CN118021821A

CN118021821A - Medicine for treating and preventing related diseases caused by virus infection and application thereof

Info

Publication number: CN118021821A
Application number: CN202410177641.8A
Authority: CN
Inventors: 王震; 阿吉艾克拜尔·艾萨; 张卓兵; 李宁; 赵波; 谢元超
Original assignee: Suzhou Wangshan Wangshui Biopharmaceutical Co ltd; Shanghai Institute of Materia Medica of CAS; Wuhan Institute of Virology of CAS
Current assignee: Suzhou Wangshan Wangshui Biopharmaceutical Co ltd; Shanghai Institute of Materia Medica of CAS; Wuhan Institute of Virology of CAS
Priority date: 2022-03-03
Filing date: 2022-03-03
Publication date: 2024-05-14
Also published as: WO2023165566A1; CN114504578A

Abstract

The present invention relates to a medicine for treating and preventing diseases caused by virus infection and its application. Specifically, the invention provides application of nucleoside analogues shown in the following formula I or pharmaceutically acceptable salts thereof in preparing medicaments for treating and/or preventing related diseases caused by virus infection, and also provides a pharmaceutical composition or a pharmaceutical kit containing the nucleoside analogues shown in the formula I or pharmaceutically acceptable salts thereof. The nucleoside analogs of the present invention exhibit satisfactory safety and tolerability in healthy subjects; the effective antiviral concentration can be achieved after multiple administration.

Description

Medicine for treating and preventing related diseases caused by virus infection and application thereof

Technical Field

The invention relates to the technical field of medical application, in particular to a medicine for treating and preventing related diseases caused by virus infection and application thereof.

Background

In the acute infectious diseases, most of the infectious diseases are viral infectious diseases, and the incidence rate and the death rate of the viral infectious diseases are high. Individuals such as viruses are extremely tiny, lack independent metabolic capability, and exist parasitically as pathogenic microorganisms. The variety of viruses is wide, and many viruses with high infectivity and pathogenicity to human beings are found, and the viruses often cause local and even global infectious diseases to outbreak, and have great harm to human society, such as influenza virus, respiratory Syncytial Virus (RSV), parainfluenza virus, atypical (SARS) virus, middle East Respiratory Syndrome (MERS) virus, ebola virus and the like. Some viruses can also infect animals, causing various light to severe diseases, and at the same time, animals become sources of infection for these viruses, making humans overwhelm them.

Coronaviruses belong to the order of the family of the viruses, the family of the coronaviridae, the genus coronavirus, and are a large class of single-stranded positive strand RNA viruses widely existing in nature and can cause respiratory, digestive and nervous system diseases in humans and animals. Coronaviruses can be divided into four genera according to phylogenetic tree: alpha, beta, gamma, delta, wherein the beta genus coronavirus can be divided into four independent subgroups A, B, C and D.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as a novel coronavirus. SARS-CoV-2, atypical virus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV) belong to the genus beta coronavirus, and these three viruses have become the most pathogenic coronaviruses for humans.

Coronaviruses can also infect a variety of mammals, including bats, pigs, dogs, cats, mice, cattle, horses, camels, etc., and these viruses are mostly of the alpha, beta genus. Porcine Epidemic Diarrhea Virus (PEDV) is a coronavirus which can cause acute intestinal infectious disease of pigs, and pigs of various ages can be infected and developed, wherein nursing pigs and newborn piglets are most seriously damaged, and the breeding industry is frequently suffered from great loss due to the burst of PEDV.

Respiratory viral infections are the most clinically common and most widely affected type of viral infectious disease, causing a large number of deaths worldwide each year. In addition to coronaviruses, influenza viruses, respiratory syncytial viruses, parainfluenza viruses and the like can cause respiratory tract infections, and are important killers threatening human life and health.

At present, the life and health of people are seriously affected by the infectious diseases caused by SARS-CoV-2 coronavirus and the like, the development of antiviral drugs with good effects is urgent, and the development of drugs for treating and/or preventing related diseases caused by viral infection is urgent in the field.

Disclosure of Invention

In a first aspect, the present invention provides the use of a nucleoside analogue or a pharmaceutically acceptable salt thereof in the manufacture of a medicament or kit for the treatment and/or prophylaxis of a disease associated with a viral infection.

In a second aspect, the invention provides a method for the treatment and/or prophylaxis of a disease associated with a viral infection comprising administering to a subject in need thereof an effective amount of a medicament comprising a nucleoside analogue or a pharmaceutically acceptable salt thereof.

In a third aspect, the present invention provides a nucleoside analogue or a pharmaceutically acceptable salt thereof for use in the treatment and/or prophylaxis of a disease associated with a viral infection.

In one or more embodiments of the first to third aspects, the virus is selected from the group consisting of:

(1) Coronavirus infecting 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);

(2) Coronaviruses that cause common cold: the common cold causing coronavirus is preferably selected from the group consisting of: human coronavirus OC43 (Human coronavirus OC 43), human coronavirus229E (Human coronavirus 229E), human coronavirus NL63 (Human coronavirus NL 63), human coronavirus HKUl (Human coronavirus HKUl);

(3) Human Respiratory Syncytial Virus (RSV);

(4) Human influenza virus: influenza a virus, influenza b virus, influenza c virus;

(5) Flaviviridae viruses: hepatitis C Virus (HCV), dengue virus (DENV), zika virus (Zika);

(6) Filoviridae viruses: marburg virus (MBV), ebola virus (EBV);

(7) Coronaviruses infecting other mammals: porcine Epidemic Diarrhea Virus (PEDV).

In one or more embodiments of the first to third aspects, the virus is SARS-CoV-2 or a variant thereof. Preferably, the variant is selected from at least one of an alpha mutant, a beta mutant, a gamma mutant, a delta mutant, an Epsilon mutant, a Zeta mutant, an Eta mutant, a Theta mutant, an iotata mutant, a kappa mutant, a muir mutant, and an omnikom mutant.

In one or more embodiments of the first to third aspects, the disease associated with viral infection is selected from the group consisting of:

(D1) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human coronavirus infection;

(D2) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human Respiratory Syncytial Virus (RSV) infection;

(D3) Common cold, high risk symptom infection, respiratory tract infection and complications thereof caused by human influenza virus infection;

(D4) Chronic hepatitis c and its complications caused by Hepatitis C Virus (HCV);

(D5) Dengue fever by dengue virus (DENV) and complications thereof;

(D6) Infection by Zika virus (Zika) and complications thereof;

(D7) Marburg virus (MBV), ebola virus (EBV) induced hemorrhagic fever and complications thereof;

(D8) Novel coronaviruses caused by SARS-CoV-2 (COVID-19);

(D9) Porcine epidemic diarrhea caused by Porcine Epidemic Diarrhea Virus (PEDV);

(D10) Any combination of the above diseases.

In one or more embodiments of the first to third aspects, the nucleoside analogue is a compound of formula I herein.

In one or more embodiments of the first to third aspects, the medicament comprises a nucleoside analogue or a pharmaceutically acceptable salt thereof in a dose of about 10 to 600mg, preferably about 50 to 300mg or 200 to 600mg, calculated as nucleoside analogue, with the non-limiting examples of such doses being 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 within these ranges being defined as the endpoints, preferably about 50mg, about 100mg, about 200mg, about 300mg, or about 600mg.

In one or more embodiments of the first to third aspects, the medicament is an oral medicament. In some embodiments, the administration is oral under fasting or normal dietary conditions.

In one or more embodiments of the first to third aspects, the dosage form of the medicament comprises a tablet, capsule, granule or solution.

In one or more embodiments of the first to third aspects, the drug administration frequency is 1,2,3 or 4 times daily, preferably twice daily.

In one or more embodiments of the first to third aspects, the drug is administered in a single dose of about 25-1200mg, preferably about 25-800mg, preferably about 50-800mg, further preferably about 200-600mg, of the nucleoside analogue. In some embodiments, the single dose of the drug is about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, 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 within these ranges, as endpoints, preferably about 200mg, about 400mg, or about 600mg, of the nucleoside analog.

In one or more embodiments of the first to third aspects, the drug is administered for a period of 1-10 days or more, preferably 1 day, 3 days, 5.5 days, 9 days, 10 days; optionally, the time of each dosing cycle is the same or different, and the interval between each dosing cycle is the same or different.

In a fourth aspect the invention provides a pharmaceutical composition comprising a nucleoside analogue or a pharmaceutically acceptable salt thereof in an amount of about 10 to 600mg, preferably about 50 to 300mg or 200 to 600mg, per unit of the pharmaceutical composition, calculated as nucleoside analogue. Preferably, non-limiting examples of such amounts 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, about 600mg, or any two of these ranges inclusive, preferably about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, or about 600mg, and a pharmaceutically acceptable carrier or adjuvant.

In one or more embodiments, the pharmaceutical composition is an oral pharmaceutical composition; preferably, the dosage forms of the pharmaceutical composition comprise tablets, capsules, granules and solutions.

In a fifth aspect, the invention provides a kit comprising 1 or more doses of a pharmaceutical composition as described herein; wherein the amount of said pharmaceutical composition in the kit is at least an amount sufficient for 1 administration cycle, wherein the amount administered per day is 25-1200mg, preferably about 200-1200mg, more preferably about 400-1200mg, still more preferably about 400-800mg of said nucleoside analogue or pharmaceutically acceptable salt thereof.

In one or more embodiments, the 1 dosing period is 1-10 days, e.g., 1 day, 3 days, 5.5 days, 9 days, or 10 days.

In one or more embodiments, the dosing period is administered 1, 2, 3 or 4 times daily, preferably 2 times daily.

In one or more embodiments, the kit contains one or more single-dose drug dosage units, wherein the single-dose drug dosage units comprise about 25-1200mg, preferably about 25-800mg, more preferably about 50-800mg, still more preferably about 200-600mg of the nucleoside analog or pharmaceutically acceptable salt thereof, as a nucleoside analog or pharmaceutically acceptable salt thereof.

In one or more embodiments, the kit contains a number of single drug dosage units that satisfy administration for at least 1 administration cycle; preferably, the administration period is 1-10 days or longer, preferably 1 day, 3 days, 5.5 days, 9 days or 10 days.

In one or more embodiments, the number of single drug dosage units in the kit is such that administration is 2 times per day for at least 3 consecutive days, preferably at least 5 consecutive days; preferably, each single pharmaceutical dosage unit contains about 200mg, about 400mg, or about 600mg of the nucleoside analog or pharmaceutically acceptable salt thereof, as calculated for the nucleoside analog or pharmaceutically acceptable salt thereof; more preferably, the nucleoside analogue is the VV116 or a free base thereof.

Drawings

Fig. 1: VV116 chinese 3 phase I study design.

Fig. 2: in vivo VV116 transformation protocol following oral administration.

Fig. 3: mean plasma 116-N1 concentration-time profile for each dose group after single dose escalation of VV 116.

Fig. 4: mean plasma 116-N1 concentration-time curves on day 1 and day 6 of the multiple dose escalation study.

Fig. 5: mean plasma 116-N1 concentration versus time curve for fasting and fed conditions.

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.

Terminology

In order that the invention may be more readily understood, certain technical terms are specifically defined below. Unless otherwise defined elsewhere herein, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a polypeptide" includes a combination of two or more polypeptides and the like.

The term "about" as used herein when referring to a measurable value (e.g., amount, duration, etc.) is intended to encompass variations of + -20% or + -10% relative to the particular value, including + -5%, + -1% and + -0.1%, as these variations are suitable for carrying out the disclosed methods.

2019 Novel coronavirus (2019-nCoV) is a novel strain of coronavirus that has never been found in humans before. The international committee for classification of viruses (ICTV) announced that the formal classification of 2019 novel coronaviruses (2019-nCoV) was named severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndromecoronavirus, sars-CoV-2) on month 2 and 11 in 2020. On the same day, the World Health Organization (WHO) announced that the formal name of the disease caused by this virus is COVID-19. Symptoms of SARS-CoV-2 infection can be classified into simple infection, mild disease, severe disease, acute respiratory distress syndrome, sepsis, septic shock, etc., mainly depending on the severity of the disease. Patients with simple infections may have non-specific symptoms such as fever, cough, sore throat, nasal obstruction, weakness, headache, muscle pain or discomfort, and atypical symptoms may occur in the elderly and immunosuppressed persons. The mild patients are mainly coughing and shortness of breath. The severe symptoms are seen in adults, teenagers or children, and the main symptoms are increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, somnolence, unconsciousness or convulsion, air extraction and the like. The lung image of acute respiratory distress syndrome is a bilateral vitreous image, but cannot be fully explained by effusion, lobular exudation or atelectasis or a lung mass shadow, with pulmonary edema as the main symptom. Sepsis patients often have fatal organ dysfunction, with septic shock being the most critical patient and a high likelihood of death.

The variant strain of SARS-CoV-2 comprises at least one of an alpha mutant, beta mutant, gamma mutant, delta mutant, epsilon mutant, zeta mutant, eta mutant, theta mutant, iota mutant, kappa mutant, muir mutant and omimetic mutant.

The term "preventing" as used herein refers to a compound or drug that, when used in a disease or disorder (e.g., cancer), reduces the frequency of symptoms of the medical disorder or delays the onset of the medical disorder in a subject as compared to a subject to whom the compound or drug (e.g., a combination product as claimed herein) was not administered.

The term "treating" as used herein refers to alleviating, alleviating or ameliorating a symptom of a disease or disorder, ameliorating a symptom of underlying metabolism, inhibiting a disease or symptom, e.g., preventing a house-hold of a disease or disorder, alleviating a disease or disorder, causing regression of a disease or disorder, alleviating a condition caused by a disease or disorder, or preventing a symptom of a disease or disorder.

The term "effective amount" or "prophylactically and/or therapeutically effective amount" as used herein refers to a sufficient amount (e.g., dose) of a drug or compound administered that will alleviate to some extent one or more symptoms of the disease or disorder being treated. The result may be a reduction and/or alleviation of the cause of a disorder or disease or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a compound or drug (e.g., a combination product as claimed in the present application) that provides for significant alleviation of the clinical symptoms of a disease or disorder without undue toxic side effects.

"Administration," "administration," and "administration" refer to introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods or delivery systems known to those of skill in the art.

An "adverse reaction" (AE) as described herein is any sign, symptom or disease that is adverse and often unintended or undesirable associated with the use of medical treatment. For example, adverse effects may be associated with activation of the immune system or expansion of immune system cells in response to treatment. Medical treatments may have one or more associated AEs, and each AE may have the same or different severity levels.

The terms "subject," "individual," "subject" include any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit, etc.), and most preferably a human. The terms "subject" and "patient" are used interchangeably herein.

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject with a compound of one aspect of the invention and that does not destroy the pharmacological activity of the compound when administered in a dosage sufficient to deliver a therapeutic amount thereof and that is non-toxic. Exemplary pharmaceutically acceptable carriers or adjuvants include inert diluents such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, etOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (including cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof; adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents and the like. The terms "mode of administration", "regimen" are used interchangeably and refer to the dosage and time of use of each therapeutic agent in the combination of the invention.

Nucleoside analogues

The term "nucleoside analog" as used herein refers to any one of the nucleoside analogs described in WO2021213288A1, or a pharmaceutically acceptable salt thereof, which is incorporated herein by reference in its entirety.

In some preferred embodiments, the nucleoside analogs used herein have the structure shown in formula I below:

Wherein:

r ₁ is cyano;

R ₂ is hydroxy or C _1-4 alkyl-COO-;

R ₃ is H or C _1-4 alkylcarbonyl optionally substituted with amino;

r ₄ is H;

x is C _1-4 alkylene, wherein 1 or more (e.g., less than 3) H in the alkylene are substituted with deuterium;

r ₅ is H, C _1-4 alkylcarbonyl optionally substituted with amino;

R ₆ is amino;

r ₇ is H;

r ₈ is H, deuterium (D) or halogen.

In some embodiments, R ₂ is C _1-3 alkyl-COO-.

In some embodiments, R ₃ is C _1-4 alkylcarbonyl optionally substituted with amino. Further preferably, R ₃ is unsubstituted C _1-4 alkylcarbonyl.

In some embodiments, X is-C (H) ₂ -. In some embodiments, X is-C (D) ₂ -.

In some embodiments, R ₅ is C _1-4 alkylcarbonyl optionally substituted with amino. Further preferably, R ₅ is unsubstituted C _1-4 alkylcarbonyl.

In some embodiments, R ₈ is deuterium.

In some embodiments, at least one of R ₂、R₃ O-and R ₅ O-is C _1-3 alkyl-COO-; preferably, at least two of R ₂、R₃ O-and R ₅ O-are C _1-3 alkyl-COO-; more preferably, R ₂、R₃ O-and R ₅ O-are both C _1-3 alkyl-COO-. In some embodiments, the C _1-3 alkyl is a C ₃ alkyl, more preferably isopropyl.

Herein, alkyl includes straight chain and branched alkyl groups. Herein, carbonyl is a-C (O) -group. Herein, the amino group is-NH ₂.

In a particularly preferred embodiment, the nucleoside analog useful in any of the uses, therapies, pharmaceutical compositions and kits described herein is VV116, the chemical formula of VV116 is as follows:

pharmaceutical composition and kit

Provided herein are compositions comprising a nucleoside analog described in any of the embodiments herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant. Pharmaceutical compositions.

The pharmaceutical compositions described herein are suitable for oral administration. The pharmaceutical compositions suitable for oral administration may be in the form of tablets, troches, capsules, troches, granules, solutions, aqueous or oily suspensions, dispersible powders or granules, syrups or elixirs and the like. It will be appreciated that when formulated into a pharmaceutical composition suitable for oral administration, the pharmaceutical composition will contain a pharmaceutically acceptable carrier or adjuvant suitable for oral administration.

The pharmaceutical compositions described herein may contain about 10-600mg, preferably about 50-300mg or 200-600mg of the nucleoside analog or pharmaceutically acceptable salt thereof per unit. Non-limiting examples of the amount of the nucleoside analog or pharmaceutically acceptable salt thereof per unit of the pharmaceutical composition 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, about 600mg, or any two of these ranges as endpoints, preferably about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, or about 600mg.

Kits described herein may contain 1 or more doses of a pharmaceutical composition described in any of the embodiments herein; wherein the pharmaceutical composition is contained in an amount that satisfies at least 1 administration cycle, wherein the amount administered per day is 25-1200mg, preferably about 200-1200mg, more preferably about 400-1200mg, still more preferably about 400-800mg of the nucleoside analog or pharmaceutically acceptable salt thereof. In some embodiments, the 1 dosing period is 1-10 days, e.g., 1 day, 3 days, 5.5 days, 9 days, or 10 days. In some embodiments, the pharmaceutical composition is contained in an amount sufficient for at least 1 dosing cycle, with a dosing frequency of twice daily.

In some embodiments, the kit contains one or more single-dose drug dosage units. In some embodiments, the single drug dosage unit comprises about 25-1200mg, preferably about 25-800mg, more preferably about 50-800mg, still more preferably about 200-600mg of the nucleoside analog or pharmaceutically acceptable salt thereof. Non-limiting examples of the amount of the nucleoside analog or pharmaceutically acceptable salt thereof in the single-dose pharmaceutical dosage unit are about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, 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 within these ranges as endpoints, preferably about 200mg, about 400mg, or about 600mg. Herein, the single drug dosage unit refers to 1 or 1 dose of drug dosage unit administered at each administration. In some embodiments, the single drug dosage unit is a pharmaceutical composition as described in any embodiment herein.

Preferably, the kit contains a number of single drug dosage units that satisfy administration for at least 1 administration cycle. In some embodiments, the administration period is 1-10 days or longer, preferably 1 day, 3 days, 5.5 days, 9 days or 10 days. The time of each dosing cycle may be the same or different, and the interval between each dosing cycle may be the same or different. Preferably, the dosing cycle is one in which the dosing frequency is 1, 2, 3 or 4 times daily, preferably twice daily.

In some embodiments, the number of single drug dosage units contained in the kit is such that administration is 2 times per day for at least 3 consecutive days, preferably at least 5 consecutive days. Preferably, each single pharmaceutical dosage unit contains about 200mg, about 400mg, or about 600mg of a nucleoside analog described in any of the embodiments herein, or a pharmaceutically acceptable salt thereof, calculated as the nucleoside analog described in any of the embodiments herein, or a pharmaceutically acceptable salt thereof. More preferably, the active ingredient contained in the pharmaceutical composition is VV116 as described herein.

In some embodiments, the kits of the invention further comprise instructions for methods of using the drug.

Use and method

Provided herein is the use of a nucleoside analog as described in any of the embodiments herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament or kit for treating and/or preventing a related disease caused by a viral infection. Also provided herein are nucleoside analogs, or pharmaceutically acceptable salts thereof, as described in any of the embodiments herein for use in the treatment and/or prevention of a disease associated with a viral infection. Also provided herein are methods of treating and/or preventing a related disorder caused by a viral infection, the method comprising administering to a subject in need thereof an effective amount of a nucleoside analog or pharmaceutically acceptable salt or pharmaceutical composition of any of the embodiments described herein.

Viruses described herein include, but are not limited to:

(3) Human Respiratory Syncytial Virus (RSV);

(6) Filoviridae viruses: marburg virus (MBV), ebola virus (EBV); and

The above viruses also include various variant strains thereof, such as an alpha mutant, beta mutant, gamma mutant, delta mutant, epsilon mutant, zeta mutant, eta mutant, theta mutant, iota mutant, kappa mutant, murrah mutant and omnikov mutant of SARS-CoV-2.

Related diseases caused by viral infection as described herein include, but are not limited to:

(D5) Dengue fever by dengue virus (DENV) and complications thereof;

(D6) Infection by Zika virus (Zika) and complications thereof;

(D8) Novel coronaviruses caused by SARS-CoV-2 (COVID-19);

(D10) Any combination of the above diseases.

In a preferred embodiment, the medicament or kit for use in the above-described embodiments is a pharmaceutical composition or kit as described in any of the preceding embodiments, or a pharmaceutical composition or kit for use in practicing the method of preventing or treating a disease as described in any of the embodiments herein.

In some embodiments, the preferred mode of administration in the methods of treating and/or preventing a disease associated with a viral infection described herein is oral; preferred frequency of administration includes 1,2, 3 or 4 times daily, preferably 2 times daily; the preferred administration period is 1-10 days, such as 1 day, 3 days, 5.5 days, 9 days or 10 days; preferred dosages are 25-1200mg, preferably about 25-800mg, more preferably about 50-800mg, still more preferably about 200-600mg of the nucleoside analog or pharmaceutically acceptable salt thereof per administration. In some embodiments, the dosage per administration is about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, 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 of these ranges of the nucleoside analog or pharmaceutically acceptable salt thereof, more preferably about 200mg, about 400mg, or about 600mg of the nucleoside analog or pharmaceutically acceptable salt thereof, per time. Preferably, the administration is oral. Preferably, administration is on an empty stomach or under normal dietary conditions, more preferably on an empty stomach. Herein, the general dietary condition refers to the daily diet of a normal individual, excluding a high-fat diet.

In a particularly preferred embodiment, provided herein is a method of treating or preventing a novel coronavirus caused by SARS-CoV-2, particularly a novel coronavirus caused by an omnikov variant, comprising administering to a patient in need thereof a nucleoside analog VV116, or a pharmaceutically acceptable salt thereof, wherein the dosing regimen is: each dose is 200-600mg of VV116, or a pharmaceutically acceptable salt thereof, calculated as VV116, administered orally on an empty stomach, 2 times daily, for at least 3 days, preferably at least 5 days, continuously.

Abbreviations

Throughout the description and examples of the present invention, the following abbreviations are used:

maximum tolerated dose of MTD

AE adverse events

QD one dose per day

IRC independent review Committee

Adverse effects of TEAE on treatment

SAE serious adverse reaction

CI confidence interval

ALT alanine aminotransferase

BID twice daily

BMI body Mass index

Concentration of C _trough valley

Dx day X

ECRF electronic medical record report form

Quality management standard for GCP (GCP clinical trial)

PK pharmacokinetics

NAG N-acetyl-beta-D-glucosaminidase

Area under AUC blood concentration-time curve

Evaluation criterion for CTCAE common adverse reaction event

The invention is further illustrated by the following examples, which should not be construed as limiting the invention. The contents of all references cited throughout the application are expressly incorporated herein by reference.

Examples

Study design

Three phase I clinical trial results were performed sequentially, study 1 and 2 being randomized, double-blind, placebo-controlled, single-dose, and multi-dose escalation studies aimed at assessing safety, tolerability, and pharmacokinetics of single and multiple escalation oral VV116 in healthy subjects; study 3 is a randomized, open, 3-cycle, crossover study aimed at observing the effects of diet on VV116 pharmacokinetics and safety (figure 1).

The present clinical trial must comply with current legal regulations and guidelines including, but not limited to, NMPA-GCP, international conference on clinical trial quality control codes (ICH-GCP), and ethical guidelines derived from the declaration of helsinki. Three clinical studies were registered at https:// clinicaltrias.gov/, accession numbers: NCT05227768, NCT05201690, NCT05221138.

Study population

Group entry criteria:

1) Age: age less than or equal to 18 years less than or equal to 45 years; the sex is unlimited;

2) Weight of: the male weight is more than or equal to 50kg, and the female weight is more than or equal to 45kg; body Mass Index (BMI) in the range of 19-26kg/m ² (including 19 and 26);

3) The health condition is good. The vital sign, physical examination, laboratory examination, thyroid B-ultrasonic examination, ophthalmic examination, electrocardiogram and B-ultrasonic examination are all normal or abnormal without clinical significance;

4) Reliable contraception measures can be taken during the test period and 3 months after taking the medicine;

5) The purpose, the content and the possible adverse reaction of the test are fully known, the clinical test is voluntarily participated and written informed consent is signed, and all test processes can be completed according to the test requirements and the test rules are complied with.

Exclusion criteria:

1) Known to have a history of allergy to the test formulation and any components thereof or related formulations;

2) Patients with allergic diseases or allergic constitutions;

3) Those who have clear diseases of the central nervous system, cardiovascular system, digestive system, respiratory system, urinary system, blood system, metabolic disorders, etc., and who need medical intervention or other diseases unsuitable for participation in clinical trials (e.g., mental history, etc.);

4) The blood donation or blood loss is more than or equal to 400mL in the first 3 months, or the use history of blood products is provided;

5) Patients who participated in other drug clinical trials within 3 months prior to enrollment;

6) Screening patients who take any prescription drugs, non-prescription drugs, chinese herbal medicines or health care products within 2 weeks before screening;

7) Screening for drug addicts or alcohol addicts, drinking at least 2 times daily or more than 14 units per week, or enthusiastic alcoholism (1 unit of about 200mL beer with 5% alcohol content or 25mL spirits with 40% alcohol content or 85mL wine with 12% alcohol content);

8) Screening those who smoke more than 10 or equal amounts of tobacco per day during the first 1 year of smoking;

9) Those who were unable to stop smoking and abstinence during the test period;

10 Hepatitis b surface antigen (HBsAg), hepatitis c virus antibody (Anti-HCV), treponema pallidum antibody, and HIV antibody positive;

11 Chest X-ray (posterior anterior) result is abnormal and clinically significant;

12 B-ultrasonic examination shows moderately severe fatty liver;

13 Screening for glutamic-pyruvic transaminase (ALT) or glutamic-oxalacetic transaminase (AST) exceeding the upper limit of normal value (ULN);

14 Glomerular filtration rate (eGFR) of less than 90mL/min/1.73m2 during screening;

15 Screening for electrocardiographic abnormalities, single examination of QTcF (heart rate corrected) men > 450ms, women > 470ms, and/or other abnormalities of clinical significance;

16 A pregnant, lactating female, or male subject partner with a child-care planner within 3 months;

17 A researcher considers other factors unsuitable for participation in the test.

Study drug information:

Test drug: VV116 tablets; specification of: 50mg, 100mg and 300mg. And (3) storing: and (5) sealing and preserving at room temperature.

Placebo: VV116 blank tablets; specification of: 50mg, 100mg and 300mg. And (3) storing: and (5) sealing and preserving at room temperature.

The placebo is tablet with no difference with the appearance (shape, color, size, package) and smell of the test medicine, contains no effective components of the test medicine, and has the components of the original formula.

The initial dose is 25mg group, because the preparation specification is 25mg (the preparation specifications are 50mg, 100 mg and 300mg, all specifications are designed by prescription in equal proportion), and 50mg of the product with the specification is adopted for administration in a mode of slicing by a drug cutter in a research center. The sponsor has made related pharmaceutical researches, the weight difference, content uniformity, friability, dissolution, content, related substances, weight loss after division and the like of the sliced half pieces all meet the quality standard, and the cut surfaces of the drug-containing and placebo products are white after division, so that the appearance characteristics are not different.

Study 1:

Single dose escalation study. Based on non-clinical toxicology data for VV116, the estimated maximum recommended starting dose was selected to be 25mg and the estimated maximum dose was selected to be 1200mg. There were 8 dose groups in the initial protocol, with an initial dose of 25mg,25mg into 6 subjects (male and female unlimited), and 8 subjects per group (male and female unlimited) of the remaining dose groups, randomly assigned to the trial and placebo groups, and evaluated for safety, tolerability, and PK profile. The number of single dose groups may be increased or decreased depending on the safety and drug generation achieved. Dosage levels on the climbing slopes were planned to be 25mg,50mg,100mg,200mg,400mg,600mg,800mg and 1000mg (dosage groups 1-8). After the 25mg dose group was administered, the safety results (including symptoms, vital signs, physical examination, etc.) of the subjects within 48 hours of administration were evaluated by the researchers, no potential safety hazard was found, and the tolerability was good.

The clinical trial of II/III phase in Wu Guoxin hospitalized patients is being carried out by obtaining clinical wholesale in Uzbexastan (hereinafter referred to as "Wuguo") at 2021, 09 months and 30 days, and adopting a random, control and open 3-group design, 2 VV116 test groups with dosages of 200mg and 300mg respectively, 2 times daily for 5 days, and a control group of Fapirrevir. Each group was planned to be in 150 cases, 100 of which were diagnosed with moderate SARS-CoV-2 infection and 50 of which were diagnosed with severe SARS-CoV-2 infection. The first group entry is completed by the test 2021 on 11 months and 3 days, and the initial safety data summarization of 2 days after the first administration of 47 subjects in the prior period is completed at present, so that the result shows that the safety is good 2 days after the first administration of the VV116, the main AE is slightly increased transaminase, SAE does not occur, and no subject exits. Based on the above results, the sponsor considers that the safety performance can basically prove the safety of 200mg of single administration under the conditions of the sample size (36 cases of test group) of 47 cases and 400-600 mg of daily dose, so that the safety risk of 200mg of single administration of the product in Chinese healthy subjects is expected to be controllable, 50mg and 100mg dose groups can be deleted, and single administration of 200mg dose group can be directly carried out.

Based on the above results, the sponsor decided to adjust the single administration dose group to 25mg,200mg,400mg,800mg and 1200mg.

The 25mg dose group received 4 subjects with VV116 tablets and 2 subjects with placebo. The remaining dose groups, each group, will have 6 subjects receiving VV116 tablets, 2 subjects receiving placebo. The 25mg dose group was sentry dosed, after the 25mg dose group was dosed, the researchers and sponsors decided that the 200 and 400mg dose groups were not sentry dosed and that the 800mg and 1200mg dose groups continued sentry dosing based on the results of the staged safety study of the in-progress clinical trial of uzbexatan and the results of the earlier study. The dose group requiring the sentinel administration (i.e., 1 subject to test drug, 1 subject to placebo) was well tolerated by the study investigator who evaluated the sentinel administration for 48 hours safety results (including symptoms, vital signs, physical examination, etc.) without finding safety hazards, and provided that the rest of the subjects in the group were dosed.

Screening was performed within 14 days prior to dosing and subjects would stay in phase i ward (hospitalization) on day-1 for standard evaluation of the inclusion group. Subjects will fasted overnight for at least 10 hours prior to dosing on day 1. The subjects were orally administered VV116 tablets or placebo at respective dosage levels with 240mL of water on day 1 under fasted conditions. All subjects remained in the phase I clinical study center until close medical monitoring was performed 48 hours post-dose, except for subjects in the 400mg dose group, which underwent exploratory material balance studies within 72 hours post-dose. Following randomized double-blind dosing, subjects will receive daily safety assessments and PK sample collection. If no safety risk is found in evaluating clinical safety data, the investigator will allow the subject to discharge as appropriate after the subject completes the evaluation on day 3 morning. Every normal person checked at discharge is followed by telephone call on day 7 (+ -1 day); if abnormal, the follow-up visit is arranged by the researcher according to the actual situation. The subjects are withdrawn in advance as much as possible according to the requirements of discharge inspection, and are withdrawn after the safety observation indexes are observed.

Before entering the next dose group, researchers and sponsors will evaluate whether dosing of the next dose group can begin, primarily for clinical safety, tolerability reviews of each dose group; the determination may be made in conjunction with PK data if necessary. In addition, the investigator and sponsor may make decisions regarding whether to make dose group adjustments or whether to make subject number adjustments based on prior study results.

Study 2:

Multiple dose escalation studies. The trial was run sequentially from the low dose group to the high dose group using an ascending-dose design, with each subject receiving only one dose level of oral administration. The oral administration was initially preset for 3 dose groups, 200mg, 400mg and 600mg, 2 times daily (12 hours apart), for 5.5 days continuously and for the last morning on day 6. Dosing was recorded on day 1 of the trial (D1), and after a safety follow-up 7 days after the last dosing was completed (D12) for the previous dose group of VV116 tablets, the subjects of the next dose group could begin dosing via a co-review of the safety confirmation by the investigator and sponsor. Each dose group was planned to group 12 subjects, with trial drug and placebo being dispensed in a 3:1 ratio.

The whole test cycle includes a screening period of up to 14 days, a multi-dosing period of 5.5 days (D1-D6), a safety observation period of 3 days and a safety follow-up period of 4 days. The subject will stay in the phase I clinical trial ward the day prior to dosing (D-1, baseline period) until after the 8 th day has completed all examinations and evaluations, and the normal subjects will follow up on day 12 (±1 day) phone call at discharge; if abnormal, the follow-up visit is arranged by the researcher according to the actual situation. The subjects are withdrawn in advance, and the subjects withdraw after completing safety observation indexes as much as possible according to the requirements of discharge inspection.

Study 3:

Food impact study. Screening was performed within 14 days prior to dosing, selecting 12 healthy subjects meeting the study group criteria. The subject must obtain signed informed consent before proceeding with the programs prescribed by the regimen. The specific administration mode is as follows: the 12 healthy subjects were randomly divided into A, B, C groups of 4 cases each, with the first cycle of administration under fasting conditions, the second cycle of administration under standard postprandial conditions, the third cycle of administration under high-fat postprandial conditions, the first cycle of administration under high-fat postprandial conditions, the second cycle of administration under fasting conditions, the third cycle of administration under standard postprandial conditions, the first cycle of administration under standard postprandial conditions, the second cycle of administration under high-fat postprandial conditions, the third cycle of administration under fasting conditions, the third cycle of administration across three cycles, and the washout period of 3 days. The single oral dose was 400mg, and 400mg VV116 tablets (. Gtoreq.10 hours) were administered in a single oral dose after overnight fast for the fasting period. 400mg VV116 tablets were administered in a single oral dose within 30 minutes after consumption of either a standard meal (total calories: about 700 kcal) or a high fat meal (total calories: about 800kcal-1000kcal from protein, carbohydrate and fat, respectively, about 150, 250 and 500-600 kcal) during both feeding periods. All subjects remained in the phase I clinical study center until 48 hours after the last dose.

Each subject had a test period of no more than 27 days, including a screening period of no more than 14 days at maximum, a 9-day dosing observation period (including D1, D4, and D7 dosing, and a 3-day washout period and safety observation period following each dosing), and a safety follow-up period of 4 days thereafter (D13). The subject will check into the phase I clinical trial ward one day (D-1) prior to dosing until day 9 (D9) after complete examination and evaluation, and leave with a visit schedule prescribed by the regimen either returned to the study center or received follow-up by telephone and completed the relevant procedures and evaluations.

Safety evaluation

Any AE and SAE occurring during the test, including vital signs, physical examination, 12-lead electrocardiogram, ophthalmic examination, clinical laboratory examination index (blood routine, blood biochemistry, urine NAG, coagulation function, urine routine + urine sediment + urine microalbumin, thyroid function) and the like, were collected. Adverse events occurring throughout the study period were evaluated according to the national cancer institute common adverse event standard terminology (NCI-CTCAE) version 5.0.

Biological sample collection

About 3ml of blood samples were collected at predetermined time points for analysis. In the 25mg single escalation dose study group, blood samples were collected at the following 15 time points: 0 (pre-dose); and 0.25,0.5,1,1.5,2,3,4,5,6,8, 12, 24, 36 and 48 hours post-administration. Thereafter, the time points were slightly adjusted according to the pharmacokinetic profile of the 25mg group. In other dose groups of the single dose escalation study, as well as in food impact studies, blood samples were collected at the following time points: 0 (pre-dose); and 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after administration.

In multiple dose escalation studies, blood samples were collected at the following time points, day 1: 0 (pre-dose); and 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours and 12 hours after administration; day 5: before each administration; day 6: 0 (pre-dose), and 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, and 48 hours post-dose.

The collected blood samples were separated by centrifugation at 1500g for 10 minutes at 4 ℃, then divided into 2 centrifuge tubes (at least 0.6mL of each plasma), frozen and stored at-80 ℃ until analysis.

Exploratory substance balance assessment was performed in a single dose escalation study in the 400mg dose group. Random urine samples of-24-0 h before administration on day 1, and urine excreted in each time interval of 0-6h, 6-12h, 12-24h, 24-48h, 48-72h after administration are collected respectively. Collecting random feces sample of-24-0 h before 1 day and feces between 1 day and 4 days after administration (i.e. all feces in 72h after administration need to be collected according to actual defecation times of the subjects, if no defecation occurs in the same day, the feces are not collected, and each feces is collected and stored separately).

Biological analysis method

LC-MS/MS method for determining the concentration of VV116 and its metabolite 116-N1 in human plasma. For VV116, VV116-D4 is selected as an internal standard. The regression coefficient was 0.9998 over the calibration range (2-2000 ng/mL). The precision of the batch is 1.1 to 6.6 percent and the precision of the batch is 4.6 to 9.6 percent. The accuracy is 85.6-102.3%.

For metabolite 116-N1, 116-N1-D4 was chosen as internal standard. The calibration curve was linear in the range of 10 to 10000ng/mL with a regression coefficient of 0.9998. The precision of the batch is 2.2 to 12.4 percent, and the precision of the batch is 2.5 to 8.2 percent. The accuracy is 90.5-100.1%.

Pharmacokinetic (PK) evaluation

Pharmacokinetic parameters of VV116 and its major metabolite 116-N1 were calculated in plasma from all dose groups of 25-1200mg using non-compartmental modeling using WinNonlin software. The main pharmacokinetic parameters are: peak time of arrival (Tmax), peak concentration (Cmax), half-life (t 1/2), area under the drug concentration-time curve (AUC 0-t) from 0 to last measurable concentration acquisition time t, area under the drug concentration-time curve (AUC 0-24 h) from 0 to 24, area under the drug concentration-time curve (AUC 0-infinity) from 0 to infinite time, elimination rate constant (Ke), apparent distribution volume (Vd/F), mean Residence Time (MRT), clearance (CL/F), cumulative excretion (Ae), excretion fraction (Fe), and the like. AUC0-t and AUC0- ≡were calculated using Linear Up Log Down rule method. Tmax and Cmax are based on actual measurements. The accumulation ratio (Rac) after repeated dosing was also analyzed in multiple escalation dose studies.

Statistical analysis

Statistical analysis was performed using SAS software version 9.4 (SAS Institute, cary, NC, USA). Descriptive statistics are expressed as arithmetic mean, standard deviation, coefficient of variation, median, maximum, minimum and geometric mean for each dose group. The frequency and percentage are calculated to summarize the classification variables.

In a single dose escalation study, the dose-exposure relationship was assessed using confidence interval criteria. Linear regression was performed. Regression equations are expressed as ln (PK) =α+β×ln (Dose), where logarithmic transformation is used for PK parameters and Dose. A 90% confidence interval for the estimated slope (β) is calculated. Where the 90% confidence interval for β is within the judgment interval, the PK parameters are considered to be linearly related to dose.

In the food impact study, PK parameters including AUC0-t, AUC0- ≡and Cmax were analyzed under different dietary conditions. The mean, and 90% confidence interval of log-transformed PK parameters were estimated using a generalized linear hybrid model with diet condition, order, and time period as fixed effects and subjects as random effects. Pair wise comparisons were made for each PK parameter (high fat meal and empty stomach, standard meal and empty stomach, high fat meal and standard meal).

Results of the study

Study was carried over between 11 months 2021 and 1 month 2022 with 86 standard-compliant adult healthy subjects, study 1 with 38 subjects, study 2 with 36 subjects, and study 3 with 12 subjects. Demographic data for the subjects in the group are shown in table 1.

Results of pharmacokinetic studies

Study 1: single dose escalation study

The VV116 rapidly hydrolyzes to its metabolite 116-N1 after oral administration, which undergoes three consecutive enzymatic phosphorylation reactions in the cell, yielding the triphosphate active form 116-NTP (see FIG. 2). Proto-drug was not detected in plasma (lower limit of quantitation was 2 ng/mL), but metabolite 116-N1 was detected and PK parameters were calculated in three studies. Table 2 summarizes the primary PK parameters of 116-N1 in each dose group after single-dose administration of VV 116. The mean plasma 116-N1 concentration versus time curve is shown in FIG. 3.

The main PK exposure parameters Cmax and AUC are dose dependent. Mean+ -SD of Cmax was 154+ -66.7, 1096+ -412, 1898+ -701, 2796+ -225 and 3086+ -778 ng/mL for the 25mg, 200mg, 400mg, 800mg and 1200mg dose groups, respectively. AUC0-t is 852+ -272, 6631+ -1603, 12759+ -2747, 25886 + -5904, and 28057 + -5145 h·ng/mL, while AUC 0-infinity for the above five dose groups are 888+ -286, 6986+ -1683, 13064 + -2727, 26233+ -5897, and 28325 + -5272 h·ng/mL, respectively. Confidence Interval (CI) criteria were used to evaluate dose linearity. Table 3 shows the dose ratio analysis. For dose intervals of 25-800mg, the slope estimates (. Beta.) for Cmax, AUC0-t, and AUC0- ≡and 90% CI thereof are 0.87 (0.74-0.99), 0.99 (0.91,1.07), and 0.98 (0.90,1.06), respectively, not entirely within the judgment interval (0.94-1.06). Nevertheless, we can conclude that AUC parameters and Cmax increase in an approximately dose-proportional manner over the dose range of 25-800 mg. However, as the dose increased from 800 to 1200mg, cmax, AUC0-t and AUC0- ≡showed no significant change. Tmax median is between 1.00 and 2.50h, and t1/2 average value is between 5.21 and 6.95 h.

Table 3: dose-proportional analysis of Cmax and AUC of plasma 116-N1 in a single dose escalation study

The research results show that: VV116 was rapidly absorbed orally, and in a single dose escalation study VV116 was rapidly hydrolyzed to metabolite 116-N1 with a mean plasma drug peak time (Tmax) of only 1.00-2.50 hours, and was rapidly absorbed. The area under the blood concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of the oral dose are dose-dependent in the 25-800mg dose range, no significant increase is seen between 800-1200mg doses, and the maximum is at 1200mg doses. The average half-life (t 1/2) value of VV116 is 5.21-6.95 hours, suggesting that the dosing frequency is set to twice daily (BID) in clinical treatment.

Study 2: multiple dose escalation study

The primary PK parameters for day 1 and day 6 116-N1 after the multi-dose VV116 are listed in table 4. The average plasma 116-N1 concentration versus time curve dose groups at day 1 and day 6 for 200mg, 400mg and 600mg are shown in FIG. 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 on day 1 in the three dose groups (200 mg group 4.72h vs 7.56h,400mg group 4.88h vs 8.12h,600mg group 5.41h vs 7.85h group). For drug exposure, cmax, AUC0-t, and AUC0- ≡increase after repeated administration. Cmax accumulation rates (Rac) for dose groups 200mg, 400mg and 600mg were 1.34, 1.18 and 1.24, respectively, and Rac for AUC0-t was 1.53, 1.41 and 1.42, respectively, indicating slight accumulation following repeated administration of VV 116.

Researchers have also found that the trough concentration of 116-N1 on days 5 and 6 is in the range of 242-345ng/mL, which is higher than the effective concentration of 116-N1 anti-omnirange variants in preclinical studies (EC 90, 186.5 ng/mL), suggesting that 200mg BID and above dose regimens can consistently maintain effective antiviral concentrations, recommended for subsequent clinical studies.

Table 5: multi-dose escalation study day 5 and day 6 116-N1 trough concentrations

Note that: data are expressed as mean (SD).

Study 3: food impact study

Key PK parameters for 116-N1 after a single oral administration of 400mg w 116 under different dietary conditions are shown in table 6, and the corresponding mean plasma drug concentration versus time curves are shown in figure 5.

The Geometric Mean Ratio (GMR) of standard meal to fasting Cmax, AUC0-t, AUC 0-infinity and 90% CI thereof 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%, respectively. The high fat meal and the GMR (90% CIs) for fasting Cmax, AUC0-t and AUC 0-infinity were 107.92% (94.56% -123.18%), 126.32% (121.01% -131.85%) and 124.67% (119.74%) -129.81%), respectively. AUC0-t and AUC0- ≡for high fat meals increased by 26.32% and 24.67%, respectively, as compared to fasting.

The median Tmax of 116-N1 in the fasting, standard meal and high fat meal is 1.5h, 3.0h and 2.5h respectively. We found that administration of VV116 under fed conditions can extend the time to peak compared to fasting conditions, but has little effect on systemic exposure of the study drug.

GMR (90% cis) for Cmax in normal and high fat diet conditions was in the equivalent range of 80% -125% compared to fasting conditions; the aucgmr (90% cis) for the normal diet was also in the range of 80-125%, whereas the AUC 0-t and AUC 0-infinity increases for the high fat diet were 26.32% and 24.67%, respectively. Since feeding had no effect on Cmax, whereas high fat diets slightly increased AUC, oral VV116 treatment on an empty stomach or under normal diet conditions was suggested.

Table 6: primary PK parameters of 116-N1 under fasting and fed conditions after single oral administration of 400mg VV116

Note that: data are expressed as mean (SD), except Tmax, which is shown as median (Min, max).

Safety study results

No deaths, no severe AEs, no grade 3 AEs and above, and no discontinuation and discontinuation of therapeutic AEs were reported in 3 studies. All AEs were recovered without treatment or intervention.

Study 1: single dose escalation study

In a single dose escalation study, no dose-related trend was observed with Adverse Events (AEs) (see table 7). VV116 group AE occurred at a lower rate than placebo group (39.3% vs. 50.0%). Except for the level 2 neutropenia of 1 subject in the 400mg dose VV116 group, the remaining AEs were all level 1. The most common drug-related AEs were sinus bradycardia, shortened electrocardiographic PR intervals, and elevated blood bilirubin.

Study 2: multiple dose escalation study

In the multiple dose escalation study, the AE incidence in VV116 group was 51.9% and 55.6% respectively with placebo group (see table 8). Dose-related AE occurrence was observed. All AEs in VV116 groups were grade 1. The most common drug-related AEs were elevated blood uric acid, dry mouth, crystalluria and nausea.

Notably, the investigator observed a temporary elevation of grade 1 ALT in only 1 subject (3.7%) in the VV116 (400 mg dose) group of multiple escalated dose studies and recovered by itself after no treatment. VV116 has a lower risk of liver toxicity than the data reported in the past for the same class of drugs, and researchers will continue to monitor liver function in patients during subsequent phase II studies.

Study 3: food impact study

The number (incidence) of subjects experiencing AE in the fasting, standard, high fat meal state was 0 (0), 2 (16.7%) and 4 (33.3%). Level 1 atrioventricular block occurred in 2 standard meal conditions and urine bacteria test positive, crystalluria, blood pressure increase and level 1 atrioventricular block occurred in 4 high fat meal conditions, respectively. All AEs were of CTCAE grade 1 severity.

The results show that VV116 exhibits satisfactory safety and tolerability in healthy subjects, and that the plasma drug concentration of active ingredient 116-N1 can rapidly peak (mean Tmax of 1.00-2.50 hours) after oral administration of VV116, with AUC and Cmax being dose-dependent over a dose range of 25-800 mg; the normal diet had no effect on AUC and Cmax after VV116 oral administration; after multiple administrations, an effective antiviral concentration is achieved at a dosage level of 200-600 mg BID.

Claims

1. Use of a nucleoside analogue or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with a viral infection, wherein the nucleoside analogue has the structure of formula I:

Wherein:

r ₁ is cyano;

R ₂ is hydroxy or C _1-4 alkyl-COO-, preferably C _1-3 alkyl-COO-;

R ₃ is H or C _1-4 alkylcarbonyl optionally substituted with amino, preferably unsubstituted C _1-4 alkylcarbonyl;

r ₄ is H;

X is C _1-4 alkylene, wherein 1 or more (e.g., less than 3) H in the alkylene are substituted with deuterium; preferably-C (H) ₂ -or-C (D) ₂ -;

R ₅ is H, optionally amino-substituted C _1-4 alkylcarbonyl, preferably unsubstituted C _1-4 alkylcarbonyl;

R ₆ is amino;

r ₇ is H;

R ₈ is H, deuterium (D) or halogen, preferably deuterium.

2. The use of claim 1 wherein at least one of R ₂、R₃ O "and R ₅ O" is C _1-3 alkyl-COO-; preferably, at least two of the R ₂、R₃ O-and R ₅ O-groups are C _1-3 alkyl-COO-; more preferably, both R ₂、R₃ O-and R ₅ O-are C _1-3 alkyl-COO-; preferably, the C _1-3 alkyl is a C ₃ alkyl, preferably isopropyl.

3. The use of claim 2, wherein the nucleoside analog is VV116 having the following chemical formula:

4. a use according to any one of claims 1 to 3, wherein the virus is selected from:

(3) Human Respiratory Syncytial Virus (RSV);

(6) Filoviridae viruses: marburg virus (MBV), ebola virus (EBV);

(7) Coronaviruses infecting other mammals: porcine Epidemic Diarrhea Virus (PEDV);

Preferably, the virus comprises a variant strain thereof; preferably, the mutant strain of SARS-CoV-2 comprises an alpha mutant, a beta mutant, a gamma mutant, a delta mutant, an Epsilon mutant, a Zeta mutant, an Eta mutant, a Theta mutant, an Iota mutant, a kappa mutant, a murray mutant and an Omikovia mutant.

5. The use according to any one of claims 1-4, wherein the disease associated with a viral infection is selected from the group consisting of:

(D1) Common cold, high risk symptom infection, respiratory tract infection, pneumonia and complications thereof caused by human coronavirus infection;

(D2) Common cold, high risk symptom infection, respiratory tract infection, pneumonia and complications thereof caused by human Respiratory Syncytial Virus (RSV) infection;

(D3) Common cold, high risk symptom infection, respiratory tract infection, pneumonia and complications thereof caused by human influenza virus infection;

(D5) Dengue fever by dengue virus (DENV) and complications thereof;

(D6) Infection by Zika virus (Zika) and complications thereof;

(D8) Novel coronaviruses caused by SARS-CoV-2 (COVID-19);

(D10) Any combination of the above diseases.

6. The use of any one of claims 1-5, wherein the medicament comprises a nucleoside analogue or a pharmaceutically acceptable salt thereof in a dose of about 10-600 mg calculated as nucleoside analogue, preferably about 50-300mg or about 200-600mg, more preferably about 50mg, about 100mg, about 200mg, about 300mg, about 400mg or about 600mg.

7. Use according to any one of claims 1-3, wherein the medicament is in an oral dosage form, preferably selected from: tablets, troches, capsules, troches, granules, solutions, aqueous or oily suspensions, dispersible powders or granules, syrups or elixirs.

8. A use according to any one of claims 1-3, wherein the drug is administered 1,2, 3 or 4 times daily, preferably twice daily, in the treatment or prophylaxis.

9. A use according to any one of claims 1 to 3, wherein in the treatment or prophylaxis the drug is administered in a single dose of about 25 to 1200mg, preferably about 25 to 800mg, further preferably about 200 to 600mg, most preferably about 200mg, about 400mg or about 600mg of the nucleoside analogue or a pharmaceutically acceptable salt thereof, calculated as nucleoside analogue.

10. A use according to any one of claims 1 to 3, wherein in the treatment or prophylaxis the drug is administered for a period of 1 to 10 days or more, preferably 1 day, 3 days, 5.5 days, 9 days, 10 days; optionally, the time of each dosing cycle is the same or different, and the interval between each dosing cycle is the same or different.

11. Use according to claim 3, wherein in the treatment or prophylaxis, a single dose of the medicament is administered orally on an empty stomach, 2 times daily for at least 3 days, preferably at least 5 days, with 200-600mg of VV116 calculated as VV 116.

12. A pharmaceutical composition comprising the nucleoside analogue of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or adjuvant; wherein the pharmaceutical composition contains about 10-600mg, preferably about 50-300mg or 200-600mg of the nucleoside analog or pharmaceutically acceptable salt thereof.

13. Pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is suitable for oral administration, preferably in a dosage form selected from the group consisting of: tablets, troches, capsules, troches, granules, solutions, aqueous or oily suspensions, dispersible powders or granules, syrups and elixirs.

14. A kit, wherein the kit contains 1 or more doses of the pharmaceutical composition of claim 12; wherein the amount of said pharmaceutical composition in the kit is at least an amount sufficient for 1 administration cycle, wherein the amount administered per day is 25-1200mg, preferably about 200-1200mg, more preferably about 400-1200mg, still more preferably about 400-800mg of said nucleoside analogue or pharmaceutically acceptable salt thereof.

15. The kit of claim 14, wherein,

The 1 administration period is 1-10 days, for example 1 day, 3 days, 5.5 days, 9 days or 10 days; and/or

The administration frequency is 1, 2, 3 or 4 times daily, preferably 2 times daily during the administration period.

16. The kit of claim 14 or 15, wherein the kit contains one or more single-dose drug dosage units, wherein the single-dose drug dosage units comprise about 25-1200mg, preferably about 25-800mg, more preferably about 50-800mg, still more preferably about 200-600mg of the nucleoside analogue or pharmaceutically acceptable salt thereof, as a nucleoside analogue or pharmaceutically acceptable salt thereof;

Preferably, the kit contains a number of single drug dosage units that satisfy administration for at least 1 administration cycle; preferably, the administration period is 1-10 days or longer, preferably 1 day, 3 days, 5.5 days, 9 days or 10 days.

17. The kit of claim 16, wherein the number of single drug dosage units in the kit is such that administration is 2 times per day for at least 3 consecutive days, preferably at least 5 consecutive days; preferably, each single pharmaceutical dosage unit contains about 200mg, about 400mg, or about 600mg of the nucleoside analog or pharmaceutically acceptable salt thereof, as calculated for the nucleoside analog or pharmaceutically acceptable salt thereof; more preferably, the nucleoside analogue is the VV116 or a free base thereof.