An analysis of recent developments in the field of orphan drug research and development in my country

Drugs, vaccines, diagnostic reagents, etc used to treat, diagnose and prevent rare diseases or rare states are called rare drugs or orphan drugs The incidence rate of rare diseases and common diseases is low, but there are many kinds of diseases, and most of them are seriously ill In addition, the rare diseases of the large population need urgent attention and attention In the past, there was almost no independent research and development in the field of rare diseases in China; in recent years, the public awareness of rare diseases has gradually improved, and a series of rare disease security measures issued by the state have stimulated the enthusiasm of drug companies to develop rare disease drugs In the past two years, some "highlights" in the field of orphan drug research and development in China are briefly analyzed here On December 28, 2017, the State Food and Drug Administration issued a new version of opinions on encouraging drug innovation to implement priority review and approval, which further clarified the scope of drug priority review and approval This includes applications for research and development of drugs for rare diseases From October 2016 to March 2018, the author made statistics on CFDA's priority review and approval catalogue, from which rare disease treatment drugs were selected to obtain the list of orphan drugs recently included in CFDA's priority review and approval, which is also the "bright spot" in the field of orphan drug development in China As shown in Table 1 Table 1 rare disease treatment drugs included in CFDA priority review and approval (2016 / 10 / 28-2018 / 03 / 28) it can be seen from the table that a total of 21 orphan drugs have been included in the priority review and approval recently, 14 clinical trial applications and 7 drug marketing applications From the perspective of indications, there are 7 coagulation factor products for hemophilia treatment, accounting for 1 / 3 of the total; other diseases include malignant hyperthermia, neuromyelitis, Charcot muscular atrophy, spinal muscular atrophy (SMA), general myasthenia gravis (GMG) and other neuromuscular diseases, type Ⅳ a mucopolysaccharide storage disease, type C Niemann peak disease and other metabolic defects, as well as retinoblastoma (RB) Chronic lymphocytic leukemia (CLL) and other rare tumors Hemophilia in the recent application products for orphan drug research and development in China, hemophilia treatment drugs can be described as "a unique branch", not only in large quantity, but also in rich categories Hemophilia is a hereditary haemorrhagic disease caused by the deficiency of coagulation factors VIII and IX the genetic mode is X-linked recessive inheritance The clinical characteristics are spontaneous joint hemorrhage and deep tissue hemorrhage, both male and female, but most of the patients are male, female patients are rare, usually carrier According to experts' estimates, the prevalence of hemophilia in China is 10-20 / 100000 At present, there are about 100000 hemophilia patients in China, among which 80% - 85% are patients with type a hemophilia (lack of coagulation factor VIII), and 15% - 20% are patients with type B hemophilia (lack of coagulation factor IX) The treatment of hemophilia is very clear, that is, alternative treatment It refers to the effect of hemostasis by supplementing exogenous coagulation factors The main therapeutic drugs are plasma derived factors and recombinant human coagulation factors Recombinant human coagulation factor VIII for injection is a specific drug for the treatment of hemophilia A Recently, Chengdu Rongsheng Pharmaceutical Co., Ltd and Shanxi Kangbao Biological Products Co., Ltd applied for the production of human coagulation factor VIII, and Beijing Northland Biotechnology Co., Ltd and Bayer medical health Co., Ltd applied for the clinical application of recombinant human coagulation factor VIII In addition to coagulation factor VIII, the treatment of hemophilia will usher in new therapeutic drugs Fitusiran is a RNAi therapy under development targeting antithrombin, which is administered subcutaneously once a month to treat hemophilia A and B The aim of this method is to reduce the level of antithrombin so that there is enough thrombin in the body to stop bleeding and prevent bleeding Fitusiran also has the potential to be used in rare hemorrhagic diseases At present, Beijing famasutik Consulting Co., Ltd has submitted the clinical application of fitusiran injection to CDE Emicizumab (ACE910) is a kind of experimental bispecific monoclonal antibody, which is developed by Japanese and foreign pharmaceutical companies, and is jointly developed by Roche and Chinese and foreign pharmaceutical companies It aims to gather coagulation factors IXa and X together These two proteins are necessary to activate the natural coagulation cascade reaction and restore the coagulation process In November 2017, fad approved the new Roche drug hemlibra (emisizumab kxwh) for routine prevention, prevention or reduction of haemorrhagic events in adult and child patients with hemophilia A A with factor VIII inhibitors At present, Roche (China) Investment Co., Ltd has submitted the clinical application of emisizumab injection to CDE The neuromuscular disease dantraline sodium is a kind of muscle relaxant which acts directly on skeletal muscle Its main action site is sarcoplasmic reticulum of skeletal muscle It can reduce muscle contraction by inhibiting the release of calcium ions from sarcoplasmic reticulum Dantraline sodium for injection is independently developed by Lizhu group for the treatment of malignant hyperthermia Malignant hyperthermia is a rare disease, a hereditary myopathy characterized by high metabolism Inebilizumab (formerly medi-551), a humanized monoclonal antibody, targets the B cell surface antigen CD19 Originally developed by MedImmune, AstraZeneca acquired the product Studies have shown that in the process of onset of optic neurmyelitis, the body will produce a large number of anti aquaporin-4 antibodies, which play an important role in the progress of the whole disease Ineblizumab can prevent plasma cells from producing such antibodies by targeting CD19 In 2017, inebilizumab was awarded the orphan drug qualification by the European Commission (EMA) for the treatment of optic neuromyelitis pedigree disease, which will provide favorable policy support for the research and development of the drug and its marketing Neuromyelitis optica (NMO) is an acute or subacute demyelinating disease in which the optic nerve and the spinal cord are involved simultaneously or successively It is a rare and life-threatening autoimmune disease of the central nervous system, characterized by the attack of the immune cells on the normal cells of the optic nerve and spinal cord, resulting in serious damage The clinical characteristics of blindness are acute or subacute Pxt3003 is the first drug for the treatment of Charcot muscular atrophy in the world At present, it has been granted the orphan drug qualification by EMA and FDA Pharnext company started the phase III clinical trial of the drug in 2015 At present, the trial is carried out in 30 centers in Europe, the United States and Canada It is expected that the trial will be completed around 2019 There is no drug for the treatment of Charcot muscular atrophy in China, so the clinical demand is urgent Charcot Marie Tooth disease is a neurodegenerative disease, mainly manifested as limb weakness, its incidence rate in the United States 5/10 million, there is no incidence rate in China, but conservative estimates of the domestic population of about 30 thousand people In May 2017, Tianshili strategically invested 20 million euros in pharnext company to obtain all the rights and interests of the drug in Greater China At present, Tianshili is launching the simultaneous research and development of dual newspapers at home and abroad Ro7034067 (also known as rg7916) is a drug designed to correct SMN2 splicing, intended for the treatment of SMA in adults and children, which is currently in phase II clinical stage in the United States Roche first submitted the clinical application of ro7034067 powder for oral solution in China Soliris, an autoimmune disease, is a complement inhibitor Soliris suppresses the damage caused by autoimmunity by inhibiting the complement cascade in autoimmunity Soliris has previously been used in the treatment of rare diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) Recently, the FDA approved soliris for the treatment of myasthenia gravis (mg) According to the pathogenesis of Mg and the clinical trials that have been completed, soliris will become one of the most important drugs in mg treatment MG is a kind of autoimmune disease involving postsynaptic membrane at neuromuscular junction, which is mainly mediated by acetylcholine receptor (AChR) antibody and participated by complement In the early stage, the extraocular muscles were involved, leading to ptosis, diplopia and other symptoms Most of the patients will develop into general mg The patients will have muscle weakness of limbs and head and neck, chewing and swallowing difficulties, and some patients will have respiratory muscle weakness Recombinant human B lymphocyte stimulator receptor antibody fusion protein for injection (trade name: tai'ai), developed by Yantai Rongchang Bioengineering Co., Ltd., is an innovative new drug for a class of biological products for treatment of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) Taiai is a fusion protein constructed from the extracellular soluble part of the BLyS receptor TACI and the FC part of human immunoglobulin IgG TACI's extracellular soluble part can neutralize BLyS and April, two key regulators of lymphocyte development and maturation, effectively block the interaction between BLyS and April and their receptors (TACI, BCMA and BAFF-R), thus effectively block the proliferation of B lymphocytes and the maturation of T lymphocytes, and can reduce the level of immunoglobulin and the number of mature B cells and total B cells in a dose-dependent manner It has the effect of inhibiting autoimmune diseases Megestat capsule has obtained the qualification of "conditional approval" from drug evaluation center in China, and the clinical trial of the drug is expected to be completed within 3 years For a long time, there is no effective treatment for C-type Niemann peak disease in China, which mainly focuses on symptomatic treatment and supportive treatment If megestat capsule can be successfully marketed, it will provide the first effective treatment drug for patients with rare C-type Niemann peak disease in China It is understood that the C-type Niemann peak disease is due to the genetic defect of lysosomal protein involved in the intracellular lipid transporter The main stage of the disease is late infancy and adolescence The main symptoms are the symptoms of the nervous system, including vertical supranuclear gaze paralysis, cerebellar ataxia, dysphonia and other symptoms The symptoms worsen rapidly Most of the patients died at the age of 10-25 Elosulfase alfa (trade name: vimizim) is the first IVA drug for the treatment of mucopolysaccharide storage in children, which was approved by FDA in February 2014 As a supplement of endogenous n-acetylgalactosamine-6-sulfatase, elosulfase Alfa can significantly improve the muscle strength, joint function and cardiopulmonary function of patients, and improve the quality of life of patients This product is a priority product for evaluation, which is applied for ind by biomarin in China There are two subtypes of mucopolysaccharidosis type Ⅳ (morquio's disease) Type Ⅳ A is galactose-6-sulfatase (GALNS) deficiency, and type Ⅳ B is β - d-galactase deficiency The disease is an autosomal recessive inheritance Its clinical characteristics are obvious growth retardation, abnormal gait and bone deformity, which are gradually significant Most patients live for 20-30 years Melphalan, a rare tumor, was first used to treat multiple myeloma In 2006, doctors began to use mefalun to treat retinoblastoma (RB), which proved to be very effective RB is a rare malignant tumor with incidence rate of 1/15000-20000 About 8000~9000 children are newly born RB each year, including 350 in the US and 1100 in China Children with RB had the first symptom of white pupil (also known as cat's eye symptom), because the tumor blocked the choroid, and the reflection of the tumor was white Ibotinib is the first Btk inhibitor on the market in the world, which is used for the treatment of rare tumors such as chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) and mantle cell lymphoma Ibrahimovic