Inhaled interferon-beta to improve outcomes in patients with SARS-CoV-2 infection

Abstract

The present invention relates to the use of inhaled interferon-beta for the prevention or reduction of the severity of lower respiratory tract (LRT) disease in patients infected with coronaviruses capable of causing acute respiratory distress syndrome, for example, for the prevention or reduction of the severity of LRT disease in COVID-19 patients infected with SARS-CoV-2. Targeting of such treatment to promote recovery is proposed based on a simple and rapid breathlessness scoring that is applicable in both home and hospital settings.

Description

Technical Field

[0001] The present invention relates to the use of inhaled interferon-beta (IFN-β) formulated for nebulizer administration, for example via the airway, for preventing or reducing the severity of lower respiratory tract (LRT) diseases, and / or improving the outcome in patients infected with the SARS-CoV-2 virus by improving the symptomatic state according to commonly used scales that are utilized in clinical practice worldwide for assessing disease severity caused by such infections (commonly referred to as COVID-19). Based on tests extending to the home environment, dyspnea severity has been proposed as a simple point-of-care criterion for guiding inhaled IFN-β administration to SARS-CoV-2-infected patients. Such administration to SARS-CoV-2-infected patients with marked or severe dyspnea has been found to significantly accelerate recovery and prevent deterioration, and thus may help reduce the need for hospitalization. The basis of the present invention was a clinical trial of inhaled IFN-β in SARS-CoV-2-infected patients, but the present invention has applicability to SARS virus and other known or future emerging coronaviruses that have the ability to cause severe acute respiratory syndrome and thus severe LRT disease in humans, or any future emerging coronavirus classified as a virus that may cause other pandemics, as will be understood.

Background Art

[0002] IFN-β-driven antiviral responses have been shown to be impaired / absent in the elderly and in those with chronic airway diseases, more specifically asthma and COPD (Agrawal et al. (2013) Gerontology 59, 421-426; Wark et al. (2005) J. Exp. Med. 937-47; Singanavagam et al. (2019) Am. J. Physiol. Lung Cell Mol. Physiol. 317(6):L893-L903). This is consistent with previously proposed uses of inhaled IFN-β for the treatment of viral-induced exacerbations of asthma and chronic obstructive pulmonary disease (COPD) caused by rhinoviruses that cause the common cold (see European Patent No. 1734987, in the name of the University of Southampton and exclusively licensed to Synairgen plc) and for the reduction of the severity of LRT disease in older adults due to rhinovirus infection (see U.S. Patent No. 7,871,603, in the name of Synairgen Research Limited). Furthermore, European Patent No. 2544705, also in the name of Synairgen Research Limited, proposes the use of inhaled IFN-β for the treatment of LRT disease associated with influenza infection. Clinical trials using inhaled IFN-β1a formulations for spraying delivered via respiratory nebulizers have been conducted to further such administrations, particularly in asthmatic or COPD patients suffering from LRT disease due to the common cold or influenza, and have yielded promising results. In all such clinical trials conducted to date (three in asthma and one in COPD patients), inhaled IFN-β upregulated pulmonary antiviral biomarkers in sputum over 24 hours post-administration, confirming successful delivery of the bioactive drug to the lungs, demonstrating proof-of-mechanism, and supporting dose selection. However, such trials have not provided evidence to suggest that inhaled IFN-β may have any beneficial effect in the prevention or treatment of severe LRT disease associated with any coronavirus capable of causing severe acute respiratory syndrome, such as SARS-CoV-2.

[0003] IFN-β has been shown to inhibit the replication of various coronaviruses, including Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2, in cell-based assays. For example, in an in vitro study using Vero cells, which are unable to express type I interferons in response to infection, either IFN-β or IFN-α demonstrated antiviral activity against SARS-CoV-2, similar to the findings for SARS-CoV and MERS viruses (Mantlo et al. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020; 179:104811). Chinese Patent Application Publication No. 1535724 (Beijing Jindike Biotech.Res.Institute) also reports cell assays using various type I interferons that demonstrate the ability to inhibit SARS virus replication, but leans more towards supporting the focus on IFN-α2b. An extension of these studies is reported in Chinese Patent Application Publication No. 1927389, which reports the use of recombinant human IFN-α2b nasal spray as a preventive measure against SARS virus infection in the upper respiratory tract. However, type I interferon formulations suitable for inhalation delivery are not taught. The only recombinant human IFN-β formulation mentioned is a commercially available injectable formulation. In light of such studies, it remains unclear what benefit inhaled IFN-β may have in the prevention or treatment of LRT disease in patients infected with any coronavirus, in particular whether it results in improved symptom status / outcomes in such patients with LRT disease requiring at least a 3 or 4 categorization on the WHO-approved Ordinal Scale for Clinical Improvement related to disease and hospitalization needs attributable to SARS virus infection.

[0004] In fact, the only reported clinical trial using IFN-β in patients with confirmed COVID-19 disease caused by SARS-CoV-2 infection investigated subcutaneous injection of IFN-β-1b in a formulation unsuitable even for inhalation, and in combination with oral administration of lopinavir-ritonavir and ribavirin (see Hung et al. (2020) Lancet 395:1695-16704 entitled “Triple combination of interferon beta-1b, lopinavir-ritonavir and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial”; first published online 8 May 2020). The clinical trial team only suggested that dual antiviral therapy with IFN-β-1b was justified for use in the tested triple combination therapy. Patients in the reported trial were randomly assigned to either a triple therapy group or a group receiving lopinavir-ritonavir alone. In the triple therapy group, patients were recruited and treated with IFN-β-1b less than 7 days after symptom onset. Patients received 1 to 3 doses of IFN-β-1b every other day, depending on the drug initiation date. If initiation was on 1 to 2 days after symptom onset, patients received all 3 doses of IFN-β. If drug administration was initiated on 3 to 4 days after symptom onset, patients received 2 doses of IFN-β. If drug administration was initiated on 5 to 6 days after symptom onset, patients received 1 dose of IFN-β. Patients treated between 7 and 14 days received no IFN-β at all. Therefore, IFN-β is suggested for early intervention in COVID-19 disease, at best by subcutaneous injection, and concerns have been raised as to whether such injections may have undesirable effects on symptom development related to inflammatory mechanisms beyond initial viral infection.

[0005] Previous studies treating MERS-infected mice with IFN-β demonstrated that treatment was only effective when administered within one day of infection, before the viral load peaked. However, delayed interferon treatment failed to inhibit viral replication, leading to increased inflammation and enhanced pro-inflammatory cytokine expression, suggesting that delayed treatment could worsen symptoms by triggering a cytokine storm (see Channappanavar et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Invest. 2019; 129(9):3625-39). This, to some extent, supports the early treatment of COVID-19 with IFN-β (and by injection), which is consistent with the human clinical trials mentioned above.

[0006] The rationale for limiting the use of IFN-β to early intervention (7 days before symptom onset) in this clinical situation can be seen as the expectation that SARS-CoV-2 viral load will peak within a few days of symptom onset, coupled with concerns that later treatment may drive a cytokine storm seen in COVID-19 patients and observed in animal models of MERS virus infection. In fact, cytokine storms and the damage they cause may be a more significant driver of severe disease than viral replication in the later stages of the disease, and it has been suggested that secondary induction of interferon may drive cytokine storms (Andreakos E. & Tsiodras S. COVID-19: lambda interferon against viral load and hyperinflammation. EMBO Mol. Med. 2020; 12(6):e12465; Jamilloux et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun. Rev. 2020; 19(7):102567).

[0007] A team from Amiens-Picarde University Hospital in France recently commented on a promising approach to treating COVID-19 in a review article titled "Therapeutic Options for Coronavirus Disease 2019 (COVID-19) - Modulation of Type I Interferon Response as a promising Strategy?" (Mary et al (May 2020) Frontiers in Public Health, 8, Article 185). While the authors noted the well-known clinical use in China of IFN-alpha-2b (see further information on IFN-alpha below) spray administration for treating LRT diseases associated with SARS-CoV, Middle East Respiratory Syndrome Coronavirus (MERS virus), and more recently, SARS-CoV-2, they did not provide any new data to support similar delivery of IFN-β with beneficial effects at any stage of COVID-19 disease. The authors merely refer to preliminary information regarding the aforementioned triplicate drug trial, and rather point to azithromycin as an interesting alternative strategy for consideration. Apart from its antibacterial role, azithromycin has been reported to increase rhinovirus-induced type I and type II IFN responses in bronchial epithelial cells from healthy donors, asthma patients, and COPD patients. Combination therapy with azithromycin and hydroxychloroquine has been tested in some French COVID-19 patients (Gautret et al. Int. J. Antimicrob. Agents (2020) 105949), and Mary et al. comment that "the possibility that azithromycin may be responsible for the rapid reduction in viral load in this subgroup of h-CQ-treated French patients should be considered."

[0008] A paper by Salard et al., titled "Type I interferons as potential treatment against COVID-19" (Antiviral Research, 178, 104791, online 7 April 2020), outlines various studies related to determining the benefits of using both IFN-α and IFN-β type I interferons in relation to virus-induced ARDS. Regarding inhalation administration, the discussion here is again limited to the administration of IFN-α and general recommendations for such administration as part of combination therapy, for example, in combination with lopinavir / ritonavir (see, e.g., Lu, H. Drug treatment options for the 2019-new coronavirus (2019-nCoV) Bioscience Trends (2020) 14(1):69-71; Dong et al. Discovering Drugs to treat coronavirus disease 2019 (COVID-19), Drug Discover. Therap. (2020) 14(1):58-60; Liu et al. Critical care response to a hospital outbreak of the 2019-nCoV infection in Shenzhen, China; Crit. Care (2020) 24-56). It should be noted that such reports on the use of inhaled IFN-α do not infer any use of IFN-β, which is consistent with the knowledge regarding type I interferons.

[0009] Type I interferons, such as IFN-α and IFN-β, are antiviral proteins that bind to the same receptor, but they differ in their antiviral and immunomodulatory properties (Ng et al. Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes. Cell, 2016; 164(3):349-52; Gibbert et al. IFN-alpha subtypes: distinct biological activities in anti-viral therapy. Br. J. Pharmacol. 2013; 168(5):1048-58). Cells produce interferons as an innate immune response to fight viral infections. This innate immune response provides the first line of defense against viruses until the adaptive immune system produces antibodies and cell-mediated responses that can eliminate the viral infection and provide long-term immunity. IFN-α is produced in large quantities by specialized leukocytes called plasmacytoid dendritic cells and is approved for use in some systemic infections, such as hepatitis. IFN-β is produced by many cell types, including epithelial cells and fibroblasts, and within these cells, it is produced as an immediate local response to viral infection, inducing an antiviral program that prepares tissues to fight the infection. IFN-β has been reported to be a more potent inhibitor of coronavirus than IFN-α in cell studies (see again the above reference by Mantlo et al.; also see Scagnolari et al. Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antiviral Ther. 2004; 9(6):1003-11 and Stockman et al. SARS: systematic review of treatment effects. PLoS Med. 2006; 3(9):e343).However, it will be understood that such cell studies do not allow for the prediction of the benefits of inhaled IFN-β in the complex clinical picture of acute lower respiratory tract disease induced by coronavirus infection.

[0010] The only mention of IFN-β administration in the above-mentioned review by Salard et al. is by injection, and here again, referring to the above-mentioned 2019 report by Channappanavar et al., the need to administer type I interferon as early as possible to optimize antiviral therapy and avoid adverse events is indicated. In fact, the authors even suggest that administering anti-interferon drugs may be more beneficial in the later stages of COVID-19 progression associated with severe LRT disease.

[0011] Viral infection naturally induces an innate immune response involving the production of type I and type II interferons, which induce antiviral genes and modulate the inflammatory response. However, like its highly homologous counterpart SARS-CoV, SARS-CoV-2 possesses a set of non-structural proteins that can interfere with both the host expression of type I interferons and downstream signaling from type I interferon receptors (Kindler et al. Interaction of SARS and MERS Coronaviruses with the Antiviral Interferon Response. Adv. Virus Res. 2016; 96:219-43; Yuen et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerging Microbes Infect. 2020; 9(1):1418-28). In line with this, it has been reported that severe COVID-19 patients exhibit impaired type I interferon activity and inflammatory responses (Hadjadj et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science (2020) 369, 718-724).

[0012] As discussed above, considerable emphasis has been placed on early administration of interferon to reduce the peak of viral replication. However, patients with high viral load and prolonged viral shedding periods have been reported to be at high risk of severe COVID-19 with severe LRT disease (Liu et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect. Dis. 2020; 20(6):656-7). Furthermore, it has not been suggested at what point in time inhaled IFN-β should be used for intervention. [Prior art documents] [License]

[0013] [License 1] European Patent No. 1734987 [License 2] U.S. Patent No. 7,871,603 [License 3] European Patent No. 2544705 [License 4] China Patent Publication No. 1535724 [Patent Document 5] China Patent Publication No. 1927389 [Non-licensed literature]

[0014] [Non-licensed Document 1] Agrawal et al.(2013) Gerontology 59, 421-426 [Non-licensed Document 2] Wark et al. (2005) J. Exp. Med. 937-47 [Non-licensed Document 3] Singanavagam et al. (2019) Am. J. Physiol. Lung Cell Mol. Physiol. 317 (6): L893-L903 [Non-licensed Document 4] Mantlo et al. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020;179:104811 [Non-licensed Document 5] Hung et al. (2020) Lancet 395: 1695 - 16704 entitled 「Triple combination of interferon beta-1b, lopinavir-ritonavir and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial」; first published on-line 8 May 2020

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[0015] For COVID-19 illness associated with SARS-CoV-2 infection, even when patients score at least 3 or at least 4 on the WHO-approved Ordinal Scale for Clinical Improvement, as shown below, data supporting the use of inhaled IFN-β to prevent or reduce the severity of LRT illness associated with SARS-CoV-2 infection, and / or to improve patient symptom status / treatment outcomes, are presented here for the first time (see also WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial Synopsis. February 18th 2020). [Table 1]

[0016] When the Ordinal Scale of Clinical Improvement (OSCI) is mentioned below, it should be understood to refer to the scoring system described above.

[0017] Here, further data from the administration of inhaled IFN-β to SARS-CoV-2 infected patients in a home setting are reported, showing that such IFN-β administration can accelerate recovery, defined as level 1 or 0 on the ordinal scale above, in such patients who exhibit significant or severe dyspnea at the initiation of IFN-β treatment. Dyspnea was scored using an approved scoring system based on the patient's responses to the following question: How severe was your dyspnea today? 0 = None - No difficulty noticed 1 = Mild to noticeable during vigorous activity (e.g., running). 2 = Moderate - Noticeable even during light activities (e.g., making a bed or carrying groceries). 3 = Noticeable - Stands out when doing laundry or getting ready. 4 = Severe - Present almost always, even at rest.

[0018] This type of dyspnea scoring forms an element of the BCSS scoring system, which was previously devised to assess the severity of respiratory disease in patients with COPD (Leidy et al. (2003) Chest, 124, 2182-2191: "The Breathlessness, Cough and Sputum Scale. The Development of Empirically Based Guidelines for Interpretation"). When the dyspnea score is referred to below, it should be understood as referring to the dyspnea scoring in this approved form.

[0019] The ability to accelerate recovery was most pronounced in SARS-CoV-2 infected individuals who showed significant or severe dyspnea, i.e., those with a score of 3 or higher on this scale. In both hospital and home cohorts, patients with significant or severe dyspnea recovered significantly slower than patients with a score of 0–2 on the dyspnea scale. In both home and hospital cohort studies, inhaled IFN-β treatment accelerated recovery in patients with significant or severe dyspnea.

[0020] Accordingly, the present invention provides an IFN-β administered by inhalation for use in preventing or mitigating the severity of lower respiratory tract disease in patients infected with a coronavirus capable of causing acute respiratory distress syndrome (ARDS), such as severe acute respiratory syndrome corresponding to its categorization as SARS virus, and / or improving one or more symptoms and / or outcomes in such infected patients.

[0021] As described above, in patients with SARS-CoV-2 infection, shortness of breath can be a contributing factor to the severity of the illness leading to hospitalization, but it can also be a noticeable problem in SARS-CoV-2 infected individuals even in a home setting, i.e., even at a score of 2 on the WHO ordinal scale (indicating a significant impact of limitations on normal activity). Marked or severe shortness of breath, i.e., a shortness of breath score of 3-4 on the above scale, is hereby proposed as a preferred criterion for targeting patients with the type of viral infection described herein, not only to prevent exacerbation but also to promote recovery. Therefore, a means of targeting effective inhaled IFN-β therapy associated with COVID-19 disease (or similar viral illness) is proposed based on a simple point-of-care shortness of breath scoring system that makes such therapy an option even in a home setting, for the purpose of promoting recovery and preventing the need for hospitalization.

[0022] The present invention will be described below primarily with reference to relevant clinical trial information relating to SARS-CoV-2 and COVID-19 patients presented herein, but by reasonable extrapolation, the present invention is considered to have applicability to any known or future emerging coronavirus (or other potentially pandemic-causing virus) capable of causing acute respiratory distress syndrome, and to other known or future emerging coronaviruses that cause severe LRT disease in humans, such as other known SARS viruses, MERS viruses, and potentially future emerging coronaviruses or other pandemic viruses capable of causing LRT disease in humans, for example, caused by zoonotic transmission.

[0023] Therefore, in its broadest embodiment, the present invention may be considered to provide an IFN-β administered by inhalation for use in preventing or reducing the severity of lower respiratory tract disease in patients infected with a virus capable of causing acute respiratory distress syndrome (ARDS), and / or improving one or more symptoms and / or outcomes in such infected patients. The virus may be a coronavirus, for example, SARS-CoV-2 which causes COVID-19 disease in humans (to be considered to include any known or future emerging SARS-CoV-2 variant, for example, any variant named by Greek letter naming in accordance with the WHO notification of May 31, 2021). This may also be a future emerging virus, for example, which arises from zoonotic transmission and may have the ability to cause similar ARDS in humans.

[0024] For example, a virus capable of causing severe LRT disease, sometimes referred to as acute respiratory distress syndrome, would be understood as a virus capable of causing LRT disease in a subgroup of people who are otherwise healthy or have a non-virus-related underlying health condition, exhibiting the potential for progression requiring hospitalization and oxygen therapy via mask or nasal prongs, according to the WHO Ordinal Scale for Clinical Improvement. In the case of coronaviruses classified as SARS, such LRT disease would generally be understood as potentially equivalent to severe acute respiratory syndrome with a potentially higher score on the same scale.

[0025] The objective of administering inhaled IFN-β according to the present invention may be to prevent patients with SARS-type viral infection capable of causing SARS infection or corresponding LRT disease, progressing from a score associated with mild disease to a score associated with severe disease, or from a level 1 severe disease to an even higher level of severity, for example, to the point of requiring mechanical ventilation. The data provided herein show how such administration may be associated with improved outcomes in that it prevents an increased progression of LRT disease severity compared to patients receiving placebo control, and that such patients are more likely to be discharged, and possibly earlier. Indeed, as described above, administration of inhaled IFN-β therapy based on dyspnea score is presented here as a convenient means of targeting such therapy in a manner that has shown significantly accelerated recovery (down to 0 or 1 on the OSCI scale) in both hospitalized and non-hospitalized patients with SARS-CoV-2 infection.

[0026] The efficacy of inhaled IFN-β may be additionally or alternatively monitored in terms of improvement of one or more symptoms, such as shortness of breath. For example, improvement may be assessed in a manner known by the Shortness of Breath, Cough and Sputum Scoring (BCSS) system or its shortness of breath scoring elements. Further details are provided in the following examples.

[0027] The present invention is provided by example and further described below with reference to clinical trial data shown by the drawings described below. [Brief explanation of the drawing]

[0028] [Figure 1] This shows the recovery of the hospital cohort of patients. Patients who received SNG001 (n=48) were more than twice as likely to recover from COVID-19 (defined as "no restrictions on activity" or "no clinical or virological evidence of infection," i.e., level 1 or 0 on the OSCI scale) compared with patients who received placebo (n=49) (HR 2.19 [95% CI 1.03~4.69], p=0.043).

[0029] [Figure 2] This study shows the recovery of patients with more severe illness (requiring oxygen therapy) upon admission. Patients treated with SNG001 (n=36) were more than twice as likely to recover by the end of the treatment period compared to the placebo group (n=28) (HR 2.60 [95% CI 0.95~7.07], p=0.062), and had higher odds of recovery at day 28 (OR 3.86 [95% CI 1.27~11.75], p=0.017). Recovery is defined as "no restrictions on activity" or "no clinical or virological evidence of infection."

[0030] [Figure 3] This report shows the discharge rate in patients with more severe illness at admission (requiring oxygen therapy). Treatment with SNG001 (n=36) increased the likelihood of discharge compared to placebo (n=28) (HR 1.72 [95% CI 0.91~3.25], p=0.096). The median time to discharge was 6 days for patients treated with SNG001 and 9 days for patients who received placebo.

[0031] [Figure 4]This shows the change in dyspnea from baseline in the patient hospital cohort. Over the treatment period, dyspnea (assessed by patients using a 5-point dyspnea score scale) was significantly reduced in patients treated with SNG001 (n=46) compared to patients treated with placebo (n=49) (difference -0.6 [95% CI -1.0 to -0.2], p=0.007).

[0032] [Figure 5] This report shows the recovery of a home cohort of SARS-CoV-2 infected patients who experienced dyspnea ≥3 (11%) at the start of treatment with inhaled IFN-β (SNG001 formulation) or placebo. Recovery is defined as "no restrictions on activity" or "no clinical or virological evidence of infection." (Placebo = 6, SNG001 treatment n = 6).

[0033] [Figure 6] This shows the changes in dyspnea status in a home cohort of SARS-CoV-2 infected patients who presented with marked / severe dyspnea at the start of treatment (a) placebo (n=6) (b) inhaled IFN-β treatment (n=6).

[0034] [Figure 7] This study shows recovery in a combined hospital and home cohort, regardless of the presence or absence of marked / severe dyspnea at the start of treatment with inhaled IFN-β (SNG001 formulation) or placebo. Recovery is defined as "no restrictions on activity" or "no clinical or virological evidence of infection" (a) recovery in patients who initiated treatment with a dyspnea score of less than 3 (placebo n=51, SNG001 n=47); (b) recovery in patients who initiated treatment with a dyspnea score of at least 3 (placebo n=36, SNG001 n=33, HR 3.41, 95% CI 1.47-7.94, p=0.004).

[0035] [Figure 8]This report shows the recovery of subgroups of hospitalized and home-care patient cohorts treated with SNG001 and placebo. Recovery is defined as “no restrictions on activity” or “no clinical or virological evidence of infection.” (a) Recovery of subgroups with a dyspnea score of at least 3 or an OSCI score of at least 3. (Placebo n=55, SNG001 n=54, HR 2.49, 95%CI 1.26–4.93, p=0.009) (b) Recovery of subgroups with a dyspnea score of at least 3 or an OSCI score of at least 4 (Placebo n=43, SNG001 n=48, HR 2.68, 95%CI 1.25–5.75, p=0.011).

[0036] [Figure 9] The results show that IFN-β1a present in the SNG100 formulation has the ability to inhibit SAR2-CoV-2, named "Wuhan-like" (Germany / BavPat1 / 2020), as well as recognized variants of interest, the alpha variant (B.1.17) and the beta variant (B.1.351), at concentrations achievable through inhalation. [Modes for carrying out the invention]

[0037] The use of inhaled IFN-β according to the present invention is currently proposed primarily in relation to the prevention or reduction of the severity of lower respiratory tract disease in patients infected with the coronavirus SARS-CoV-2, and / or the improvement of one or more symptoms and / or outcomes in such infected patients. However, SARS-CoV-2 is just one example of a coronavirus that has recently emerged as the causative pathogen of a severe respiratory illness commonly known as virus-induced acute respiratory distress syndrome (ARDS). Other previously known coronaviruses in this category include another severe acute respiratory syndrome coronavirus (SARS-CoV, also known as SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS virus). As stated above, the present invention is equally applicable to any such coronavirus, whether known or likely to emerge in the future. Well-known information in the field of respiratory viruses regarding coronavirus-induced ARDS can be found, for example, by referring to Luyt et al. Virus-induced acute respiratory distress syndrome: epidemiology, management and outcome. Presse Med. 2011; 40(12 Pt 2):e561-8 and Horie et al. Emerging pharmacological therapies for ARDS: COVID-19 and beyond. Intensive Care Med. 2020; 46(12)2265-2283.

[0038] The severity of respiratory illnesses caused by such coronaviruses is likely related to their zoonotic origin (jumping from non-human animal hosts to human hosts, sometimes via intermediate hosts) (Heeney et al. (2006) J. Intern. Med. 260, 399-408). In the absence of a vaccine, human hosts lack specific immunity to the new pathogen, increasing their chances of infection, replication within susceptible cells, and tissue damage. However, the overall risk is balanced by the virus's ability to spread within a population. Unfortunately, in the case of SARS-CoV-2, the virus is well-suited for human-to-human transmission and spreads rapidly from person to person (Chan et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395(10223):514-23). As a result, by July 2020, the COVID-19 pandemic had resulted in approximately 14 million cases and 600,000 deaths worldwide (https: / / covid19.who.int / ), and many affected patients still face the risk of long-term health consequences due to damage to the lungs and other organs (George et al. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir. Med. (2020) 8, 807-815). Furthermore, the lockdown measures taken to control the spread of the virus worldwide have had enormous economic consequences (https: / / www.ons.gov.uk / economy / grossdomesticproductgdp / articles / coronavirusandtheimpactonoutputintheukeconomy / may2020).Despite reports of multiple targeted and non-targeted interventions, some of which are discussed above, new treatments for COVID-19 remain a high-priority requirement.

[0039] While many people infected with SARS-CoV-2 are asymptomatic, the spread of the virus to the lungs of susceptible individuals causes diffuse alveolar damage, allowing fluid to leak from capillaries into the alveolar space. This fluid then accumulates, restricting the normal exchange of oxygen and carbon dioxide, leading to respiratory failure (Buja et al. The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathol. 2020; 48:107233).When infected with SARS-CoV-2, the median incubation period is approximately 4-5 days before the onset of symptoms, and 97.5% of symptomatic patients develop symptoms within 11.5 days (Guan et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. (2020) 382(18):1708-20; Lauer et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann. Intern. Med. 2020; 172(9):577-82; Pung et al. Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures. Lancet. 2020; 395(10229):1039-46 and Li et al. Early Transmission Dynamics in Wuhan, China, of Novel See Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020; 382(13):1199-207.

[0040] COVID-19 patients typically present with fever, dry cough, shortness of breath, headache, and fatigue. Progression to pneumonia usually occurs 1-2 weeks after the onset of symptoms and is accompanied by decreased oxygen saturation, worsening blood gases, multifocal ground-glass opacities, or patchy / segmental sclerosis on chest X-ray or CT. Severe COVID-19 cases progress to acute respiratory distress syndrome (ARDS) on average about 8-9 days after the onset of symptoms (Huang et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506; Wang et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020, 323(11):1061-1069). SARS-CoV-2 infection in the lungs is accompanied by a severe downstream cytokine cascade known as a "cytokine storm," which suggests an overactive immune response whose dysregulation contributes to lung injury, ARDS, sepsis, and organ failure, and can be fatal in the most severe cases (Rageb et al. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol. 2020; 11:1446). The present invention is applicable to any coronavirus that presents a similar clinical picture associated with the development of ARDS (or alternatively, severe acute respiratory syndrome).

[0041] Coronaviruses are a large family of enveloped RNA viruses that mostly infect birds and mammals. SARS-CoV-2 is a beta-coronavirus that has 79% genetic homology to SARS-CoV and 98% homology to the bat coronavirus RaTG13 (Zhou et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature, 2020; 579(7798):270-3). This virus diffuses into respiratory droplets and infects nasal, bronchial, and alveolar epithelial cells through the binding of its viral spike protein to its cell receptor, ACE2 (Walls et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. (2020) 180, 281-292).

[0042] Due to their susceptibility to errors in viral replication, RNA viruses, such as SARS-CoV-2, accumulate mutations, resulting in a certain degree of sequence diversity. Nevertheless, different strains of SARS-CoV-2 can be recognized through sequencing and phylogenetic tree analysis. An example of such phylogenetic analysis using rapid sequencing of isolates is reported, for example, in Meredith et al. Rapid Implementation of SARS-CoV-2 sequencing to investigate cases of health-care associated COVID-19: a prospective genomic surveillance study in The Lancet, published online 14th July 2020. The sequence of the amplified SARS virus genome can be compared to the NCBI reference sequence NC_045512.2 or the equivalent GenBank reference sequence MN908947.3 for SARS-CoV-2 corresponding to the whole genome of the SARS-CoV-2 isolate Wuhan-Hu-1 (Wu et al. Nature 579, 265-269). Therefore, it can be expected that SARS2-CoV-2 variants can be recognized and have high homology to the reference genome, e.g., at least 90%, at least 95%, at least 98%, and at least 99%. Such sequencing surveillance may also enable the identification of any new SARS viruses that infect humans. The use of inhaled IFN-β is considered preferable in preventing or mitigating the severity of lower respiratory tract disease in humans infected with any SARS-CoV virus, particularly any SARS-CoV-2 virus strain.

[0043] Properties of interferon beta for administration When used herein, the terms IFN-beta or IFN-β will be understood to refer to any form or analogue of IFN-β that retains the biological activity of natural IFN-β and preferably retains the activity of IFN-β present in the lungs, particularly in the lung epithelium, when induced by viral infection, such as influenza or rhinovirus infection.

[0044] IFN-β may be identical to or contain the sequence of human IFN-β1a or human IFNβ-1b. However, IFN-β may also be a variant of such a native sequence, for example, a variant having at least 80%, at least 85%, at least 90%, or at least 95-99% identity. It may have one or more chemical modifications, as long as the desired biological activity is preserved.

[0045] Preferably, the IFN-β is recombinant IFN-β produced in vitro in cells by, for example, the expression of polypeptides from a recombinant expression vector, and purified from such cultures.

[0046] For example, human recombinant IFN-β1a available from Rentschler Biopharma SE or Akron Biotechnology, LLC (Akron Biotech) is preferred.

[0047] Formulation and dosage IFN-β for inhalation administration will generally be formulated as an aqueous solution, preferably at a neutral or near-neutral pH, for example, about pH 6-7, preferably pH 6.5. Methods for formulating IFN-β for airway delivery in aqueous solutions are well known; see, for example, U.S. Patent No. 6,030,609 and European Patent No. 2544705. Preferably, such aqueous formulations that do not contain mannitol, human serum albumin (HSA), and arginine, which are present in IFN-β formulations for injection, will be used. The composition may preferably contain an antioxidant, for example, methionine, for example, DL-methionine. Such ready-to-use formulations of IFN-β1a are also commercially available and can be prepared, for example, in syringes at appropriate dilutions of IFN-β, and are available, for example, from Vetter Pharma. It may be compatible with the formulation designated herein as SNG001 (with possible variations in the exact IFN-β1a concentration) previously used in the clinical trials mentioned above in patients exhibiting viral exacerbations of asthma or COPD. Further details of this formulation are available in European Patent No. 2544705 and the following examples herein. The concentration of IFN-β1a may be adjusted as discussed below. The exact preferred concentration of IFN-β, or more specifically IFN-β1a, may vary depending on the exact delivery method.

[0048] SNG001 has been shown to inhibit a wide range of viruses in cell-based assays. Of particular relevance, SNG001 has been shown to inhibit post-MERS-CoV viral shedding in cell-based assays with similar potency against literature-reported and other viral types. See also the illustrative cell-based assays reported to confirm SNG001's ability to be active against various SARS-CoV-2 variants at concentrations applicable to inhalation delivery. This reflects the generally proposed mechanisms supporting the therapeutic use proposed here.

[0049] Rather than formulations with a lower pH, IFN-β formulations with a neutral or near-neutral pH, such as pH 6.5, are particularly preferred. Low pH is known to induce coughing. In a Phase II trial of SNG001 in asthma patients, coughing occurred in less than 10% of patients, and the incidence was no different from that seen with placebo.

[0050] Delivery may be carried out using any device for aerosolizing liquid formulations that retain IFN-β activity, such as a nebulizer. Various nebulizers for drug delivery are commercially available, and for example, the I-neb or Ultra nebulizers from Philips Respironics and Aerogen, respectively, may be used. Both devices have been shown to enable convenient inhalation delivery of IFN-β1a while retaining IFN-β activity after aerosolization.

[0051] Dosage A suitable IFN-β dose for any inhalation delivery mode may be established by dose-escalation studies evaluating the induced antiviral response in the lungs, and is generally a dose that ensures a robust antiviral response within 24 hours after dose administration, preferably a dose that supports a once-daily administration regimen. This may be evaluated by referring to appropriate biomarkers.

[0052] For nebulizer delivery of aqueous formulations containing IFN-β1a, aqueous formulations such as those discussed above, containing approximately 11-13 MIU / ml of IFN-β1a (e.g., 11-12 MIU / ml), may be found to be suitable.

[0053] A preferred once-daily administration schedule is achieved by delivering 0.5 ml or about 0.5 ml of an aqueous formulation containing approximately 11-12 MIU / ml IFN-β1a, preferably 12 MIU / ml IFN-β1a, from an I-neb nebulizer (Phillips Respronics), and other nebulizers that provide similar efficiency of airway delivery may be suitable. When using alternative nebulizers, it may be necessary to adjust the dose to account for differences in the efficiency of drug delivery to the lungs. Once-daily delivery may be preferred. Delivery may be over several days, for example, 3 days or more, 5 days or more, or 7 days or more, for example, up to 14-15 days or more, to alleviate LRT disease and preferably to restore the score improvement to a lower score, for example, to restore to at least an OSCI score of 1.

[0054] Timing of administration As mentioned above, previous instructions recommended that if there is any consideration to alleviate LRT disease in patients associated with coronavirus infection capable of causing severe acute respiratory syndrome (ARDS), such as the severe acute respiratory syndrome observed in COVID-19 patients after infection with SARS-CoV-2, then administration of IFN-β should be limited to early intervention from the onset of symptoms, more specifically up to 7 days prior, and if anything, the dose should be gradually reduced before that point (see again Hung et al. (2020) Lancet 395:1695-16704 entitled "Triple combination of interferon beta-1b, lopinavir-ritonavir and ribavirin in the treatment of patients admitted to hospital with covid-19: an open-label, randomised, phase 2 trial"; first published online 8 May 2020). In contrast, the data presented herein not only demonstrate for the first time that inhaled IFN-β administration may be beneficial in alleviating LRT disease caused by SAR2-CoV-2 infection, but also demonstrate for the first time that such intervention may be beneficial even in patients presenting with symptoms equivalent to LRT disease, requiring at least 3 or even 4 clinical scores on the Ordinal Scale for Clinical Improvement. Such patients would generally have established LRT disease requiring hospitalization and would generally experience symptoms of SARS-CoV-2 infection affecting their activity. Such patients would generally have had symptoms of such infection for at least 7 days. For patients in the studies reported herein, the median time from symptom onset to initiation of inhaled IFN-β treatment was more than 9 days.

[0055] Accordingly, according to the present invention, IFN-β, for example recombinant IFN-β1a, may be administered by inhalation to patients with severe LRT disease, such as a viral infection capable of causing SARS-CoV-2, more specifically, a coronavirus infection, at a stage corresponding to a score of at least 3 or at least 4 on the WHO Ordinal Scale for Clinical Improvement. Use may include patients at least 7 days after the onset of symptoms of the viral infection, for example, at least 9 days after the onset of symptoms of the viral infection. Generally, such administration would be performed before the patient reaches a score of 5 or before the patient reaches a score of 6. Preferably, the administration would be performed before any mechanical ventilation. Such administration has been shown to offer a higher probability, compared to placebo, of preventing the patient from progressing to a higher score, such as requiring intensive care and / or non-invasive ventilation or possibly mechanical ventilation, and rather promoting a return to a lower score. It would be desirable that the administration of inhaled IFN-β does not result in an increase in score.

[0056] Efficacy may be assessed daily by evaluating dyspnea or obtaining a BCSS score. Generally, administration will be continued with improvement in dyspnea or BCSS score. Preferably, this will be accompanied by achieving a reduction of one or more stages on the WHO Ordinal Scale for Clinical Improvement, preferably one or more stages in score, within 14 days or less, less than 7 days, more preferably less than 6 days, e.g., 5 days, and even more preferably less than 4 days, e.g., within 3 days. Preferably, administration of inhaled IFN-β will be accompanied by achieving, for example, no restriction of activity or no clinical or virological evidence of infection within 14 days of IFN-β administration. The overall desirable outcome will be discharge earlier than expected in the absence of treatment beyond oxygen supplementation via mask or nasal prongs.

[0057] As described above, preferred targeting of inhaled IFN-β therapy may be based on a dyspnea score, more specifically, a dyspnea score of 3 or 4 (equivalent to marked or severe dyspnea). This is desirable for SARS-CoV-2 infected individuals in a home setting and with an OSCI score of 2 (equivalent to activity restriction) to an OSCI score of 1 or 0 that does not require hospitalization. See Figure 5 and examples.

[0058] Therefore, hereby proposed is an inhaled IFN-β for use in the treatment of patients according to the present invention suffering from a viral infection, more specifically, a disease resulting from, for example, SARS-CoV-2 infection, wherein a dyspnea score of 3-4 is used as a determinant for the administration of the inhaled IFN-β in either a hospital or home setting.

[0059] Therefore, this simple point-of-care targeting of inhaled IFN-β therapy to SARS-CoV-2 infected patients based on single-symptom scoring (dyspnea) is demonstrated here as a significant contribution to the clinical management of such patients, which was not predicted by any prior knowledge of interferon type I action.

[0060] Combination therapy The data presented here support the use of inhaled IFN-β as the sole therapeutic agent for preventing or reducing the severity of LRT disease in patients with coronavirus infection, as discussed above. However, it will be understood that such administration of IFN-β is not excluded by one or more other therapeutic agents that may help improve one or more symptoms in patients caused by the viral infection. The use of inhaled IFN-β may be combined with, for example, a corticosteroid, such as dexamethasone, or any other agent previously proposed to prevent or reduce the severity of LRT disease in coronavirus-infected individuals prone to ARDS, such as lopinavir-ritonavir and / or ribavirin or intravenous remdesivir (an RNA polymerase inhibitor that has been shown to shorten the time to discharge in COVID-19 patients but does not reduce respiratory viral load). Such combination therapies may include, as necessary, simultaneous, sequential, or separate administrations of IFN-β and the other therapeutic agent. Of particular interest is the potential combination of inhaled IFN-β and dexamethasone (The RECOVERY Collaborative Group, Dexamethosone in Hospitalised Patients with Covid-19 - Preliminary Report, N. England J. Med. 17 July 2020). Of particular interest is the potential addition of inhaled corticosteroids. The combined use of such corticosteroids and IFN-β, for example, as a single pharmaceutical composition for aerosol delivery to the airways, has been previously proposed for use in mitigating viral exacerbations of asthma or COPD (see European Patent No. 1734987).

[0061] Treatment method In another embodiment, the present invention provides a method for preventing or reducing the severity of lower respiratory tract disease in patients infected with coronavirus or other pandemic-causing viruses capable of causing acute respiratory distress syndrome (ARDS), and / or improving one or more symptoms and / or outcomes in such infected patients, the method comprising the step of administering IFN-β by inhalation. IFN-β may be administered as a sole therapeutic agent or in combination with one or more additional therapeutic agents to aid in the improvement of one or more symptoms resulting from the same viral infection, as discussed above. As described above, prior to such administration, a significant or severe dyspnea score may be determined, and such administration may be performed in a home or hospital setting, preferably for the purpose of promoting recovery to at least 1 on the OSCI.

[0062] The present invention also provides the use of IFN-β for preparing compositions for use in methods of preventing or reducing the severity of lower respiratory tract diseases disclosed herein, wherein the compositions are administered by inhalation. As described above, such administration would generally involve using any device for aerosolizing liquid formulations that retain IFN-β activity, such as a nebulizer. [Examples]

[0063] A comparison of the efficacy and safety of inhaled interferon-beta compared to placebo in patients hospitalized with COVID-19 caused by SARS-CoV-2.

[0064] Protocol Overview This was a randomized, double-blind, parallel-group, placebo-controlled trial of inhaled recombinant IFN-β1a, formulated as an aqueous formulation at a neutral pH for delivery by spray to patients with confirmed SARS-CoV-2 infection. Ninety-eight hospitalized patients with confirmed SARS-CoV-2 infection (recruited from nine specialized hospital facilities in the UK between March 30, 2020, and May 27, 2020) were randomized to receive either inhaled IFN-β (n=48) or placebo (n=50) for 14 days. Patients were randomized within 24 hours of a positive test result for initial treatment (except in cases where the positive test result occurred before hospitalization). Inclusion criteria included hospitalization due to the severity of COVID-19 disease, being 18 years of age or older, and having a SARS-CoV-2 infection (determined by either a positive RT-PCR test result or a positive point-of-care test result in the presence of strong clinical suspicion).

[0065] The patient groups were uniformly matched for mean age (56.5 years for placebo and 57.8 years for SNG001), comorbidities, and mean duration of pre-registration COVID-19 symptoms (9.8 days for placebo and 9.6 days for SNG001).

[0066] Patients received inhaled IFN-β or placebo (IFN-β-free formulation buffer) via a portable mesh nebulizer (I-neb, Philips Respironics, supplied from Chichester, UK). The primary endpoint was prevention of severe lower respiratory tract disease, as determined by a stepwise progression on a 9-point Ordinal Scale for Clinical Improvement.

[0067] Recombinant IFN-β1a preparation The formulation (referred to as SNG001) provides recombinant IFN-β1a (manufactured by Rentschler Biopharma SE or Akron Biotechnology, LLC) as a buffered aqueous solution at pH 6.5. The composition is shown in the table below. Unlike some other commercially available preparations, it does not contain mannitol, human serum albumin, or arginine. The formulation was supplied by Vetter Pharma in ready-to-use syringes. [Table 2]

[0068] As described above, SNG001 has been shown to inhibit a wide range of viruses in cell-based assays. Of particular relevance, SNG001 has been shown to inhibit post-MERS-CoV viral shedding in cell-based assays with similar efficacy against those reported in the literature and other virus types (Scagnolari et al. Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antivir. Ther. 2004 Dec; 9(6):1003-11; Sheahan et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 2020 Jan 10; 11(1):222; Spiegel et al. The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein. J. Clin. Virol. 2004 Jul; 30(3):211-3).

[0069] In all clinical trials conducted to date with inhaled SNG001 (three for asthma and one for chronic obstructive pulmonary disease [COPD]), it has been shown to upregulate pulmonary antiviral biomarkers in sputum over 24 hours post-administration, confirming the successful delivery of a biologically active drug to the lungs, demonstrating proof-of-mechanism, and supporting dose selection.

[0070] Dose escalation studies using selected nebulizers established the target lung dose that induced an antiviral response in the lungs 24 hours after dose administration. Dosage protocol The SNG001 nebulizer solution was placed in a glass syringe containing 0.65 ml of an IFN-β1a aqueous solution with an IFN-β1a concentration of 12 MIU / ml. The contents of one syringe were filled into an I-neb nebulizer fitted with a 0.53 ml chamber. The patient inhaled either one dose or a placebo solution per day. The nebulizer was used in its tidal breathing mode. In this mode, the I-neb delivers short pulses of aerosol with each inhalation and requires the patient to use tidal breathing.

[0071] Respiration and other assessments In addition to daily assessments referencing the Ordinal Scale for Clinical Improvement, patients in the study also underwent BCSS assessments and pneumonia assessments.

[0072] BCSS rating BCSS is a patient-reported outcome measure designed as a daily diary in which patients are asked to record the severity of three symptoms: shortness of breath, cough, and sputum.

[0073] Each symptom is represented by a single item on a 5-point scale ranging from 0 to 4, with higher scores indicating more severe symptoms. The total score is expressed as the sum of the scores for the three items, ranging from 0 to 12. A mean decrease of 1 point on the BCSS total scale signifies a significant reduction in symptom severity.

[0074] This evaluation was conducted once a day at the same time (+ / - 3 hours) each day. Where possible, the forms were completed by the patient. However, where necessary, on-site staff read the questions to the patient either in person or via telephone / video link.

[0075] The BCSS questions and possible answers are as follows: 1. How severe was your shortness of breath today? 0 = None - No difficulty noticed 1 = Mild to noticeable during vigorous activity (e.g., running). 2 = Moderate - Noticeable even during light activities (e.g., making a bed or carrying groceries). 3 = Noticeable - Stands out when doing laundry or getting ready. 4 = Severe - Present almost always, even at rest. 2. How was your cough today? 0 = No cough - Not noticing a cough 1 = Rare - Cough occurs occasionally. 2 = Occasionally - Less than once an hour 3 = Frequent - Once or more times per hour 4 = Almost always - Coughing is constant or unavoidable. 3. How many problems did you experience with phlegm today? 0 = None - No problems noticed. 1 = Mild - There were almost no problems. 2 = Moderate - Problems are noticeable. 3 = Significant - A major problem occurred. 4 = Severe - There were problems almost constantly.

[0076] Findings supporting the benefits of IFN-β administration to COVID-19 patients. The odds of developing a severe illness during the treatment period were 72% lower in patients treated with SNG001 compared to the placebo group. More specifically, the odds of developing a severe illness (e.g., requiring ventilation or death) during the treatment period were significantly lower by 72% in patients treated with SNG001 compared to those treated with placebo (OR 0.28 [95% CI 0.07~1.08], p=0.064).

[0077] The test results showed that SNG001 significantly reduced the number of hospitalized COVID-19 patients who progressed from requiring oxygen (score 4 on the WHO Ordinal Scale for Clinical Improvement) to requiring ventilation (score 5 or higher).

[0078] Patients who received SNG001 were more than twice as likely to recover from COVID-19 (defined as "no restrictions on activity" or "no clinical or virological evidence of infection") compared to patients who received placebo (HR 2.19 [95% CI 1.03~4.69], p=0.043). See Figure 1.

[0079] In patients with more severe illness upon admission (i.e., those requiring oxygen therapy), those treated with SNG001 (n=28) were more than twice as likely to recover by the end of the treatment period compared to the placebo group (n=36), and had higher odds of recovery on day 28. See Figure 2. Here, recovery was defined as "no restrictions on activity" or "no clinical or virological evidence of infection."

[0080] In patients with more severe illnesses upon admission (i.e., those requiring oxygen therapy), treatment with SNG001 increased the likelihood of discharge. The median time to discharge was 6 days for patients treated with SNG001 and 9 days for patients treated with placebo. See Figure 3.

[0081] Throughout the treatment period, shortness of breath, one of the main symptoms of severe COVID-19, was significantly reduced in patients treated with SNG001 compared to those treated with placebo (p=0.007). See Figure 4.

[0082] Three subjects died after being randomized to placebo. No deaths were observed among subjects treated with SNG001.

[0083] As described above, by day 28, patients who received SNG001 treatment and had a more severe illness at the time of admission (i.e., those requiring oxygen supplementation) had significantly better odds of recovery (OR 3.86 [95% CI 1.27~11.75], p=0.017).

[0084] Interestingly, efficacy analyses show no evidence of a correlation between the therapeutic effect of inhaled SNG001 and the duration of previous COVID-19 symptoms. This contradicts previous suggestions that IFN-β use should be limited to early intervention within 7 days of symptom onset.

[0085] Administration of inhaled IFN-β to SARS-CoV-2 infected individuals in a home environment. The trial discussed above, which involved hospitalized patients, was expanded to a cohort of 120 SARS-CoV-2 infected patients in a home setting. All patients were considered to be at risk of disease progression requiring hospitalization (over 65 years of age, or over 50 years of age with risk factors). All participants in the trial had either a score of 1 (no activity restrictions) or a score of 2 (activity restrictions but not requiring hospitalization) on the WHO ordinal scale at the start of treatment. Here again, either SNG001 or placebo was inhaled once daily via a mesh nebulizer. Participants were provided with remote device training, and the trial was conducted using video calls.

[0086] Participants were evaluated for worsening of their condition and, if initially scoring 2, for recovery to a score of 1 or 0 without rebound. Only two patients worsened to a score of 3 or higher, and both received placebo. This was consistent with expectations for at-risk SARS-CoV-2 infection.

[0087] In addition to the overall disease score on the WHO ordinal scale, which was assessed daily, participants in the study were also scored daily for dyspnea on the dyspnea scoring scale shown above and repeated below. Shortness of breath scoring based on questions: How severe was your shortness of breath today? 0 = None - No difficulty noticed 1 = Mild to noticeable during vigorous activity (e.g., running). 2 = Moderate - Noticeable even during light activities (e.g., making a bed or carrying groceries). 3 = Noticeable - Stands out when doing laundry or getting ready. 4 = Severe - Present almost constantly, even at rest.

[0088] Of particular interest, as shown in Figure 5, was the unpredictable finding that SNG001 had a clear effect on promoting recovery compared to placebo in 11% of patients who had a dyspnea score of at least 3 at the start of treatment. The ability of SNG001 to significantly promote improvement in dyspnea in patients with significant or severe dyspnea at the start of treatment, compared to placebo, is also shown in Figures 6a and 6b.

[0089] Therefore, inhaled IFN-β is considered a useful point-of-care treatment for SARS-CoV-2 patients experiencing significant to severe dyspnea at home, with the aim of accelerating recovery and reducing the risk of progression to the point of requiring hospitalization. Furthermore, by combining data from hospital and home-based study cohorts, we demonstrate here that the same dyspnea scoring system (a score of 3–4, equivalent to marked or severe dyspnea) is a simple and rapid criterion that may be useful in targeting COVID-19 patients, whether in a hospital setting or at home, for inhaled IFN-β therapy aimed at accelerating recovery. While there was no significant difference in recovery rates between SNG001 and placebo treatment in patients with dyspnea scores of 0, 1, or 2, patients with dyspnea scores of 3 or 4 who received SNG001 showed significantly accelerated recovery compared to similar patients who received placebo. See Figures 7a and 7b.

[0090] Patients who were given a score of 3 or 4 for shortness of breath and received SNG001 were more than three times more likely to recover than patients who received a placebo [HR 3.41 (95% CI, 1.47, 7.94) p=0.004].

[0091] The usefulness of a simple dyspnea scoring system for categorizing COVID-19 patients for treatment with inhaled IFN-β to promote recovery is further supported by Figures 8a and 8b, which show the recovery percentage with treatment (SNG001 or placebo) for subgroups of hospitalized and home-care patients based on the overall disease severity score or a dyspnea score of at least 3 on the WHO Ordinal Scoring Scale: Group 1: dyspnea score of at least 3 or ordinal score of at least 3, Group 2: dyspnea score of at least 3 or ordinal score of at least 4. Patients with significant dyspnea or an OSCI score of 3 or 4 showed a very significant effect of SNG001.

[0092] Therefore, the targeting of inhaled IFN-β therapy to SARS-CoV-2 infected patients based on a simple dyspnea scoring system is shown here as a significant contribution to the clinical management of such patients, which was not foreseen by any prior knowledge of the effects of such interferons. Targeting of inhaled IFN-β therapy in hospitalized COVID-19 patients based on marked / severe dyspnea has been shown as a means to promote recovery, which could be converted to home-bound COVID-19 patients who have dyspnea problems but do not yet exhibit an overall disease severity that justifies the need for a hospital bed.

[0093] In vitro study to confirm the ability of IFN-β1a present in inhaled formulations to inhibit SARS-CoV-2 variants. To supplement the studies discussed above, in vitro experiments were conducted to confirm that SNG001 at concentrations achievable by inhalation delivery is active against both the alpha and beta variants of SAR2-CoV-2 (currently named according to the WHO Greek alphabet labeling scheme for such variants), as well as the "Wuhan-like" SAR2-CoV-2 (Germany / BavPat1 / 2020). The alpha and beta variants were previously referred to as B.1.1.7 and B1.351, respectively, or commonly as the UK Kent variant and the South Africa variant, respectively. See the WHO website and the notice on the naming of SAR2-CoV-2 variants issued on May 31, 2021.

[0094] Vero E6 cells were treated with SNG001 preparations at various concentrations before and after infection with SARS-CoV-2, as described above. 16–24 hours after infection, the presence of SAR2-CoV-2 viral protein was determined using immunohistochemistry. SNG001 strongly reduced the virus to undetectable levels in cells infected with either the "Wuhan-like" virus or the above variants. 90% inhibition (IC) 90 The concentrations readily achievable after inhalation delivery of IFN-β, which were found to provide the desired effect, were 3.2, 3.4, and 4.0 IU / ml, as shown in Figure 9.

[0095] This data further supports the use of the claimed inhaled IFN-β in preventing or mitigating the severity of lower respiratory tract disease associated with the SARS-CoV-2 virus, including known variants and potential future emerging variants, through a general mechanism as an inhaled broad-spectrum antiviral product. The present invention includes the following embodiments. <1> Interferon-beta (IFN-β) administered by inhalation, for use in preventing or reducing the severity of lower respiratory tract disease in patients infected with coronavirus or other pandemic-causing viruses capable of causing acute respiratory distress syndrome (ARDS), and / or improving one or more symptoms and / or outcomes in such infected patients. <2> The aforementioned patient is infected with the coronavirus. <1> IFN-β for use as described above. <3> The aforementioned coronavirus is the SARS virus, which has the ability to cause severe acute respiratory syndrome. <2> IFN-β for use as described above. <4> The aforementioned coronavirus is SARS-CoV-2. <3> IFN-β for use as described above. <5> The aforementioned IFN-β is recombinant human IFN-β1a. <1> from <4> IFN-β for use as described in any of the following. <6> The IFN-β is formulated in an aqueous solution with a pH of approximately 6-7, for example, pH 6.5, preferably excluding mannitol, human serum albumin, and arginine. <1> from <5> IFN-β for use as described in any of the following. <7> Administration to the airway includes aerosolization of the liquid formulation of IFN-β. <1> from <6> IFN-β for use as described in any of the following. <8> The administration is done using a nebulizer. <7> IFN-β for use as described above. <9> The administration of IFN-β is as an inhalation dose once daily. <1> from <8> IFN-β for use as described in any of the following. <10> The patient is evaluated to have a score of at least 3 or at least 4 on the WHO Ordinal Scale for Clinical Improvement at the time of the first administration of IFN-β. <1> from <9> IFN-β for use as described in any of the following. <11> The aforementioned patient does not show an increase in score on the same scale after IFN-β administration. <10> IFN-β for use as described above. <12> The patient shows a decrease of 1 or more points on the same scale during the period of IFN-β administration, preferably within 14 days or less, for example, less than 7 days, more preferably less than 6 days, for example 5 days, and even more preferably less than 4 days, for example within 3 days. <11> IFN-β for use as described above. <13> After initiating IFN-β administration, improvement in shortness of breath and / or the Breathlessness, Cough and Sputum Score (BCSS) is observed. <1> from <12> IFN-β for use as described in any of the following. <14> The patient was assessed to have a dyspnea score of 3-4 at the time of initial treatment with IFN-β, and the score was as follows: 0 = None - No difficulty noticed 1 = Mild to noticeable during vigorous activity (e.g., running). 2 = Moderate - Noticeable even during light activities (e.g., making a bed or carrying groceries). 3 = Noticeable - Stands out when doing laundry or getting ready. 4 = Severe - Present almost always, even at rest. Determined based on the patient's responses to questions regarding the degree of dyspnea, <1> from <13> IFN-β for use as described in any of the following. <15> A dyspnea score of 3-4 is used as a determinant for administering inhaled IFN-β. <14> IFN-β for use as described above. <16> The patient is in a home environment equivalent to an OSCI score of 2 or less, and a dyspnea score of at least 3 is used as a determinant for the administration of inhaled IFN-β. <15> IFN-β for use as described above. <17> The IFN-β is administered by inhalation in combination with the administration of one or more additional therapeutic agents to aid in the improvement of one or more symptoms caused by the same viral infection, with each additional agent being administered simultaneously, separately, or sequentially. <1> from <13> IFN-β for use as described in any of the following. <18> It is administered in combination with corticosteroids. <17> IFN-β for use as described above.

Claims

1. A pharmaceutical composition for use in reducing the severity of lower respiratory tract disease in patients infected with SARS-CoV-2 or other coronaviruses capable of causing acute respiratory distress syndrome (ARDS), and / or improving one or more symptoms and / or outcomes in such infected patients, The pharmaceutical composition comprises interferon-beta (IFN-β), The aforementioned interferon-beta is administered by inhalation. The patient is evaluated to have a score of at least 3 or at least 4 on the WHO Ordinal Scale for Clinical Improvement at the time of the first administration of IFN-β. Pharmaceutical composition.

2. A pharmaceutical composition for use in reducing the severity of lower respiratory tract disease in patients infected with SARS-CoV-2 or other coronaviruses capable of causing acute respiratory distress syndrome (ARDS), and / or improving one or more symptoms and / or outcomes in such infected patients, The pharmaceutical composition comprises interferon-beta (IFN-β), The aforementioned interferon-beta is administered by inhalation. The patient was assessed to have a dyspnea score of 3-4, and the score was determined to be on the following scale: 0 = None - No difficulty noticed 1 = Mild – Noticeable during strenuous activity (e.g., running). 2 = Moderate – Noticeable even during light activities (e.g., making a bed or carrying groceries). 3 = Noticeable - Noticeable when doing laundry or getting ready. 4 = Severe - Present almost always, even at rest. This is determined based on the patient's responses to questions regarding the degree of dyspnea, A pharmaceutical composition in which the 3-4 dyspnea scores described above are used as determinants for the administration of inhaled IFN-β.

3. The pharmaceutical composition according to claim 2, wherein the patient is in a home environment equivalent to an OSCI score of 2 or less, and a dyspnea score of at least 3 is used as a determinant for the administration of inhaled IFN-β.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein improvement in shortness of breath and / or the Breathlessness, Cough and Sputum Score (BCS) is observed after initiation of IFN-β administration.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the IFN-β is recombinant human IFN-β1a.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the IFN-β is formulated in an aqueous solution with a pH of 6 to 7, for example, pH 6.5, and preferably excludes mannitol, human serum albumin, and arginine.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein administration to the airway includes aerosolization of the liquid formulation of IFN-β.

8. The pharmaceutical composition according to claim 7, wherein administration is by the use of a nebulizer.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the administration of IFN-β is as an inhalation dose once daily.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the IFN-β is administered by inhalation in combination with the administration of one or more further therapeutic agents to aid in the improvement of one or more symptoms caused by the same viral infection, and each of the further agents is administered simultaneously, separately, or sequentially.

11. The pharmaceutical composition according to claim 10, which is administered in combination with a corticosteroid.

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