENEZ FJ.

Headache. 2015 Feb;55(2):276-86. doi: 10.1111/head.12493. Epub 2015 Jan 22

 

Histaminase activity in serum of patients with migraine.

Apartamenty Galeria Krajewska M, W.

Neurol Neurochir Pol. 1973;7(1):55-8. Polish. No abstract available.

 

Histamine and histamine intolerance.

Maintz L, Novak N.

Am J Clin Nutr. 2007 May;85(5):1185-96. Review.

 

 

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