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Migraine is characterized by recurrent light-to-severe headaches, which usually lead to headaches, severely affect the quality of sleep, nausea, anxiety, depression, etc., affecting young people’s social skills and academic performance, and directly affecting adults. The decline in labor capacity affects about 10% of the world’s population, and the incidence of females is three times that of men. There are approximately 36 million migraine patients in the United States, 8 million in Japan, and approximately 13 million in China. Since the pathological mechanism has not yet been fully elucidated, there is currently no drug that can completely cure migraine.

The presence of triptans in 1990s was only a relief from migraine headaches and did not prevent migraine attacks. Since the triptan drugs, there have been no breakthrough migraine drugs on the market. In April 2014, FDA approved topiramate (approved for the prevention of epilepsy in 1996 and approved for the prevention of adult migraine in 2004) for the prevention of migraine attacks in adolescents. In 2015, the American College of Headache/Neuropathology Society released new The recommended recommendations for migraine treatment guidelines are still the triptans (almotriptan, eletriptan, rotrotriptan, sumatriptan and zolmitriptan), ergotamine derivatives (dihydroergotamine nasal spray) With inhalants and old drugs such as non-steroidal anti-inflammatory drugs (diclofenac and ibuprofen), migraine is a disease whose medical needs are far from being met.

However, with the development of pathological mechanisms, it has been found that the release of calcitonin gene-related peptide (CGRP) is significantly increased during the onset of migraine and is positively related to the degree of headache. Therefore, people try to relieve headaches by inhibiting the activity of CGRP. And prevent migraine attacks. At present, CGRP has been identified as the most potential target for migraine treatment and prevention, and the development of CGRP receptor antagonists will also be highly competitive. Some analysts predict that the first-to-market CGRP inhibitor migraine drugs will have a maximum annual sales of 12.5 billion U.S. dollars, while latecomers will not be able to accumulate billions of U.S. dollars.

Since CGRP and its receptors are widely distributed in vivo, the complete inhibition of this signaling pathway by oral small molecule CGRP receptor antagonists will inevitably lead to serious side effects. Two oral CGRP inhibitors (MK-0974 and MK) in Merck -3207) It was because of the inability to solve the hepatotoxicity problem that it failed in 2011. With the knowledge of Merck, the pharmaceutical companies turned their attention to locally injected monoclonal antibodies. At present, there are four leading companies: Teva, Eli Lilly, Alder Biopharmaceuticals, and Amgen.

At present, Teva is the leading one in terms of development progress and efficacy data. Phase IIb studies showed that after one week of TEV-48125 treatment, the number of headache days per month was significantly reduced compared with placebo (6 vs 3.34 days), and over 50% of patients had a 50% reduction in headache days. In the subgroup analysis, 15% of patients had no headache attack after 3 months of treatment, and 1 /3 of patients had a headache reduction of 75% or more, which was significantly better than Elimination and Amgen.

Of course, this is not to say that small molecule CGRP inhibitors will not work. Teva announced on November 25th that Hepatares has obtained a worldwide exclusive development, production and promotion right for a series of new small-scale CGRP inhibitors, and paid $10 million in advance for this purpose. And promised to pay $400 million for R&D and listing miles and sales. Heptares has several candidate small molecule CGRP inhibitors that are expected to enter Phase I clinical in 2016. Michael Hayden, President and Chief Scientific Officer of Teva Global Research, said: “Heptares has a world-leading technology platform based on the G protein coupled receptor (GPCR) structure to design and develop drug candidates, and is expected to develop breakthrough migraine treatments. The drug, which is a very favorable supplement to our monoclonal antibody, TEV-48125.” It seems Teva doesn’t want to put eggs in one basket.

In addition, Allergan purchased a Merck East oral migraine drug development project in July for $250 million in cash packages, including MK-1602 (phase II) and earlier phase MK-8031. Allergan’s flagship product is Botox, a type of botulinum toxin product known for its anti-wrinkle beauty. However, Allergan is developing an indication for the treatment of migraine in Botox. A result announced at the International Headache Conference in May this year shows that botox treatment is 1/3 The number of headache days decreased by more than 75%, and the number of days of headache in 47% of patients decreased by more than 50%. Just don’t know if there is any gender bias in this study. Will a female migraine patient have a Botox injection that will feel beautiful from head to toe? The headache is forgotten by a good mood? 🙂

Even more dramatic, Teva, who is determined to be a leader in migraine, has just signed a cooperation with Hepparts to sign a small molecule CGRP inhibitor. Pfizer-Allergan signed a strategic cooperation agreement with Hepparts around November 30. With its GPCR technology platform, it has collaborated on the development of 10 small-molecule drugs that cover multiple disease areas. Why is it dramatic? Because TEV-48125 (LBR-101, RN-307) used to belong to Pfizer. Interested friends should check it out for themselves.

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