Arvelle therapeutics: dedicated to the development of new antiepileptic drug cenobamate

Wen Yingjiao Yanli Epilepsy is one of the three major central nervous system diseases in human being, the prevalence is second only to stroke, which is a central nervous system disease caused by abnormal brain nerves and excessive discharge At the onset of the disease, the central nervous system of the patient will have sudden, repeated or transient loss of function According to the data of the World Health Organization, there are about 50 million epileptics in the world, and 2 million new epileptics are found every year In 2017, the international anti epileptic alliance revised the classification of epileptic seizures The types of epileptic seizures were divided into comprehensive onset, focal onset and unknown onset The types of epilepsy were divided into comprehensive epilepsy, focal epilepsy, comprehensive epilepsy and focal epilepsy, and unknown types of epilepsy It is worth noting that many epileptics contain multiple types of seizures The difficulty of epilepsy treatment lies in the diversity and heterogeneity of seizure types Drugs are the main treatment of epilepsy, used to reduce the frequency of seizures, control symptoms At present, there are many antiepileptic drugs on the market Taking the 1980s as the watershed, they are divided into traditional drugs (such as carbamazepine, phenobarbital, sodium valproate, etc.) and new drugs (such as levetiracetam, oxcarbazepine, lamotrigine, etc.) Although there are many kinds of drugs, about 30% of epilepsy patients in the world can not be effectively controlled In addition, according to the global epilepsy burden report released by the lancet from 1990 to 2016, although the incidence of epilepsy in the world has improved in 26 years, epilepsy is still one of the important causes of death Therefore, major pharmaceutical companies around the world are stepping up the research and development of new antiepileptic drugs with better efficacy, less adverse reactions and less drug interactions In early 2019, axovant gene therapeutics (NASDAQ: axon) announced the establishment of arvelle therapeutics, an independent operating subsidiary On February 18, 2019, the company completed a round of 180 million US dollars financing, which is the largest round a financing in the field of biotechnology in Europe in 2019 Arvelle therapeutics, headquartered in Basel, Switzerland, is committed to promoting the development and commercialization of the new antiepileptic drug cenobamate (trade name: xcopri) in Europe Cenobamate is a new star in the global anti epileptic drug market in recent years This drug is independently developed by SK life science, a subsidiary of SK biopharmaceuticals, a Korean enterprise It can reduce the seizure frequency of focal epilepsy, and its target is GABAAR (the corresponding indications of this target are mainly anxiety, insomnia, sedation and epilepsy, and several drugs with the same target have been listed) At present, the exact mechanism of the therapeutic effect of cenobamate is not clear SK biopharmaceuticals thinks that it may work through two mechanisms: positive regulation of GABAA receptor activity, enhancement of inhibitory signal; inhibition of excitatory signal by inhibition of persistent sodium ion flow Focal epilepsy refers to the seizure originated from a limited part of the brain In the early stage of epilepsy, if the head or eyes incline to one side, there is a premonition of panic, fear, etc before the seizure, when there are auditory hallucinations, visual hallucinations and other symptoms, most of them are focal epilepsy Clinical trials have shown that cenobamate can significantly reduce the frequency of focal seizures, and 20% of patients achieve zero seizures in the maintenance period On November 25, 2019, cenobamate was approved by the US FDA to be marketed for the treatment of adult focal epilepsy The approval is based on the results of two global, randomized, double-blind, placebo-controlled studies (study 013, study 017) and a large, global, multicenter, open label safety study Study 013 included a 6-week drip and a 6-week maintenance period The data showed that the median seizure frequency was reduced by 56% with a 200mg / day dose of cenobamate, compared with 22% in the placebo group A post maintenance analysis showed that 28% of the patients in the cenobamate treatment group reported zero seizure, compared with 9% in the placebo group Study 017 included a 6-week drip period and a 12 week maintenance period The study included 100 mg / day, 200 mg / day and 400 mg / day dose xcopi The data showed that In the maintenance period, 4%, 11% and 21% of the patients in the three dose groups reported zero seizure, compared with 1% in the placebo group It is understood that cenobamate is expected to be available in the United States in the second quarter of 2020 The right to develop and commercialize the drug in Europe belongs to arvelle therapeutics On February 14, 2019, arvelle therapeutics and SK biopharmaceuticals signed a US $430 million technology export agreement, and the two sides will cooperate to promote the commercialization of cenobamate in Europe Sk biopharmaceuticals will receive US $100 million of contract payment without additional refund conditions, and arvelle therapeutics will pay the rest of the contract payment after the market sales license and other targets are reached Sk biopharmaceuticals will also receive royalties based on the size of the sale after the drug is sold Arvelle therapeutics plans to apply to the European Union for a marketing license in 2020 to treat adult focal epilepsy In addition, the company will also conduct phase II and phase III clinical trials on cenobamate, involving a total of 1900 patients We will focus on the Chinese market There are about 9 million epileptics in China, with an annual increase of 400000 to 500000 epileptics At present, most of the antiepileptic drugs in the Chinese market are imported, and domestic brands are mainly generic drugs However, many domestic enterprises are developing new antiepileptic drugs The new antiepileptic drugs in our country were sorted out Chlorobutylamine was first discovered and synthesized by Peking University, and then developed by Desa pharmaceutical industry with permission from Peking University It has been used in clinical research in China, and is currently in phase II clinical treatment for epilepsy In vivo pharmacokinetics and in vitro metabolic transformation of rats showed that there were many CYP450 subtypes involved in the metabolism of chlorobutylamine in vitro, which inhibited cyp2c12 metabolic activity, and inhibited CYP1A1 / 2, cyp2d1 and cyp2c13 activities to a certain extent Payne Gabin overcomes the problems of unstable chemical structure and poor metabolic characteristics of retigabin It is a new generation of antiepileptic candidate drug targeting potassium channel KCNQ, with full independent intellectual property rights The preclinical study showed that compared with retigabine, pinegabine has the characteristics of excellent chemical stability and high distribution in the brain, which not only reduces the risk of pigmentation, but also significantly improves its antiepileptic effect in vivo, and shows good antiepileptic effect in a variety of animal models including refractory epilepsy models Payne Gabin was approved to carry out clinical research in November 2018 In June 2019, Hainan pharmaceutical released a notice that Haikou pharmaceutical factory, the holding subsidiary of the company, intends to transfer Payne Gabin technology The mechanism of antiepileptic action of benzoxazine is to produce GABA like activity by activating GABA neurotransmitter system, so as to have antiepileptic effect Benzoxazine is a new structure compound, which has double patents at home and abroad Its pharmacodynamics shows that it can resist epilepsy caused by many reasons Its curative effect is better than that of the listed antiepileptic drugs Its neurotoxicity is significantly lower than that of the listed drugs, and its tolerance is good Wx0005 is a new drug jointly developed by Harbin Pharmaceutical Group Technology Center and Shanghai yaomingkant new drug development Co., Ltd It is a class 1 new drug under the National Chemical Registration classification and has independent intellectual property rights in the world The proposed application of the new drug is epilepsy The target of the new drug is sodium channel and pde1 double target, which can not only prevent epilepsy, but also improve the cause of epilepsy Brain damage.