| Background: Leukemia is a malignant hematologic disorder with a high mortality rate,and is the most common major malignant disease with a high incidence rate in children,seriously endangering human health.Currently,drug therapy remains the main treatment for leukemia.In 2019,the National Health Commission jointly released the first batch of encouraged generic drug lists with several departments,which included expired patents and short supply of anti-leukemic drugs such as cyclophosphamide,methotrexate,mercaptopurine,and thiopurine.The country pays great attention to the anti-leukemic drug market,and researching anti-leukemic drugs has important practical significance.Objective: This study analyzed the global development trend of drugs for the treatment of leukemia,grasps the patent layout and research hotspots,explores the patent development status and regional competition situation of anti-leukemia drugs,and provides reference for the development,innovation,research and imitation of domestic leukemia drugs.Patent analysis and adverse reaction signal data mining analysis were carried out for the anti-leukemia drugs cyclophosphamide,methotrexate,azathioprine and mercaptopurine currently encouraged by the state,in order to provide reference for domestic enterprises to improve the synthesis path of anti-leukemia drugs currently encouraged by the state,improve their drug inserts and carry out post-marketing safety evaluation of drugs.Methods: This study extracted global anti-leukemia drug patent data and patent data for four target drugs,namely cyclophosphamide,methotrexate,mercaptopurine,and thiopurine,from the IncoPat global patent database.Conduct descriptive statistics and text clustering analysis on the patent data.Extract adverse drug reaction(ADR)information for the four target drugs from the US Food and Drug Administration Adverse Event Reporting System(FAERS),and conduct data mining research on the ADR information using reporting odds ratio(ROR),proportional reporting ratio(PRR),and Medicines and Healthcare Products Regulatory Agency(MHRA)methods.Extract target drug ADR signals,and discuss and analyze high-risk signals such as signals not mentioned in the instructions and gender differences in ADR signals in combination with literature reports.Results: 1.As of May 2021,the IncoPat global patent database has collected a total of 94,448 invention patents for anti-leukemia drugs,resulting in 27,995 patent families after merging.The United States has the highest number of patent applications for anti-leukemia drugs(9,450),followed by Japan(8,094)and China(6,469).In terms of patent holders,Novartis Ag from Switzerland owns the most patents(1,304),followed by Genentech Inc(947)and Pfizer Prod Inc(891),both from the United States.The main countries/organizations for patent publication are Japan,China,and the World Intellectual Property Organization(WIPO).The United States holds a large number of high-value patents.Currently,the research hotspots for anti-leukemia drugs include targeted drugs such as antibody drugs and protein kinase inhibitors,as well as small molecule drugs such as monoclonal antibodies.2.Among the four target drugs,methotrexate has the most related patents with a total of 76(46.63%),followed by cyclophosphamide with 51 patents(31.29%),and thiopurine has the least with only10 patents(6.13%).The patents for compound formulations of the four target drugs have all expired,and most of the formulation patents have also expired.However,a series of new formulation patents,such as sustained-release agents,lyophilized agents,suspensions,nanomaterials,and targeted molecular formulations,are still within their protection period.2.In recent years,the number of patent applications and publications of several drugs has been higher than the historical number,among which the number of cyclophosphamide and methotrexate related patents has increased more,and the number of azathioprine and mercaptopurine patents is small,and the market vacancy is large.Most of the patent applications for the four drugs are preparation patents,and the patents of new dosage forms of drugs have become a hot spot in research and development.3.From Q1 2019 to Q4 2021,FAERS received a total of 28,015 ADR reports for the four target drugs,with methotrexate having the highest number of reports(90.79%).The proportion of cyclophosphamide and methotrexate ADRs in the 60-74 age group was the highest,accounting for 23.29%and 28.63%,respectively.Thiopurine ADRs were highest in the 18～44 age group(25.09%),while mercaptopurine ADRs were highest in the age group under 18 years old(55.91%).Except for mercaptopurine,female patients had a higher incidence of ADRs than male patients for the other three drugs.Pharmacists and doctors were the main reporters of ADR reports,and developed countries were the main reporting countries.The age and gender distribution of patients with severe ADR reports were basically consistent with the overall distribution of reports.4.The common adverse reactions of the four target drugs are nausea,vomiting,febrile neutropenia,and drug ineffectiveness,mainly involving gastrointestinal disorders,blood and lymphatic system disorders,etc.In children,common ADRs include febrile neutropenia and drug ineffectiveness.There were a total of 25,499 patient outcomes recorded in serious ADR reports,including 9,390 serious ADR outcomes.Cyclophosphamide had the highest proportion of deaths caused by ADRs(15.83%),while mercaptopurine had the highest proportion of hospitalizations or extended hospital stays caused by ADRs(55.46%).5.Among the ADR signals detected by the three signal mining methods,methotrexate had the most signals(724)and mercaptopurine had the least(54).The four main drug ADR signals were "blood and lymphatic system diseases," "benign,malignant,and unspecified tumors(including cystic and polypoid)," and "infectious and infestive diseases." Three gender-specific high-risk ADR signals were detected for cyclophosphamide,110 gender-specific ADR signals were detected for methotrexate,and one male-specific high-risk ADR signal was detected for sulfasalazine.No gender-specific high-risk signals were detected for mercaptopurine.Conclusion: 1.Anti-leukemia drugs are in a period of rapid development,and the United States has an absolute advantage in terms of the number and quality of patent applications and patent value for anti-leukemia drugs.2.Companies can make new dosage forms of target drugs their research and development focus,combining imitation and innovation to seize the market.3.There are differences in gender,age,clinical manifestations and other factors among patients in ADR reports of target drugs,and medical staff should pay attention to individualized medication and timely monitoring of high-risk signals in clinical practice.4.The top 20 high-risk ADR signals among the four drugs are mostly related to various types of tumors,blood and lymphatic system diseases,infections,and invasive diseases.Mercaptopurine has the most adverse reaction signals not explicitly mentioned in the package insert.Methotrexate has the most ADR gender difference signals,with far more women than men,while mercaptopurine has not unearthed ADR gender difference signals. |
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