A new generation of anti-flu drugs - Baloxavir marboxil.

TextThe hydrogen peroxide influenza is an acute respiratory infectious disease caused by influenza virus, mainly spread through contact and air droplets, and is high in winter and summerApril 2020, the Bureau of Disease Control and Prevention released an overview of the 2019 national statutory epidemic of infectious diseases, of which the number of influenza reported cases was the highest, up to 3.5 million cases, the incidence rate of 253 per 100,000, an increase of 359 percent over last year, a significant increasethe 2018 first-in-class anti-flu drug Baloxavir marboxil is listed in multiple countries, and the EvaluatePharma database shows that Baloxavir marboxil has global sales of $245 million in 2018compared to oseltamivir, Baloxavir marboxil has the advantage of no course of treatment (oseltamivir continuous treatment for 5 days), only one day administration, disease symptom relief time compared to oseltamivir, virus drops and safety than oseltamivir and other advantagesthis may break the pattern that neuraminidase inhibitors have dominated the influenza market for nearly 20 years and provide a new treatment mechanism for influenza, which has attracted wide attention from the industryBaloxavirmarboxil is the first new cap-dependent nucleic acid endoenzyme inhibitor developed by Yano Yi, Japan, which produces the active metabolite Baloxavir acid by the metabolism of Argyatchiacetyadia (AADAC)Haseko has a partnership agreement with Roche, which has commercial promotion rights outside Japan and TaiwanBaloxavirmarboxil has developed two dosage forms of tablets and granulesMarch 2018, the tablet was approved for the first time in Japan for the treatment of patients with acute and non-complications of influenza aged 12 and over, and in September of the same year, the granule was approved for listing in Japan; In March 2020, Roche filed with the FDA for the listing of tablets and granules for influenza prevention for the age of 1 and the listing application for treatment of influenza under 12 years of age, and on June 10, 2020, Roche filed a request for listing of Baloxavir marboxil tablets in China to be accepted by NMPABaloxavirmarboxil develops influenza RNA polymerases consisting of polymerase acid proteins (PA), alkaline polymerase 1 (PB1) and 2 (PB2) to play a critical role in virus replication and transcriptionvirus mRNA transcription depends on the unique "cap-snatching" mechanism :P B2 binding with the host 5'-cap transcription, cap-dependent nucleic acid endoenzyme in PA is cut within the position of about 12 nucleotides in 5'-cap, and the cut-down cap structure is used as a primer for viral mRNA transcription, inhibiting the nucleic acid endoenzyme inhibits mRNA transcription, which in turn inhibits viral replicationFigure 1The action mechanism of Cap-dependent nucleic acid endoenzyme inhibitors is disclosed by the structure of the PA protein active site, which mainly acts through two divalent metal ion manganese ions, and many scientists then begin to design structures that can be mated with metal ions, based on its earlier development of Dolutegravir, is achieved by two divalent metal ion ligation seisy enzyme suppression, the difference is that Dolutegravir is a mating with magnesium ionsYinnoYi earlier designed to get HIV-1 integrated enzyme inhibitor monocyclic metformin (compound 1), the structure of the key drug action group 3-hydroxyl-4-oxygen-2-methylate with 2 magnesium ion sesame, showing inhibition activity, but compound 1 in activity and selectivity is not significantstudies have shown that the hexacyclo-ring plays an important role in the spatial location control of key pharmaceutical groups, and therefore introduces a double-ring structure (compound 2)the compound is effective for wild viruses and not for mutant virusesfurther structural modification of binary cyclomidequinone, and significantly improved activity in mutant viruses after the introduction of hydroxy (compound 3)but the introduction of hydroxyl has a problem in controlling hand and post-configuration stability, so it is considered to increase the structural stability of hydroxyl binding in the ring, and to obtain tricyclic metalymidone (compound 4)determine the mother core, the opponent and the replacement base were examined separately to obtain DolutegravirFigure 2Dolutegravir's research and development process and Baloxaviracid derivatives are based on dolutegravir design ideas, extracting the key structures of molecular interaction with ions, and obtaining Baloxavir acid for structural modification of the parent nucleusBaloxavir acid and CEN protein crystal structure showed that Baloxavir acid's 7-hydroxyl-6, 8-dipyrinle base and 2 manganese ions formed a mating bond, further confirming the structural design rationality, the structure of this part also forms a hydrogen bond with three water molecules, while the dibenzene and sulfur part interact with the CEN part of the amino acid residue semofthe active molecule in mice only 4.2%, the seven hydroxyl series of derivation, and finally obtained Baloxavir marboxil, bioavailability increased to 14.6%, improve the absorption of molecules in the bodyFigure 3The Baloxavir acid and CEN protein complex crystal structure clinical outcomes Clinical Outcomes Clinical Outcomes Phase III (CAPSTONE-1) study was a randomized, double-blind, control trial that recruited patients aged 12-64 who were diagnosed with influenza and had no more than 48h of flu symptomspatients aged 20-64 were randomly grouped at 2:2:1, given a single Baloxavir marboxil (40 mg for patients under 80 kg, 80 mg for 80 kg or more), oseltamivir (75mg twice a day) and a placebo for five consecutive days, and 12-19 years of age with Baloxavir marboxil and a placebo, respectivelyclinical results showed that Baloxavir marboxil had a shorter fever-off time (24.5h) than a placebo (42.0h), and that the symptom-relieving time baloxavir marboxil was similar to oseltamivir (53.5h vs53.8h)in addition, the virus decreased by a greater margin than placebo and oseltamivir, and after treatment of 24h, Baloxavir marboxil, oseltamivir and placebo decreased by 4.4, 2.5 and 1.2 log10TCID50 compared to the baseline average virus titer Baloxavir marboxil significantly reduced the time to stop the virus release (24h) compared to placebo (96h) and oseltamivir (72h) In terms of safety, the overall incidence of Baloxavir marboxil adverse events (20.7%) was lower than placebo (24.6%) and oseltamivir (24.8%), and the rate of common adverse drug-related events was lower than oseltamivir (8.4%), and placebo (4.4% vs.3.9%) The common adverse events in the Baloxavir marboxil were diarrhea (3.0%), bronchitis (2.6%), nasopharyngitis (1.5%), nausea (1.3%), sinusitis (1.1%) and elevated ALT levels (1.0%) it is clear that Baloxavir marboxil has significant advantages in terms of efficacy and safety , Baloxavir marboxil was approved by the FDA in October 2019 to treat people at high risk of influenza complications over the age of 12, the first antiviral drug to show clinical lysmic benefits in populations at high risk of influenza complications, based on the results of the Clinical Phase III (CAPSTONE-2) trial CAPSTONE-2 clinical trial is also a randomized, double-blind, controlled trial that recruited people at high risk of flu complications over the age of 12 clinical results revealed that Baloxavir marboxil had a shorter time (73h) of improved symptoms than in the placebo group (102h) and no statistical difference with oseltamivir (81.0h) Baloxavir marboxil significantly shortens the time of cessation of the virus release, with a median time of 48h, oseltamivir and a placebo of 96h, significantly reducing the incidence of influenza-related complications by 2.8%, oseltamivir 4.6%, and placebo 10.4% patent analysis and domestic enterprise layout original research company in the domestic application for three compound patents and one crystal patent, two patent licensing, the other two in the real trial stage the compound patent CN102803260 protects the active metabolite Baloxavir acid, while CN103228653 patent protects various types of derivative precursor drugs, but does not include Baloxavir marboxbox The structure of the l' il, while CN107709321 protects Baloxavir marboxil, and if the patent is granted, the compound patent will expire in 2036, and the crystal patent, if granted, is one year later currently has nine pharmaceutical companies and two colleges and universities in China have applied for Baloxavir marboxil-related process synthesis patents, including Oselave imitation large household Guangdong Dongsunshine Pharmaceuticals may be mainly due to the baloxavir marboxil molecule in the presence of three hand centers, high process requirements, so a number of domestic enterprises began to optimize the layout of the process and apply for patent protection, so as to make a reserve for late generic drug cost control also indirectly see that a number of domestic enterprises on the drug's concern and interest Table 1 Baloxavir marboxil-related patent summary as the first new mechanism in nearly 20 years, The anti-flu drug Baloxavir marboxil has now entered the domestic listing review and approval, combined with its domestic patent filing protection, the original research drug will dominate the domestic market for nearly 15 years look forward to the future performance of Baloxavir marboxil in the domestic anti-flu market, whether a new generation of anti-flu drugs can break through the domestic anti-flu market, we wait and see References 1 Overview of the 2019 National Epidemic of Statutory Infectious Diseases The Bureau of Disease Prevention and Control Takeshi Noshi, Mitsutaka Kitanoet al In vitro manization of baloxavir acid, a first-in-class cap-dependent endonuclease op of the influenza virus polymerase PA subunit Antiviral Research, 2018, 180:109-117 Brian A Johns, Takashi Kawasujiet al Carbamoyl Pyridone HIV-1 Integrase Des A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and Discovery the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744) J Med Chem 2013, 56, 14, 5901-5916 Shinya Omoto, Valentina Speranzini et al Characterization of variant of the virus virus et al Characterization of the virus virus inducs by-treatment treatment with the datonuclease baroxavir marboxil Scientific Reports, 2018, 8:9633 Substituted polycyclic ketone derivatives and their precursors CN107709321 Frederick G Hayden, M.D et al Baloxavir Marboxil for Untinged Influenza in Adults and Teens N Engl J Med 2018, 379:913-923 FDA review report,