WO2023165566A1 - 治疗、预防由病毒感染引起的相关疾病的药物及其用途 - Google Patents

治疗、预防由病毒感染引起的相关疾病的药物及其用途 Download PDF

Info

Publication number
WO2023165566A1
WO2023165566A1 PCT/CN2023/079315 CN2023079315W WO2023165566A1 WO 2023165566 A1 WO2023165566 A1 WO 2023165566A1 CN 2023079315 W CN2023079315 W CN 2023079315W WO 2023165566 A1 WO2023165566 A1 WO 2023165566A1
Authority
WO
WIPO (PCT)
Prior art keywords
virus
days
administration
day
coronavirus
Prior art date
Application number
PCT/CN2023/079315
Other languages
English (en)
French (fr)
Inventor
王震
艾萨阿吉艾克拜尔
张卓兵
李宁
赵波
谢元超
Original Assignee
苏州旺山旺水生物医药有限公司
中国科学院上海药物研究所
中国科学院武汉病毒研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州旺山旺水生物医药有限公司, 中国科学院上海药物研究所, 中国科学院武汉病毒研究所 filed Critical 苏州旺山旺水生物医药有限公司
Publication of WO2023165566A1 publication Critical patent/WO2023165566A1/zh

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/16Antivirals for RNA viruses for influenza or rhinoviruses
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the technical field of medical applications, in particular to medicines for treating and preventing related diseases caused by viral infections and their applications.
  • viruses are pathogenic microorganisms that are extremely small, lack independent metabolic capabilities, and exist in a parasitic manner. There are many kinds of viruses. At present, many viruses with high infectivity and pathogenicity to humans have been discovered. These viruses often cause outbreaks of local or even global infectious diseases and are extremely harmful to human society, such as influenza virus , respiratory syncytial virus (RSV), parainfluenza virus, atypical pneumonia (SARS) virus, Middle East respiratory syndrome (MERS) virus, Ebola virus, etc. Some viruses can also infect animals and cause various mild to severe diseases. At the same time, animals have also become the source of infection of these viruses, making it difficult for humans to guard against them.
  • RSV respiratory syncytial virus
  • SARS atypical pneumonia
  • MERS Middle East respiratory syndrome
  • Ebola virus etc.
  • Some viruses can also infect animals and cause various mild to severe diseases. At the same time, animals have also become the source of infection of these viruses, making it difficult for humans to guard against them.
  • Coronaviruses belong to the order Neveviridae, Coronaviridae, and Coronaviridae. They are a large class of single-stranded positive-sense RNA viruses that widely exist in nature and can cause respiratory, digestive tract, and nervous system diseases in humans and animals. According to the phylogenetic tree, coronaviruses can be divided into four genera: ⁇ , ⁇ , ⁇ , and ⁇ , among which ⁇ coronaviruses can be divided into four independent subgroups A, B, C and D.
  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2), also known as the novel coronavirus pneumonia virus, has caused a continuous pandemic worldwide since the end of 2019, resulting in a severe epidemic since the Spanish flu pandemic in 1918. , another very serious global public health event.
  • SARS-CoV-2, atypical pneumonia virus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) all belong to the genus ⁇ coronavirus. At present, these three viruses have become the most pathogenic to humans. of coronavirus.
  • Coronaviruses can also infect a variety of mammals, including bats, pigs, dogs, cats, mice, cattle, horses, camels, etc. Most of these viruses belong to the ⁇ and ⁇ genera.
  • Porcine epidemic diarrhea virus (PEDV) is a coronavirus that can cause acute intestinal infectious diseases in pigs. Pigs of all ages can be infected, and among them, suckling pigs and newborn piglets are the most seriously affected. The outbreak of PEDV caused heavy losses.
  • Respiratory tract viral infection is the most common and most widely affected type of viral infectious disease clinically, causing a large number of deaths worldwide every year.
  • influenza virus influenza virus
  • respiratory syncytial virus respiratory syncytial virus
  • parainfluenza virus etc.
  • respiratory tract infection and pneumonia are important killers that threaten human life and health.
  • the first aspect of the present invention provides the use of nucleoside analogs or pharmaceutically acceptable salts thereof in the preparation of medicines or kits for treating and/or preventing related diseases caused by viral infections.
  • the second aspect of the present invention provides a method for treating and/or preventing related diseases caused by viral infection, which comprises administering an effective amount of a drug containing a nucleoside analog or a pharmaceutically acceptable salt thereof to an individual in need.
  • the third aspect of the present invention provides nucleoside analogs or pharmaceutically acceptable salts thereof for treating and/or preventing related diseases caused by viral infections.
  • the virus is selected from:
  • Coronaviruses that infect humans severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV);
  • coronaviruses causing the common cold are preferably selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC43), human coronavirus 229E (Human coronavirus229E), human coronavirus NL63 (Human coronavirus coronavirus NL63), human coronavirus HKUl (Human coronavirus HKUl);
  • influenza virus influenza A virus, influenza B virus, influenza C virus;
  • Flaviviridae viruses hepatitis C virus (HCV), dengue virus (DENV), Zika virus (Zika);
  • Filoviridae viruses Marburg virus (MBV), Ebola virus (EBV);
  • the virus is SARS-CoV-2 or a variant thereof.
  • the variant is selected from the group consisting of Alpha mutants, Beta mutants, Gamma mutants, Delta mutants, Epsilon mutants, Zeta mutants, Eta mutants, Theta mutants, Iota mutants, Kappa mutants At least one of strains, Mu mutant strains and Omicron mutant strains.
  • the related diseases caused by the virus infection are selected from the following group:
  • D2 Common cold, infection with high-risk symptoms, respiratory tract infection, pneumonia and its complications caused by human respiratory syncytial virus (RSV) infection;
  • RSV human respiratory syncytial virus
  • D7 Hemorrhagic fever and its complications caused by Marburg virus (MBV) and Ebola virus (EBV);
  • D9 Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV);
  • the nucleoside analog is a compound represented by formula I herein.
  • the drug contains a nucleoside analog or a pharmaceutically acceptable salt thereof in a dose of about 10-600 mg based on the nucleoside analog, Preferably about 50-300mg or 200-600mg, the non-limiting examples of the above dosage are about 10mg, about 20mg, about 25mg, about 40mg, about 50mg, about 60mg, about 80mg, about 90mg, about 100mg, about 110mg, about 150mg, about 180mg, about 200mg, about 250mg, about 290mg, about 300mg, about 310mg, about 350mg, about 400mg or about 600mg or any two values in these ranges as the range formed by the endpoint, preferably about 50mg, about 100mg, About 200 mg, about 300 mg, or about 600 mg.
  • the drug is an oral drug. In some embodiments, the drug is administered orally on an empty stomach or with normal food.
  • the dosage form of the drug includes tablet, capsule, granule or solution.
  • the administration frequency of the drug is 1 time, 2 times, 3 times or 4 times a day, preferably twice a day.
  • the single administration dose of the drug is about 25-1200 mg, preferably about 25-800 mg, preferably about 50 mg based on nucleoside analogs. -800 mg, more preferably about 200-600 mg.
  • the drug is administered at a single dose of about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450mg, about 500mg, about 550mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1100mg, about 1200mg or any two values in these ranges as the range formed by the endpoint, preferably about 200mg, about 400mg or about 600mg.
  • the administration cycle of the drug is 1-10 days or longer, preferably 1 day, 3 days, 5.5 days, 9 days, 10 days;
  • the time of each administration cycle is the same or different, and the interval between each administration cycle is the same or different.
  • the fourth aspect of the present invention provides a pharmaceutical composition, each unit of which contains nucleoside analogues or pharmaceutically acceptable salts thereof in a content of about 10-600 mg, preferably about 50-300mg or 200-600mg.
  • non-limiting examples of the above content are about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 150 mg, about 180 mg, About 200mg, about 250mg, about 290mg, about 300mg, about 310mg, about 350mg, about 400mg, about 600mg or any two values in these ranges as the range formed by the endpoint, preferably about 50mg, about 100mg, about 200mg, about 300mg , about 400mg or about 600mg, and a pharmaceutically acceptable carrier or auxiliary material.
  • the pharmaceutical composition is an oral pharmaceutical composition; preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, granules, and solutions.
  • the fifth aspect of the present invention provides a kit containing one or more doses of any one of the pharmaceutical compositions herein; wherein, the quantity of the pharmaceutical composition in the kit at least satisfies one dose
  • the dosage of the drug cycle, wherein, the daily dosage is 25-1200mg, preferably about 200-1200mg, more preferably about 400-1200mg, further preferably about 400-800mg of the nucleoside analogue or its pharmaceutically acceptable Accepted salt.
  • the one administration cycle is 1-10 days, such as 1 day, 3 days, 5.5 days, 9 days or 10 days.
  • the administration frequency is 1, 2, 3 or 4 times a day, preferably 2 times a day.
  • the kit contains one or more single pharmaceutical dosage units, wherein said single pharmaceutical dosage unit comprises about 25 nucleoside analogs or pharmaceutically acceptable salts thereof. - 1200 mg, preferably about 25-800 mg, more preferably about 50-800 mg, further preferably about 200-600 mg of said nucleoside analog or a pharmaceutically acceptable salt thereof.
  • the number of single pharmaceutical dosage units contained in the kit is sufficient for the administration of at least 1 dosing cycle; preferably, the dosing cycle is 1-10 days or longer The time is preferably 1 day, 3 days, 5.5 days, 9 days or 10 days.
  • the quantity of the single drug dosage unit in the kit satisfies the administration of at least 3 consecutive days, preferably at least 5 consecutive days, twice a day; preferably, each single drug
  • the dosage unit contains about 200 mg, about 400 mg or about 600 mg of said nucleoside analog or a pharmaceutically acceptable salt thereof; more preferably, said nucleoside analog or a pharmaceutically acceptable salt thereof;
  • the glycoside analogue is said VV116 or its free base.
  • Figure 1 Design scheme of 3 phase I studies of VV116 in China.
  • Figure 2 The in vivo transformation process of VV116 after oral administration.
  • Figure 3 Mean plasma 116-N1 concentration-time profiles for each dose group after single dose escalation of VV116.
  • Figure 4 Mean plasma 116-N1 concentration-time profiles on days 1 and 6 in the multiple dose escalation study.
  • Figure 5 Mean plasma 116-N1 concentration-time profiles under fasting and fed conditions.
  • 2019 novel coronavirus (2019-nCoV) is a new strain of coronavirus that has never been found in humans before.
  • ICTV International Committee on Taxonomy of Viruses
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • WHO World Health Organization
  • the symptoms of SARS-CoV-2 infection are mainly pneumonia, which can be divided into simple infection, mild pneumonia, severe pneumonia, acute respiratory distress syndrome, sepsis, and septic shock according to the severity of the disease.
  • Patients with uncomplicated infection may have nonspecific symptoms such as fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or malaise, Atypical symptoms may occur in the elderly and immunosuppressed persons.
  • Patients with mild pneumonia mainly present with cough and shortness of breath. Severe pneumonia can be seen in adults, adolescents or children. The main symptoms are increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, lethargy, unconsciousness or convulsions, and gasping.
  • the lung imaging of acute respiratory distress syndrome is bilateral ground-glass opacity, but it cannot be completely explained by effusion, lobar effusion, or atelectasis or pulmonary block, and pulmonary edema is the main symptom. Patients with sepsis often have fatal organ dysfunction, and septic shock is the most critical patient with a high probability of death.
  • Mutant strains of SARS-CoV-2 include Alpha Mutant, Beta Mutant, Gamma Mutant, Delta Mutant, Epsilon Mutant, Zeta Mutant, Eta Mutant, Theta Mutant, Iota Mutant, Kappa Mutant At least one of strains, Mu mutant strains and Omicron mutant strains.
  • prevention means that, when used for a disease or disorder (such as cancer), the compound or drug (such as the combination product claimed in this application) is compared to a subject who is not administered the compound or drug (such as the combination product claimed herein).
  • the medicament is capable of reducing the frequency or delaying the onset of symptoms of a medical condition in a subject.
  • treating refers to alleviating, alleviating or ameliorating the symptoms of a disease or disorder, ameliorating underlying metabolically Regression of a disease or disorder, alleviation of a condition caused by a disease or disorder, or arrest of symptoms of a disease or disorder.
  • an "effective amount” or “prophylactically and/or therapeutically effective amount” refers to a sufficient amount (e.g., dose) of a drug or compound administered that will alleviate to some extent the effects of the disease or condition being treated. one or more symptoms. The result may be a reduction and/or alleviation of the cause of a condition or disease or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic use is an amount of a compound or drug (eg, a combination product claimed herein) that provides a significant reduction in the clinical symptoms of a disease or disorder without undue toxic side effects.
  • administering refers to introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods or delivery systems known to those skilled in the art.
  • AE adverse effect
  • a medical treatment may have one or more associated AEs, and each AE may be of the same or a different level of severity.
  • subject include any organism, preferably an animal, more preferably a mammal (eg rat, mouse, dog, cat, rabbit, etc.), and most preferably a human.
  • subject and patient are used interchangeably herein.
  • pharmaceutically acceptable carrier or adjuvant refers to a compound that can be administered together with one aspect of the present invention Non-toxic carriers or adjuvants that are non-toxic to a subject and that do not destroy the pharmacological activity of the compound when administered at a dose sufficient to deliver a therapeutic amount of the compound.
  • Exemplary pharmaceutically acceptable carriers or excipients include inert diluents such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol , 1,3-butanediol, dimethylformamide, oils (including cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and dehydrated Fatty acid esters of sorbitol, and mixtures thereof; auxiliary agents, such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavoring agents and aromatic agents, etc.
  • administration mode and “dosage regimen” are used interchangeably and refer to the dosage and time of use of each therapeutic agent in the combination of the present invention.
  • nucleoside analog refers to any nucleoside analog described in WO2021213288A1, or a pharmaceutically acceptable salt thereof, which is incorporated herein by reference in its entirety.
  • nucleoside analogs used herein have the structure shown in Formula I below:
  • R 1 is cyano
  • R 2 is hydroxyl or C 1-4 alkyl-COO-
  • R 3 is H or C 1-4 alkylcarbonyl optionally substituted by amino
  • R4 is H
  • X is C 1-4 alkylene, wherein, one or more (such as within 3) H in the alkylene is substituted by deuterium;
  • R 5 is H, C 1-4 alkylcarbonyl optionally substituted by amino
  • R 6 is amino
  • R7 is H
  • R 8 is H, deuterium (D) or halogen.
  • R 2 is C 1-3 alkyl-COO-.
  • R 3 is C 1-4 alkylcarbonyl optionally substituted with amino. Further preferably, R 3 is unsubstituted C 1-4 alkylcarbonyl.
  • X is -C(H) 2- . In some embodiments, X is -C(D) 2- .
  • R 5 is C 1-4 alkylcarbonyl optionally substituted with amino. Further preferably, R 5 is not Substituted C 1-4 alkylcarbonyl.
  • R 8 is deuterium
  • At least one of R 2 , R 3 O- and R 5 O- is C 1-3 alkyl-COO-; preferably, at least two of R 2 , R 3 O- and R 5 O- one is C 1-3 alkyl-COO-; more preferably, R 2 , R 3 O- and R 5 O- are all C 1-3 alkyl-COO-.
  • the C 1-3 alkyl is a C 3 alkyl, more preferably isopropyl.
  • the alkyl group includes linear and branched chain alkyl groups.
  • a carbonyl group is a -C(O)- group.
  • amino is -NH 2 .
  • the nucleoside analogue that can be used in any of the uses, therapies, pharmaceutical compositions and kits described in the present invention is VV116, and the chemical structural formula of VV116 is as follows:
  • This article provides a nucleoside analogue or a pharmaceutically acceptable salt thereof according to any embodiment herein and a pharmaceutically acceptable carrier or adjuvant. pharmaceutical composition.
  • the pharmaceutical compositions described herein are pharmaceutical compositions suitable for oral administration.
  • the dosage form of the pharmaceutical composition suitable for oral administration can be tablets, lozenges, capsules, buccal tablets, granules, solutions, aqueous or oily suspensions, dispersible powders or granules, syrups or elixirs, etc. . It should be understood that when formulated into a pharmaceutical composition suitable for oral administration, the pharmaceutical composition contains pharmaceutically acceptable carriers or excipients suitable for oral administration.
  • the pharmaceutical composition described herein may contain about 10-600 mg, preferably about 50-300 mg or 200-600 mg of said nucleoside analog or a pharmaceutically acceptable salt thereof per unit.
  • Non-limiting examples of the content of the nucleoside analog or a pharmaceutically acceptable salt thereof in the pharmaceutical composition per unit are about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, About 90mg, about 100mg, about 110mg, about 150mg, about 180mg, about 200mg, about 250mg, about 290mg, about 300mg, about 310mg, about 350mg, about 400mg, about 600mg or any two values in these ranges formed as endpoints
  • the range is preferably about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 600 mg.
  • the kit described herein may contain one or more doses of the pharmaceutical composition described in any embodiment herein; wherein, the quantity of the contained pharmaceutical composition at least satisfies the dosage of one administration cycle, wherein, every day
  • the dosage is 25-1200 mg, preferably about 200-1200 mg, more preferably about 400-1200 mg, further preferably about 400-800 mg of the nucleoside analog or a pharmaceutically acceptable salt thereof.
  • the 1 administration cycle is 1-10 days, such as 1 day, 3 days, 5.5 days, 9 days or 10 days.
  • the amount of the pharmaceutical composition contained satisfies the dosage for at least one dosing cycle, and in this dosing cycle, the dosing frequency is twice a day.
  • the kit contains one or more single pharmaceutical dosage units.
  • said single pharmaceutical dosage unit comprises about 25-1200 mg, preferably about 25-800 mg, more preferably about 50-800 mg, further preferably about 200-600 mg of said nucleoside analog or a pharmaceutically acceptable one thereof. Accepted salt.
  • Non-limiting examples of the content of the nucleoside analog or a pharmaceutically acceptable salt thereof in the single pharmaceutical dosage unit are about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg , about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1100mg, about 1200mg or any two values in these ranges as the range formed by the endpoint, preferably about 200mg, about 400mg or about 600mg.
  • the single drug dosage unit refers to 1 or 1 dose of drug dosage unit administered at each administration.
  • the single pharmaceutical dosage unit is a pharmaceutical composition according to any embodiment herein.
  • the number of single drug dosage units contained in the kit is sufficient for the administration of at least one administration cycle.
  • the administration cycle is 1-10 days or longer, preferably 1 day, 3 days, 5.5 days, 9 days or 10 days.
  • the timing of each dosing cycle can be the same or different, and the interval between each dosing cycle can be the same or different.
  • the daily dosing frequency is 1 time, 2 times, 3 times or 4 times a day, preferably twice a day.
  • said kit contains said single pharmaceutical dosage unit in an amount sufficient for at least 3 consecutive days, preferably at least 5 consecutive days, twice daily administration.
  • each single pharmaceutical dosage unit contains about 200 mg, about 400 mg or about 600 mg of the nucleoside analog or pharmaceutically acceptable salt thereof according to any embodiment herein. Nucleoside analogs or pharmaceutically acceptable salts thereof. More preferably, the active ingredient contained in the pharmaceutical composition is VV116 described herein.
  • the kit of the invention further comprises instructions for the method of use of the medicine.
  • nucleoside analog or a pharmaceutically acceptable salt thereof in the preparation of a medicament or kit for treating and/or preventing related diseases caused by viral infection.
  • nucleoside analog or a pharmaceutically acceptable salt thereof according to any embodiment herein for use in the treatment and/or prevention of related diseases caused by viral infection.
  • a method for treating and/or preventing related diseases caused by viral infection comprising administering to an individual in need thereof an effective amount of the nucleoside analogs described in any embodiment herein or a pharmaceutically acceptable salt or pharmaceutical composition.
  • Viruses described herein include, but are not limited to:
  • Coronaviruses that infect humans severe acute respiratory syndrome coronavirus SARS-CoV (Severe acute respiratory syndrome coronavirus, SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), Middle East respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus, MERS-CoV);
  • coronaviruses causing the common cold are preferably selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC43), human coronavirus 229E (Human coronavirus229E), human coronavirus NL63 (Human coronavirus coronavirus NL63), human coronavirus HKUl (Human coronavirus HKUl);
  • influenza virus influenza A virus, influenza B virus, influenza C virus;
  • Flaviviridae viruses hepatitis C virus (HCV), dengue virus (DENV), Zika virus (Zika);
  • Filoviridae viruses Marburg virus (MBV), Ebola virus (EBV); and
  • the above-mentioned viruses also include its various mutant strains, such as the Alpha mutant strain, Beta mutant strain, Gamma mutant strain, Delta mutant strain, Epsilon mutant strain, Zeta mutant strain, Eta mutant strain, Theta mutant strain of SARS-CoV-2 strains, Iota mutants, Kappa mutants, Mu mutants and Omicron mutants.
  • D2 Common cold, infection with high-risk symptoms, respiratory tract infection, pneumonia and its complications caused by human respiratory syncytial virus (RSV) infection;
  • RSV human respiratory syncytial virus
  • D7 Hemorrhagic fever and its complications caused by Marburg virus (MBV) and Ebola virus (EBV);
  • D9 Porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV);
  • the medicine or kit in the above use is the pharmaceutical composition or kit described in any of the above embodiments, or is used to implement the disease prevention or treatment methods described in any of the embodiments herein.
  • the preferred mode of administration is oral; the preferred frequency of administration includes 1, 2, 3 or 4 times a day , preferably 2 times a day; the preferred administration cycle is 1-10 days, such as 1 day, 3 days, 5.5 days, 9 days or 10 days; the preferred dosage is 25- 1200 mg, preferably about 25-800 mg, more preferably about 50-800 mg, further preferably about 200-600 mg of the nucleoside analog or a pharmaceutically acceptable salt thereof.
  • each dose administered is about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg , about 700mg, about 800mg, about 900mg, about 1100mg, about 1200mg, or any two values in these ranges as the range formed by the endpoint, or a pharmaceutically acceptable salt thereof, more preferably about 200mg, about 400mg or about 600mg of a nucleoside analog or a pharmaceutically acceptable salt thereof.
  • the drug is administered on an empty stomach or with a normal diet, more preferably on an empty stomach.
  • the normal dietary condition refers to the daily diet of a normal individual, excluding high-fat diet.
  • a method for treating or preventing the novel coronavirus pneumonia caused by SARS-CoV-2, especially the novel coronavirus pneumonia caused by the omecroron variant comprising administering Nucleoside analogue VV116 or its pharmaceutically acceptable salt for patients in need, wherein, the dosage regimen is: each administration dose is 200-600 mg of VV116 or its pharmaceutically acceptable salt in terms of VV116, daily Twice, continuous administration for at least 3 days, preferably at least 5 days, and oral administration on an empty stomach.
  • MTD maximum tolerated dose AE adverse event QD One dose per day IRC Independent Review Committee TEAE treatment-related adverse reactions SAE serious adverse reaction CI confidence interval ALT alanine aminotransferase BID twice daily BMI body mass index C trough concentration Dx day X eCRF electronic medical record report form GCP Good Clinical Practice for Drug Clinical Trials PK Pharmacokinetics NAG N-acetyl- ⁇ -D-glucosaminidase AUC area under the plasma concentration-time curve CTCAE evaluation criteria for common adverse events
  • Studies 1 and 2 are randomized, double-blind, placebo-controlled, single-dose and multiple-dose escalation studies, aiming to evaluate single and multiple escalation oral VV116 in healthy subjects The safety, tolerability and pharmacokinetics of VV116;
  • Study 3 is a randomized, open-label, 3-period, crossover study designed to observe the effect of diet on the pharmacokinetics and safety of VV116 ( Figure 1).
  • Age 18 years old ⁇ age ⁇ 45 years old; gender is not limited;
  • Body weight male ⁇ 50kg, female ⁇ 45kg; body mass index (BMI) in the range of 19-26kg/ m2 (including 19 and 26);
  • HBeAg Hepatitis B surface antigen
  • Anti-HCV hepatitis C virus antibody
  • Treponema pallidum antibody HIV antibody positive
  • Chest X-ray (posteroanterior) results are abnormal and have clinical significance;
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Test drug VV116 tablet; specifications: 50mg, 100mg and 300mg. Storage: Store at room temperature, sealed.
  • Placebo VV116 blank tablet; specifications: 50mg, 100mg and 300mg. Storage: Store at room temperature, sealed.
  • the placebo is a tablet that has no difference in appearance (shape, color, size, packaging) and smell from the test drug, does not contain the active ingredient of the test drug, and is composed of the original formula.
  • the starting dose is 25mg group, because the preparation specification does not have 25mg (preparation specifications are: 50, 100, 300mg, each specification is designed in proportion to the prescription), the product with 50mg specification is administered in the research center by cutting into slices.
  • the sponsor has done relevant pharmaceutical research, and the weight difference, content uniformity, friability, dissolution rate, content, related substances, and weight loss of the second half of the tablet after slicing all meet the quality standards.
  • the cutting surfaces are all off-white, and there is no difference in appearance.
  • the estimated maximum recommended starting dose was selected as 25 mg, and the estimated maximum dose was selected as 1200 mg.
  • the initial dose is 25mg
  • 6 subjects men and women are not limited
  • 8 subjects male and female are not limited
  • the safety, tolerability and PK characteristics were evaluated.
  • the number of single-dose groups may be increased or decreased based on the safety and pharmacokinetic data obtained.
  • the escalating dose levels are planned to be 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg and 1000 mg (dose groups 1-8). After the administration of the 25mg dose group, the researchers evaluated the safety results (including symptoms, vital signs, physical examination, etc.) within 48 hours of administration of the subjects and found no potential safety hazards, and the drug was well tolerated.
  • Uzbekistan This product obtained the clinical approval in Uzbekistan (hereinafter referred to as "Uzbekistan") on September 30, 2021.
  • Phase II/III clinical trials among hospitalized patients with new crowns in Uzbekistan are underway, using a randomized, controlled, and open 3-group design.
  • Two VV116 test groups, the doses were 200mg and 300mg, twice a day, for 5 days, and the control group was Favipiravir.
  • Each group plans to enroll 150 cases, of which 100 cases are confirmed as moderate SARS-CoV-2 infection and 50 cases are confirmed as severe SARS-CoV-2 infection.
  • the trial completed the enrollment of the first case on November 3, 2021.
  • the preliminary safety data summary of 47 subjects 2 days after the first administration has been completed.
  • the main AE is Transaminases were mildly elevated, no SAE occurred, and no subjects withdrew.
  • the sponsor believes that with a sample size of 47 cases (36 cases in the test group) and a daily dose of 400-600 mg, the safety performance can basically prove the safety of a single dose of 200 mg, so it is expected that this product will be available in China.
  • the safety risk of a single administration of 200mg in healthy subjects is controllable, the 50mg and 100mg dose groups can be deleted, and the single administration of the 200mg dose group can be directly performed.
  • the sponsor decided to adjust the single dose group to 25mg, 200mg, 400mg, 800mg and 1200mg.
  • the 25mg dose group 4 subjects received VV116 tablets, and 2 subjects received placebo.
  • 6 subjects in each group will receive VV116 tablets, and 2 subjects will receive placebo.
  • the 25mg dose group underwent sentinel administration. After the 25mg dose group completed the administration, according to the phased safety research results of the ongoing clinical trial in Uzbekistan and the results of the previous study of this study, the investigator and the sponsor decided on the 200 and 400mg dose groups Sentinel administration was not performed, and sentinel administration was continued in the 800mg and 1200mg dose groups.
  • the researchers evaluated the 48-hour safety results of the sentinel administration (including symptoms, vital signs, physical examination, etc.) and found no safety hazards. And it is well tolerated. On this premise, the rest of the subjects in this group can be administered.
  • the screening will be carried out within 14 days before the administration, and the subjects will be admitted to the phase I ward (hospitalization) on the -1 day for evaluation of the inclusion criteria. Subjects will fast overnight for at least 10 hours prior to dosing on Day 1. Under fasting conditions, the 1st Subjects were orally administered VV116 tablets or placebo at respective dose levels with 240 mL of water every day. All subjects remained in the Phase I clinical study center until 48 hours after dosing for close medical monitoring, except subjects in the 400 mg dose group, who underwent an exploratory material balance study within 72 hours after dosing. After randomized double-blind dosing, subjects will receive daily safety assessments and PK sample collection.
  • the investigator will allow the subject to be discharged from the hospital as appropriate after completing the evaluation on the morning of the third day. Those with normal examinations at the time of discharge will be followed up by telephone on the 7th day ( ⁇ 1 day); if abnormal, follow-up will be arranged by the investigator according to the actual situation. Subjects who quit early will try to follow the requirements of the discharge inspection and complete the observation of safety observation indicators before quitting.
  • investigators and sponsors Before entering the next dose group, investigators and sponsors will mainly review the clinical safety and tolerability of each dose group to evaluate whether the administration of the next dose group can be started; if necessary, it can be judged in conjunction with PK data. In addition, investigators and sponsors can make a decision on whether to adjust the dose group or whether to adjust the number of subjects based on the results of previous studies.
  • the entire trial cycle includes a screening period of no more than 14 days, a 5.5-day multi-dose administration period (D1-D6), a 3-day safety observation period and a 4-day safety follow-up period.
  • the subjects will be admitted to the Phase I clinical trial ward one day before the administration (D-1, baseline period), and will not leave until all inspections and evaluations are completed on the 8th day. ⁇ 1 day) telephone follow-up; if abnormal, follow-up follow-up will be arranged by the researcher according to the actual situation.
  • Early exit subjects try to complete the safety observation indicators according to the requirements of the discharge inspection and exit.
  • Food Effects Study Screening was carried out within 14 days before administration, and 12 healthy subjects who met the study inclusion criteria were selected. Subjects must obtain signed informed consent before performing the procedures specified in the protocol.
  • the specific administration method is as follows: 12 healthy subjects were randomly divided into three groups A, B, and C, with 4 cases in each group. Group A was administered under fasting conditions in the first cycle, and administered under standard postprandial conditions in the second cycle. Drugs were administered under high-fat postprandial conditions in the third period. Group B was administered under high-fat postprandial conditions in the first period, administered under fasting conditions in the second period, and administered under standard postprandial conditions in the third period.
  • the first cycle was administered under standard postprandial conditions, the second cycle was administered under high-fat postprandial conditions, the third cycle was administered under fasting conditions, three cycles of cross-administration, and the washout period was 3 days.
  • a single oral dose of 400 mg was administered, for the fasting period, a single oral dose of 400 mg VV116 tablet was administered after an overnight fast ( ⁇ 10 hours). 30 minutes after consumption of a standard meal (total calories: about 700kcal) or a high-fat meal (total calories: about 800kcal-1000kcal from protein, carbohydrates and fat about 150, 250 and 500-600kcal respectively) during two feeding sessions
  • a single oral dose of 400 mg VV116 tablet was administered internally. All subjects remained in the Phase I clinical study center until 48 hours after the last dose.
  • the trial period for each subject does not exceed 27 days, including a screening period of no more than 14 days, a 9-day dosing observation period (including D1, D4 and D7 administration, and 3 days after each administration) washout period and safety observation period), and then a safety follow-up period of 4 days (D13).
  • Subjects will be admitted to the phase I clinical trial ward one day before the administration (D-1), and will not leave until the ninth day (D9) after all inspections and evaluations are completed, and at the same time return to the research center according to the visit arrangement specified in the protocol or pass Receive follow-up visits by phone and complete relevant procedures and assessments.
  • AEs and SAEs that occurred during the trial, including vital signs, physical examination, 12-lead electrocardiogram, ophthalmological examination, clinical laboratory test indicators (blood routine, blood biochemistry, urine NAG, coagulation function, urine routine + urine sediment + urine microalbumin, thyroid function), etc.
  • Adverse events that occurred throughout the study period were assessed and graded according to the National Cancer Institute Terminology for Common Adverse Events (NCI-CTCAE) version 5.0.
  • Blood samples of approximately 3 ml were collected at predetermined time points for analysis.
  • blood samples were collected at the following 15 time points: 0 (pre-dose); and post-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 , 12, 24, 36 and 48 hours. Afterwards, the time point was slightly adjusted according to the pharmacokinetic profile of the 25 mg group.
  • blood samples were collected at the following time points: 0 (pre-dose); and 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour after dosing, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours.
  • Collected blood samples were separated by centrifugation at 1500 g for 10 minutes at 4°C, then split into 2 centrifuge tubes (at least 0.6 mL plasma each), frozen and stored at -80°C until analysis.
  • 116-N1-D4 was chosen as the internal standard.
  • the calibration curve was linear from 10 to 10 000 ng/mL with a regression coefficient of 0.9998.
  • the within-assay precision ranged from 2.2 to 12.4%, and the between-assay precision ranged from 2.5 to 8.2%.
  • the accuracy is 90.5-100.1%.
  • the pharmacokinetic parameters of VV116 and its main metabolite 116-N1 in the plasma of all dose groups of 25-1200mg were calculated by WinNonlin software with non-compartmental model method.
  • the main pharmacokinetic parameters are: peak time (Tmax), peak concentration (Cmax), half-life (t1/2), area under the drug concentration-time curve from 0 o'clock to the collection time t of the last measurable concentration ( AUC0-t), the area under the drug concentration-time curve from 0 to 24 hours (AUC0-24h), the area under the drug concentration-time curve from 0 to infinite time (AUC0- ⁇ ), the elimination rate constant (Ke ), apparent volume of distribution (Vd/F), mean residence time (MRT), clearance (CL/F), cumulative excretion (Ae) and excretion fraction (Fe), etc.
  • AUC0-t and AUC0- ⁇ are calculated using the Linear Up Log Down rule method. Tmax and Cmax are based on actual measurements. In the multiple ascending dose study, the
  • PK parameters including AUC0-t, AUC0- ⁇ , and Cmax under different dietary conditions were analyzed. Means, mean differences, and 90% confidence intervals of log-transformed PK parameters were estimated using generalized linear mixed models with dietary condition, sequence, and period as fixed effects and subject as a random effect. Pairwise comparisons (high-fat meal versus fasting, standard meal versus fasting, high-fat meal versus standard meal) were performed for each PK parameter.
  • VV116 is rapidly hydrolyzed to its metabolite 116-N1, which undergoes three consecutive enzymatic phosphorylation reactions in cells to produce the active form of triphosphate 116-NTP (see Figure 2).
  • the parent drug was not detected in plasma (lower limit of quantitation 2 ng/mL), but its metabolite 116-N1 was detected, and PK parameters were calculated in three studies.
  • Table 2 summarizes the main PK parameters of 116-N1 in each dose group after a single dose of VV116. The mean plasma 116-N1 concentration-time curves are shown in Figure 3.
  • the main PK exposure parameters, Cmax and AUC, were dose-dependent.
  • Mean ⁇ SD for Cmax were 154 ⁇ 66.7, 1096 ⁇ 412, 1898 ⁇ 701, 2796 ⁇ 225, and 3086 ⁇ 778 ng/mL for the 25 mg, 200 mg, 400 mg, 800 mg, and 1200 mg dose groups, respectively.
  • the AUC0-t of the above five dose groups were 888 ⁇ 286, 6986 ⁇ 1683, 13064 ⁇ 2727, 26233 ⁇ 5897 and 28325 ⁇ 5272 h ⁇ ng/mL.
  • Confidence interval (CI) criteria were used to assess dose linearity. Table 3 shows the dose proportional analysis.
  • VV116 is absorbed rapidly after oral administration.
  • VV116 can be rapidly hydrolyzed into the metabolite 116-N1 after oral administration.
  • the average plasma drug peak time (Tmax) is only 1.00-2.50 hours, and the absorption is rapid.
  • the area under the oral dose plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) are dose-dependent in the dose range of 25-800mg, there is no significant increase between the doses of 800-1200mg, and the highest is the highest at the dose of 1200mg.
  • the average half-life (t 1/2) of VV116 was 5.21-6.95 hours, suggesting that the dosing frequency was set to twice a day (BID) in clinical treatment.
  • the main PK parameters of 116-N1 on day 1 and day 6 after multiple doses of VV116 are listed in Table 4.
  • the mean plasma 116-N1 concentration-time curves on day 1 and day 6 of 200mg, 400mg and 600mg dose groups are shown in the figure 4.
  • Table 5 shows the trough concentrations of 116-N1 on days 5 and 6.
  • the average t1/2 on day 6 was longer than that on day 1 (4.72h vs 7.56h in the 200mg group, 4.88h vs 8.12h in the 400mg group, 5.41h vs 7.85h in the 600mg group).
  • Cmax, AUC0-t, and AUC0- ⁇ increased after repeated dosing.
  • the Cmax accumulation rates (Rac) of the dose groups 200mg, 400mg and 600mg were 1.34, 1.18 and 1.24, respectively, and the Rac of AUC 0-t were 1.53, 1.41 and 1.42, respectively, indicating slight accumulation after repeated administration of VV116.
  • the researchers also found that the trough concentrations of 116-N1 in the 200mg group on days 5 and 6 were in the range of 242-345 ng/mL, which was higher than the effective concentration of 116-N1 anti-Omicron variants in preclinical studies ( EC90, 186.5ng/mL), suggesting that the dose regimen of 200mg BID and above can sustainably maintain the effective antiviral concentration, and is recommended for follow-up clinical research.
  • the geometric mean ratio (GMR) and its 90% CI of standard meal and fasting Cmax, AUC0-t, AUC0- ⁇ were 106.60% (93.40%-121.67%), 119.52% (114.50%-124.76%) and 118.21% ( 113.53%-123.08%), respectively in the equivalent range of 80%-125%.
  • the GMRs (90%CIs) of Cmax, AUC0-t and AUC0- ⁇ during high-fat meal and fasting were 107.92% (94.56%-123.18%), 126.32% (121.01%-131.85%) and 124.67% (119.74%), respectively -129.81%), respectively.
  • AUC0-t and AUC0- ⁇ of high-fat meal increased by 26.32% and 24.67%, respectively.
  • the GMRs (90% CIs) of Cmax under the normal diet and high-fat diet conditions were in the equivalent range of 80%-125%; the AUC GMRs (90% CIs) of the normal diet were also 80-125% range, while the AUC 0-t and AUC 0- ⁇ increases of high-fat diet were 26.32% and 24.67%, respectively. Since eating has no effect on Cmax, but high-fat diet slightly increases AUC, it is recommended to take VV116 orally on an empty stomach or under normal diet conditions.
  • VV116 has a lower risk of hepatotoxicity, and researchers will continue to monitor liver function in patients in subsequent phase II studies.
  • the number (incidence) of subjects experiencing AEs under fasting, standard meal, high fat meal states was 0 (0), 2 (16.7%) and 4 (33.3%).
  • Grade 1 atrioventricular block occurred in 2 cases with standard meal, and positive urine bacteria test, crystalluria, elevated blood pressure, and grade 1 atrioventricular block occurred in 4 cases with high-fat meal. All AEs were CTCAE grade 1 in severity.
  • VV116 showed satisfactory safety and tolerability in healthy subjects.
  • the plasma drug concentration of the active ingredient 116-N1 could reach its peak rapidly (mean Tmax was 1.00-2.50 hours), AUC and Cmax are dose-dependent in the dose range of 25-800mg; ordinary diet has no effect on AUC and Cmax of VV116 after oral administration; after multiple administrations, the effective antiviral concentration can be reached at the dose level of 200-600mg BID.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及治疗、预防由病毒感染引起的相关疾病的药物及其用途。具体而言,本发明提供下式I所示的核苷类似物或其药学上可接受的盐在制备治疗和/或预防由病毒感染引起的相关疾病的药物中的用途,本发明还提供含有式I所示结构的核苷类似物或其药学上可接受的盐的药物组合物或药盒。本发明的核苷类似物在健康受试者中表现出令人满意的安全性和耐受性;多次给药后能达到有效的抗病毒浓度。

Description

治疗、预防由病毒感染引起的相关疾病的药物及其用途 技术领域
本发明涉及医药用途技术领域,具体涉及治疗、预防由病毒感染引起的相关疾病的药物及其用途。
背景技术
在急性传染病中,绝大部分都是病毒性传染病,病毒性传染病的发病率高,死亡率也很高。病毒一类个体极其微小、缺乏独立代谢能力、以寄生方式存在的病原微生物。病毒的种类繁多,目前,已发现了许多对人类具有高传染性和高致病性的病毒,这些病毒常造成地方性甚至全球性传染病暴发,对人类社会有极大的危害,如流感病毒、呼吸道合胞病毒(RSV)、副流感病毒、非典型性肺炎(SARS)病毒、中东呼吸综合征(MERS)病毒、埃博拉病毒等。一些病毒也可感染动物,引起各种轻到重度疾病,同时,动物也成为这些病毒的传染源,令人类对其防不胜防。
冠状病毒属于套式病毒目、冠状病毒科、冠状病毒属,是自然界广泛存在的一大类单股正链的RNA病毒,可引起人和动物呼吸道、消化道和神经系统疾病。根据系统发育树,冠状病毒可分为四个属:α、β、γ、δ,其中β属冠状病毒又可分为四个独立的亚群A、B、C和D群。
严重急性呼吸综合征冠状病毒2(SARS-Cov-2),又称之为新型冠状肺炎病毒,自2019年底开始在全球范围内引起了持续性的大流行,造成了自1918年西班牙大流感后,又一次非常严重的全球公共卫生事件。SARS-CoV-2、非典型性肺炎病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)同属于β属冠状病毒,目前,这三种病毒已成为对人类致病能力最强的冠状病毒。
冠状病毒也可感染多种哺乳动物,包括蝙蝠、猪、犬、猫、鼠、牛、马、骆驼等,这些病毒多为α、β属。猪流行性腹泻病毒(PEDV)是一种能引起猪急性肠道传染病的冠状病毒,各种年龄的猪都能感染发病,其中,尤以哺乳猪、新生仔猪受害最为严重,养殖业常因PEDV的爆发而蒙受重大损失。
呼吸道病毒感染是临床上最常见的、影响最广的一类病毒感染性疾病,每年都会造成全球大量人口死亡。除冠状病毒外,流感病毒、呼吸道合胞病毒、副流感病毒等也可引起呼吸道感染,导致肺炎,是威胁人类生命健康的重要杀手。
目前,针对SARS-CoV-2冠状病毒等导致的感染性疾病严重影响了人们的生命健康,研发效果好的抗病毒药物迫在眉睫,本领域迫切需要开发用于治疗和/或预防由病毒感染引起的相关疾病的药物。
发明内容
本发明第一方面提供了核苷类似物或其药学上可接受的盐在制备治疗和/或预防由病毒感染引起的相关疾病的药物或药盒中的用途。
本发明第二方面提供了治疗和/或预防由病毒感染引起的相关疾病的方法,其包含向有需要的个体施用有效量的含核苷类似物或其药学上可接受的盐的药物。
本发明第三方面提供了用于治疗和/或预防由病毒感染引起的相关疾病的核苷类似物或其药学上可接受的盐。
在所述第一方面到第三方面的一个或多个实施方案中,所述病毒选自:
(1)感染人的冠状病毒:重症急性呼吸综合征冠状病毒SARS-CoV(Severe acute respiratory syndrome coronavirus,SARS-CoV)、2019新型冠状病毒(2019-nCoV或SARS-CoV-2)、中东呼吸综合征冠状病毒MERS-CoV(Middle East respiratory syndrome coronavirus,MERS-CoV);
(2)致普通感冒的冠状病毒:所述的致普通感冒的冠状病毒优选选自下组:人冠状病毒OC43(Human coronavirus OC43)、人冠状病毒229E(Human coronavirus229E)、人冠状病毒NL63(Human coronavirus NL63)、人冠状病毒HKUl(Human coronavirus HKUl);
(3)人呼吸道合胞病毒(RSV);
(4)人流感病毒:甲型流感病毒、乙型流感病毒、丙型流感病毒;
(5)黄病毒科病毒:丙型肝炎病毒(HCV)、登革热病毒(DENV)、寨卡病毒(Zika);
(6)丝状病毒科病毒:马尔堡病毒(MBV)、埃博拉病毒(EBV);
(7)感染其他哺乳动物的冠状病毒:猪流行性腹泻病毒(PEDV)。
在所述第一方面到第三方面的一个或多个实施方案中,所述病毒为SARS-CoV-2或其变异株。优选地,所述变异株选自阿尔法突变株、贝塔突变株、伽马突变株、德尔塔突变株、Epsilon突变株、Zeta突变株、Eta突变株、Theta突变株、Iota突变株、卡帕突变株、缪突变株和奥密克戎突变株中的至少一种。
在所述第一方面到第三方面的一个或多个实施方案中,所述病毒感染引起的相关疾病选自下组:
(D1)人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
(D2)人呼吸道合胞病毒(RSV)感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
(D3)人流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
(D4)丙型肝炎病毒(HCV)引起的慢性丙型肝炎及其并发症;
(D5)登革热病毒(DENV)引起的登革热及其并发症;
(D6)寨卡病毒(Zika)引起的感染及其并发症;
(D7)马尔堡病毒(MBV)、埃博拉病毒(EBV)引起的出血热及其并发症;
(D8)SARS-CoV-2引起的新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19);
(D9)猪流行性腹泻病毒(PEDV)引起的猪流行性腹泻;
(D10)上述疾病的任意组合。
在所述第一方面到第三方面的一个或多个实施方案中,所述核苷类似物如本文式I所示的化合物。
在所述第一方面到第三方面的一个或多个实施方案中,所述药物中包含以核苷类似物计剂量为约10~600mg的核苷类似物或其药学上可接受的盐,优选为约50-300mg或200-600mg,上述剂量非限制性实施例为约10mg、约20mg、约25mg、约40mg、约50mg、约60mg、约80mg、约90mg、约100mg、约110mg、约150mg、约180mg、约200mg、约250mg、约290mg、约300mg、约310mg、约350mg、约400mg或约600mg或这些范围内任意两个数值作为端点形成的范围,优选为约50mg、约100mg、约200mg、约300mg、或约600mg。
在所述第一方面到第三方面的一个或多个实施方案中,所述药物为口服药物。在一些实施方案中,空腹或普通饮食条件下口服给药。
在所述第一方面到第三方面的一个或多个实施方案中,所述药物的剂型包括片剂、胶囊剂、颗粒剂或溶液剂。
在所述第一方面到第三方面的一个或多个实施方案中,所述药物给药频率为每日给药1次、2次、3次或4次,优选为每日两次。
在所述第一方面到第三方面的一个或多个实施方案中,所述药物单次给药剂量以核苷类似物计为约25-1200mg,优选为约25-800mg,优选为约50-800mg,进一步优选为约200-600mg。在一些实施方案中,所述药物的单次给药剂量以核苷类似物计为约25mg、约50mg、约100mg、约150mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约700mg、约800mg、约900mg、约1100mg、约1200mg或这些范围内任意两个数值作为端点形成的范围,优选为约200mg、约400mg或约600mg。
在所述第一方面到第三方面的一个或多个实施方案中,所述药物的给药周期为1-10天或更长时间,优选为1天、3天、5.5天、9天、10天;任选地,每个给药周期的时间相同或不同,且每个给药周期之间的间隔相同或不同。
本发明第四方面提供了一种药物组合物,每单元的该药物组合物包含以核苷类似物计含量为约10~600mg的核苷类似物或其药学上可接受的盐,优选为约50-300mg或200-600mg。优选地,所述上述含量的非限制性实施例为约10mg、约20mg、约25mg、约40mg、约50mg、约60mg、约80mg、约90mg、约100mg、约110mg、约150mg、约180mg、约200mg、约250mg、约290mg、约300mg、约310mg、约350mg、约400mg、约600mg或这些范围内任意两个数值作为端点形成的范围,优选为约50mg、约100mg、约200mg、约300mg、约400mg或约600mg,以及药学上可接受的载体或辅料。
在一个或多个实施方案中,所述药物组合物为口服药物组合物;优选地,所述的药物组合物的剂型包括片剂、胶囊剂、颗粒剂、溶液剂。
本发明第五方面提供了一种药盒,所述药盒含有1剂或多剂本文任一项所述的药物组合物;其中,药盒中所述药物组合物的数量至少满足1个给药周期的给药量,其中,每天的给药量为25-1200mg、优选约200-1200mg、更优选约400-1200mg、进一步优选约400-800mg的所述核苷类似物或其药学上可接受的盐。
在一个或多个实施方案中,所述1个给药周期为1-10天,例如1天、3天、5.5天、9天或10天。
在一个或多个实施方案中,所述给药周期中,给药频次为每日1次、2次、3次或4次,优选每日2次。
在一个或多个实施方案中,所述药盒含有一个或多个单次药物剂量单元,其中,所述单次药物剂量单元包含以核苷类似物或其药学上可接受的盐计约25-1200mg、优选约25-800mg、更优选约50-800mg、进一步优选约200-600mg的所述核苷类似物或其药学上可接受的盐。
在一个或多个实施方案中,所述药盒所含的单次药物剂量单元的数量满足至少1个给药周期的给药;优选地,所述给药周期为1-10天或更长时间,优选为1天、3天、5.5天、9天或10天。
在一个或多个实施方案中,所述药盒中所述单次药物剂量单元的数量满足至少连续3天、优选至少连续5天,每天2次的给药;优选地,每个单次药物剂量单元含有以所述核苷类似物或其药学上可接受的盐计约200mg、约400mg或约600mg的所述核苷类似物或其药学上可接受的盐;更优选地,所述核苷类似物为所述VV116或其游离碱。
附图说明
图1:VV116中国3项I期研究设计方案。
图2:口服后VV116体内转化流程。
图3:单次剂量递增VV116后各剂量组的平均血浆116-N1浓度-时间曲线。
图4:多次剂量递增研究中第1天和第6天的平均血浆116-N1浓度-时间曲线。
图5:空腹和进食条件下的平均血浆116-N1浓度-时间曲线。
具体实施方式
以下,将详细地描述本发明。在进行描述之前,应当理解的是,在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义,而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上,根据与本发明的技术方面相应的含义和概念进行解释。因此,这里提出的描述仅仅是出于举例说明目的的优选实例,并非意图限制本发明的范围,从而应当理解的是,在不偏离本发明的精神和范围的情况下,可以由其获得其他等价方式或改进方式。
术语
为了更易于理解本发明,下文具体定义某些科技术语。除非本文中别处另有明确说明,否则本文所用的科技术语皆具有本发明所属技术领域的普通技术人员通常所了解的含义。
除非该内容被另外明确说明,否则本说明书以及所附权利要求中所用的单数形式"一个"、"一种"和"该"包括复数指代。因此,例如,提及"一种多肽"包括了两种或更多种多肽等的组合。
本文所述的“约”在指代可测量数值(如量、持续时间等)时意在涵盖相对于具体数值±20%或±10%的变化,包括±5%、±1%和±0.1%,因为这些变化适于进行所公开的方法。
2019新型冠状病毒(2019-nCoV)是以前从未在人类中发现的冠状病毒新毒株。2020年2月11日,国际病毒分类委员会(ICTV)宣布,2019新型冠状病毒(2019-nCoV)的正式分类名为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndromecoronavirus 2,SARS-CoV-2)。同日,世界卫生组织(WHO)宣布,由这一病毒导致的疾病的正式名称为COVID-19。SARS-CoV-2感染的症状主要以肺炎为主,依据病情的轻重程度可分为单纯性感染、轻症肺炎、重症肺炎、急性呼吸窘迫综合症、脓毒症、脓毒症休克等。单纯性感染的患者可能有非特异性症状,例如发热、咳嗽、咽痛、鼻塞、乏力、头痛、肌肉疼痛或不适,老 年人和免疫抑制者可能会出现非典型症状。轻症肺炎的患者主要以咳嗽、呼吸急促为主。重症肺炎可见于成人、青少年或儿童,主要症状为呼吸频率增加,严重的呼吸衰竭或呼吸困难,中心型发绀、嗜睡、意识不清或惊厥、抽气等。急性呼吸窘迫综合症的肺部影像为双侧磨玻璃影,但不能完全由积液、大叶渗出或者肺不张或者肺部块影解释,以肺水肿为主要症状。脓毒症患者往往有致命的器官功能障碍,脓毒性休克是最为危重的患者,死亡可能性较高。
SARS-CoV-2的变异株包括阿尔法突变株、贝塔突变株、伽马突变株、德尔塔突变株、Epsilon突变株、Zeta突变株、Eta突变株、Theta突变株、Iota突变株、卡帕突变株、缪突变株和奥密克戎突变株中的至少一种。
在本文使用的术语“预防”是指当用于疾病或病症(例如癌症)时,与未施用化合物或药物(例如,本申请要求保护的组合产品)的受试者相比,所述化合物或药物能降低受试者体内的医学病症症状的频率或推迟其发病。
在本文中使用的术语“治疗”是指减轻、缓解或改善疾病或病症的症状,改善潜在的代谢引起的的症状,抑制疾病或症状,例如阻止疾病或病症的房展、缓解疾病或病症、引起疾病或病症的消退、缓解疾病或病症引起的病况、或阻止疾病或病症的症状。
在本文中使用的术语“有效量”或“预防和/或治疗有效量”是指施用的药物或化合物的足够量(例如,剂量),其将在一定程度上减轻被治疗的疾病或病症的一种或多种症状。结果可以是缩小和/或减轻病症或疾病原因或任意其它期望的生物系统的改变。例如,用于治疗用途的“有效量”是提供以使疾病或病症的临床症状显著减轻、而不产生过度的毒副作用的化合物或药物(例如,本申请要求保护的组合产品)的量。
“施用”、“给与”及“给药”是指采用本领域技术人员已知的各种方法或递送系统中的任意一种将包含治疗剂的组合物引入受试者。
本文所述的“不良反应”(AE)是与使用医学治疗相关的任何不利的和通常无意的或不期望的迹象、症状或疾病。例如,不良反应可能与在响应治疗时免疫系统的激活或免疫系统细胞的扩增相关。医学治疗可以具有一种或多种相关的AE,并且每种AE可以具有相同或不同的严重性水平。
术语“受试者”、“个体”、“对象”包括任何生物体,优选动物,更优选哺乳动物(例如大鼠、小鼠、狗、猫、兔等),且最优选的是人。术语“受试者”和“患者”在本文中可以互换使用。
术语“药学上可接受的载体或辅料”是指可以与本发明的一个方面的化合物一起施用 于受试者并且当以足以递送治疗量化合物的剂量施用时不破坏其药理学活性并且无毒的载体或辅料。示例性的药学上可接受的载体或辅料包括惰性稀释剂,如水或其他溶剂、增溶剂及乳化剂,如乙醇、异丙醇、碳酸乙酯、EtOAc、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(包括棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油及芝麻油)、甘油、四氢糠醇、聚乙二醇及脱水山梨糖醇的脂肪酸酯,及其混合物;助剂,如湿润剂、乳化剂及悬浮剂、甜味剂、调味剂和芳香剂等。术语“给药方式”、“给药方案”可互换使用,是指本发明组合中每一治疗剂的使用剂量及时间。
核苷类似物
本文所述“核苷类似物”指WO2021213288A1中描述的任意一个核苷类似物、或其药学上可接受的盐,本文以引用的方式将其全文纳入本文。
在一些优选的实施方案中,本文所用的核苷类似物具有下式I所示的结构:
式中:
R1为氰基;
R2为羟基或C1-4烷基-COO-;
R3为H或任选被氨基取代的C1-4烷基羰基;
R4为H;
X为C1-4亚烷基,其中,该亚烷基中的1个或多个(如3个以内)H被氘取代;
R5为H、任选被氨基取代的C1-4烷基羰基;
R6为氨基;
R7为H;
R8为H、氘(D)或卤素。
在一些实施方案中,R2为C1-3烷基-COO-。
在一些实施方案中,R3为任选被氨基取代的C1-4烷基羰基。进一步优选地,R3为未取代的C1-4烷基羰基。
在一些实施方案中,X为-C(H)2-。在一些实施方案中,X为-C(D)2-。
在一些实施方案中,R5为任选被氨基取代的C1-4烷基羰基。进一步优选地,R5为未 取代的C1-4烷基羰基。
在一些实施方案中,R8为氘。
在一些实施方案中,R2、R3O-和R5O-中至少一个为C1-3烷基-COO-;优选地,R2、R3O-和R5O-中至少两个为C1-3烷基-COO-;更优选地,R2、R3O-和R5O-都为C1-3烷基-COO-。在一些实施方案中,所述C1-3烷基为C3烷基,更优选为异丙基。
本文中,烷基包括直链和支链烷基。本文中,羰基为-C(O)-基团。本文中,氨基为-NH2
在特别优选的实施方案中,可用于本发明所述的任一用途、疗法、药物组合物及药盒的核苷类似物为VV116,VV116化学结构式如下:
药物组合物和药盒
本文提供含有本文任一实施方案所述的核苷类似物或其药学上可接受的盐以及药学上可接受的载体或辅料。药物组合物。
本文所述的药物组合物是适于口服给药的药物组合物。适于口服给药的药物组合物的剂型可以是片剂、锭剂、胶囊剂、含片、颗粒剂、溶液剂、水性或油性悬浮液、可分散的粉末或小颗粒、糖浆或酏剂等。应理解,当配制成适于口服给药的药物组合物时,药物组合物中含有适于口服给药的药学上可接受的载体或辅料。
本文所述的药物组合物每单元可含有约10-600mg、优选约50-300mg或200-600mg的所述核苷类似物或其药学上可接受的盐。每单元所述药物组合物中所述核苷类似物或其药学上可接受的盐的含量的非限制例子为约10mg、约20mg、约25mg、约40mg、约50mg、约60mg、约80mg、约90mg、约100mg、约110mg、约150mg、约180mg、约200mg、约250mg、约290mg、约300mg、约310mg、约350mg、约400mg、约600mg或这些范围内任意两个数值作为端点形成的范围,优选为约50mg、约100mg、约200mg、约300mg、约400mg或约600mg。
本文所述的药盒可含有1剂或多剂本文任一实施方案所述的药物组合物;其中,所含有的药物组合物的数量至少满足1个给药周期的给药量,其中,每天的给药量为25-1200mg、优选约200-1200mg、更优选约400-1200mg、进一步优选约400-800mg的所述核苷类似物或其药学上可接受的盐。在一些实施方案中,所述1个给药周期为1-10天,例如1天、 3天、5.5天、9天或10天。在一些实施方案中,所含有的药物组合物的数量满足至少1个给药周期的给药量,该给药周期中,给药频次为每日两次。
在一些实施方案中,所述药盒含有一个或多个单次药物剂量单元。在一些实施方案中,所述单次药物剂量单元包含约25-1200mg、优选约25-800mg、更优选约50-800mg、进一步优选约200-600mg的所述核苷类似物或其药学上可接受的盐。所述单次药物剂量单元中所述核苷类似物或其药学上可接受的盐的含量的非限制性例子为约25mg、约50mg、约100mg、约150mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约700mg、约800mg、约900mg、约1100mg、约1200mg或这些范围内任意两个数值作为端点形成的范围,优选为约200mg、约400mg或约600mg。本文中,所述单次药物剂量单元指每次给药时给予的1个或1剂药物剂量单元。在一些实施方案中,所述单次药物剂量单元为本文任实施方案所述的药物组合物。
优选地,所述药盒所含的单次药物剂量单元的数量满足至少1个给药周期的给药。在一些实施方案中,所述给药周期为1-10天或更长时间,优选为1天、3天、5.5天、9天或10天。每个给药周期的时间可相同或不同,且每个给药周期之间的间隔可相同或不同。优选地,所述给药周期中,每天的给药频率为每日给药1次、2次、3次或4次,优选为每日两次。
在一些实施方案中,所述药盒所含的所述单次药物剂量单元的数量满足至少连续3天、优选至少连续5天,每天2次的给药。优选地,每个单次药物剂量单元含有以本文任一实施方案所述的核苷类似物或其药学上可接受的盐计约200mg、约400mg或约600mg的本文任一实施方案所述的核苷类似物或其药学上可接受的盐。更优选地,所述药物组合物中所含的活性成分为本文所述的VV116。
在一些实施方案中,本发明所述的药盒还包含药物使用方法的说明书。
用途和方法
本文提供本文任一实施方案所述的核苷类似物或其药学上可接受的盐在制备治疗和/或预防由病毒感染引起的相关疾病的药物或药盒中的用途。本文还提供用于治疗和/或预防由病毒感染引起的相关疾病的本文任一实施方案所述的核苷类似物或其药学上可接受的盐。本文还提供治疗和/或预防由病毒感染引起的相关疾病的方法,该方法包括包含向有需要的个体施用有效量的本文任一实施方案所述的核苷类似物或其药学上可接受的盐或药物组合物。
本文所述的病毒包括但不限于:
(1)感染人的冠状病毒:重症急性呼吸综合征冠状病毒SARS-CoV(Severe acute  respiratory syndrome coronavirus,SARS-CoV)、2019新型冠状病毒(2019-nCoV或SARS-CoV-2)、中东呼吸综合征冠状病毒MERS-CoV(Middle East respiratory syndrome coronavirus,MERS-CoV);
(2)致普通感冒的冠状病毒:所述的致普通感冒的冠状病毒优选选自下组:人冠状病毒OC43(Human coronavirus OC43)、人冠状病毒229E(Human coronavirus229E)、人冠状病毒NL63(Human coronavirus NL63)、人冠状病毒HKUl(Human coronavirus HKUl);
(3)人呼吸道合胞病毒(RSV);
(4)人流感病毒:甲型流感病毒、乙型流感病毒、丙型流感病毒;
(5)黄病毒科病毒:丙型肝炎病毒(HCV)、登革热病毒(DENV)、寨卡病毒(Zika);
(6)丝状病毒科病毒:马尔堡病毒(MBV)、埃博拉病毒(EBV);和
(7)感染其他哺乳动物的冠状病毒:猪流行性腹泻病毒(PEDV)。
上述病毒也包括其各种变异毒株,如SARS-CoV-2的阿尔法突变株、贝塔突变株、伽马突变株、德尔塔突变株、Epsilon突变株、Zeta突变株、Eta突变株、Theta突变株、Iota突变株、卡帕突变株、缪突变株和奥密克戎突变株。
本文所述的由病毒感染引起的相关疾病包括但不限于:
(D1)人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
(D2)人呼吸道合胞病毒(RSV)感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
(D3)人流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
(D4)丙型肝炎病毒(HCV)引起的慢性丙型肝炎及其并发症;
(D5)登革热病毒(DENV)引起的登革热及其并发症;
(D6)寨卡病毒(Zika)引起的感染及其并发症;
(D7)马尔堡病毒(MBV)、埃博拉病毒(EBV)引起的出血热及其并发症;
(D8)SARS-CoV-2引起的新型冠状病毒肺炎(COVID-19);
(D9)猪流行性腹泻病毒(PEDV)引起的猪流行性腹泻;
(D10)上述疾病的任意组合。
在优选的实施方案中,上述用途中的药物或药盒为前文任一实施方案所述的药物组合物或药盒,或者为用于实施本文任一实施方案所述的疾病预防或治疗方法的药物组合物或药盒。
在一些实施方案中,本文所述的治疗和/或预防由病毒感染引起的相关疾病的方法中,优选的给药方式是口服;优选的给药频次包括每日1、2、3或4次,优选每日2次;优选的给药周期为1-10天,如1天、3天、5.5天、9天或10天;优选的给药剂量为每次25- 1200mg、优选约25-800mg、更优选约50-800mg、进一步优选约200-600mg的所述核苷类似物或其药学上可接受的盐。在一些实施方案中,每次给药剂量为约25mg、约50mg、约100mg、约150mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约700mg、约800mg、约900mg、约1100mg、约1200mg或这些范围内任意两个数值作为端点形成的范围的所述核苷类似物或其药学上可接受的盐,更优选为每次约200mg、约400mg或约600mg的核苷类似物或其药学上可接受的盐。优选地,口服给药。优选地,空腹或普通饮食条件下给药,更优选空腹服药。本文中,所述普通饮食条件指正常个体的日常饮食,不包括高脂饮食。
在特别优选的实施方案中,本文提供一种治疗或预防由SARS-CoV-2引起的新型冠状病毒肺炎,尤其是由奥密克戎变异株引起的新型冠状病毒肺炎的方法,该方法包括给予需要的患者核苷类似物VV116或其药学上可接受的盐,其中,给药方案为:每次的给药剂量以VV116计为200-600mg的VV116或其药学上可接受的盐,每日2次,连续给药至少3天、优选至少5天,空腹口服给药。
缩略语
贯穿于本发明的说明书及实施例中,使用以下缩略语:
MTD 最大耐受剂量
AE 不良事件
QD 每天一个剂量
IRC 独立审查委员会
TEAE 与治疗相关的不良反应
SAE 严重不良反应
CI 置信区间
ALT 丙氨酸转氨酶
BID 每日两次
BMI 体重指数
Ctrough 谷浓度
Dx 第X天
eCRF 电子病历报告表
GCP 药物临床试验质量管理规范
PK 药代动力学
NAG N-乙酰-β-D-氨基葡萄糖苷酶
AUC 血药浓度-时间曲线下面积
CTCAE 常见不良反应事件评价标准
本发明通过以下实施例进一步阐述,但所述实施例不应被解释为限制本发明。整个申请中引用的所有参考文献的内容通过引用的方式明确并入本文。
实施例
研究设计
先后进行了三项I期临床试验成果,研究1和2为随机、双盲、安慰剂对照、单剂量和多剂量递增研究,旨在评估在健康受试者中单次和多次递增口服VV116的安全性、耐受性和药代动力学;研究3是一项随机、开放、3周期、交叉研究,旨在观察饮食对VV116药代动力学和安全性的影响(图1)。
本临床试验必须遵守现行法律法规和指导原则,它们包括但不限于NMPA-GCP、国际协调会议临床试验质量管理规范(ICH-GCP)以及源于《赫尔辛基宣言》的伦理准则。三项临床研究登记在https://clinicaltrials.gov/,登记号分别为:NCT05227768,NCT05201690,NCT05221138。
研究人群
入组标准:
1)年龄:18周岁≤年龄≤45周岁;性别不限;
2)体重:男性≥50kg,女性≥45kg;体重指数(BMI)在19-26kg/m2范围内(含19和26);
3)健康状况良好。生命体征、体格检查、实验室检查、甲状腺B超、眼科检查、心电图和B超检查均正常或异常无临床意义;
4)在试验期间及服药后3个月将能采取可靠的避孕措施;
5)充分了解本试验的目的、内容和可能出现的不良反应,自愿参加临床试验并签署书面知情同意书,能按试验要求完成全部试验过程并遵守试验规定。
排除标准:
1)已知对试验制剂及其任何成分或相关制剂有过敏史;
2)有过敏性疾病患者或过敏体质者;
3)有中枢神经系统、心血管系统、消化系统、呼吸系统、泌尿系统、血液系统、代谢障碍等的明确疾病且需要医学干预或其他不适合参加临床试验的疾病(如精神病史等) 者;
4)入选前3个月内有过献血或失血≥400mL者,或有血液制品使用史;
5)入选前3个月内参加过其他药物临床试验者;
6)筛选前2周内服用过任何处方药、非处方药、中草药或保健品者;
7)筛选前1年内是毒品吸食者或酒精成瘾者,每日饮酒至少2次或每周饮酒14个单位以上,或者热衷酗酒(1单位≈200mL酒精含量为5%的啤酒或25mL酒精含量为40%的烈酒或85mL酒精含量为12%的葡萄酒);
8)筛选前1年内嗜烟,每日吸烟多于10支或等量烟草者;
9)试验期间不能戒烟、戒酒者;
10)乙型肝炎表面抗原(HBsAg)、丙型肝炎病毒抗体(Anti-HCV)、梅毒螺旋体抗体和HIV抗体阳性者;
11)胸部X线片(后前位)结果异常且有临床意义者;
12)B超检查显示中重度脂肪肝者;
13)筛选时谷丙转氨酶(ALT)或谷草转氨酶(AST)超过正常值上限(ULN);
14)筛选时肾小球滤过率(eGFR)<90mL/min/1.73m2;
15)筛选时心电图异常,单次检查QTcF(经心率校正)男性>450ms,女性>470ms,和/或具有临床意义的其他异常;
16)妊娠、哺乳期妇女或者男性受试者配偶在3个月内有育儿计划者;
17)研究者认为有不适合参加试验的其他因素者。
研究药物信息:
试验药:VV116片剂;规格:50mg、100mg和300mg。储存:室温,密封保存。
安慰剂:VV116空白片剂;规格:50mg、100mg和300mg。储存:室温,密封保存。
安慰剂为与试验药物外观(形状、颜色、大小、包装)、气味均无差异,不含试验药物有效成分,组份为原配方的片剂。
起始剂量为25mg组,因制剂规格无25mg(制剂规格为:50、100、300mg,各规格均采用处方等比例设计),采用50mg规格产品在研究中心用切药器切片的方式给药。申办者已做过相关药学研究,切片后半片的重量差异、含量均匀度、脆碎度、溶出度、含量、有关物质及分割重量损失等均符合质量标准,且含药和安慰剂产品分割后切割面均显类白色,外观性状无差异。
研究1:
单次剂量递增研究。根据VV116的非临床毒理学数据,估算的最大推荐起始剂量选择为25mg,估算的最大剂量选择为1200mg。最初方案中设有8个剂量组,起始剂量为25mg,25mg剂量组入组6名受试者(男女不限),其余剂量组每组入组8名受试者(男女不限),随机分配至试验药组和安慰剂组,评估安全性、耐受性和PK特征。单次给药剂量组的数量可能会根据所获得的安全性和药代数据增加或减少。爬坡的剂量水平计划为25mg,50mg,100mg,200mg,400mg,600mg,800mg和1000mg(剂量组1-8)。25mg剂量组完成给药后,研究者评估受试者给药48小时内的安全性结果(包括症状、生命体征、体格检查等)未发现安全隐患,且耐受性良好。
本品于2021年09月30日在乌兹别克斯坦(以下简称“乌国”)获得临床批件,乌国新冠住院患者中的II/III期临床试验正在进行,采用随机、对照、开放3组设计,2个VV116试验组,剂量分别为200mg和300mg,每天2次,用药5天,对照组为法匹拉韦。每组计划入组150例,其中100例确诊为中度SARS-CoV-2感染,50例确诊为重度SARS-CoV-2感染。该试验2021年11月3日完成首例入组,目前完成了前期47例受试者首次用药后2天的初步安全性数据汇总,结果表明VV116首次用药后2天安全性良好,主要AE为转氨酶轻度升高,未发生SAE,无受试者退出。基于以上结果,申办者认为47例的样本量(试验组36例)和每日剂量400~600mg情况下,安全性表现已经基本能证明单次给药200mg的安全性,因此预期本品在中国健康受试者中单次给药200mg的安全性风险可控,可以删除50mg和100mg剂量组,直接进行200mg剂量组的单次给药。
基于以上结果,申办方决定将单次给药剂量组调整为25mg,200mg,400mg,800mg和1200mg。
25mg剂量组有4名受试者接受VV116片,2名受试者接受安慰剂。其余剂量组,每组将有6名受试者接受VV116片,2名受试者接受安慰剂。25mg剂量组进行了哨兵给药,25mg剂量组完成给药后,根据乌兹别克斯坦进行中的临床试验的阶段性安全性研究结果以及本研究前期研究结果,研究者和申办方决定200和400mg剂量组不进行哨兵给药,800mg和1200mg剂量组继续进行哨兵给药。需要进行哨兵给药的剂量组(即1名接受试验药,1名接受安慰剂),研究者评估哨兵给药48小时安全性结果(包括症状、生命体征、体格检查等)未发现安全隐患,且耐受性良好,在此前提下,该组别其余受试者方可给药。
在给药前14天内进行筛选,受试者将在第-1天入住Ⅰ期病房(住院),进行入组标准评估。在第1天给药之前,受试者将禁食过夜至少10个小时。在禁食条件下,第1 天用240mL水以各自的剂量水平口服给予受试者VV116片剂或安慰剂。所有受试者均留在I期临床研究中心,直至给药后48小时进行密切的医学监测,除了400mg剂量组的受试者,其在给药后的72小时内进行探索性物质平衡研究。随机双盲给药后,受试者将接受每日安全性评估和PK样本采集。如果在评估临床安全性数据时未发现安全隐患,研究者将在第3天早晨受试者完成评估后酌情允许其出院。出院时各项检查正常者则于第7天(±1天)电话随访;如果异常,则由研究者根据实际情况安排跟踪随访。提前退出受试者尽量按照出院检查的要求、完成安全性观察指标观察后退出。
在进入下一剂量组之前,研究者和申办者将主要针对每个剂量组的临床安全性、耐受性审查评估是否可开始下一个剂量组的给药;必要时可结合PK数据进行判断。另外,研究者和申办者可根据前期研究结果做出是否进行剂量组调整或是否进行受试者例数调整的决定。
研究2:
多次剂量递增研究。本试验采用剂量递增设计,依次从低剂量组向高剂量组序贯进行,每例受试者只能接受一个剂量水平的口服给药。口服给药初步预设3个剂量组,200mg、400mg和600mg,每日2次口服给药(间隔12小时),连续给药5.5天,第6天早晨给药为末次给药。给药第一天记为试验第1天(D1),当VV116片的前一个剂量组完成末次给药后7天(D12)的安全性随访后,经研究者和申办者共同审阅确认安全性,下一剂量组的受试者方可开始给药。每个剂量组计划入组12例受试者,按照3:1的比例分配试验药物和安慰剂。
整个试验周期包括一个最长不超过14天的筛选期、5.5天的多剂量给药期(D1-D6),3天的安全性观察期和4天的安全性随访期。受试者将在给药前一天(D-1,基线期)入住I期临床试验病房,直至第8天完成全部检查和评估后方可离开,出院时各项检查正常者则于第12天(±1天)电话随访;如果异常,则由研究者根据实际情况安排跟踪随访。提前退出受试者尽量按照出院检查的要求完成安全性观察指标后退出。
研究3:
食物影响研究。在给药前14天内进行筛选,选择符合研究入组标准的12例健康受试者。受试者在进行方案规定的各项程序前,必须获得已签署的知情同意书。具体给药方式见下:将12例健康受试者随机分为A、B、C三组,每组4例,A组第一周期空腹条件下给药,第二周期标准餐后条件下给药,第三周期高脂餐后条件下给药,B组第一周期高脂餐后条件下给药,第二周期空腹条件下给药,第三周期标准餐后条件下给药,C组 第一周期标准餐后条件下给药,第二周期高脂餐后条件下给药,第三周期空腹条件下给药,三周期交叉给药,清洗期3天。单次口服给药剂量为400mg,对于空腹期间,在禁食过夜后施用单次口服剂量的400mg VV116片剂(≥10小时)。在两个喂食期间,在标准餐(总卡路里:约700kcal)或高脂餐(总卡路里:约800kcal-1000kcal,分别来自蛋白质,碳水化合物和脂肪约150、250和500-600kcal)消耗后30分钟内施用单次口服剂量的400mg VV116片剂。所有受试者都留在I期临床研究中心,直到最后一次给药后48小时。
每位受试者的试验周期不超过27天,包括一个最长不超过14天的筛选期、9天给药观察期(包括D1、D4和D7给药,及每次给药后的3天清洗期和安全观察期),以及之后4天(D13)的安全性随访期。受试者将在给药前一天(D-1)入住I期临床试验病房,直至第9天(D9)完成全部检查和评估后方可离开,同时按照方案规定的访视安排返回研究中心或通过电话接受随访并完成相关流程和评估。
安全性评价
收集试验期间发生的任何AE和SAE,包括生命体征、体格检查,12导联心电图、眼科检查、临床实验室检查指标(血常规、血生化、尿NAG、凝血功能、尿常规+尿沉渣+尿微量白蛋白、甲状腺功能)等。根据国家癌症研究所常见不良事件标准术语(NCI-CTCAE)5.0版,对整个研究期间所出现的不良事件进行评估,对不良事件分级。
生物样品采集
在预定的时间点收集约3ml血液样品用于分析。在25mg单次递增剂量研究组中,在以下15个时间点收集血液样品:0(给药前);和给药后0.25,0.5,1,1.5,2,3,4,5,6,8,12,24,36和48小时。之后,根据25mg组的药代动力学特征略微调整时间点。在单次剂量递增研究的其他剂量组以及食物影响研究中,在以下时间点收集血液样品:0(给药前);和给药后10分钟,20分钟,30分钟,45分钟,1小时,1.5小时,2小时,3小时,4小时,6小时,8小时,12小时,24小时和48小时。
在多次剂量递增研究中,在以下时间点收集血液样品,第1天:0(给药前);和给药后10分钟,20分钟,30分钟,45分钟,1小时,1.5小时,2小时,3小时,4小时,6小时,8小时和12小时;第5天:每次给药前;第6天:0(给药前),和给药后10分钟,20分钟,30分钟,45分钟,1小时,1.5小时,2小时,3小时,4小时,6小时,8小时,12小时,24小时和48小时。
通过在4℃,1500g离心10分钟分离收集的血液样品,然后分成2个离心管(每个至少0.6mL血浆),冷冻并在-80℃下储存直至分析。
在400mg剂量组的单次剂量递增研究中进行探索性物质平衡评估。分别收集第1天给药前-24-0h的随机尿样、用药后0-6h、6-12h、12-24h、24-48h、48-72h各时间间隔内所有排泄的尿液。分别收集第1天给药前-24-0h的随机粪样、给药后第1天至第4天之间的粪便(即给药后72h内的所有粪便均需采集,根据受试者实际排便次数采集,如果当天未排便,则不采集,且每一次便均单独收集储存)。
生物分析方法
LC-MS/MS方法,用于测定人血浆中VV116及其代谢物116-N1的浓度。对于VV116,选择VV116-D4作为内标。在校准范围(2-2000ng/mL)下,回归系数为0.9998。批内精密度为1.1至6.6%,批间精密度为4.6至9.6%。准确度为85.6-102.3%。
对于代谢物116-N1,选择116-N1-D4作为内标。校准曲线在10至10 000ng/mL范围内呈线性,回归系数为0.9998。批内精密度为2.2至12.4%,批间精密度为2.5至8.2%。准确度为90.5-100.1%。
药代动力学(PK)评价
采用WinNonlin软件用非房室模型法计算25-1200mg所有剂量组血浆中VV116及其主要代谢产物116-N1的药代动力学参数。主要药代动力学参数有:达峰时间(Tmax)、峰浓度(Cmax)、半衰期(t1/2)、从0时到最后一个可测定浓度的采集时间t的药物浓度-时间曲线下面积(AUC0-t)、从0时至24时的药物浓度-时间曲线下面积(AUC0-24h)、从0时到无限时间的药物浓度-时间曲线下面积(AUC0-∞)、消除速率常数(Ke)、表观分布容积(Vd/F)、平均驻留时间(MRT)、清除率(CL/F)、累积排泄量(Ae)和排泄分数(Fe)等。AUC0-t和AUC0-∞使用Linear Up Log Down规则方法计算。Tmax和Cmax基于实际测量值。在多次递增剂量研究中,还分析了重复给药后的蓄积比(Rac)。
统计分析
使用SAS软件9.4版(SAS Institute,Cary,NC,USA)进行统计分析。描述性统计表示为每个剂量组的算术平均值、标准偏差、变异系数、中值、最大值、最小值和几何平均值。计算频率和百分比以总结分类变量。
在单次剂量递增研究中,使用置信区间标准评估剂量-暴露关系。进行了线性回归。回归方程表示为ln(PK)=α+β×ln(Dose),其中对数变换用于PK参数和剂量。计算估计斜率(β)的90%置信区间。在β的90%置信区间在判断区间内的情况下,认为PK 参数与剂量呈线性相关。
在食物影响研究中,分析了不同饮食条件下的PK参数,包括AUC0-t、AUC0-∞和Cmax。采用广义线性混合模型估计对数转换后的PK参数的均值、均差和90%置信区间,其中饮食条件、顺序和时期作为固定效应,而受试者作为随机效应。对每个PK参数进行成对比较(高脂餐与空腹、标准餐与空腹、高脂餐与标准餐)。
研究结果
研究在2021年11月至2022年1月间,共纳入86名符合标准的成年健康受试者,研究1纳入38名受试者,研究2纳入36名受试者,研究3纳入12名受试者。入组受试者的人口学统计数据如表1所示。
药代动力学研究结果
研究1:单次剂量递增研究
VV116口服后迅速水解为其代谢物116-N1,其在细胞中经历三个连续的酶促磷酸化反应,产生三磷酸活性形式116-NTP(见图2)。血浆中未检测到原型药物(定量下限为2ng/mL),但检测到其代谢物116-N1,并计算了三项研究中的PK参数。表2总结了单剂量给药VV116后每个剂量组中116-N1的主要PK参数。平均血浆116-N1浓度-时间曲线如图3所示。
主要的PK暴露参数Cmax和AUC是剂量依赖性的。对于25mg、200mg、400mg、800mg和1200mg剂量组,Cmax的平均值±SD分别为154±66.7、1096±412、1898±701、2796±225和3086±778ng/mL。AUC0-t为852±272、6631±1603、12759±2747、25886±5904和28057±5145h·ng/mL,而上述五个剂量组的AUC0-∞分别为888±286、6986±1683、13064±2727、26233±5897和28325±5272h·ng/mL。置信区间(CI)标准用于评估剂量线性关系。表3展示了剂量比例分析。对于25-800mg剂量间隔,Cmax、AUC0-t和AUC0-∞的斜率估计值(β)及其90%CI分别为0.87(0.74-0.99)、0.99(0.91,1.07)和0.98(0.90,1.06),不完全在判断区间(0.94-1.06)内。尽管如此,我们可以得出结论,在25-800mg的剂量范围内,AUC参数和Cmax以近似剂量比例的方式增加。然而,随着剂量从800增加到1200mg,Cmax、AUC0-t和AUC0-∞没有显示出显着变化。Tmax中位数在1.00~2.50h之间,t1/2平均值在5.21~6.95h之间。
表3:单次剂量递增研究中血浆116-N1的Cmax和AUC的剂量比例分析
研究结果显示:VV116口服吸收迅速,在单次剂量递增研究中,口服VV116后可迅速水解为代谢产物116-N1,平均血浆药物达峰时间(Tmax)仅为1.00-2.50小时,吸收迅速。口服剂量血药浓度-时间曲线下面积(AUC)和最大血浆药物浓度(Cmax)在25-800mg剂量范围内呈剂量依赖性,800-1200mg剂量间无明显增加,1200mg剂量时最高。VV116平均半衰期(t 1/2)值为5.21-6.95小时,提示在临床治疗中给药频率设置为每日两次(BID)。
研究2:多次剂量递增研究
多剂量VV116后第1天和第6天116-N1的主要PK参数列于表4。200mg、400mg和600mg在第1天和第6天的平均血浆116-N1浓度-时间曲线剂量组如图4所示。表5显示了第5天和第6天116-N1的谷浓度。
三个剂量组中,第6天的平均t1/2均比第1天长(200mg组4.72h vs 7.56h,400mg组4.88h vs 8.12h,600mg组5.41h vs 7.85h团体)。至于药物暴露,重复给药后Cmax、AUC0-t和AUC0-∞增加。剂量组200mg、400mg和600mg的Cmax累积率(Rac)分别为1.34、1.18和1.24,AUC 0-t的Rac分别为1.53、1.41和1.42,表明重复给药VV116后显示出轻微的累积。
研究者还发现,200mg组在第5天和第6天116-N1的谷浓度在242-345ng/mL范围内,高于临床前研究中116-N1抗奥密克戎变异株的有效浓度(EC90,186.5ng/mL),提示200mg BID及以上剂量方案可持续维持有效抗病毒浓度,推荐用于后续临床研究。
表5:多剂量递增研究第5天和第6天116-N1谷浓度
注:数据以平均值(SD)表示。
研究3:食物影响研究
不同饮食条件下单次口服400mg VV116后116-N1的关键PK参数见表6,相应的平均血浆药物浓度-时间曲线如图5所示。
标准餐与空腹Cmax、AUC0-t、AUC0-∞的几何平均比(GMR)及其90%CI分别为106.60%(93.40%-121.67%)、119.52%(114.50%-124.76%)和118.21%(113.53%-123.08%),分别在80%-125%的等效范围内。高脂餐与空腹时Cmax、AUC0-t和AUC0-∞的GMR(90%CIs)分别为107.92%(94.56%-123.18%)、126.32%(121.01%-131.85%)和124.67%(119.74%)-129.81%),分别。与空腹相比,高脂餐的AUC0-t和AUC0-∞分别增加了26.32%和24.67%。
116-N1在空腹、标准餐、高脂餐的中位Tmax分别为1.5h、3.0h和2.5h。我们发现,与空腹条件相比,在进食条件下给予VV116可以延长达到峰值的时间,但对研究药物的系统暴露影响不大。
与空腹条件相比,普通饮食和高脂饮食条件下Cmax的GMR(90%CIs)在80%-125%的等效范围内;普通饮食的AUC GMR(90%CIs)也在80-125%范围内,而高脂饮食的AUC 0-t和AUC 0-∞增幅分别为26.32%和24.67%。由于进食对Cmax无影响,而高脂饮食略增加AUC,建议在空腹或在普通饮食条件下口服VV116治疗。
表6:单次口服400mg VV116后116-N1在空腹和进食条件下的主要PK参数
注:数据表示为平均值(SD),Tmax除外,其显示为中值(Min,Max)。
安全性研究结果
3项研究未报告死亡、未发生严重AE、未发生3级及以上AE,也未出现停药及中断治疗的AE。所有AE均在未治疗或未干预情况下恢复。
研究1:单次剂量递增研究
在单次剂量递增研究中,未观察到剂量与不良事件(AE)相关趋势(见表7)。VV116组AE发生率低于安慰剂组(39.3%vs.50.0%)。除在400mg剂量VV116组中1名受试者发生2级中性粒细胞减少症外,其余AE均为1级。最常见的药物相关性AE为窦性心动过缓、心电图PR间期缩短和血胆红素升高。
研究2:多次剂量递增研究
在多次剂量递增研究中,VV116组的AE发生率与安慰剂组分别为51.9%和55.6%(见表8)。观察到AE发生与剂量相关性。VV116组所有AE均为1级。最常见的药物相关性AE为血尿酸升高、口干、结晶尿和恶心。
值得注意的是,研究者仅在多次递增剂量研究中VV116(400mg剂量)组观察到1位受试者(3.7%)出现暂时性1级ALT升高,且未经治疗后自行恢复。相较同类药物在过往报告的数据,VV116具有较低的肝毒性风险,研究者将继续在后续的II期研究中监测患者中的肝功能。
研究3:食物影响研究
在空腹、标准餐、高脂餐状态下经历AE的受试者数量(发生率)为0(0)、2(16.7%)和4(33.3%)。2例标准餐状态下出现1级房室传导阻滞,4例高脂餐状态下分别出现尿细菌试验阳性、结晶尿、血压升高和1级房室传导阻滞。所有AE的严重程度均为CTCAE1级。
结果显示,VV116在健康受试者中表现出令人满意的安全性和耐受性,口服VV116后,有效成分116-N1的血浆药物浓度可迅速达到峰值(平均Tmax为1.00-2.50小时),AUC和Cmax在25-800mg剂量范围内呈剂量依赖性;普通饮食对VV116口服后的AUC和Cmax无影响;多次给药后,在200~600mg BID的剂量水平下达到有效的抗病毒浓度。

Claims (17)

  1. 核苷类似物或其药学上可接受的盐在制备治疗和/或预防由病毒感染引起的相关疾病的药物中的用途,其中,所述核苷类似物具有下式I所示的结构:
    式中:
    R1为氰基;
    R2为羟基或C1-4烷基-COO-,优选为C1-3烷基-COO-;
    R3为H或任选被氨基取代的C1-4烷基羰基,优选为未取代的C1-4烷基羰基;
    R4为H;
    X为C1-4亚烷基,其中,该亚烷基中的1个或多个(如3个以内)H被氘取代;优选为-C(H)2-或-C(D)2-;
    R5为H、任选被氨基取代的C1-4烷基羰基,优选为未取代的C1-4烷基羰基;
    R6为氨基;
    R7为H;
    R8为H、氘(D)或卤素,优选为为氘。
  2. 如权利要求1所述的用途,其中,所述R2、R3O-和R5O-中至少一个为C1-3烷基-COO-;优选地,所述R2、R3O-和R5O-中至少两个为C1-3烷基-COO-;更优选地,所述R2、R3O-和R5O-都为C1-3烷基-COO-;优选地,所述C1-3烷基为C3烷基,优选为异丙基。
  3. 如权利要求2所述的用途,其中,所述核苷类似物为VV116,其化学结构式如下:
  4. 如权利要求1-3中任一项所述的用途,其中,所述病毒选自:
    (1)感染人的冠状病毒:重症急性呼吸综合征冠状病毒SARS-CoV(Severe acute respiratory syndrome coronavirus,SARS-CoV)、2019新型冠状病毒(2019-nCoV或SARS-CoV-2)、中东呼吸综合征冠状病毒MERS-CoV(Middle East respiratory syndrome coronavirus,MERS-CoV);
    (2)致普通感冒的冠状病毒:所述的致普通感冒的冠状病毒优选选自下组:人冠状病毒OC43(Human coronavirus OC43)、人冠状病毒229E(Human coronavirus229E)、人冠状病毒NL63(Human coronavirus NL63)、人冠状病毒HKUl(Human coronavirus HKUl);
    (3)人呼吸道合胞病毒(RSV);
    (4)人流感病毒:甲型流感病毒、乙型流感病毒、丙型流感病毒;
    (5)黄病毒科病毒:丙型肝炎病毒(HCV)、登革热病毒(DENV)、寨卡病毒(Zika);
    (6)丝状病毒科病毒:马尔堡病毒(MBV)、埃博拉病毒(EBV);
    (7)感染其他哺乳动物的冠状病毒:猪流行性腹泻病毒(PEDV);
    优选地,所述病毒包括其变异毒株;优选地,所述SARS-CoV-2的突变株包括阿尔法突变株、贝塔突变株、伽马突变株、德尔塔突变株、Epsilon突变株、Zeta突变株、Eta突变株、Theta突变株、Iota突变株、卡帕突变株、缪突变株和奥密克戎突变株。
  5. 如权利要求1-4中任一项所述的用途,其中,所述病毒感染引起的相关疾病选自下组:
    (D1)人冠状病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
    (D2)人呼吸道合胞病毒(RSV)感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
    (D3)人流感病毒感染引起的普通感冒、高危症状感染、呼吸道感染、肺炎及其并发症;
    (D4)丙型肝炎病毒(HCV)引起的慢性丙型肝炎及其并发症;
    (D5)登革热病毒(DENV)引起的登革热及其并发症;
    (D6)寨卡病毒(Zika)引起的感染及其并发症;
    (D7)马尔堡病毒(MBV)、埃博拉病毒(EBV)引起的出血热及其并发症;
    (D8)SARS-CoV-2引起的新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19);
    (D9)猪流行性腹泻病毒(PEDV)引起的猪流行性腹泻;
    (D10)上述疾病的任意组合。
  6. 如权利要求1-5中任一项所述的用途,其中,所述药物包含以核苷类似物计剂量为约10~600mg的核苷类似物或其药学上可接受的盐,优选为约50-300mg或约200-600mg,更优选为约50mg、约100mg、约200mg、约300mg、约400mg或约600mg。
  7. 如权利要求1-3中任一项所述的用途,其中,所述药物为口服剂型,优选选自:片剂、锭剂、胶囊剂、含片、颗粒剂、溶液剂、水性或油性悬浮液、可分散的粉末或小颗粒、糖浆或酏剂。
  8. 如权利要求1-3中任一项所述的用途,其中,所述治疗或预防中,所述药物的给药频率为每日给药1次、2次、3次或4次,优选为每日两次。
  9. 如权利要求1-3中任一项所述的用途,其中,所述治疗或预防中,所述药物单次给药剂量以核苷类似物计为约25-1200mg,优选为约25-800mg,进一步优选为约200-600mg,最优选为约200mg、约400mg或约600mg的所述核苷类似物或其药学上可接受的盐。
  10. 如权利要求1-3中任一项所述的用途,其中,所述治疗或预防中,所述药物的给药周期为1-10天或更长时间,优选为1天、3天、5.5天、9天、10天;任选地,每个给药周期的时间相同或不同,且每个给药周期之间的间隔相同或不同。
  11. 如权利要求3所述的用途,其中,所述治疗或预防中,所述药物的单次给药剂量以所述VV116计为200-600mg的VV116,每日2次,连续给药至少3天、优选至少5天,空腹口服给药。
  12. 一种药物组合物,其中,该药物组合物含有权利要求1-3中任一项所述的核苷类似物或其药学上可接受的盐以及药学上可接受的载体或辅料;其中,所述药物组合物含有约10-600mg、优选约50-300mg或200-600mg的所述核苷类似物或其药学上可接受的盐。
  13. 如权利要求书12所述的药物组合物,其中,所述药物组合物适于口服给药,其剂型优选选自:片剂、锭剂、胶囊剂、含片、颗粒剂、溶液剂、水性或油性悬浮液、可分散的粉末或小颗粒、糖浆和酏剂。
  14. 一种药盒,其中,所述药盒含有1剂或多剂权利要求12所述的药物组合物;其中,药盒中所述药物组合物的数量至少满足1个给药周期的给药量,其中,每天的给药量为25-1200mg、优选约200-1200mg、更优选约400-1200mg、进一步优选约400-800mg的所述核苷类似物或其药学上可接受的盐。
  15. 如权利要求14所述的药盒,其中,
    所述1个给药周期为1-10天,例如1天、3天、5.5天、9天或10天;和/或
    所述给药周期中,给药频次为每日1次、2次、3次或4次,优选每日2次。
  16. 如权利要求14或15所述的药盒,其中,所述药盒含有一个或多个单次药物剂量单元,其中,所述单次药物剂量单元包含以核苷类似物或其药学上可接受的盐计约25-1200mg、优选约25-800mg、更优选约50-800mg、进一步优选约200-600mg的所述核苷类似物或其药学上可接受的盐;
    优选地,所述药盒所含的单次药物剂量单元的数量满足至少1个给药周期的给药;优选地,所述给药周期为1-10天或更长时间,优选为1天、3天、5.5天、9天或10天。
  17. 如权利要求16所述的药盒,其中,所述药盒中所述单次药物剂量单元的数量满足至少连续3天、优选至少连续5天,每天2次的给药;优选地,每个单次药物剂量单元含有以所述核苷类似物或其药学上可接受的盐计约200mg、约400mg或约600mg的所述核苷类似物或其药学上可接受的盐;更优选地,所述核苷类似物为所述VV116或其游离碱。
PCT/CN2023/079315 2022-03-03 2023-03-02 治疗、预防由病毒感染引起的相关疾病的药物及其用途 WO2023165566A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210205921.6A CN114504578A (zh) 2022-03-03 2022-03-03 治疗、预防由病毒感染引起的相关疾病的药物及其用途
CN202210205921.6 2022-03-03

Publications (1)

Publication Number Publication Date
WO2023165566A1 true WO2023165566A1 (zh) 2023-09-07

Family

ID=81553727

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/079315 WO2023165566A1 (zh) 2022-03-03 2023-03-02 治疗、预防由病毒感染引起的相关疾病的药物及其用途

Country Status (2)

Country Link
CN (2) CN114504578A (zh)
WO (1) WO2023165566A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114504578A (zh) * 2022-03-03 2022-05-17 苏州旺山旺水生物医药有限公司 治疗、预防由病毒感染引起的相关疾病的药物及其用途
WO2024051793A1 (en) * 2022-09-09 2024-03-14 Shanghai Vinnerna Biosciences Co., Ltd. METHODS ANS KITS FOR TREATING SARS-CoV-2 INFECTION

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111961057A (zh) * 2020-05-26 2020-11-20 李小冬 一种α构型核苷及其在治疗猫冠状病毒感染的应用
WO2021213288A1 (zh) * 2020-04-20 2021-10-28 中国科学院上海药物研究所 核苷类似物或含有核苷类似物的组合制剂在抗病毒中的应用
CN114504578A (zh) * 2022-03-03 2022-05-17 苏州旺山旺水生物医药有限公司 治疗、预防由病毒感染引起的相关疾病的药物及其用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116098917A (zh) * 2020-02-27 2023-05-12 河南真实生物科技有限公司 核苷类化合物在治疗冠状病毒感染性疾病中的用途
CN112661801A (zh) * 2020-12-18 2021-04-16 成都阿奇生物医药科技有限公司 一种核苷类似物及其氘代物及其制备方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021213288A1 (zh) * 2020-04-20 2021-10-28 中国科学院上海药物研究所 核苷类似物或含有核苷类似物的组合制剂在抗病毒中的应用
CN111961057A (zh) * 2020-05-26 2020-11-20 李小冬 一种α构型核苷及其在治疗猫冠状病毒感染的应用
CN114504578A (zh) * 2022-03-03 2022-05-17 苏州旺山旺水生物医药有限公司 治疗、预防由病毒感染引起的相关疾病的药物及其用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COX ROBERT M., WOLF JOSEF D., LIEBER CAROLIN M., SOURIMANT JULIEN, LIN MICHELLE J., BABUSIS DARIUS, DUPONT VENICE, CHAN JULIE, BAR: "Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets", NATURE COMMUNICATIONS, vol. 12, no. 1, XP093088172, DOI: 10.1038/s41467-021-26760-4 *
WEI, DAIBAO ET AL.: "Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 46, 11 August 2021 (2021-08-11), XP086796993, DOI: 10.1016/j.bmc.2021.116364 *
XIE, YUANCHAO ET AL.: "Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2", CELL RESEARCH, vol. 31, 28 September 2021 (2021-09-28), XP037606810, DOI: 10.1038/s41422-021-00570-1 *

Also Published As

Publication number Publication date
CN114504578A (zh) 2022-05-17
CN118021821A (zh) 2024-05-14

Similar Documents

Publication Publication Date Title
WO2023165566A1 (zh) 治疗、预防由病毒感染引起的相关疾病的药物及其用途
US20200323843A1 (en) Use of levocetirizine and montelukast in the treatment of viral infection caused by coronavirus
RU2685706C2 (ru) Фармацевтические композиции, содержащие 15-гэпк, и способы лечения астмы и заболеваний легких с их применением
CN112135625A (zh) 一种预防或治疗covid-19新冠肺炎的药物、食物及其应用
US20230190652A1 (en) Composition for the treatment of covid-19 and treatment method
Li et al. A double-blind, randomized, placebo-controlled multicenter study of oseltamivir phosphate for treatment of influenza infection in China
Hayden et al. Comparative therapeutic effect of aerosolized and oral rimantadine HC1 in experimental human influenza A virus infection
JP7399976B2 (ja) Covid-19新型コロナ肺炎を予防又は治療する医薬品、食品及びその使用
RU2237475C1 (ru) Комбинированный препарат для устранения симптомов простудных заболеваний и гриппа (варианты)
US20060084683A1 (en) Method for preventing the onset of asthma
JP7546566B2 (ja) 疣贅の治療
WO2022024108A1 (en) Ezrin peptide (hep-1) for use in the treatment of coronavirus disease
JP7543427B2 (ja) 抗新型コロナウイルス感染症の医薬品、食品、及び使用
RU2763024C1 (ru) Мефлохин и его комбинации для лечения и профилактики коронавирусной инфекции
RU2824607C2 (ru) 2-(имидазол-4-ил)-этанамид пентандиовой-1,5 кислоты или его фармацевтически приемлемая соль для лечения covid-19 и ее симптомов
EP3906934B1 (en) Application of dalargin for the prevention of viral respiratory infections and prevention of the development of complications during viral respiratory infections
WO2021211085A1 (ru) Способ профилактики и лечения заболеваний, вызванных вирусами, имеющими оболочку, в том числе коронавирусами(варианты) и набор фармацевтических препаратов для его осуществления
JP2001213774A (ja) ウイルス感染症予防剤
JP5457393B2 (ja) 抗インフルエンザウイルス用医薬組成物
CN115054611A (zh) 一种用于治疗小儿肺炎的药物及其用途
CN113952330A (zh) 草棉黄素在制备治疗鼻炎的药物中的应用
BR102019014081A2 (pt) compostos imunomoduladores e/ou seus sais farmaceuticamente aceitáveis, composição farmacêutica compreendendo compostos imunomoduladores e uso de compostos imunomoduladores na preparação de uma composição farmacêutica para tratamento de doenças virais

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23762964

Country of ref document: EP

Kind code of ref document: A1