Analysis of drug development and market status of rare multiple sclerosis in 2019

By Zhang Yuefei Make up ginger With the introduction of favorable policies in China, the diagnosis, treatment and drug research and development of rare diseases in China are gradually on the right track, and many foreign drugs have begun to enter the Chinese market, with increasingly fierce competition In order to understand the general trend and direction of drug development of multiple sclerosis and provide basis for drug research and development, this paper discusses the pathogenesis, drug development strategy and drug market analysis of multiple sclerosis In recent years, the frequent introduction of relevant policies represents the importance and substantive promotion of the prevention and control of rare diseases at the national level With the policy promoting the "niche" market, drug research and development in the field of rare diseases in China will become a new "blue ocean" in the future Figure 1 overview of China's MS related policies Multiple sclerosis (MS) is a chronic and disabling disease, characterized by inflammatory demyelination of central nervous system (CNS) As shown in Figure 1, myelin sheath is a membrane on the surface of axon of neuron, which plays an insulating role and prevents the electrical signal "leakage" of nerve conduction In MS pathological process, the immune system will attack the myelin sheath, leading to the damage of nerve cells and axons, thus affecting the transmission of nerve electrical signals Figure 1 Schematic diagram of neuron demyelination If neurons are compared to "cables" that transmit signals, then the myelin sheath is equivalent to the "sheath" of this "cable" for insulation This "cable sheath" of MS patients is seriously worn, which will lead to serious leakage, affect signal transmission, and cause a variety of pathological manifestations related to nerve injury MS symptoms are often manifested as visual impairment, limb weakness, sensory abnormality and ataxia, which will cause paralysis Figure 2 classification and sex composition of multiple sclerosis MS is mainly divided into recurrent remission type MS (RRMS) and primary progressive type MS (PPMS) About 15% of MS patients are of PPMS type, and the disease is gradually aggravating RRMS is the main type of MS, accounting for 85% of MS patients During the course of relapse and remission, the circulation of RRMS patients basically recovered after each attack, leaving no or only slight sequelae About 50% of RRMS no longer have relapse remission process after 10-15 years of illness, and then become the secondary progressive MS (SPMS) with slowly progressive aggravation In addition, the proportion of female patients in RRMS is 2-3 times that of male patients, and gender does not affect the occurrence of PPMS Referring to the drugs that have been on the market and clinical stage II and stage III, the drug development strategies for multiple sclerosis are mainly divided into three types: new immunomodulators, targeted s1pr modulators and nerve repair agents The new immunomodulator can slow down the myelin sheath damage by inhibiting the MS autoimmune process, and has stronger safety and effectiveness than the early immunomodulator When there are more than ten drugs on the market, see Table 1 Table 1 overview of new immunomodulator MS drugs on the market (part) At present, the specific situation of some new immunomodulator MS drugs on the market is as follows: (1) Aurelizumab, a new immunomodulator, is a CD20 humanized monoclonal antibody jointly developed by Baijian and Genentech (acquired by Roche) It can selectively target CD20 + B cells to alleviate the damage of myelin sheath and axon mediated by aurelizumab Compared with the traditional immunomodulator IFN β 1a, ocrelizumab showed a 47% reduction in relapse rate in phase III study (Opera I and opera II), showing a good effect At present, Roche is responsible for development and global commercialization, and has been approved in Canada, Australia, Mexico, Argentina and other countries (2) Dimethyl fumarate has been a blockbuster drug in the field of Baijian MS since it was launched in April 2013 In September 2019, at the 35th session of the European Committee for multiple sclerosis treatment and Research (ECTRIMS), the phase 3 evolve-ms-1 test data released by Baijian confirmed the long-term remission effect of dimethyl fumarate on MS for more than 10 years Taking dimethyl fumarate for more than 10 years can not only keep the incidence of the disease at a low level, but also increase the negative effects This good news will help Baijian to further expand the market position of dimethyl fumarate (3) Diroximel fumarate is a new drug developed early by Alkermes, and Baijian is responsible for global development and commercialization Diroximel fumarate is a prodrug of Monomethyl Fumarate Because of the oral controlled release technology of Alkermes, it can reduce the gastrointestinal tract stimulation caused by Monomethyl Fumarate Diroximel fumarate is an upgraded version of Baijian's Dimethyl fumarate with better effectiveness and safety On November 22, 2019, diroximel fumarate was officially launched in the United States, which will help to further improve the market share of Baijian in MS drug market (4) Natalizumab, a drug of Baijian, can inhibit the occurrence of diseases in early MS treatment, and alleviate the symptoms of disability and cognitive impairment Pegylated interferon beta-1a and interferon beta-1a had no adverse effects on pregnant women and infants There are opicinumab and biib-061 in the research and development pipeline of Baijian MS, both of which are nerve repair agents that directly promote the regeneration of myelin sheath In addition, there is a clinical phase I drug Burton tyrosine kinase inhibitor biib091 (5) Sanofi's teriflunomide is the first oral disease correction drug approved in China to treat Ms it took only 58 days from its approval to its market, setting the fastest market speed of rare disease drugs in China Telifloxamide in the domestic market has improved the compliance of MS patients, effectively reduced the frequency of clinical recurrence and delayed the progress of disability As the first MS oral treatment drug approved for marketing in China, telifloxamide has certain first-hand advantages (6) Alemtuzumab, developed jointly by Sanofi and Bayer, was awarded MS orphan drug qualification by Mexico in 2014 However, in 2019, the European Drug Administration's pharmacovigilance risk assessment committee recommended limiting the use of alemtuzumab in adult MS, which may have adverse effects in the future S1pr (sphingosine 1-phosphate receptor, sphingosine 1-phosphate receptor) is a member of G-protein-coupled receptor family, which can mediate inflammatory response, allergic response and participate in the migration of immune cells The changes of S1P (sphingosine-1-phosphate) concentration in blood, secondary lymphoid organs and lymph can regulate the homing and outflow of lymphocytes Table 2 overview of MS drug development of targeted s1pr modulator (part) Fingolimod (FTY720), developed by Novartis, is the world's first oral drug to treat MS and the first in class drug targeting s1pr By binding with the s1pr on the cell surface, the receptor can further sink in and degrade, inhibit the outflow of lymphocytes from the secondary lymphoid organs, prevent the lymphocytes from reaching the position of inflammatory damage, and play the role of immune regulation, as shown in Figure 3 Fig 3 Schematic diagram of FTY720 inhibiting lymphocyte outflow Fingolimod has been listed by the drug evaluation center (CDE) of the State Drug Administration as the first batch of overseas new drugs urgently needed in clinical practice, and approved for listing in China in 2019 Since its listing in 2010, the sales volume of fengomod has continued to grow In view of the adverse reactions of fengomod, Novartis has developed the second generation of MS drug siponimod, which is a new generation of selective s1pr regulator and has been included in the priority review list by China's CDE In addition, tetracosactide, an orphan drug of Novartis muscular dystrophy, can also be used to treat Ms Nerve repair is a new way of thinking beyond the target immune response, which has the potential to improve the disability Nerve repair agents directly target the signal proteins produced by myelin, promote the regeneration of myelin, and play a protective role At present, the drugs under study are mainly in clinical phase II, in which opicinumab can target LINGO-1, a membrane protein that can inhibit the formation of myelin sheath, and enhance the axonal myelin regeneration; CNM Au 8, a nano crystalline gold particle suspension, can enhance the biological energy of cells, thus promoting the myelin regeneration of damaged axons Table 3 overview of drug development of MS for nerve repair (partial) There are about 2.3 million people suffering from multiple sclerosis in the world, and the drug market is about US $23 billion At present, there are 28 drugs on the market, 14 drugs in the registration stage, 4 drugs in the pre registration stage and 24 drugs in the clinical phase III among them, Biogen has the largest number of MS drugs on the market, with 6 drugs Figure 4 approved number of drugs in global pharmaceutical companies During 2018-2019, the global MS drug market sales are concentrated, and leading enterprises such as Biogen, Novartis, Roche and Sanofi account for a large market share, as shown in Table 4 Table 4 sales volume of some MS drug markets in 2018-2019 (USD million) In addition, Merck Serono's interferon beta-1a, cladribine, Teva's glatiramer acetate, Bayer's interferon beta-1b, etc all have good market shares and deserve attention According to the data of birth defects research center of Fudan University, the number of rare diseases in China is about 16.8 million Many of these patients are undiagnosed and untreated In recent years, with the introduction of various policies, the diagnosis, treatment and drug research and development of rare diseases in China are gradually on the right track At the same time, many foreign drugs have begun to enter the Chinese market, with increasingly fierce competition Taking the MS field described in this paper as an example, there are many R & D pipelines and strong strength of multinational pharmaceutical enterprises, and the competitiveness of domestic enterprises is slightly insufficient As practitioners, how to choose the research and development field of rare diseases and how to formulate corresponding research and development strategies are all issues worthy of deep consideration After all, although rare diseases are small, they are a big business.