New use of zireuzolivir

Abstract

This invention relates to novel uses of zrepsouvir, specifically disclosing its use in the preparation of medicaments for the prevention or treatment of sequelae of human respiratory syncytial virus infection.

Description

Technical Field

[0001] This invention relates to the technical field of antiviral infection, and to a novel use of zrepsovil, specifically, to the use of zrepsovil in the preparation of medicaments for the prevention or treatment of sequelae of human respiratory syncytial virus infection. Background Technology

[0002] Human respiratory syncytial virus (RSV) is an enveloped, single-stranded RNA virus that is highly contagious and a common cause of acute lower respiratory tract infections in adults. RSV epidemics typically exhibit a pronounced seasonal pattern and geographical gradients. Its two main strains, RSV-A and RSV-B (both with multiple genotypes), circulate simultaneously or alternately. The virus is easily transmitted through close contact with aerosolized droplets or contaminated objects, as well as through inoculation via the nasal mucosa or conjunctiva. The incubation period after infection is 2 to 8 days, initially confined to the nasopharynx, but can develop into bronchiolitis and pneumonia. Immunity to RSV, particularly in infants and young children, does not provide long-term protection, so recurrent infections are common throughout a person's life. Healthy adults usually experience only mild symptoms after infection, but serious complications can occur in high-risk groups (such as children under 5 years of age, individuals ≥75 years of age, immunocompromised individuals, and / or those with severe pulmonary / cardiovascular comorbidities). It is estimated that in 2019, respiratory syncytial virus (RSV) caused approximately 33 million cases of lower respiratory tract infection, 3.6 million hospitalizations, and more than 100,000 deaths among children under the age of 5 worldwide, with nearly 70% of the deaths occurring outside of healthcare facilities.

[0003] Despite decades of significant efforts in developing antiviral drugs against respiratory syncytial virus (RSV), the primary treatment for acute RSV infection remains supportive care, including fluid resuscitation, supplemental oxygen, airway aspiration, and mechanical ventilation as needed (American Academy of Pediatrics. Respiratory syncytial virus. In: Kimberlin DW, Brady MT, Jackson MA, editors. Red Book: 2018–2021 Report of the Committee on Infectious Diseases. Elk Grove Village: American Academy of Pediatrics; 2018. pp. 682–92). Ribavirin is the only approved antiviral therapy for RSV disease. However, due to concerns about its genotoxicity and healthcare worker safety, as well as the inconvenience of its delivery route (aerosol), its use is currently limited to life-threatening RSV infections in immunocompromised patients, and is only approved for pediatric patients in nebulized form. RSV immunoprophylaxis has become an important means of preventing severe RSV infection in high-risk infants and young children. Between 2022 and 2023, RSV maternal vaccines and long-acting monoclonal antibodies (mAbs) were approved for the prevention of lower respiratory tract infections (LRTIs) caused by respiratory syncytial virus (RSV). These are indicated for all infants born during or approaching the first RSV epidemic season, as well as high-risk children under the age of 2. Studies have shown that these measures are highly effective and practical in preventing severe RSV-induced LRTIs and have been rapidly adopted in many high-income countries. However, accessibility in low- and middle-income countries (LMICs) remains very limited.

[0004] Lower respiratory tract infections caused by respiratory syncytial virus (RSV) occurring early in life are associated with long-term respiratory sequelae, including recurrent lower respiratory tract infections, recurrent wheezing, asthma, and impaired lung function, and these effects may persist into adulthood as chronic respiratory diseases. As reported in a population-based prospective birth cohort study (Rosas-Salazar C, Chirkova T, Gebretsadik T, et al. Respiratory syncytial virus infection during infancy and asthma during childhood in the USA (INSPIRE): a population-based, prospective birth cohort study. Lancet 2023; 401:1669–80) and a systematic review of 74 studies (Fauroux B, Simoes EAF, Checchia PA, et al. The burden and longterm respiratory morbidity associated with respiratory syncytial virus infection in early childhood. Infect Dis Ther 2017; 6:173–97.), there is a clear association between respiratory syncytial virus (RSV) lower respiratory tract infection and wheezing recurrence and long-term asthma risk in early childhood. This association appears to be more pronounced in younger children infected with respiratory syncytial virus (RSV) (Zar HJ, Cacho F, Kootbodien T, et al. Early-life respiratory syncytial virus disease and long-term respiratory health. Lancet Respir Med 2024; 12:810–21.). Some studies suggest that more severe disease and higher viral loads increase the risk of wheezing recurrence and asthma in early-life children, while others have not found this association.It is not yet convincingly established whether this association is causal or whether there is a shared predisposition to allergies (Driscoll AJ, Arshad SH, Bont L, et al. Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization sponsored meeting. Vaccine 2020; 38:2435–48; Shi T, Ooi Y, Zaw EM, et al. Association between respiratory syncytial virus-associated acute lower respiratory infection in early life and recurrent wheeze and asthma in later childhood. J Infect Dis 2020; 222(suppl 7):S628–33).Evidence suggests that early childhood respiratory syncytial virus (RSV) infection reduces T-cell function and may increase the predisposition to allergic airway diseases; however, the role of this immune change in the etiology of wheezing recurrence in early life children remains unclear (Shi T, Ooi Y, Zaw EM, et al. Association between respiratory syncytial virus-associated acute lower respiratory infection in early life and recurrent wheeze and asthma in later childhood. J Infect Dis 2020; 222(suppl 7):S628–33; Krishnamoorthy N, Khare A, Oriss TB, et al. Early infection with respiratory syncytial virus impairs regulatory T-cell function and increases susceptibility to allergic asthma. Nat Med 2012; 18:1525–30.).

[0005] Existing research shows that while vaccination or antibody injection can effectively prevent RSV lower respiratory tract infections in high-risk children, their long-term effects on the development of asthma and recurrent wheezing are unclear and require further research to confirm. For example, some studies have shown that palizumab prophylaxis in preventing RSV infection has no effect on recurrent wheezing or asthma (Palivizumab prophylaxis in preterminfants and subsequent wheezing / asthma: 10-year follow-up study, Pediatr Pulmonol. 2024 Mar; 59(3):743-749), while other studies have shown that palizumab prophylaxis in preterm infants significantly reduces the incidence of recurrent wheezing in the first 6 years (Palivizumab Prophylaxis in Preterm Infants and Subsequent Recurrent Wheezing. Six-Year Follow-up Study, AmJ Respir Crit Care Med. 2017 Jul 1; 196(1):29-38).

[0006] Furthermore, while ribavirin, the only approved treatment for acute respiratory syncytial virus (RSV) infection, can inhibit RSV replication during the active replication phase through multiple mechanisms, several clinical studies and meta-analyses have found no significant long-term benefit in reducing wheezing, asthma, or other respiratory sequelae following RSV infection. Krilov and colleagues reported the first study aimed at determining whether ribavirin treatment for RSV lower respiratory tract infection (RSV-LRTI) could reduce long-term sequelae. Between 1986 and 1987, 33 children treated with ribavirin for RSV-LRTI and 67 age-matched control children not treated with ribavirin were monitored for 5 to 6 years. Children in the ribavirin treatment group had more severe illness at presentation, but there was no difference in long-term outcomes between the two groups in terms of reactive airway disease (RAD) or lung function (Krilov LR, Mandel FS, Barone SR, Fagin JC, Bronchiolitis Study Group. Follow-up of children with respiratory syncytial virus bronchiolitis in 1986 and 1987: potential effect of ribavirin on long-term pulmonary function. Pediatr Infect Dis J, 1997; 16:273–276). Lang et al. enrolled 54 children who had participated in randomized trials of ribavirin treatment in a 9-year follow-up study to assess the long-term effects of this antiviral drug. Of these, 28 children received ribavirin treatment and 26 received placebo. There were no differences between the two groups in all assessed indicators, including recurrent lower respiratory tract infection, wheezing, and lung function, suggesting that ribavirin treatment has no long-term benefit (Long CE, Voter KZ, Barker WH, Hall CB. Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo. Pediatr Infect Dis J 1997;16:1023–1028).Rodriguez et al. (Rodriguez WJ, Arrobio J, Fink R, Kim HW, Milburn C. Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Ribavirin Study Group. Arch Pediatr Adolesc Med 1999; 153:469–474) conducted a third long-term follow-up study, involving 24 patients treated with ribavirin and 11 placebo-treated controls. Of these, 13 patients treated with ribavirin and 6 placebo-treated controls underwent pulmonary function testing (PFT). The researchers reported only minimal improvement in respiratory outcomes. Over a period of up to seven years, there were no differences between the two groups in reactive airway disease, wheezing, or pneumonia. There were no differences in the results of the methacholine challenge test between the two groups, but among the 6 participants receiving the placebo, 0 had normal or mildly abnormal lung function test results, while this number was 6 among the 13 participants receiving ribavirin (p = 0.04). Therefore, these long-term follow-up studies suggest that antiviral treatment does not make a real difference in long-term prognosis.

[0007] Several compounds have been proposed as RSV inhibitors and have entered Phase I or II clinical trials, such as EDP-938, Sisunatovir, ASC10, and VV116. However, approved or clinically investigated antiviral drugs only focus on acute viral clearance and symptom relief, lacking solutions for long-term adverse consequences.

[0008] Therefore, there is a need to provide methods for treating or preventing sequelae of respiratory syncytial virus infection.

[0009] In view of this, the present invention is proposed. Summary of the Invention

[0010] Ziresovir (CAS No. 1422500-60-4), also known as Ziresovir, RO-0529, AK0529, and Aisvir, is a respiratory syncytial virus fusion protein inhibitor. Its structural formula is as follows:

[0011]

[0012] This invention provides the use of ziresoxir in significantly reducing the sequelae of RSV infection.

[0013] Solution for solving the problem

[0014] One of the objectives of this invention is to provide the use of ziresoxir in the preparation of medicaments for the prevention or treatment of sequelae of human respiratory syncytial virus infection.

[0015] Preferably, the human respiratory syncytial virus (HRRSV) infection population includes infants, children, or adults.

[0016] Preferably, the population infected with the human respiratory syncytial virus is infants aged 1 to 24 months.

[0017] Preferably, the population infected with the human respiratory syncytial virus is infants aged 1 to 6 months.

[0018] Preferably, the sequelae of human respiratory syncytial virus infection are selected from the group consisting of: cough, wheezing, asthma, shortness of breath, reactive airway disease, recurrent respiratory infections, and impaired lung function.

[0019] Preferably, the sequelae of the human respiratory syncytial virus infection are selected from the group consisting of wheezing and / or asthma.

[0020] Preferably, the application reduces at least one sequela selected from the group consisting of: annual number of wheezing attacks, number of wheezing attacks, and probability of developing asthma.

[0021] Preferably, the application reduces the annualized incidence of asthma by at least 30%, more preferably at least 50%, and even more preferably at least 70%.

[0022] Preferably, the application reduces the rate of wheezing attacks by at least 30%, more preferably at least 40%, and even more preferably at least 60%.

[0023] Preferably, the application reduces the prevalence of asthma by at least 30%, more preferably at least 40%, and even more preferably at least 50%.

[0024] Preferably, the biological dosage of ziresorvir is about 1 to 20 mg / kg / day, more preferably 2 to 15 mg / kg / day, and even more preferably 4 to 12 mg / kg / day.

[0025] Preferably, the frequency of use of ziresoxir is twice daily.

[0026] A second objective of this invention is to provide the use of a pharmaceutical composition in the preparation of a medicament for the prevention or treatment of sequelae of human respiratory syncytial virus infection, said pharmaceutical composition comprising ziresoxir and at least one pharmaceutically acceptable excipient.

[0027] Preferably, the excipients include one or more of the following: fillers, excipients, stabilizers, diluents, binders, disintegrants, lubricants, flow aids, wetting agents, effervescent agents, colorants, sweeteners, flavorings, preservatives, dispersants, film-forming agents, plasticizers, pore-forming agents, opacifiers, retardants, and solvents.

[0028] Preferably, the dosage form of the drug or drug composition is a powder, pill, tablet, capsule, oral liquid, aerosol, or injection, and preferably a capsule.

[0029] A third objective of this invention is to provide a method for preventing or treating sequelae of human respiratory syncytial virus infection, the method comprising administering an effective dose of ziresorvir to a person in need, the effective dose being 1–20 mg / kg / day, preferably 2–15 mg / kg / day, and more preferably 4–12 mg / kg / day.

[0030] Preferably, the ziresoxir is administered during the treatment of acute infections.

[0031] Preferably, the effective dose is administered twice daily.

[0032] Preferably, the effective dose is administered orally for 5 consecutive days.

[0033] Preferably, the human respiratory syncytial virus (HRRSV) infection population includes infants, children, or adults.

[0034] Preferably, the population infected with human respiratory syncytial virus is infants aged 1 to 24 months, more preferably infants aged 1 to 6 months.

[0035] Preferably, the sequelae of human respiratory syncytial virus infection are selected from the group consisting of: cough, wheezing, asthma, shortness of breath, reactive airway disease, recurrent respiratory infections, and impaired lung function.

[0036] Preferably, the sequelae of the human respiratory syncytial virus infection are selected from the group consisting of wheezing and / or asthma.

[0037] Preferably, the method reduces at least one sequela selected from the group consisting of: annual number of wheezing attacks, number of wheezing attacks, and probability of developing asthma.

[0038] Preferably, the method reduces the annualized incidence of asthma by at least 30%, more preferably at least 50%, and more preferably at least 70%.

[0039] Preferably, the method reduces the rate of wheezing attacks by at least 30%, more preferably at least 40%, and more preferably at least 60%.

[0040] Preferably, the method reduces the prevalence of asthma by at least 30%, more preferably at least 40%, and more preferably at least 50%.

[0041] The effects of the invention

[0042] This invention demonstrates that zilesuovir is a promising treatment for respiratory syncytial virus (RSV)-associated bronchiolitis, and importantly, it has shown good efficacy and tolerability in patients as young as 6 months and under. In addition to significantly reducing symptoms and viral load during acute treatment, zilesuovir also provides long-term benefits, such as reducing the incidence of post-infectious wheezing, which has potentially significant benefits for children's respiratory health. Attached Figure Description

[0043] Figure 1 A diagram illustrating the process of intercellular fusion induced by AK0529 inhibiting respiratory syncytial virus (RSV) fusion (F) protein.

[0044] Figure 2 This is an overview of the clinical trial study design for this invention. * indicates the safety analysis set (n=188) of patients aged 6 months and below in this study. This represents the intention-to-treat infection analysis set (n=150) of patients 6 months and younger in this study.

[0045] Figure 3 This invention presents the changes in WBCS scores (primary endpoint) and their sub-items in patients 6 months and younger. A represents the change in WBCS scores from baseline over time, and B represents the change in WBCS scores and their sub-items from baseline on day 3. All graphs show the least squares mean, and error bars represent 95% confidence intervals. Treatment difference represents the difference in changes in WBCS scores and their sub-items from baseline between different groups; negative values ​​indicate a greater decrease in baseline in the ziresoxir group than in the placebo group. RSV represents respiratory syncytial virus. WBCS represents the Wang's bronchiolitis clinical score.

[0046] Figure 4 The endpoints related to RSV viral load in patients with 6 months or less of infection in this invention are as follows: A represents the change in respiratory syncytial virus (RSV) viral load from baseline, with the graph showing the least squares mean and the error bar representing the 95% confidence interval. Treatment difference represents the difference in RSV viral load change from baseline between different groups; a negative value indicates that the decrease in RSV viral load from baseline was greater in the ziresoxir group than in the placebo group. B represents the proportion of patients with viral load below the lower limit of quantification (LLOQ). LLOQ (lower limit of quantification) represents the lower limit of quantification.

[0047] Figure 5 The Kaplan-Meier time curves for the first parent-reported wheezing in subjects 6 months and younger during the follow-up period in this invention are recorded as truncated. The number of patients included those who did not report any wheezing episodes during the two-year follow-up period, as well as those who interrupted follow-up or were unable to complete the full follow-up for other reasons. NE indicates that the patient could not be evaluated. Detailed Implementation

[0048] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0049] Respiratory syncytial virus (RSV) primarily affects children under two years old, especially infants under six months old, easily causing lower respiratory tract infections such as wheezing pneumonia, which can lead to respiratory failure and difficulty breathing in severe cases. RSV infection not only has immediate effects but can also cause long-term sequelae such as wheezing and asthma, having a lifelong impact on children's lung function.

[0050] The inventors have discovered that zrepsouvir has a good therapeutic effect on respiratory syncytial virus (RSV)-associated bronchiolitis, especially in young infants. Zrepsouvir can significantly alleviate RSV infection symptoms, reduce viral load, and improve clinical symptoms. More importantly, zrepsouvir can also significantly reduce the symptoms of RSV infection sequelae, particularly significantly reducing the incidence of wheezing reported by parents, which has potentially important benefits for children's respiratory health. Based on this, the present invention is proposed.

[0051] One of the objectives of this invention is to provide the use of ziresoxir in the preparation of medicaments for the prevention or treatment of sequelae of human respiratory syncytial virus infection.

[0052] In this invention, zrepsorvir is manufactured using conventional raw materials that are commercially available. It can also be synthesized using known and publicly disclosed methods. Zrepsorvir, its preparation, crystal structure, and preparation process are described in international publications WO2013020993A1, WO2017009316A1, and WO2015110446A1. The entire contents of each of these documents are incorporated herein by reference.

[0053] In a preferred embodiment, diseases caused by human respiratory syncytial virus (RSV) infection include bronchiolitis caused by RSV and pneumonia caused by RSV.

[0054] In a preferred embodiment, zorexovir is provided for use in the preparation of a medicament for reducing or alleviating the sequelae of human respiratory syncytial virus infection.

[0055] In a preferred embodiment, the human respiratory syncytial virus (HRRSV) infection is carried out in infants, children, or adults.

[0056] In a preferred embodiment, the human respiratory syncytial virus (HRRSV) infection population consists of infants aged 1 to 24 months.

[0057] In a preferred embodiment, the human respiratory syncytial virus (HRRSV) infection is carried out on infants aged 1 to 6 months.

[0058] In a preferred embodiment, the sequelae of human respiratory syncytial virus infection are selected from the group consisting of: cough, wheezing, asthma, shortness of breath, reactive airway disease, recurrent respiratory infections, and impaired lung function.

[0059] In a preferred embodiment, the sequelae of the human respiratory syncytial virus infection are selected from the group consisting of wheezing and / or asthma.

[0060] The medicament or pharmaceutical composition of the present invention can be administered intravenously, orally, rectally, or sublingually. In another embodiment, the route of administration is oral. In one embodiment, the route of administration is intravenous injection. In another embodiment, the route of administration is rectal administration. In yet another embodiment, the route of administration is sublingual.

[0061] In this invention, the dosage of zrepsorvir administered to the subject is based on the subject's weight. In a preferred embodiment, the biological dosage of zrepsorvir is approximately 1–20 mg / kg / day, for example, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, and 20 mg / kg / day. In a preferred embodiment, the biological dosage of zrepsorvir is approximately 2–15 mg / kg / day.

[0062] In a preferred embodiment, the biological dosage of ziresorvir is approximately 4–12 mg / kg / day.

[0063] In a preferred embodiment, the drug is administered once, twice, three times, or four times daily, preferably twice daily.

[0064] In a preferred embodiment, the drug administration cycle is 1-10 days or longer, preferably 1 day, 3 days, 5 days, 7 days, 9 days, or 10 days; optionally, the duration of each administration cycle may be the same or different, and the interval between each administration cycle may be the same or different.

[0065] In a preferred embodiment, the application reduces the annualized incidence of asthma by at least 30%, preferably at least 50%, and more preferably at least 70%. For example, the application reduces the annualized incidence of asthma by 30%-80%, 35%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-75%, 35%-75%, 40%-75%, 45%-75%, 50%-75%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, and 72%.

[0066] In a preferred embodiment, the application reduces the incidence of wheezing attacks by at least 30%, preferably at least 40%, and more preferably at least 60%. For example, the application reduces the annualized incidence of wheezing by 30%-80%, 35%-80%, 40%-80%, 50%-80%, 60%-80%, 30%-70%, 35%-70%, 40%-70%, 50%-70%, 60%-70%, 30%-65%, 35%-65%, 40%-65%, 50%-65%, 55%-65%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, and 61.5%.

[0067] In a preferred embodiment, the application reduces the annualized incidence of asthma by at least 30%, preferably at least 40%, and more preferably at least 50% of the asthma prevalence. For example, the application reduces the annualized incidence of asthma by 30%-60%, 35%-60%, 40%-60%, 50%-60%, 30%-55%, 35%-55%, 40%-55%, 45%-55%, 50%-55%, 30%, 35%, 40%, 45%, 50%, and 51.3%.

[0068] A second objective of this invention is to provide the use of a pharmaceutical composition in the preparation of a medicament for the prevention or treatment of sequelae of human respiratory syncytial virus infection, said pharmaceutical composition comprising ziresoxir and at least one pharmaceutically acceptable excipient.

[0069] In a preferred embodiment, the excipients include one or more of the following: fillers, excipients, stabilizers, diluents, binders, disintegrants, lubricants, flow aids, wetting agents, effervescent agents, colorants, sweeteners, flavorings, preservatives, dispersants, film-forming agents, plasticizers, pore-forming agents, opacifiers, retardants, and solvents.

[0070] In a preferred embodiment, the dosage form of the drug or drug composition is a powder, pill, tablet, capsule, oral liquid, aerosol, or injection.

[0071] In a preferred embodiment, the dosage form of the drug or drug composition is a capsule.

[0072] A third objective of this invention is to provide a method for preventing or treating sequelae of human respiratory syncytial virus infection, the method comprising administering an effective dose of ziresorvir to a person in need, the effective dose being 1–20 mg / kg / day, preferably 2–15 mg / kg / day, and more preferably 4–12 mg / kg / day.

[0073] In a preferred embodiment, ziresoxir is administered during the treatment of acute infection.

[0074] In a preferred embodiment, the effective dose is administered twice daily. For example, the effective dose is administered orally for 5 consecutive days.

[0075] In a preferred embodiment, the human respiratory syncytial virus (HRRSV) infection is carried out in infants, children, or adults.

[0076] In a preferred embodiment, the human respiratory syncytial virus (HRRSV) infection population is infants aged 1 to 24 months, for example, infants aged 1 to 6 months.

[0077] In a preferred embodiment, the sequelae of human respiratory syncytial virus infection are selected from the group consisting of: cough, wheezing, asthma, shortness of breath, reactive airway disease, recurrent respiratory infections, and impaired lung function.

[0078] In a preferred embodiment, the sequelae of the human respiratory syncytial virus infection are selected from the group consisting of wheezing and / or asthma.

[0079] In a preferred embodiment, the method reduces at least one sequela selected from the group consisting of: annual number of wheezing attacks, number of wheezing attacks, and probability of developing asthma.

[0080] In a preferred embodiment, the method reduces the annualized incidence of asthma by at least 30%, preferably at least 50%, and more preferably at least 70%. For example, the method reduces the annualized incidence of asthma by 30%-80%, 35%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-75%, 35%-75%, 40%-75%, 45%-75%, 50%-75%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, and 72%.

[0081] In a preferred embodiment, the method reduces the incidence of wheezing attacks by at least 30%, preferably at least 40%, and more preferably at least 60%. For example, the method reduces the annualized incidence of wheezing by 30%-80%, 35%-80%, 40%-80%, 50%-80%, 60%-80%, 30%-70%, 35%-70%, 40%-70%, 50%-70%, 60%-70%, 30%-65%, 35%-65%, 40%-65%, 50%-65%, 55%-65%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, and 61.5%.

[0082] In a preferred embodiment, the method reduces the annualized incidence of wheezing by at least 30% of the asthma prevalence, preferably at least 40%, and more preferably at least 50%. For example, the method reduces the annualized incidence of wheezing by 30%-60%, 35%-60%, 40%-60%, 50%-60%, 30%-55%, 35%-55%, 40%-55%, 45%-55%, 50%-55%, 30%, 35%, 40%, 45%, 50%, and 51.3%.

[0083] As used herein, “and / or” means “any one or both” of the elements so combined, that is, elements that exist together in some cases and separately in others. Therefore, as a non-limiting example, when used in conjunction with open-ended language such as “includes”, “A and / or B” may in some embodiments refer only to A (optionally including elements other than B); in other embodiments, only to B (optionally including elements other than A); in still other embodiments, to both A and B (optionally including other elements); and so on.

[0084] As used herein, when numerical values ​​are listed individually or as part of a range of values, it should be understood that the values ​​may vary above and below the values ​​with reasonable variance for the values, as would be recognized by those skilled in the art.

[0085] As used herein, the term “approximately” or “about” applied to one or more values ​​of interest means a value similar to the reference value. In some embodiments, the term refers to a range of values ​​falling within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the reference value, unless otherwise stated or apparent from the context.

[0086] As used herein, the term "prevention" refers to preventing or at least reducing the likelihood of infection by at least one pathogenic microorganism in a human or animal organism. Administration of ziresorvir can effectively prevent or reduce clinical symptoms or indicators associated with sequelae of RSV infection after treatment.

[0087] As used herein, the term "treatment" refers to resistance to infection by at least one pathogenic microorganism in a human or animal organism. Administration of ziresorvir reduces infection-related symptoms (wheezing, asthma, etc.) and / or prevents / reduces the risk of complications, particularly superinfections.

[0088] As used in this article, the term "biological dosage" refers to the standard dosage of a substance (such as a drug, toxin, chemical reagent, radiation, etc.) given to an organism (human or animal) or biological system (such as a cell or microorganism) to achieve a specific purpose (such as treatment, experimentation, disinfection, etc.).

[0089] Example 1

[0090] 1.1 Preparation of ziresorvir AK0529

[0091] Zyresovir was prepared according to the method described in Examples 1-13 of International Application WO2015110446A1.

[0092] 1.2 Preparation of AK0529 capsules and placebo capsules

[0093] The composition of the AK0529 capsules and placebo capsules used in this disclosure is shown in the table below:

[0094]

[0095]

[0096] The method for preparing the AK0529 capsules used in this disclosure includes:

[0097] 1. Preparation of the isolation layer: After slowly adding Opadry to an appropriate amount of water to form a suspension, the isolation layer is coated.

[0098] 2. Preparation of drug layer: After dispersing the AK0529 compound in an aqueous solution of hydroxypropyl methylcellulose to form a suspension, a drug layer coating was performed.

[0099] 3. Preparation of the enteric coating: Mix Eutrapine L30D-55 with a water-based anti-adhesive and plasticizer to form an emulsion. HTP

[0100] 20 is added to an appropriate amount of water to form a suspension, and then an enteric coating is applied.

[0101] 4. Capsule preparation: Add talc and colloidal silica to the coated microspheres, mix carefully and process into capsules.

[0102] The preparation method for placebo capsules is the same as that for AK0529 capsules.

[0103] 1.3 Preclinical Studies of AK0529

[0104] 1.3.1 Drug resistance localization test

[0105] To determine the molecular target of AK0529, resistance localization studies were conducted, and drug-resistant mutants were screened in the presence of AK0529. By gradually increasing the concentration of AK0529, drug-resistant viral isolates were obtained after multiple passages. The respiratory syncytial virus (RSV) genome of the drug-resistant isolates was amplified by reverse transcription polymerase chain reaction (RT-PCR) and sequenced to identify the viral protein targeted by the inhibitor. During the third generation of passages, each drug-resistant isolate exhibited different single nucleotide substitutions in the F gene, resulting in amino acid changes such as aspartic acid (Asp) 486 to asparagine (Asn) (D486N), aspartic acid 489 to alanine (Ala) (D489A), aspartic acid 489 to valine (Val) (D489V), and aspartic acid 489 to tyrosine (Tyr) (D489Y). All mutations conferring resistance to AK0529 were located in the hypervariable region (HRC) at the C-terminus of the RSV-F protein. These data indicate that AK0529 targets the RSV F protein.

[0106] 1.3.2 Cell Fusion Assay

[0107] The mechanism of action of AK0529 was further confirmed by experiments inhibiting the cell fusion process induced by respiratory syncytial virus (RSV) F protein. RSV-F expression was induced in RSV F protein-stabilized cell lines using 1 μg / mL tetracycline. AK0529 was then added to RSV-F-expressing cells after serial dilutions. Cell fusion was observed under a microscope 3 days after the addition of AK0529.

[0108] like Figure 1As shown, in the absence of AK0529, RSV F protein induces cell fusion and the formation of multinucleated giant cells, as indicated by the red dots (left image). When 0.1 μM of AK0529 is present, RSV F protein-induced multinucleated giant cell formation is completely inhibited (right image). These results further confirm that AK0529 is an RSV F protein inhibitor, as no other RSV viral proteins besides the F protein were present under these experimental conditions.

[0109] Example 2

[0110] This example describes a Phase III clinical trial (AIRFLO) of ziresorcinol (AK0529) against respiratory syncytial virus (RSV) infection in infants and young children (AIRFLO ClinicalTrials.gov number: NCT04231968). This was a randomized, double-blind, placebo-controlled study evaluating the efficacy, safety, and tolerability of AK0529 in hospitalized infants and young children with RSV infection. The study protocol and participant enrollment are outlined below. Figure 2 As shown.

[0111] 2.1 Subjects

[0112] Subjects were eligible for enrollment if they met the following criteria: age 1 to 24 months (adjusted for preterm infants), weight 2.5 to 20.0 kg, hospitalized for a diagnosis of respiratory syncytial virus (RSV) infection, and confirmed virologically for RSV infection within 36 hours prior to receiving the first dose of zilesoxvir or placebo in the trial. Subjects also needed to have a WBCS score of at least 5 (range 0 to 12, with higher scores indicating greater severity of symptoms and signs) at the time of their first dose of zilesoxvir or placebo, and must have received the first dose within 7 days of the onset of RSV infection symptoms.

[0113] Exclusion criteria:

[0114] 1. Children who have used any research-prohibited drugs (prohibited drugs include interferon, ribavirin, and traditional Chinese medicines that are explicitly listed as having antiviral effects in the drug instructions) within 72 hours before the expected medication, or who have used inhaled or systemic glucocorticoids within 24 hours before the administration.

[0115] 2. Children whose medical history is known to be HIV positive (or whose mothers are children under 6 months old), or whose researchers highly suspect that they are HIV positive;

[0116] 3. Children with known concurrent influenza virus infection;

[0117] 4. Children with known bacterial pneumonia;

[0118] 5. Children who require the use of vasopressors or vasoactive drugs at the time of enrollment;

[0119] 6. Children with gastrointestinal diseases that researchers believe may seriously affect the absorption of the study drug;

[0120] 7. Children with bronchopulmonary dysplasia requiring assisted ventilation at the time of enrollment, except for those whose assisted ventilation needs are due to RSV infection.

[0121] 8. Children whose medical history indicates a risk of hypercapnia, except for hypercapnia caused by RSV infection;

[0122] 9. Children with airway malformations and congenital heart disease;

[0123] 10. Children with kidney failure, including those with kidney abnormalities that may be related to renal insufficiency (such as kidney dysplasia, polycystic kidney disease, clinical conditions of kidney dysplasia);

[0124] 11. Children with clinical evidence of liver decompensation (such as liver disease with coagulation abnormalities or encephalopathy);

[0125] 12. Children with congenital metabolic disorders (such as mitochondrial diseases, carbohydrate metabolism disorders, glycogen storage diseases);

[0126] 13. Children with chronic or persistent feeding difficulties;

[0127] 14. Children who are known or suspected of having primary immunodeficiency diseases (such as congenital agammaglobulinemia);

[0128] 15. Children with active or uncontrolled respiratory, cardiac, hepatic, central nervous system, or renal diseases unrelated to RSV infection at baseline, or children with other medical conditions deemed unsuitable for enrollment by the investigator;

[0129] 16. Children with a history of epilepsy or a history of epileptic seizures, including febrile seizures;

[0130] 17. The child or their family has a history of severe allergies or allergies to multiple substances;

[0131] 18. The parents or guardians of the subjects are employees of the researchers or the testing institution of this trial (such persons will directly participate in this trial or any other trial under the management of the researchers of such testing institution), or are family members of the researchers or their employees of this trial.

[0132] 19. Children who participated in other drug or device clinical trials within 30 days prior to screening;

[0133] 20. Children who have any other reason that the researchers deem unsuitable for participation in this study.

[0134] 2.2 Experimental Design and Supervision

[0135] This randomized, double-blind, placebo-controlled trial was conducted in two parts across 30 clinical research centers in 28 hospitals in China. The first part assessed safety and pharmacokinetic parameters, while the second part evaluated efficacy. The study design and related procedures are as follows: Figure 1 As shown.

[0136] 2.3 Randomization

[0137] The randomization table for participants was pre-generated by independent statisticians using the Medidata Randomization and Trial Material Supply Management System (RTSM). In both parts of the trial, participants were randomly assigned in a 2:1 ratio to receive either ziresuvir or placebo. Block randomization was employed (part I with 20 participants per block and part II with 100 participants per block), and no stratification was performed.

[0138] The experimental grouping and dosing regimen are as follows:

[0139] Experimental drug group 1: Subjects weighing ≥2.5 to <5.0 kg: AK0529 capsules (10 mg / capsule), one capsule orally twice daily for 5 consecutive days.

[0140] Experimental drug group 2: Subjects weighing ≥5.0 to <10.0 kg: AK0529 capsules (10 mg / capsule), 2 capsules orally each time, twice a day, for 5 consecutive days.

[0141] Experimental drug group 3: Subjects weighing ≥10.0 to <20.0 kg: AK0529 capsules (40 mg / capsule), one capsule orally twice daily for 5 consecutive days.

[0142] Control group 1: Subjects weighing ≥2.5 to <5.0 kg: Placebo capsule (10 mg / capsule), one capsule orally twice daily for 5 consecutive days.

[0143] Control group 2: Subjects weighing ≥5.0 to <10.0 kg: Placebo capsules (10 mg / capsule), 2 capsules orally twice daily for 5 consecutive days.

[0144] Control group 3: Subjects weighing ≥10.0 to <20.0 kg: Placebo capsule (40 mg / capsule), one capsule orally twice daily for 5 consecutive days.

[0145] Zyrexovir or placebo is administered every 12 hours (within a ±2-hour time window) for 5 days, based on the first dose on day 1. An independent data and safety monitoring committee will review the safety data and determine whether zyrexovir or placebo should be discontinued.

[0146] The second part of the trial was initiated after the completion of the first part. Participants received either zirexovir or a placebo for 5 days, followed by a 9-day safety follow-up period. The study protocol was revised to extend the follow-up period to 6 months and 2 years to assess the frequency, duration, and treatment of parent-reported wheezing episodes, as well as the frequency of asthma diagnoses. Parent-reported wheezing was defined as the first wheezing episode observed by parents after each participant returned home from hospital. Parents were required to record each subsequent wheezing episode. Data from the follow-up period were collected by nurses and physicians through multiple telephone interviews over 2 years, recorded using a standard form, and a comprehensive assessment was conducted every 6 months.

[0147] 2.4 Endpoint Indicators and Evaluation

[0148] The first part of the trial did not include efficacy endpoints. The Data and Safety Monitoring Board reviewed the participants' safety data to determine whether further recruitment should continue. Three safety assessments were conducted after recruiting 6, 18, and 54 participants, respectively.

[0149] Efficacy assessment was conducted in the second part of the trial. The primary efficacy endpoint was the change in the Wang bronchiolitis clinical score (WBCS) from baseline to day 3 (48 hours after the first administration of zirexovir or placebo). This scoring tool was used to assess the severity of respiratory rate (0-3 points), wheezing (0-3 points), respiratory muscle retraction (0-3 points), and general condition (0 or 3 points), with a total score ranging from 0 to 12. The scoring criteria for each sub-item are as follows:

[0150] The scoring criteria for respiratory rate are: 0 points (≤30 breaths per minute), 1 point (31-45 breaths per minute), 2 points (46-60 breaths per minute), or 3 points (>60 breaths per minute).

[0151] The wheezing score is as follows: 0 points indicates no wheezing, 1 point indicates wheezing can only be heard at the end of expiration or with the aid of a stethoscope, 2 points indicates wheezing can be heard throughout the entire expiration process or without the aid of a stethoscope, and 3 points indicates wheezing can be heard during both inhalation and exhalation without the aid of a stethoscope, or wheezing cannot be heard due to very little air intake.

[0152] The scoring criteria for respiratory muscle retraction are: 0 points (no muscle depression), 1 point (depression only in the intercostal muscles), 2 points (jugular notch depression is visible), or 3 points (accompanied by severe signs such as nasal flaring).

[0153] General condition rating criteria: 0 points indicates normal condition, 3 points indicates irritability, lethargy and feeding difficulties.

[0154] Where possible, each subject should be scored by the same researcher within one hour of the first dose administered each day from day 1 to day 6, or until the subject withdraws from the trial early.

[0155] The key secondary endpoint was the change in respiratory syncytial virus (RSV) viral load from baseline to day 5 (96 hours after the first administration of zirexovir or placebo). Viral samples were collected from the same anatomical site in the same subject via nasopharyngeal aspiration one hour before the first dose each day, on day 6, and on day 14. If a subject withdrew from the trial early, a sample was collected before withdrawal. Viral load was determined using TaqMan quantitative reverse transcription polymerase chain reaction (RT-PCR). The proportion of subjects with viral loads below the lower limit of quantitation (LLOQ) was calculated.

[0156] Other secondary endpoints included: changes in bronchiolitis scores from baseline to day 3 for subjects with a baseline score of 8 or higher; changes in bronchiolitis scores from baseline to day 3 for subjects 6 months and younger; the proportion of subjects with symptom relief on day 3 (defined as a bronchiolitis score of 0 or 1); the proportion of subjects with a bronchiolitis score that decreased by at least 75% from baseline on day 3; the time from the first administration of zirexovir or placebo to the first symptom relief; the time it took for the bronchiolitis general condition sub-score to decrease to 0 for subjects with general symptoms at baseline; and the median time for a bronchiolitis score that decreased by at least 75% from baseline. For subjects admitted to the intensive care unit (ICU), length of hospital stay was assessed. Subjects were discharged when clinical symptoms and signs improved (i.e., wheezing ceased, cough lessened, and fever subsided for more than 3 days). Respiratory syncytial virus (RSV) F gene sequencing was performed to monitor for the emergence of resistance mutations and to detect co-infections with other respiratory viruses.

[0157] Adverse events and serious adverse events were monitored throughout the trial and coded using the Medical Dictionary of Drug Regulatory Activities, version 24.1. The Data and Safety Monitoring Board assessed safety signals.

[0158] 2.5 Data Statistics and Analysis

[0159] In the second part of the trial, the efficacy analysis was conducted in the intention-to-treat population, which included all subjects diagnosed with respiratory syncytial virus (RSV) infection by reverse transcription polymerase chain reaction (RT-PCR) and who received at least one dose of zirexovir or placebo after randomization. Safety data were analyzed in the safety analysis population, which included all subjects who received at least one dose of zirexovir or placebo after randomization in either Part I or Part II of the trial.

[0160] The primary efficacy endpoint was analyzed using a repeated measures mixed model. The model used the change in Wang's bronchiolitis clinical score from day 2 to day 6 relative to baseline (day 1) as the dependent variable, with assessment time point, experimental group, and the interaction between assessment time point and experimental group as fixed effects. The model was adjusted for baseline covariates, including baseline bronchiolitis score, age (≤6 months or >6 months to 24 months), and time to onset of respiratory syncytial virus (RSV) infection. For the key secondary efficacy endpoint of change in RSV viral load from baseline to day 5, RSV viral load was log-transformed and analyzed using a repeated measures model with restricted maximum likelihood estimation. Details of the models used to analyze these endpoints and other statistical methods are described in the usual practices of the art.

[0161] In the second part of the trial, the primary efficacy endpoint and key secondary efficacy endpoint were tested for superiority using a stratified fixed-order method at a two-sided significance level of 0.05. Subgroup analyses of the primary endpoint and key secondary endpoint (i.e., change in RSV viral load, 75% reduction in WBCS score from baseline, and proportion of patients with disease remission) were pre-specified in patients ≤6 months of age. Other analyses presented in this disclosure are post-hospital analyses, and their p-values ​​should be considered nominal values. The proportion of subjects with a 75% reduction in WBCS score, the proportion of subjects with remission, the time from first dose to first discharge during the study period, and the time from first dose to first discontinuation of oxygen during the study period were analyzed using the Cochran-Mantel-Haenszel test and logistic regression analysis. Time-event variables (including parent-reported wheezing during the 2-year follow-up period) were compared using Kaplan-Meier analysis, stratified log-rank test, and Cox proportional hazards regression model. The cumulative incidence of parent-reported wheezing during the entire 2-year follow-up period was analyzed using the Cochran-Mantel-Haenszel test, and the annualized incidence of parent-reported wheezing was analyzed using a negative binomial regression model. Viral load and WBCS score were compared at each time point using t-tests. On days 3 and 5, Spearman's rank correlation coefficients were used to assess the correlation between RSV viral load and changes in WBCS score relative to baseline, as well as the correlation between changes in blood oxygen saturation (SpO2) and the numerical and absolute values ​​of changes in WBCS score relative to baseline. All statistical analyses were performed using SAS version 9.4 software (SAS Institute).

[0162] 2.6 Results of Phase III Clinical Trial

[0163] 2.6.1 Trial population

[0164] like Figure 2As shown, of the 355 patients aged 1 to 24 months who underwent screening, 311 were enrolled in the study and randomized in Parts 1 and 2: 205 (66%) were assigned to the zilesoxvir group and 106 (34%) to the placebo group. 302 participants received at least one dose of the investigational drug, and 188 of these participants, aged 6 months or younger (125 in the zilesoxvir group and 63 in the placebo group), underwent a safety analysis. Part 1 of this study aimed to assess safety and pharmacokinetics. Part 2 of this study included 150 patients (100 in the zilesoxvir group and 50 in the placebo group) who constituted the intention-to-treat infection (ITT-i) population, and this population was analyzed for efficacy.

[0165] In the zilesuzumab group, 33 (26%) of the 125 patients were female and 92 (74%) were male. In the placebo group, 15 (24%) of the 63 patients were female and 48 (76%) were male. The baseline mean WBCS score at baseline was 6.8 (standard deviation 1.7) in the zilesuzumab group and 6.9 (standard deviation 1.8) in the placebo group. 63 (50%) patients in the zilesuzumab group and 26 (41%) patients in the placebo group required oxygen or noninvasive positive pressure ventilation at baseline. In the intention-to-treat infection (ITT-i) population, 96 (96%) of the 100 patients in the zilesuzumab group and 47 (94%) of the 50 patients in the placebo group completed the study. In the zorexoni group, 3 patients (3%) discontinued the study due to adverse events (1 case each of thrombocytopenia, anomalous pulmonary venous connection, and rash), while no patients in the placebo group discontinued the study due to adverse events.

[0166] 2.6.2 Pharmacokinetics

[0167] Pharmacokinetic-pharmacodynamic correlation analysis showed that a trough concentration of at least 130 ng / mL was associated with a greater reduction in clinical symptom scores (indicating symptom improvement) and a greater reduction in viral load; and a minimum dose of 2 mg / kg body weight was required to achieve a trough concentration of 130 ng / mL in more than 80% of participants.

[0168] Twelve hours after administration, the steady-state mean trough concentration of zilesuovir in the blood was 378 ± 217 ng / mL, exceeding the target concentration of 130 ng / mL.

[0169] 2.6.3 Treatment Efficacy

[0170] The treatment duration ranged from 0.5 to 5.1 days in both groups, with a mean treatment duration of 4.9 days and a median of 5.0 days in the zinesuzumab group and a mean treatment duration of 4.8 days and a median of 5.0 days in the placebo group. On day 3 (48 hours after baseline), patients 6 months or younger treated with zinesuzumab showed a significant improvement in the primary endpoint (i.e., the change in Wang's Bronchiolitis Clinical Score [WBCS] relative to baseline) compared to patients treated with placebo (least square mean -3.5 points vs. -2.2 points in placebo patients, a difference of -1.2 points between groups (-1.9 to -0.6; P = 0.0004), meaning that zinesuzumab resulted in an additional 54.5% reduction in WBCS score compared to placebo (e.g., ...). Figure 3 (As shown in A). Compared with placebo, zilesuovir treatment also resulted in a statistically significant reduction in all sub-items of the WBCS Clinical Score (WBCS) from baseline to day 3 (e.g., Figure 3 B). On day 3, there was a significant difference in mean WBCS scores between the ziresorvir group and the placebo group (3.4 vs. 4.7; P = 0.0002), and significant differences were also observed on days 4 and 5.

[0171] During treatment, regarding the key secondary endpoint (reduction in viral load), on day 5 (96 hours after baseline), the viral load reduction in the zorexoni group was -2.51 log [missing value]. 10 The copy number / mL [95% CI -2.87 to -2.14] was greater than that in the placebo group (-1.87 log [95% CI -2.87 to -2.14]). 10 Copies / mL [-2.35 to -1.38], the difference was -0.64 log 10 The viral load decreased by 77% compared to the placebo group (-1.20 to -0.09; P = 0.024). Ziresoxir also showed an advantage in reducing viral load on day 3 (-0.45 log [value missing]). 10 Copy / mL; P = 0.049; Figure 4 A). On day 5, 27 of the 93 patients treated with zorizovib (29% [95% CI 20–39]) had viral loads below the lower limit of quantitation (LLOQ), compared to only 7 of the 46 patients treated with placebo (15% [6–29]) with LLOQs. Figure 4 B). On day 5, there was a significant difference in mean respiratory syncytial virus (RSV) viral load between the ziresorcinolone group and the placebo group (5.0 log...). 10 Copy / mL [95% CI 4.6–5.4] vs 5.7 log 10 Copy / mL [5.3–6.1]; P = 0.011).

[0172] These results demonstrate that treatment with zrepsouvir resulted in significant clinical improvement and a greater reduction in viral load compared to placebo. The antiviral effect of zrepsouvir was observed as early as day 3. The delayed effect of zrepsouvir in reducing viral load is consistent with the mechanism of action of F protein inhibitors, which inhibit viral entry into cells but have no direct effect on intracellular viruses.

[0173] 2.6.4 Follow-up Results

[0174] Among the enrolled participants, 116 infants aged 6 months and under who were hospitalized for respiratory syncytial virus (RSV) infection (78 received zilesuovir and 38 received placebo) were followed up for 24 months after discharge. The mean follow-up time was 15.33 months (standard deviation 9.44) in the zilesuovir group and 17.14 months (standard deviation 9.02) in the placebo group.

[0175] The hazard ratio for the first parent-reported time to wheezing recurrence was 0.41 in the ziresorcinol group and the placebo group (e.g., Figure 5 (As shown). The mean annualized incidence of wheezing reported by parents was 0.18 times in the ziresoxvir group and 0.65 times in the placebo group, which was 3.6 times lower in the ziresoxvir group than in the placebo group (the mean annualized incidence of wheezing in the ziresoxvir group was 27.78% of that in the placebo group), meaning the mean annualized incidence of wheezing in the ziresoxvir group was reduced by 72.3% compared to the placebo group. In randomized infants under 6 months of age who reported wheezing during follow-up, during the 2-year follow-up period, there were a mean of 1.2 wheezing episodes per patient in the ziresoxvir group (standard deviation 0.6) and 3.1 wheezing episodes per patient in the placebo group (standard deviation 4.4), which was 2.6 times lower in the ziresoxvir group than in the placebo group (the wheezing episode rate in the ziresoxvir group was 38.7% of that in the placebo group), meaning the wheezing episode rate in the ziresoxvir group was reduced by 61.5%. One patient in the zilesuovir group and two patients in the placebo group experienced three or more wheezing episodes within one year. During follow-up, the proportion of patients diagnosed with asthma in the zilesuovir group (2 out of 78 [2.56%]) was lower than that in the placebo group (2 out of 38 [5.26%]) (the prevalence of asthma in the zilesuovir group was 48.7% in the placebo group), meaning the prevalence of asthma in the zilesuovir group was 51.3% lower than that in the placebo group.

[0176] This data indicates that treatment with zorexavir can reduce the annual number of wheezing episodes, the number of wheezing episodes, and the likelihood of developing asthma reported by parents in patients 6 months and younger, providing significant long-term benefits to infants and young children with RSV infection.

[0177] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. Use of zilesuovir in the preparation of drugs for the prevention or treatment of sequelae of human respiratory syncytial virus (RSV) infection.

2. The application according to claim 1, characterized in that, The human respiratory syncytial virus (HRRSV) infection can affect infants, children, or adults.

3. The application according to claim 2, characterized in that, The population infected with human respiratory syncytial virus (HRSV) is infants aged 1 to 24 months.

4. The application according to claim 3, characterized in that, The population infected with human respiratory syncytial virus is infants aged 1 to 6 months.

5. The application according to claim 1, characterized in that, The sequelae of human respiratory syncytial virus infection are selected from the group including: cough, wheezing, asthma, shortness of breath, reactive airway disease, recurrent respiratory infections, and impaired lung function.

6. The application according to claim 5, characterized in that, The sequelae of human respiratory syncytial virus infection are selected from the group including wheezing and / or asthma.

7. The application according to any one of claims 1 to 6, characterized in that, The application reduces at least one sequela selected from the following groups: annual number of wheezing attacks, number of wheezing attacks, and probability of developing asthma.

8. The application according to any one of claims 1 to 7, characterized in that, The application reduces the annualized incidence of asthma by at least 30%, preferably at least 50%, and more preferably at least 70%.

9. The application according to any one of claims 1 to 7, characterized in that, The application reduces the rate of wheezing attacks by at least 30%, preferably at least 40%, and more preferably at least 60%.

10. The application according to any one of claims 1 to 7, characterized in that, The application reduces the prevalence of asthma by at least 30%, preferably at least 40%, and more preferably at least 50%.

11. The application according to claim 1, characterized in that, The biological dosage of ziresorvir is 1–20 mg / kg / day, preferably 2–15 mg / kg / day, and more preferably 4–12 mg / kg / day.

12. The application according to claim 11, characterized in that, Ziresorvir is to be used twice daily.

13. Use of a pharmaceutical composition in the preparation of a medicament for the prevention or treatment of sequelae of human respiratory syncytial virus infection, said pharmaceutical composition comprising ziresoxir and at least one pharmaceutically acceptable excipient.

14. The application according to any one of claims 1 to 13, characterized in that, The dosage form of the drug or drug composition is powder, pill, tablet, capsule, oral liquid, aerosol or injection, preferably capsule.

Images