CN116472054A - Inhaled interferon-beta for improving prognosis of SARS-CoV-2 infected patient - Google Patents

Abstract

The present invention relates to the use of inhaled interferon-beta for preventing or alleviating the severity of Lower Respiratory Tract (LRT) disease in a patient infected with a coronavirus capable of causing acute respiratory distress syndrome, for example, in a patient infected with a covd-19 of SARS-CoV-2. It is suggested that such treatments be targeted to promote healing based on simple and rapid dyspnea scores, which are applicable in both home and hospital settings.

Description

Inhaled interferon-beta for improving prognosis of SARS-CoV-2 infected patient

Technical Field

The present invention relates to the use of inhaled interferon-beta (IFN-beta), for example formulated for aerosol administration through the airways, to improve prognosis of patients infected with SARS-CoV-2 virus by preventing or alleviating the severity of Lower Respiratory Tract (LRT) disease and/or improving the symptomatic state of the disease, assessed on the scale commonly used in clinical practice worldwide to assess the severity of the disease caused by such infection, commonly referred to as COVID-19. On the basis of tests extended to the home environment, the severity of dyspnea has been proposed as a simple point of care (point of care) standard for use as an indicator of administration of inhaled IFN- β to SARS-CoV-2 infected patients. It has been found that such administration to patients with SARS-CoV-2 infection that have significant or severe dyspnea can significantly accelerate recovery and prevent exacerbation, and thus can help reduce the need for hospitalization. Although the basis of the present invention is a clinical trial of inhaled IFN- β for SARS-CoV-2 infected patients, it will be appreciated that the present invention is applicable to any future occurring coronavirus that has the ability to cause severe acute respiratory syndrome and is therefore classified as SARS virus, and other known or future occurring coronaviruses, or other viruses that may cause a pandemic, that cause severe LRT disease in humans.

Background

IFN- β driven antiviral responses have been demonstrated in the elderly and in patients with chronic airway diseases(more particularly asthma and COPD) Gerontology in people suffering from injury/defect (Agrawal et al (2013)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 the previously proposed treatment of viral-induced asthma and Chronic Obstructive Pulmonary Disease (COPD) exacerbations caused by rhinoviruses causing the common cold using inhaled IFN- β (see EP1734987B under the name of university of nanampton (University of Southampton) and exclusive approval to synair plc) and the previously proposed use of inhaled IFN- β to reduce the severity of LRT disease in elderly persons caused by rhinovirus infection (see US 7,871,603B under the name Synairgen Research Limited). Furthermore, EP2544705B, also under the name Synairgen Research Limited, proposes the use of inhaled IFN- β for the treatment of LRT diseases associated with influenza infection. Clinical trials for nebulization delivery by breath-driven nebulizers using inhaled IFN- β1a formulations have been conducted to further conduct such administration, particularly in asthmatic or COPD patients suffering from LRT disease due to cold or influenza, with encouraging results. In all such clinical trials conducted so far (3 asthma and 1 COPD patients), inhaled IFN- β upregulated pulmonary antiviral biomarkers in sputum within 24 hours after administration, demonstrated successful delivery of bioactive drugs to the lungs, demonstrated mechanism of-of-mechanism, and supported dose selection. However, these experiments do not provide any basis for assuming that inhaled IFN- β can have any beneficial effect in preventing or treating severe LRT disease associated with any coronavirus that can cause severe acute respiratory syndrome (e.g., SARS-CoV-2).

In cell-based assays, IFN- β has been shown to inhibit replication of various coronaviruses, including the middle east respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. For example, in vitro studies using Vero cells have shown that either IFN- β or IFN- α has antiviral activity against SARS-CoV-2, similar to the findings of SARS-CoV and MERS virus (Mantlo et al anti activities of type I interferons to SARS-CoV-2infection.Antiviral Res.2020;179:104811). CN1535724a (institute of biotechnology, golden, beijing) also reported cellular assays with various type I interferons, indicating their ability to inhibit SARS virus proliferation, but more likely to be concerned with IFN- α2b (if any evidence). An extension of these studies is reported in CN1927389a, where the use of recombinant human IFN- α2b nasal sprays as a prophylactic measure against SARS virus infection in the upper respiratory tract is reported. However, no type I interferon formulation suitable for inhaled delivery is taught; the only mentioned formulation of recombinant human IFN- β is a commercial formulation for injection. From these studies, it is still unknown whether inhaled IFN- β would have any benefit in preventing or treating LRT disease in patients infected with any coronavirus, particularly in improving the symptomatic status/outcome of those LRT disease patients with disease caused by SARS virus infection and in need of hospitalization, classified on the WHO approved clinical improvement rating scale as at least 3 or 4.

Indeed, the only reported clinical trial with IFN- β therapy for patients diagnosed with COVID-19 disease caused by SARS-CoV-2 infection investigated only subcutaneous injections of IFN- β -1b, the formulation of which was not even suitable for inhaled administration, and combined with oral administration of lopinavir-ritonavir and ribavirin (see Hung et al (2020) Lancet 395:1695-16704, titled 'Triple combination of interferon beta-1b, lopinavir-ritonavir and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, random, phase 2 three' first published online at 5.8 days 2020). The same clinical trial team only suggested that dual antiviral treatment of IFN- β -1b was necessary, as was employed for the triple therapy studied. In the reported trial, patients were randomized to the triple treatment group or to the lopinavir-ritonavir alone group. In the triplet group, patients were recruited and treated with IFN- β -1b less than 7 days after symptoms developed; depending on the date of start of the drug administration, they received one to three doses of IFN- β -1b every other day. If the symptoms appear on the 1-2 days, patients receive all 3 doses of IFN- β. If drug administration is initiated on days 3-4 of the onset of symptoms, the patient receives two doses of IFN- β. If drug administration is initiated on days 5-6 of the onset of symptoms, the patient receives a dose of IFN- β. For patients receiving treatment between day 7 and day 14, IFN- β is not administered at all. Thus, early intervention in covd-19 disease is recommended, preferably by subcutaneous injection of IFN- β, but care should be taken if such injection would adversely affect the progression of symptoms associated with inflammatory mechanisms other than the initial viral infection.

Previous studies using IFN- β to treat MERS infected mice showed that treatment was effective only during the day of infection before viral load peaked, whereas delayed interferon treatment failed to inhibit viral replication and resulted in increased inflammation and enhanced expression of pro-inflammatory cytokines, suggesting that delayed treatment may exacerbate symptoms by causing cytokine storms (see Channappanavar et al IFN-I response timing relative to virus replication determines MERS coronavirus infection outmatrices J. Clin. Invest.2019;129 (9): 3625-39). This supports early treatment of covd-19 with IFN- β (and by injection) in agreement with (if any evidence of) the human clinical trial described above.

In this clinical setting, the rationale that limits the use of IFN- β to early intervention (7 days before symptoms appear) can be seen as the expectation that SARS-CoV-2 viral load will peak within days of symptoms appearance, and the concern that later treatment may trigger cytokine storms, which is observed in COVID-19 patients and in animal models of MERS virus infection. In fact, it has been suggested that cytokine storms and the lesions they cause may be driving factors for severe disease that are more important than viral replication in advanced stages of the disease, and 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; jamiloux et al, shield we stimulate or suppress immune responses in COVID-19Cytokine and anti-cytokine interactions. Autoimmun. Rev.2020;19 (7): 102567).

A team at the university of French Amens-Picard Hospital was recently entitled' Therapeutic Options for Coronavirus Disease 2019 (COVID-19) -Modulation of TypeIInterferon Response as a promising Strategy？’(Mary et al(May 2020)Frontiers in Public Health,8Article 185) reviews a possible approach to treat COVID-19 disease. They noted that IFN-alpha-2 b nebulized administration was widely used in China (see more information on IFN-alpha below) in the hope of treating LRT diseases associated with SARS-CoV, middle east respiratory syndrome coronavirus (MERS virus) and most recently SARS-CoV-2, but did not provide new data to support similar delivery of IFN-beta with beneficial effects at any stage of COVID-19 disease. They only noted preliminary information on the triple drug assay described above, indicating that azithromycin represents an interesting alternative research strategy (if any evidence). In addition to its antibacterial effect, azithromycin has been reported to increase rhinovirus-induced type I and type II IFN responses in bronchial epithelial cells from healthy donors, asthmatic individuals and COPD patients. Combination treatment with azithromycin and hydroxychloroquine has been tested in some French COVID-19 patients (Gautret al Int. J. Antimicrob. Agents (2020) 105949) and Mary et al commented that "the possibility that azithromycin might be responsible for the rapid reduction in viral load in this French patient sub-population treated with h-CQ must be considered". "

One of the problems of salarad et al is 'Type I interferons as potential treatment against COVID-19' (Antiviral Research,178the article by online publication at 104791, 4/7/2020 reviews various studies related to judging the benefits of using type I interferons (including IFN- α and IFN- β) on virus-induced ARDS. With respect to inhaled administration, discussion is again limited to administration of IFN- α and it is generally recommended to combine such administration of IFN- α as part of a combination therapy, e.g., with lopinavir/ritonavir (see, e.g., lu, H.drug treatment options for the 2019-new corenavir (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 parts; liu et al; crit. Care (2020) 24-56). These reports on the use of inhaled IFN-alpha do not infer the use of any IFN-beta, which is notable and consistent with the knowledge of type I interferonA kind of electronic device.

Although Type I interferons such as IFN- α and IFN- β are antiviral proteins that bind the same receptor, they differ in antiviral and immunomodulatory properties (Ng et al alpha and Beta Type 1Interferon 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). The cells produce interferon as an innate immune response to combat viral infections. It is this innate immune response that provides the first line of defense against viruses until the adaptive immune system produces antibodies and cell-mediated responses that clear viral infections and can provide long-term immunity. IFN- α is produced in large quantities by special leukocytes called plasmacytoid dendritic cells and is approved for certain systemic infections, such as hepatitis. IFN- β is produced by many types of cells, including epithelial cells and fibroblasts, in which IFN- β is produced as an immediate local response to a viral infection and triggers an antiviral program, preparing the tissue against the infection. IFN- β has been reported to be a more potent coronavirus inhibitor than IFN- α in cellular studies (see again the Mantlo et al references above; see also Scagnoloari et al incorporated sensitivity of SARS-coronavirus to a combination of human type I and type II Interferons. Anti-tier Ther.2004;9 (6): 1003-11 and Stockman et al SARS: systematic review of treatment effects. PLoS Med.2006;3 (9): e 343). However, it is understood that such cellular studies cannot predict the benefit of inhaled IFN- β in complex clinical settings of acute lower respiratory disease induced by coronavirus infection.

In the review of Sallard et al, supra, the only reference to IFN- β administration was by injection, and reference to the 2019 report of Channetaanavir et al, supra, again indicated that the need for early administration of any type I interferon was felt to optimize antiviral treatment and avoid adverse events. Indeed, the authors even suggested that administration of anti-interferon drugs might be more beneficial in the late stages of the progression of covd-19 associated with severe LRT disease.

Viral infections naturally elicit an innate immune response, including the production of type I and type II interferons that induce antiviral genes and regulate inflammatory responses. However, like the highly homologous SARS-CoV, SARS-CoV-2 possesses a range of nonstructural proteins that prevent 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. Viruses Res.2016;96:219-43;Yuen et al.SARS-CoV-2nsp13,nsp14,nsp15 and orf6 function as potent interferon antagonists.Emerging Microbes Infect.2020;9 (1): 1418-28). In agreement therewith, severe patients with COVID-19 have been reported to exhibit impaired type I interferon activity and inflammatory response (Hadjadj et al, impared type I interferon activity and inflammatory responses in severe COVID-19 components, science (2020) 369, 718-724).

Although as noted above, early administration of interferon has been emphasized quite well to reduce the peak of viral replication, patients with high viral load and long viral shedding periods have been reported to have a higher risk of severe COVID-19 with severe LRT disease (Liu et al, visual dynamics in mild and severe cases of COVID-19.Lancet Infect.Dis.2020;20 (6): 656-7). Furthermore, there has been no suggestion of intervention with inhaled IFN- β at any point in time.

Disclosure of Invention

The data now first suggest that the use of inhaled IFN- β to prevent or reduce the severity of LRT disease associated with SARS-CoV-2 infection and/or to improve the symptomatic status/therapeutic outcome of a patient is supported, even in the WHO approved clinical improvement rating scale described below, by a score of at least 3 or at least 4 for COVID-19 disease associated with SARS-CoV-2 infection (see also WHO R & D Blueprint novel Coronavirus COVID-19Therapeutic Trial Synopsis.2020, 2 months 18).

Clinical improvement rating scale

Reference hereinafter to the clinical improvement rating scale (OSCI) is understood to refer to the scoring system given above.

Data on administration of inhaled IFN- β to SARS-CoV-2 infected patients in a home setting has been additionally reported, indicating that such IFN- β administration can accelerate recovery for patients exhibiting significant or severe dyspnea at the onset of IFN- β therapy, defined as grade 1 or grade 0 in the above-mentioned scale. Dyspnea is scored using a well-known scoring system based on patient response to: how difficult you breathe today?

0 = none-not aware of any difficulties

1 = mild-evident when strenuous activities (e.g. running) are performed

2 = moderate-even when light activities (such as bedding or carrying debris) are performed

3 = evident-evident when washing or dressing

4 = severe-almost always sustained, even at rest.

This dyspnea score forms an element of the BCSS scoring system previously designed for assessing the severity of respiratory disease in COPD patients (Leidy et al (2003) Chest,1242182-2191, 'The Breathlessness, cough and spray scale.the Development of Empirically Based Guidelines for Interpretation'). The dyspnea score referred to hereinafter is to be understood as scoring dyspnea in this recognized manner.

The ability to accelerate recovery is most pronounced in SARS-CoV-2 infected individuals who exhibit a dyspnea of greater than or equal to 3 (i.e., exhibit significant or severe dyspnea) on this scale. Patients with significant or severe dyspnea recover significantly slower than patients scored 0-2 on the dyspnea scale in hospital and home cohorts. In both home and hospital cohort studies, inhaled IFN- β therapy accelerates recovery in patients with significant or severe dyspnea.

Accordingly, the present invention provides IFN- β for use in preventing or lessening the severity of lower respiratory tract disease in a patient infected with a coronavirus capable of causing Acute Respiratory Distress Syndrome (ARDS), such as severe acute respiratory syndrome comparable to the classification of SARS virus, and/or ameliorating one or more symptoms and/or consequences in a patient so infected, wherein the IFN- β is administered by inhalation.

As mentioned above, in the case of SARS-CoV-2 infected patients, dyspnea is a symptom that not only exacerbates the severity of the disease, resulting in hospitalization, but is also a significant problem in SARS-CoV-2 infected individuals, even in the home setting, i.e., a score of 2 (with a significant limiting impact on normal activity), for example, in the WHO scale. Significant or severe dyspnea, i.e. having a dyspnea score of 3-4 on the above scale, is now suggested as a preferred criterion for patients suffering from viral infections of the type described herein in order to not only prevent deterioration, but also promote rehabilitation. Thus, based on a simple point-of-care dyspnea score, a method of effective inhaled IFN- β therapy against COVID-19 disease (or similar viral disease) was proposed that makes this therapy an option even in the home setting in an effort to accelerate recovery and prevent the need for hospitalization.

The invention will be described hereinafter primarily with reference to SARS-CoV-2 and related clinical trial information relating to the patient with COVID-19 as described herein, but by reasonable inference the invention is believed to be applicable to any known or future-occurring coronavirus having the ability to cause acute respiratory distress syndrome (or other viruses that may cause pandemic) as well as other known or future-occurring coronaviruses that cause severe LRT disease in humans, such as other known SARS viruses, MERS viruses, and possible future-occurring coronaviruses or other pandemic viruses that are capable of causing LRT disease in humans, such as by zoonotic transmission.

Accordingly, in its broadest aspect, the present invention may be seen as providing IFN- β for use in preventing or alleviating the severity of lower respiratory tract disease in a patient infected with a virus capable of causing Acute Respiratory Distress Syndrome (ARDS), and/or ameliorating one or more symptoms and/or consequences in a patient so infected, wherein the IFN- β is administered by inhalation. The virus may be a coronavirus, such as SARS-CoV-2 that causes COVID-19 disease in humans (which is considered to include any known or future occurring variant of SARS-CoV-2, such as any variant specified by Greek letter designations according to the WHO bulletin of 5.31 of 2021). It may be a future occurring virus, for example, caused by zoonotic transmission, and may cause similar ARDS in humans.

Viruses capable of causing severe LRT disease (e.g., also known as acute respiratory distress syndrome) are understood to be viruses having the ability to cause LRT disease, which suggests that hospitalization is required and that, according to WHO clinical improvement rating scale, there is a potential for progression to oxygen therapy through masks or nasal tubes, at least in otherwise healthy persons or subgroups of persons with potentially non-virus related health conditions. Where coronaviruses are classified as SARS, it will be appreciated that such LRT diseases may generally be referred to as severe acute respiratory syndrome, on the same scale, corresponding to a potentially higher score.

According to the invention, the purpose of administering inhaled IFN- β may be to prevent a patient suffering from a SARS infection or a SARS-type viral infection that is capable of causing a comparable LRT disease from progressing from a score associated with mild disease to a score associated with severe disease, or from one grade of severe disease to a higher grade of severity, e.g., to a need for mechanical ventilation. The data presented now demonstrate how such administration can be correlated with improved outcomes in preventing increased progression of LRT disease severity, and that such patients are more likely to be discharged and possibly more rapidly, than placebo-controlled patients. Indeed, as noted above, administration of inhaled IFN- β therapy based on dyspnea score is now considered a simple approach to targeting such therapy, exhibiting significantly accelerated recovery (down to 0 or 1 in the OSCI scale) in both hospitalized and non-hospitalized patients with SARS-CoV-2 virus infection.

The effectiveness of inhaled IFN- β may additionally or alternatively be monitored in terms of improvement in one or more symptoms (e.g., dyspnea). For example, improvement may be assessed in a known manner by the dyspnea, cough and sputum scoring (BCSS) system described above, or dyspnea scoring elements therein. Further details are provided in the following examples.

The invention is further described below with reference to clinical trial data provided in the examples and illustrated by the accompanying drawings as described below.

Drawings

Fig. 1:

rehabilitation of patient cohorts in hospitals. Patients receiving SNG001 (n=48) were more than twice as likely to recover from covd-19 (defined as "no restriction of activity" or "no clinical or virological evidence of infection", i.e. grade 1 or 0 on OSCI scale) than patients receiving placebo (n=49) (HR 2.19[95% CI 1.03-4.69]; p=0.043).

Fig. 2:

rehabilitation of patients with heavy illness (requiring supplemental oxygen therapy) at admission. Patients receiving SNG001 treatment (n=36) had more than twice the likelihood of having recovered at the end of the treatment period than the placebo group (n=28) (HR 2.60[95% CI 0.95-7.07]; p=0.062), and had a greater chance of recovery on day 28 (OR 3.86[95% CI 1.27-11.75]; p=0.017). Rehabilitation is defined as "no restriction of activity" or "no clinical or virologic evidence of infection".

Fig. 3:

patients with heavy illness (requiring supplemental oxygen therapy) are discharged at the time of admission. SNG001 (n=36) treatment increased the probability of discharge (HR 1.72[95% CI 0.91-3.25]; p=0.096) compared to placebo (n=28). The median discharge time for patients receiving SNG001 treatment was 6 days and for patients receiving placebo was 9 days.

Fig. 4:

changes in dyspnea from baseline in hospital patient cohorts. During treatment, dyspnea (assessed by the patient according to the 5-point dyspnea score scale) was significantly reduced (difference-0.6 [95% CI-1.0 to-0.2 ]; p=0.007) in patients receiving SNG001 compared to patients receiving placebo (n=49).

Fig. 5:

at the beginning of inhalation IFN- β (SNG 001) or placebo treatment, SARS-CoV-2 infection patients with dyspnea of 3 (11%) had recovery from home cohorts. Rehabilitation is defined as "no restriction of activity" or "no clinical or virologic evidence of infection". (placebo n=6; sng001 treatment n=6).

Fig. 6:

changes in dyspnea status in the family cohort of SARS-CoV-2 infected patients, patients exhibiting significant/severe dyspnea at the beginning of treatment: (a) Placebo (n=6) is provided (b) treated with inhaled IFN- β (n=6).

Fig. 7:

rehabilitation in combination with hospital and home cohorts with or without significant/severe dyspnea was initiated with inhaled IFN- β (SNG 001 formulation) or placebo treatment. Rehabilitation is defined as "no restriction of activity" or "no clinical or virologic evidence of infection". (a) Patients with dyspnea scores less than 3 at the beginning of treatment recovered (placebo n=51; sng001 n=47). (b) Patients with dyspnea scores of at least 3 at the beginning of treatment recovered (placebo n=36; sng001 n=33; hr 3.41;95% CI 1.47-7.94; p=0.004).

Fig. 8:

recovery of a subset of hospitalized and home patient cohorts treated with SNG001 and placebo. Rehabilitation is defined as "no restriction of activity" or "no clinical or virologic evidence of infection". (a) Recovery from a subgroup with dyspnea score of at least 3 or 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 from a subgroup with dyspnea score of at least 3 or OSCI score of at least 4 (placebo n=43; sng001 n=48; hr 2.68;95% CI 1.25-5.75; p=0.011).

Fig. 9:

the results show the ability of IFN- β1a present in SNG100 formulations to inhibit SARS-CoV-2 designated Germany/BavPat 1/2020 and the putative variants of interest, the alpha variant (B.1.17) and the beta variant (B.1.351), at concentrations attainable by inhalation use.

Detailed Description

The use of inhaled IFN- β according to the present invention is currently primarily proposed for use in preventing or reducing the severity of lower respiratory tract disease in patients infected with the coronavirus SARS-CoV-2, and/or ameliorating one or more symptoms and/or consequences in patients so infected. However, SARS-CoV-2 is only one example of a coronavirus that has emerged in recent years as a causative agent of severe respiratory disease, commonly known as virus-induced Acute Respiratory Distress Syndrome (ARDS). Other previously known coronaviruses in this class include another severe acute respiratory syndrome coronavirus (SARS-CoV, also known as SARS-CoV-1) and middle east respiratory syndrome coronavirus (MERS virus). As mentioned above, the invention is equally applicable to any such coronavirus, whether known or likely to occur in the future. Well known information in the field of respiratory viruses regarding coronavirus-induced ARDS can be found, for example, in Luyt et al virus-induced acute respiratory distress syndrome: epidemic technology, management and outcam. Pressure Med.2011;40 (12 Pt 2) e561-8 and Horie et al, ringing pharmacological therapies for ARDS, COVID-19and beyond.Intensive Care Med.2020;46 (12) 2265-2283.

The cause of the severity of respiratory disease caused by such coronaviruses is thought to be probably related to their zoonotic origin (jumping from non-human animal hosts to human hosts, sometimes through intermediate hosts) (heney et al (2006) j.inter.med.260,399-408). In the absence of a vaccine, the human host lacks specific immunity to the new pathogen, which increases the chances of the virus infecting and replicating in susceptible cells and causing tissue damage. However, the ability of viruses to spread among the population balances the overall risk. Unfortunately, in the case of SARS CoV-2, the virus is well suited for human-to-human transmission and rapidly transmits from human to human (Chan et al Afamily cluster of pneumonia associated with the 2019novel coronavirus indicating person-to-person transmission: a study of a family cluster.Lancet.2020;395 (10223): 514-23). Thus, by 7 months 2020, the COVID-19 pandemic has resulted in about 1400 thousands of cases worldwide, about 60 thousandsHuman death (https:// covid19.Who. Int /) and for many affected patients there is still a risk of long-term health consequences due to injury to their lungs and other organs (George et al pullonary fibrosis and COVID-19:the potential role for antifibrotic therapy.Lancet Respir.Med. (2020) 8,807-815). Although a variety of targeted and non-targeted interventions have been reported, some of which have been discussed above, new therapies for covd-19 remain a highly prioritized requirement.

Although many people who infect SARS-CoV-2 are asymptomatic, transmission of the virus to the lungs of susceptible individuals can result in diffuse alveolar lesions, leaking fluid from capillaries to the alveolar space where it accumulates and restricts 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 3autopsies from Houston,Texas,and review of autopsy findings from other United States cities.Cardiovasc Pathol.2020;48:107233). At the time of infection with SARS-CoV-2, the median latency period is approximately 4-5 days before symptoms occur, and 97.5% of symptomatic patients develop symptoms within 11.5 days (see Guan et al 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. International. Med 2020;172 577-82; pung et al invest of three clusters of COVID-19 in Singapore:implications for surveillance and response measures.Lancet.2020;395 (10229) 1039-46 and Li et al N.Engl. J.Med.2020;382 (13):1199-207).

Covd-19 patients often present with fever, dry cough, shortness of breath, headache, and weakness. Progression to pneumonia usually occurs 1-2 weeks after onset of symptoms, involving reduced oxygen saturation, worsening blood gas, multifocal ground glass shadows, or patchy/segmental realisation in chest X-rays or CT. Severe cases of covd-19 progress to Acute Respiratory Distress Syndrome (ARDS), on average about 8-9 days after symptoms appear (Huang et al Lancet.2020;395 (10223): 497-506;Wang et al.JAMA.2020,323 (11): 1061-1069). SARS-CoV-2 infection in the lung is accompanied by a deep downstream cytokine cascade called "cytokine storm", which suggests that the immune response is overactive, its deregulation leads to lung injury, ARDS, sepsis, organ failure, and in the worst case may be fatal (Rageb et al. The COVID-19Cytokine Storm;What We Know So Far.Front Immunol.2020;11:1446). The invention is applicable to any coronavirus which exhibits similar clinical symptoms associated with the progression of ARDS, otherwise known as severe acute respiratory syndrome.

Coronaviruses are a large family of enveloped RNA viruses that primarily infect birds and mammals. SARS-CoV-2 is a beta coronavirus, has 79% genetic homology to SARS-CoV, and 98% homology to bated coronavirus RaTG13 (Zhou et al A pneumonia outbreak associated with a new coronavirus of probable bat origin, nature,2020;579 (7798): 270-3). It spreads through the respiratory tract droplets and infects nasal, bronchial and alveolar epithelial cells by binding of viral spike protein to its cellular receptor ACE2 (Walls et al structure, function, and Antigenicity of the SARS-CoV-2Spike Glycoprotein.Cell (2020) 180, 281-292).

RNA viruses such as SARS-CoV-2 accumulate mutations due to the error-prone nature of the viral replication process, resulting in some sequence diversity. However, different SARS-CoV-2 strains can be identified by sequencing and phylogenetic sequence trees. For example, an illustration of phylogenetic tree analysis of this isolate was reported by Merdith et al in online publication Rapid Implementation of SARS-CoV-2sequencing to investigate cases of health-care associated COVID-19:a prospective genomic surveillance study in The Lancet, 7.14, 2020. Amplified SARS virus genomic sequences can be compared to the NCBI reference sequence NC_045512.2 or the equivalent GenBank reference sequence MN908947.3 of SARS-CoV-2 (Wu et al Nature 579, 265-269). The SARS2-CoV-2 variant can thus be identified and can be expected to have a high degree of homology, e.g., at least 90%, at least 95%, at least 98%, at least 99%, with the reference genome. This sequencing monitoring also allows the identification of any novel SARS virus that infects humans. The use of inhaled IFN- β is considered to be the preferred method of preventing or lessening the severity of lower respiratory tract disease in humans infected with any SARS-CoV virus, particularly any strain of SARS-CoV-2 virus.

Properties of Interferon beta for administration

The term IFN- β as used herein will be understood to refer to any form of IFN- β or analog thereof that retains the biological activity of native IFN- β and preferably retains the activity of IFN- β that is present in the lung, particularly in the lung epithelium, when induced by a viral infection such as influenza or rhinovirus infection.

The IFN- β may be identical to the sequence of human IFN- β1a or human IFN- β1b or comprise the sequence of human IFN- β1a or human IFN- β1b. However, IFN- β may also be a variant of such a native sequence, e.g., a variant having at least 80%, at least 85%, at least 90%, at least 95-99% identity. It may have one or more chemical modifications provided that the desired biological activity is retained.

The IFN- β is preferably a recombinant IFN- β, e.g., produced in cells in vitro by expression of the polypeptide from a recombinant expression vector, and purified from such a culture.

Preferred are human recombinant IFN- β1a, e.g., obtainable from Rentschler Biopharma SE or Akron Biotechnology, LLC (Akron Biotech).

Formulations and modes of administration

IFN- β for administration by inhalation is typically formulated as an aqueous solution, preferably at or near neutral pH, e.g., about pH 6-7, preferably e.g., pH 6.5. Methods of formulating IFN- β for airway delivery in aqueous solutions are well known, see, e.g., U.S. Pat. No. 6,030.609 and European patent No. 2544705. Preferably, aqueous formulations are used that are free of mannitol, human Serum Albumin (HSA) and arginine, which are present in injectable IFN- β formulations. The composition may preferably contain an antioxidant, such as methionine, e.g. DL-methionine. Such ready-to-use formulations of IFN- β1a are also commercially available, e.g., prepared in syringes at appropriate dilutions of IFN- β, e.g., from Vetter Pharma. It may be in accordance with a formulation herein designated SNG001, as mentioned above, previously in clinical trials for patients exhibiting viral exacerbations of asthma or COPD (subject to possible variations in the precise IFN- β1a concentration). Further details of this formulation are available in European patent No. 2544705 and the examples below. The concentration of IFN- β1a can be adjusted as follows. The precise preferred concentration of IFN- β, or more specifically IFN- β1a, may vary with the precise mode of delivery.

In cell-based assays, SNG001 has been shown to inhibit a broad range of viruses. Of particular relevance, in cell-based assays, SNG001 has been shown to inhibit viral shedding following infection with the middle east respiratory syndrome-coronavirus (MERS-CoV), similar to the efficacy reported in the literature and against other viral types. See also the cell-based assays reported in the examples, which demonstrate the ability of SNG001 to have activity against various SARS-CoV-2 variants at concentrations suitable for inhaled delivery. This reflects the generally proposed mechanism that supports the therapeutic use now proposed.

IFN- β formulations that are neutral or about neutral in pH, such as pH 6.5, are particularly preferred, as opposed to lower pH formulations. Low pH is known to cause cough. In phase II trials of SNG001 in asthmatic patients, cough occurred in <10% of patients with no difference in incidence from placebo.

Delivery may be by any aerosolization device that retains the IFN- β activity of the liquid formulation, such as a nebulizer. Various nebulizers for drug delivery are commercially available and may be used, for example, I-neb or Ultra nebulizers manufactured by Philips Respironics and Aerogen, respectively. Both of these devices have been shown to be capable of convenient inhalation delivery of IFN- β1a and retain IFN- β activity after aerosolization.

Dosage of

For any inhaled delivery regimen, the appropriate IFN- β dose may be determined by a dose escalation study that evaluates the antiviral response induced in the lungs, which is typically a dose that ensures a strong antiviral response within 24 hours after dose administration, preferably supporting a once-daily regimen of administration. This can be assessed by reference to appropriate biomarkers.

For nebulizer delivery of an aqueous formulation containing IFN- β1a, it has been found that such an aqueous formulation containing about 11-13MIU/ml IFN- β1a, e.g., 11-12MIU/ml, is suitable.

By delivering 0.5ml or about 0.5ml of an aqueous formulation containing about 11-12MIU/ml, preferably 12MIU/ml IFN- β1a from an I-nebuliser (Phillips Respronics), a suitable once-a-day dosing regimen has been achieved and can be found to be suitable for other nebulisers providing similar airway delivery efficiencies. If an alternative nebulizer is used, the dose may need to be adjusted to account for differences in the efficiency of drug delivery to the lungs. Preferably once daily. Delivery may last for several days, e.g., 3 days or more, 5 days or more, or 7 days or more, e.g., up to 14-15 days or more, to alleviate LRT disease, and preferably gradually improve the score back to a lower score, e.g., to at least OSCI score 1.

Timing of application

As noted above, previous indications have shown that if complete consideration is given to alleviating LRT disease in patients associated with coronavirus infection that can cause Acute Respiratory Distress Syndrome (ARDS), such as severe acute respiratory syndrome observed in patients with COVID-19 after infection with SARS-CoV-2, administration of IFN- β is recommended to be limited to intervention early from the onset of symptoms, more specifically, before 7 days, and the dose should be reduced stepwise (if any sign) before this point in time (see again Hung et al (2020) Lancet 395:1695-16704, titled "Triple combination of interferon beta-1b, lopinavir-ritonavir and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-labl, randomised, phase 2 three"; first published online at 5 months 8 of 2020). In contrast, the data now provided not only demonstrate for the first time that administration of IFN- β by inhalation can be beneficial in alleviating LRT disease caused by SARS-CoV-2 infection, but that such intervention is beneficial even in patients exhibiting symptoms equivalent to LRT disease, and therefore a clinical score of at least 3 or even at least 4 must be assigned on the clinical improvement rating scale. Such patients typically suffer from LRT disease requiring hospitalization and often experience symptoms of SARS-CoV-2 infection that affect activity. Their symptoms of such infection typically last for at least 7 days. For those patients in the study reported herein, the median time from onset of symptoms to onset of treatment with inhaled IFN- β was over 9 days.

Thus, according to the invention, IFN- β, such as recombinant IFN- β1a, may be administered by inhalation to a patient suffering from a viral infection, more specifically, for example, a coronavirus (e.g., SARS-CoV-2) infection, which is capable of causing severe LRT disease, at a stage corresponding to a score of at least 3 or at least 4 in the WHO clinical improvement rating scale. Applications may include patients 7 days or more after the onset of symptoms of viral infection, e.g., 9 days or more after the onset of symptoms of viral infection. Typically, such administration will be performed before the patient reaches score 5 or before the patient reaches score 6. Preferably will be administered prior to any mechanical ventilation. It has been shown that such administration provides a greater likelihood of preventing the patient from progressing to a higher score than placebo, e.g. requiring intensive care and/or non-invasive ventilation or possibly mechanical ventilation, and more support for backing off to a lower score. Ideally, administration of inhaled IFN- β will not be accompanied by an increase in score.

Effectiveness may be assessed daily by assessing dyspnea or obtaining a BCSS score. Generally, administration will continue with an improvement in dyspnea or BCSS score. Desirably, the WHO clinical improvement rating scale will be reduced by one or more ratings, preferably within, for example, 14 days or less, less than 7 days, more preferably less than 6 days, for example, 5 days, still more preferably less than 4 days, for example, 3 days. Ideally, administration of inhaled IFN- β will be accompanied by no restriction of activity or no clinical or virological evidence of infection, e.g., within 14 days or less of administration of IFN- β. The overall expected result would be an earlier discharge than expected without any treatment except for oxygen supplementation through a mask or nasal cannula.

As noted above, it has been found that preferred targeting of inhaled IFN- β therapy can be based on dyspnea scores, more particularly a dyspnea score of 3 or 4 (equivalent to overt or severe dyspnea). This translates into home settings and SARS-Cov-2 infected individuals with OSCI scores where a rapid improvement from OSCI score 2 (equivalent to activity limitation) to OSCI score 1 or 0 is expected without hospitalization. See fig. 5 and illustration.

Thus, there is now proposed an inhaled IFN- β according to the present invention for use in the treatment of a patient suffering from a disease caused by a viral infection, more specifically, for example, a SARS-CoV-2 viral infection, wherein a dyspnea score of 3-4 is used as a determinant of administration of the inhaled IFN- β in a hospital or home setting.

Thus, this simple immediate care of targeting inhaled IFN- β therapy for SARS-CoV2 infected patients based on a single symptom score (dyspnea) is now considered an important contribution to clinical management of such patients, which was previously unpredictable from any knowledge of type I interferon effects.

Combination therapy

While the data now provided support the use of inhaled IFN- β as the sole therapeutic to prevent or reduce the severity of LRT disease in patients with coronavirus infection, as described above, it should be understood that such IFN- β administration does not preclude the use with one or more other therapeutic agents that may help ameliorate one or more symptoms caused by a viral infection in a patient. The use of inhaled IFN- β may be combined with administration of, for example, a corticosteroid (e.g., dexamethasone) or any other previously proposed drug (e.g., lopinavir and/or ribavirin or intravenous rituximab, an RNA polymerase inhibitor that has been shown to shorten the discharge time of COVID-19 patients but not reduce respiratory viral load) for preventing or lessening the severity of LRT disease in individuals susceptible to ARDS coronavirus infection. Such combination therapy may include simultaneous, sequential or separate administration of IFN- β and another suitable therapeutic. Of particular interest may be the combination of inhaled IFN- β and dexamethasone (The RECOVERY Collaborative Group, dexamethosone in Hospitalised Patients with Covid-19-Preliminary Report, N.England J.Med.17July 2020). Of particular interest may be the additional administration 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 previously been proposed for the alleviation of viral exacerbations of asthma or COPD (see EP 1734987B).

Therapeutic method

In another aspect, the invention provides a method of preventing or alleviating the severity of lower respiratory tract disease in a patient infected with coronavirus or other virus capable of causing Acute Respiratory Distress Syndrome (ARDS) potentially causing a pandemic and/or ameliorating one or more symptoms and/or consequences in a patient so infected, wherein the method comprises administering IFN- β by inhalation. IFN- β may be administered as a sole therapeutic, or in combination with one or more other therapeutic agents, to help ameliorate one or more symptoms caused by the same viral infection as described above. As mentioned above, such administration may preferably be performed prior to determining a score corresponding to a significant or severe dyspnea, and may be performed in a home or hospital setting in order to accelerate rehabilitation, preferably down to OSCI of at least 1.

The invention also provides the use of IFN- β in the manufacture of a composition for use in a method of preventing or reducing the severity of a lower respiratory disease disclosed herein, wherein the composition is administered by inhalation. As noted above, such administration will typically employ a device, such as a nebulizer, that atomizes the liquid formulation that retains IFN- β activity.

Examples

Comparison of efficacy and safety of inhaled interferon-beta and placebo administered to patients hospitalized with covd-19 due to SARS-CoV-2.

Scheme overview

This is a randomized, double-blind, parallel, placebo-controlled trial of inhaled recombinant IFN- β1a formulated as an aqueous formulation of neutral pH for delivery by nebulization to patients diagnosed with SARS-CoV-2 infection. 98 hospitalized patients diagnosed with SARS-CoV-2 infection (recruited from 9 specialty hospitals in the united kingdom during the period of 30 to 27 days of 3 to 5 months in 2020) were randomly assigned to receive either inhaled IFN- β therapy (n=48) or placebo therapy (n=50) for 14 days. Patients were randomized to receive the first treatment within 24 hours of positive detection (unless positive detection occurred prior to hospitalization). Inclusion criteria included patients admitted due to the severity of covd-19 disease, patients aged 18 years or older and suffering from SARS-CoV-2 infection (as determined by RT-PCR detection positive results or immediate care detection positive with strong clinical suspicion).

The patient groups were matched evenly in terms of mean age (placebo 56.5 years old, SNG001 57.8 years old), mean duration of complications and pre-group covd-19 symptoms (placebo 9.8 days, SNG001 9.6 days).

Patients received either inhaled IFN- β or placebo (formulation buffer without IFN- β) from a portable mesh nebulizer (I-neb, provided by Philips Respironics from Qischen, UK). The primary endpoint was prevention of severe lower respiratory disease, as determined by grade shift in the 9-point clinical improvement grade scale.

Formulations of recombinant IFN- β1a

This formulation (referred to as SNG 001) provides recombinant IFN- β1a (manufactured by Rentschler Biopharma SE or Akron Biotechnology, LLC) formulated as an aqueous solution at pH 6.5. The compositions are listed in the following table. Unlike some other commercial formulations, it does not contain mannitol, human serum albumin or arginine. The formulation was provided by Vetter Pharma in a ready-to-use syringe.

SNG001 formulation:

composition of the components	Quantity (per milliliter)	Function of
IFN-β1a	About 12MIU/ml	Active ingredient
			Sodium dihydrogen phosphate dihydrate	5.92mg	Buffer component
Disodium hydrogen phosphate dihydrate	2.13mg	Buffer component
			Sodium citrate	20.58mg	Chelating agent, buffer component
Methionine	0.30mg	Stabilizers, antioxidants
			Water and its preparation method	1ml	Solvent(s)

As noted above, SNG001 has been shown to inhibit a broad range of viruses in cell-based assays. Of particular relevance, SNG001 has been shown to inhibit viral shedding following infection with the middle east respiratory syndrome-coronavirus (MERS-CoV) in cell-based assays, similar to the efficacy reported in the literature and for other viral types (Scagnolari et al, increased sensitivity of SARS-coronavirus to acombination of human type I and type II Interferons. Anti. 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.2004Jul;30 (3): 211-3).

In all previous clinical trials of inhaled SNG001 (3 for asthma, 1 for chronic obstructive pulmonary disease [ COPD ]), it was shown to up-regulate pulmonary antiviral biomarkers in sputum within 24 hours after administration, confirming successful delivery of bioactive drugs to the lungs, demonstrating the mechanism of-of-mechanism and supporting dose selection.

The dose escalation trial using the selected nebulizer determines the target pulmonary dose that induces an antiviral response in the lungs that occurs 24 hours after dose administration.

Administration protocol

SNG001 nebulizer solution was present in a glass syringe containing 0.65ml IFN-. Beta.1a in water at an IFN-. Beta.1a concentration of 12MIU/ml. An I-nebuliser fitted with a 0.53ml chamber was filled with the contents of 1 syringe. The patient inhaled one dose or placebo solution per day. The nebulizer is used in tidal breathing mode. In this mode, I-neb delivers a short pulse aerosol at each inhalation and requires the patient to take tidal breathing.

Respiration and other assessment

In addition to once daily evaluation with reference to the clinical improvement rating scale, patients in the trial received BCSS evaluation and pneumonia evaluation.

BCSS evaluation

BCSS is a patient reported outcome measure designed as a daily diary, requiring the patient to record the severity of three symptoms: dyspnea, cough and sputum.

Each symptom is represented by a single item and is evaluated by a 5-score scale in the range of 0-4, with higher scores indicating more severe symptoms. Total score is expressed as the sum of three scores ranging from 0 to 12. An average 1-score decrease in the total BCSS indicates a significant decrease in symptom severity.

The evaluation was performed once per day at the same time (+/-3 hours). Where possible, by the patient. However, if desired, the field staff may read the problem to the patient face-to-face or via a telephone/video link.

The questions and possible answers to BCSS are as follows:

1. how difficult you breathe today?

0 = none-not aware of any difficulties

1 = mild-evident when strenuous activities (e.g. running) are performed

2 = moderate-even when light activities (such as bedding or carrying debris) are performed

3 = evident-evident when washing or dressing

4 = severe-almost always sustained, even at rest

2. How does you cough today?

0 = no cough-no awareness of cough

1 = few coughs-sometimes coughs

2 = occasional cough-less than every hour

3 = frequent coughing-one or more times an hour

4 = almost always continuous-uninterrupted cough or cough is required

3. What are you today because of how much trouble there is phlegm?

0 = none-not aware of any trouble

1 = mild-rarely causes trouble

2 = moderate-obvious trouble

3 = significant-causes great trouble

4 = severe-almost persistent trouble

Research results support that IFN- β administration is beneficial to COVID-19 patients

The incidence of severe disease during treatment was reduced by 72% in patients receiving SNG001 compared to placebo. More specifically, patients receiving SNG001 had a significantly reduced probability of developing severe disease (e.g., requiring ventilation OR causing death) during treatment by 72% (OR 0.28[95% CI0.07-1.08]; p=0.064) compared to patients receiving placebo.

The experimental results show that SNG001 greatly reduced the number of hospitalized covd-19 patients WHO progressed from requiring oxygen (WHO clinical improvement rating scale score 4) to requiring ventilation (score 5 or more).

Patients receiving SNG001 were more than twice as likely to recover from covd-19 (defined as "no restriction of activity" or "no clinical or virological evidence of infection") than those receiving placebo (HR 2.19[95% CI 1.03-4.69]; p=0.043). See fig. 1.

For patients with more severe disease at admission (i.e. requiring supplemental oxygen therapy), patients treated with SNG001 (n=28) were more than twice as likely to recover at the end of the treatment period than the placebo group (n=36) and had a greater chance of recovering on day 28. See fig. 2. Rehabilitation is again defined as "no restriction of activity" or "no clinical or virological evidence of infection".

For patients with more severe disease at the time of admission (i.e., in need of supplemental oxygen therapy), SNG001 treatment increases the likelihood of discharge. The median discharge time for patients receiving SNG001 treatment was 6 days and for patients receiving placebo treatment was 9 days. See fig. 3.

During the treatment period, patients receiving SNG001 had significantly reduced dyspnea (one of the major symptoms of severe covd-19) (p=0.007) compared to patients receiving placebo. See fig. 4.

Three subjects died after being randomized to placebo. There was no mortality in subjects treated with SNG 001.

As described above, by day 28, patients with more severe disease at admission (i.e., in need of supplemental oxygen therapy) and receiving SNG001 treatment had significantly better recovery odds (OR 3.86[95% CI 1.27-11.75]; p=0.017).

Interestingly, efficacy analysis showed no evidence of a correlation between the therapeutic effect of inhaled SNG001 and the prior duration of the covd-19 symptoms. This is in contrast to previous proposals which suggest that IFN- β use should be limited to early interventions after symptoms occur, i.e. less than 7 days.

Administration of inhaled IFN- β to SARS-CoV-2 infected individuals in a Home Environment

The above experiments performed in hospitalized patients were extended to a cohort of 120 SARS-CoV-2 infected patients in a home setting. All patients were considered to progress to high risk patients (> 65 years, or >50 years, with risk factors) who required hospitalization. At the beginning of treatment, all participants in the WHO scale were either on score 1 (no activity restriction) or on score 2 (activity restriction, but no hospitalization was required). SNG001 or placebo was inhaled again once daily through the mesh nebulizer. The participants were provided with remote equipment training and the trial was conducted by video call.

Participants were assessed for deterioration and, when initially scored as 2, were assessed for recovery to scores of 1 or 0 without rebound. Only two patients had deteriorated to a score of 3 or above and both received placebo. This is consistent with the expectation of individuals at risk of SARS-CoV-2 infection.

In addition to daily assessment of overall disease scores on the WHO rating scale, participants in the trial scored dyspnea daily according to the dyspnea score scale described above and reiterated below:

dyspnea score for how difficult you breathe today?

0 = none-not aware of any difficulties

1 = mild-evident when strenuous activities (e.g. running) are performed

2 = moderate-even when light activities (such as bedding or carrying debris) are performed

3 = evident-evident when washing or dressing

4 = severe-almost always sustained, even at rest.

Of particular interest is the unpredictable finding that for 11% of patients with dyspnea scores of at least 3 at the beginning of treatment, the effect of SNG001 on promoting recovery compared to placebo is evident, as shown in figure 5. Figures 6a and 6b also illustrate the ability of SNG001 to significantly promote an improvement in dyspnea status in patients with significant or severe dyspnea at the beginning of treatment compared to placebo.

Thus, inhaled IFN- β is considered a useful immediate care treatment for SARS-CoV-2 patients who present significant to severe dyspnea at home in an effort to accelerate recovery and reduce the risk of progressing to hospitalization.

Furthermore, by combining data from hospital and home study cohorts, it is now shown that the same dyspnea score (score 3-4 corresponds to significant or severe dyspnea) is a simple and rapid criterion that can be effectively used for inhalation IFN- β therapy for a patient with COVID-19 in a hospital setting or home in an effort to accelerate recovery. Although no significant difference was observed in recovery rate between SNG001 and placebo treatment in patients with dyspnea scores of 0, 1, or 2, patients with a dyspnea score of 3 or 4 receiving SNG001 were found to exhibit significantly accelerated recovery compared to such patients receiving placebo. See fig. 7a and 7b.

Patients with dyspnea scores of 3 or 4 and administered SNG001 were found to be more than 3 times more likely to recover than patients receiving placebo [ HR 3.41 (95% CI;1.47,7.94) p=0.004 ].

Figures 8a and 8b further support the utility of simple dyspnea scores in classifying covd-19 patients receiving inhaled IFN- β therapy to promote recovery, figures 8a and 8b show the percentage recovery in the subset of hospitalized and home patients receiving treatment (SNG 001 or placebo) based on the WHO scale of overall disease severity score or at least a 3 dyspnea score: group 1: a dyspnea score of at least 3, or a grade score of at least 3; group 2: dyspnea score of at least 3, or a rating score of at least 4. Those patients exhibiting significant dyspnea or OSCI scores of 3 or 4 exhibited highly significant effects of SNG 001.

Thus, targeting inhaled IFN- β therapy for SARS-CoV2 infected patients based on a simple dyspnea score is now considered an important contribution to the clinical management of such patients, which was not previously predicted by any knowledge of the effects of such interferons. Targeting inhaled IFN- β therapy in hospitalized COVID-19 patients on the basis of significant/severe dyspnea is considered a means of promoting rehabilitation, which can be transferred to COVID-19 patients who have dyspnea problems in the home but have not yet shown the severity of the overall disease symptoms requiring a hospital bed.

In vitro studies demonstrated the ability of IFN- β1a in inhaled formulations to inhibit SARS-CoV-2 variant

To supplement the experiments discussed above, in vitro experiments were performed to confirm that SNG001 has activity against the alpha and beta variants of SARS-CoV-2 (now named such variants by the WHO Greek letter labeling scheme) at concentrations attainable by inhalation delivery, designated SARS-CoV-2 by Germany/BavPat 1/2020. The alpha and beta variants were previously referred to as b.1.1.7 and B1.351, respectively, or commonly referred to as the uk kente variant and south africa variant, respectively. See WHO website and notifications published on day 31, 5, 2021 regarding the name of SARS-CoV-2 variants.

Vero E6 cells were treated with SNG001 preparations at different concentrations before and after infection with SARS-CoV-2 as described above. The presence of SARS-CoV-2 viral protein is determined by immunostaining 16-24 hours after infection. SNG001 effectively reduced the virus in cells infected with SARS-CoV-2 designated Germany/BavPat 1/2020 or any of the variants described above to undetectable levels. As shown in FIG. 9, IFN- β was found to have 90% inhibition upon inhalation (IC ₉₀ ) The readily attainable concentrations of (3.2), (3.4) and (4.0) IU/ml.

This data further supports the use of inhaled IFN- β in preventing or lessening the severity of lower respiratory tract disease associated with SARS-CoV-2 virus, extending to known variants and future possible variants by the general mechanism of inhaled broad spectrum antiviral products.

Claims (18)

1. An interferon-beta (IFN- β) for use in preventing or alleviating the severity of lower respiratory tract disease in a patient infected with coronavirus or other virus capable of causing Acute Respiratory Distress Syndrome (ARDS) potentially causing a pandemic virus, and/or ameliorating one or more symptoms and/or consequences in a patient so infected, wherein the interferon-beta is administered by inhalation.

2. The IFN- β of claim 1, wherein the patient is infected with coronavirus.

3. The IFN- β of claim 2, wherein the coronavirus is a SARS virus capable of causing severe acute respiratory syndrome.

4. The IFN- β of claim 3, wherein the coronavirus is SARS-CoV-2.

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

6. The IFN- β of any one of claims 1 to 5, wherein the IFN- β is formulated in an aqueous solution at about pH 6 to 7, e.g., pH 6.5, and preferably omits mannitol, human serum albumin, and arginine.

7. The IFN- β of any one of claims 1 to 6, wherein administering to the airway comprises atomizing a liquid formulation of the IFN- β.

8. The IFN- β of claim 7, wherein the administration is by use of a nebulizer.

9. The IFN- β of any one of claims 1 to 8, wherein the administration of IFN- β is as a single daily inhaled dose.

10. The IFN- β of any one of claims 1 to 9, wherein the patient is assessed as having a score on the WHO clinical improvement rating scale of at least 3 or at least 4 at the time of first administration of IFN- β.

11. The IFN- β of claim 10, wherein the patient does not increase the score on the same scale after administration of IFN- β.

12. The IFN- β of claim 11, wherein the patient has a decrease in score of 1 or more on the same scale over a period of time of IFN- β administration, preferably a decrease in score of 1 or more over 14 days or less, such as less than 7 days, more preferably less than 6 days, such as 5 days, still more preferably less than 4 days, such as 3 days.

13. The IFN- β of any one of claims 1 to 12, wherein dyspnea and/or improvement in dyspnea, cough and sputum score (BCSS) is observed after administration of the IFN- β is initiated.

14. The IFN- β of any one of claims 1 to 13, wherein upon first treatment with IFN- β, the patient is assessed as having a dyspnea score of 3 to 4 determined based on the patient's response to querying the level of dyspnea on the following scale:

0 = none-not aware of any difficulties

1 = mild-evident when strenuous activities (e.g. running) are performed

2 = moderate-even when light activities (such as bedding or carrying debris) are performed-3 = significant-significant when washing or dressing

4 = severe-almost always sustained, even at rest.

15. The IFN- β of claim 14, wherein dyspnea score 3-4 is used as a determinant of administration of inhaled IFN- β.

16. The IFN- β of claim 15, wherein the patient is in a home environment equivalent to an OSCI score of no more than 2 and a dyspnea score of at least 3 is used as a determinant of administration of inhaled IFN- β.

17. The IFN- β of any one of claims 1 to 13, wherein the IFN- β is administered by inhalation in combination with one or more other therapeutic agents to help ameliorate one or more symptoms caused by the same viral infection, wherein each other therapeutic agent is administered simultaneously, separately or sequentially.

18. The IFN- β of claim 17, wherein the IFN- β is administered in combination with a corticosteroid.