Drugs for Acute Treatment of Migraine

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Monoclonal antibodies of CGRP receptors

Monoclonal antibodies are extremely advantageous as they have high target specificity, do not involve liver or kidney metabolism, and have a long half-life. The efficacy of these antibodies against the CGRP ligand or CGRP receptor were investigated recently in order to help determine the importance of these potentially new migraine preventive treatments..

LY2951742 is a humanised monoclonal antibody which binds selectively and potently to the CGRP receptors. In a phase II, randomised, double blind, placebo controlled clinical trial conducted by (Dodick et al. 2014), the antibody LY2951742 was found to be well tolerated and generally effective in treating patients with frequent attacks. Patients suffering from episodic migraine were subcutaneously administered 150 mg of the antibody every 2 weeks over the 3-months study period.When compared to the placebo group, the LY2951742 group showed significant reductions in the average number of migraine days in the 3-month study period. After the trial, the most common adverse effect of the LY2951742 found was upper respiratory tract infections and viral infections. Since the adverse effects were mild in intensity, no patients withdrew from the study and no serious treatments took place.

Another monoclonal antibody used against CGRP in migraine preventive treatment is ALD403. The antibody was injected into patients suffering from episodic migraine in a phase II study in order to compare the frequency of migraine days at 8 weeks to migraine days at baseline (Dodick et al. 2014) .According to the results, three fourth of the patients in the antibody group experienced a reduction in migraine days by almost 50%and the others experienced a 75% reduction. Additionally, 16% of the people treated with ALD403 did not suffer from any migraine attack for the 12 week study period. The treatment was generally safe and well tolerated with mild temporary adverse effects; thus there was no withdrawal of participants and no serious treatments took place.

One other phase II study conducted used three different doses (7 mg, 21 mg, and 70 mg) of AMG 334, another monoclonal antibody to CGRP, and compared it to the placebo( Lenz, Silberstein & Dodick 2015). The results showed that the highest dose was the most effective in reducing the average monthly migraine days and were found similar when tested in patients with chronic migraine.

In non-human primates and in a phase I study, the monoclonal antibody to CGRP receptors TEV-48125 was tested extensively. Single injected doses of the antibody ranging from 0·2 mg to 2000 mg and several injected doses of 300 mg were well tolerated in healthy volunteers and no adverse effects were reported.

The effectiveness of the monoclonal antibodies raises questions about the target sites of anti-migraine action. The Triptan and the Gepant class antagonists are small molecule and can partially pass the blood-brain barrier (BBB); hence may have effects in the CNS during migraine attacks. However, the monoclonal antibodies are large molecules and do not readily penetrate through the blood brain barrier. Thus they can be effectively excluded from having a major site of action within the central nervous system (Olesen et al. 2004; Hewitt et al. 2011).

.There is very little doubt that blocking the CGRP pathway is an effective preventive strategy of migraine, and the results of ongoing studies are expected to give similar outcomes. However, there are also several limitations of this therapeutic strategy.

None of the above mentioned monoclonal antibodies has been tested long enough and thus possible adverse effects cannot be excluded on long-term use. The effects of these antibodies will need to be investigated in Phase III, randomised, placebo-controlled trials for long period of time in order to ensure positive results.Additionally, the findings of these trials show that the drugs are injected instead of given as oral formulation; this is also mentioned in the media article published in The Washington Post. From the social perspective, this could be an issue affecting many of the migraine patients as injections are extremely costly and therefore not every patient will be able to afford it.

Conclusion

For decades, various therapeutic targets and treatments have been studied in order to prevent migraine. But not all of them were efficacious to migraine prevention. Developing drugs to treat migraine attacks has been disappointing as none of them were specifically designed for migraine prevention. The relevance of calcitonin gene-related peptide (CGRP) to the pathophysiology of migraine was well studied though various clinical trials. Several CGRP receptor antagonists were intravenously administered to migraine patients and was found to be effective in reducing the levels of CGRP during migraine attacks. However for a number of side effects including issues of liver toxicity, the development of CGRP antagonists were terminated. Promising results from studies with antibodies against CGRP suggests that these antibodies might be a new preventive therapy for many migraine patients. The target specificity and long half-lives of these antibodies make them suitable in preventing migraine headaches.

Recently an article was published in The Washington Post which reported the issue of migraine prevention treatments in the US. The title of the article in its entirety gives hope to migraine patients of a cure long wished for. However, the evidence it uses is not very accurately provided and thus deceives the reader into believing in the promised cure. Suspicions only arise because of the fact that a cure has been found very suddenly by three different companies, whereas there had been no long-lasting remedies till now. Suspicions also arise when the article mentions that the studies conducted showed drastic reduction in migraine pain by almost 50%.The limited number of participants in the experiments carried out by these companies also rouse suspicions in the effectiveness of the remedy, as does the manner in which the writer writes “Teva will report” indicating that reports have not yet been finalised in the accuracy of this remedy.

References

Amrutkar, D, Ploug, K, Hay-Schmidt, A, Porreca, F, Olesen, J & Jansen-Olesen, I 2012, 'mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system', Pain, vol. 153, no. 4, pp. 830-838.

Berger, A, Bloudek, L, Varon, S & Oster, G 2012, 'Adherence with Migraine Prophylaxis in Clinical