Use of inhaled interferon-beta to treat virus-induced exacerbations in COPD patients receiving systemic corticosteroid therapy.

Abstract

The present invention provides interferon-beta (IFN-β) for use in the treatment of viral-induced COPD exacerbations in patients treated with systemic corticosteroids, wherein the IFN-β is administered by inhalation, for example by use of a nebulizer.

Description

Technical Field

[0001] The present invention relates to the use of inhaled interferon-beta (IFN-β) formulated, for example, for nebulizer administration via the airway, for treating COPD patients whose condition is worsened by viral infection and who are also receiving treatment with systemic corticosteroids.

Background Art

[0002] Chronic obstructive pulmonary disease (COPD) is a lung condition characterized by airflow limitation that is not fully reversible. This airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to pathogenic stimuli. Most cases of COPD are associated with long-term smoking. Symptoms of COPD include cough, excessive sputum production, and shortness of breath.

[0003] Exacerbation of COPD is defined as the worsening of COPD symptoms beyond normal day-to-day variation and is associated with irreversible loss of lung function and thus acceleration of disease progression. Exacerbations have a profound impact on the quality of life of patients (patients typically require several weeks to recover) and represent a major medical burden. Exacerbations are currently treated with systemic corticosteroids and / or antibiotics. Systemic treatment includes oral medications (administered orally) or drugs delivered directly intravenously (intravenously or IV) or intramuscularly (intramuscularly). Systemic corticosteroids circulate to various body sites via the bloodstream.

[0004] Respiratory viral infections, such as colds and influenza, are a major driver of exacerbations in patients with lung disease when the infection spreads from the upper airway to the lungs and worsens existing lung inflammation. Furthermore, there is increasing evidence that viral infections, particularly in COPD, increase susceptibility to subsequent bacterial infections. Therefore, there is strong theoretical justification for developing antiviral therapies to prevent or treat exacerbations of COPD.

[0005] In preclinical studies, researchers have found that lung cells from COPD patients and / or long-term smokers are more susceptible to respiratory viral infections, explaining why infections are more likely to spread to the lungs (Schneider et al. (2010) Am. J. Respir. Crit. Care Med. 182(3), 332-340). Interferon-beta (IFN-β) is produced by cells, particularly relevant lung epithelial cells, in response to viral infections and modulates the body's antiviral response. Further experiments have shown that IFN-β pretreatment protects lung cells from COPD patients from infections by a range of respiratory viruses associated with COPD exacerbations.

[0006] Deficiencies in the IFN-β-mediated antiviral response are also associated with worse outcomes in viral challenge studies conducted in patients with COPD and COPD with more frequent exacerbations (Hilzendeger et al. (2016) Int. J. Chron. Obstruct. Pulmon. Dis. 11, 1485-1494; Mallia et al. (2011) Am. J. Respir. Crit. Care Med. 183(6), 734-742).

[0007] IFN-β-driven antiviral responses have been shown to be impaired or absent in the elderly and 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. 201(6): 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 virally induced exacerbations of asthma and chronic obstructive pulmonary disease (COPD) caused by viruses that cause the common cold, such as rhinovirus (see European Patent No. 1734987, in the name of the University of Southampton and exclusively licensed to Synairgen plc) and for reducing the severity of LRT disease in the elderly caused by infection with viruses that cause the common cold, such as rhinovirus (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.

[0008] Clinical trials using inhaled IFN-β formulations for nebulization delivered via respiratory nebulizers have been conducted to further such administrations, particularly in asthma 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 (Djukanovic et al (2014) Am. J. Respir. Crit. Care Med. 190(2):145-54), confirmed successful delivery of the bioactive drug to the lungs, demonstrated proof-of-mechanism, and supported dose selection.

[0009] Inhaled corticosteroids help reduce airway inflammation and are widely used as part of combination therapy for COPD patients, particularly those with a history of exacerbations. Indeed, Singanayagam et al. (Nature Communications (2018) 9:2229) reported that inhaled corticosteroids suppressed inflammation and immune responses in rhinovirus-infected mice. However, this was also associated with impaired pulmonary viral control, increased mucus production, and a lack of antimicrobial peptide response. Inhaled corticosteroids also suppressed IFN-β induction, and recombinant IFN-β administration could improve the reduced immune response. The study also reported that during exacerbations, IFN-β mRNA levels decreased in sputum from COPD patients taking inhaled corticosteroids, while paradoxically, the expression of several antiviral genes increased, and there were no significant differences in the levels of these biomarkers between patients treated with or without inhaled corticosteroids. However, two weeks after the onset of exacerbation, IFN-β levels returned to baseline, but antiviral gene expression remained elevated only in the group not treated with inhaled corticosteroids. Although the actual effect of recombinant IFN-β on COPD patients with viral infection was not investigated, Singanayagam et al. hypothesized that inhaled IFN-β may have a protective effect by replacing endogenous IFN-β whose production was suppressed by the action of inhaled corticosteroid therapy, and that this effect should be further investigated. The study by Singanayagam et al. is consistent with other studies demonstrating the ability of corticosteroids to suppress IFN-β production (McCoy CE et al, J. Biol. Chem. 2008;283(21); 14277-14285), but it is also known that corticosteroids may affect downstream signaling from type I interferon receptors (Diez D. et al BMC Med Genomics 2012; 5;27 and Flammer JR et al Mol Cell Biol 2010; 30(19): 4564-4572).It is unknown whether these two effects are equally sensitive to inhibition by corticosteroids, and importantly, it is unknown how much IFN-β may be required to overcome the corticosteroid inhibitory effect on the IFN signaling pathway.

[0010] While inhaled corticosteroids are used as a control agent for some COPD patients, current guidelines recommend increasing the dose of corticosteroids, usually by administering oral corticosteroids, if COPD patients are experiencing acute exacerbations, regardless of whether they are hospitalized or in the community, unless there are serious contraindications (https: / / www.nice.org.uk / guidance / ng115 / chapter / recommendations#systemic-corticosteroids). The study by Singanayagam et al. did not examine the effects of systemic corticosteroids, so it remained unclear whether inhaled IFN-β could have any benefit in the prevention or treatment of COPD in patients whose disease is acutely exacerbated by viral infection and who are also being treated with systemic corticosteroids. While preclinical studies by Singanayagam et al. may suggest that such an approach is reasonable, Ranieri et al. (JAMA, 2020:323(8):725-733 published 17 February 2020) reported the results of the INTEREST clinical trial, which examined the effects of intravenous IFN-β on mortality and days without mechanical ventilation in patients with moderate to severe acute respiratory distress syndrome (ARDS). The results showed that in adults with moderate to severe ARDS, intravenous administration of IFN-β did not provide a significant benefit compared to placebo in terms of mortality and days without mechanical ventilation over a 28-day period. The results did not support the use of IFN-β in the management of ARDS, but a post-hoc analysis of the study identified a therapeutic benefit in patients treated with IFN-β but not with systemic corticosteroids compared to patients treated with both IFN-β and systemic corticosteroids (Jalkanen J et al. Intensive Care Med. 19:1-4, 2020; published May 2020).In the paper, this difference was explained by ex vivo studies using human lung tissue or human primary pulmonary endothelial cells in which corticosteroid treatment inhibited IFN signaling and the expression of STAT1, IRF9, and differentiation antigen group 73 (CD73) by IFN-β. The latter biomarkers are important molecules that prevent vascular leakage and harmful leukocyte infiltration into the lungs in ARDS patients. Both studies warned that the use of IFN-β in patients receiving systemic corticosteroids should be carefully considered due to the corticosteroid's ability to inhibit IFN-β signaling. Ranieri et al. stated that this warning is relevant not only to patients with ARDS but also to all studies in which IFN-β is administered in combination with systemic corticosteroids, but Jalkanen et al. strongly recommended against using systemic glucocorticoids with type I interferon due to the adverse effects of this combination.

[0011] Therefore, there are conflicting views in the prior art regarding whether IFN-β therapy is a viable treatment option for COPD patients receiving systemic corticosteroid therapy. In fact, the current state of the technology strongly cautions against IFN-β therapy in this context.

[0012] Here, for the first time, data supporting the use of inhaled IFN-β for treating COPD patients whose condition has worsened due to viral infection and who are also receiving systemic corticosteroid treatment is presented. [Overview of the Initiative]

[0013] Accordingly, the present invention provides an interferon-beta (IFN-β) for use in the treatment of virus-induced COPD exacerbations in patients treated with systemic corticosteroids, wherein the interferon-beta is administered by inhalation.

[0014] In the context of this invention, "to treat" or "to cure" is understood to relate to the improvement of lung function or symptoms, or the prevention of secondary bacterial infections in COPD patients being treated with systemic corticosteroids for virally induced exacerbations of the disease. This may be evaluated by improvement of lung function parameters, such as peak expiratory flow rate (PEFR), shortness of breath, cough, sputum production or suppuration (related to bacterial infection), or the prevention of exacerbation of symptoms caused by secondary bacterial infections.

[0015] The present invention will be described below primarily with reference to common respiratory viruses and exacerbations of COPD-related symptoms in humans. By reasonable extrapolation, the present invention is considered applicable to any known virus that infects the respiratory tract and causes cold-like symptoms. Thus, in some embodiments, the virus causing exacerbations of COPD symptoms may be rhinovirus, influenza, RSV, adenovirus, parainfluenza, human metapneumovirus, or coronavirus. Coronavirus in the context of this disclosure is understood to mean a type of coronavirus that typically causes cold-like symptoms, but not highly pathogenic coronaviruses such as SARS-CoV, MERS-CoV, or SARS-CoV-2, the virus that causes COVID-19.

[0016] Therefore, in its broadest embodiment, the present invention may be considered to provide an IFN-β for use in reducing the severity of virus-induced exacerbations in COPD patients treated with systemic corticosteroids, wherein the IFN-β is administered by inhalation.

[0017] Systemic corticosteroids, typically delivered orally or by injection, are widely used to treat acute exacerbations of COPD to alleviate symptoms associated with inflammation of lung tissue. Corticosteroids may be selected from prednisolone, hydrocortisone, dexamethasone, methylprednisolone, or prednisone, or combinations thereof.

[0018] In the context of the present invention, systemic corticosteroids are understood to refer to corticosteroids administered to a patient that act throughout the patient's entire body and not locally on any particular point or area of ​​the body.

[0019] The goal of treatment with inhalable IFN-β is to alleviate the symptoms of virus-induced exacerbations in COPD patients receiving systemic treatment with corticosteroids. The mechanism of action may be that the recombinant IFN-β delivered to the patient overcomes the inhibitory effect of corticosteroids on the induction of IFN-β gene expression and / or the suppression of the IFN-β-driven antiviral response, or that the delivered IFN-β overcomes the lack of naturally expressed IFN-β in the patient, for example, due to the patient's age or inability to produce IFN-β.

[0020] The effectiveness of inhaled IFN-β may be monitored in relation to improvement in lung function or pulmonary symptoms, for example, by evaluating peak expiratory flow rate (PEFR), a measure of lung function.

[0021] PEFR is a person's maximum expiratory velocity, measured by a peak flow meter. This is a handheld device used to monitor a person's ability to exhale air. It measures the airflow through the bronchi and thus the degree of airway obstruction. Patients can measure their PEFR before and after taking any COPD medication and / or before and after taking the inhalable IFN-β used in this invention. An example of a suitable PEFR monitor is the eMini-Wright Digital Peak Flow Meter (Model 3210001) from Clement Clarke International.

[0022] COPD patients with virus-induced exacerbation treated with systemic corticosteroids and / or antibiotics and treated with inhalable IFN-β according to the invention are typically over 50 years of age and / or have improved breathlessness after treatment, as determined by the BCSS test (Breathless, Cough and Sputum Scale). Typically, the patients are in the age range of 40 to 90 years. Preferably, the age range may be 60 to 85 years. The lower end of the age range may be 40, 50, 60, 70 or 80 years. The upper end of the age range may be 90, 80, 70, 60 or 50 years. Any combination of these lower and upper ranges is contemplated by the invention. Patients treated according to the invention typically have a forced expiratory volume in one second (FEV) of 55 to 65%.

[0023] The BCSS test is a patient-reported outcome scale in which patients are asked to record the severity of three symptoms: breathlessness, cough and sputum.

[0024] Each symptom is represented by a single item scored on a 5-point scale ranging from 0 to 4, with higher scores indicating more severe symptoms. The total score ranges from 0 to 12 and is represented as the sum of the 3-item scores. An average decrease of 1 point on the total BCSS scale means a significant reduction in the severity of symptoms.

[0025] This assessment is typically performed once a day at the same time each day (+ / - 3 hours).

[0026] The BCSS questions and possible answers are as follows.

[0027] 1. How severe was your breathing difficulty today? 0 = None - Not aware of any difficulty 1 = Mild - Noticeable when doing strenuous activity (e.g., running) 2 = Moderate - Noticeable even when doing light activity (e.g., making the bed or carrying groceries) 3 = Marked - Noticeable when washing or dressing 4 = Severe - Almost always present, even at rest

[0028] 2. How was your cough today? 0 = No cough - Not aware of cough 1 = Rare - Cough occurs sometimes 2 = Occasionally - Less than once an hour 3 = Frequent - Once or more an hour 4 = Almost always - Cough is incessant or cannot be avoided

[0029] 3. How much trouble did you have with phlegm today? 0 = None - Not aware of any trouble 1 = Mild - Little trouble 2 = Moderate - Trouble is noticeable 3 = Marked - Big trouble occurred 4 = Severe - Almost always had trouble

[0030] The present invention is provided by way of example and will be further described below by reference to clinical trial data shown in the drawings described below.

Brief Description of the Drawings

[0031] [Figure 1] Up - regulation of the gene expression of the IFN - β - dependent antiviral biomarker MX1 in lung (sputum) cells 24 hours after administration of inhalable IFN - β demonstrates that inhalable IFN - β can turn on antiviral defense in the lungs of COPD patients not receiving systemic corticosteroids.

[0032] [Figure 2]Gene expression of the IFN-β-dependent antiviral biomarker MX1 ​​was similarly upregulated in lung (sputum) cells in response to inhalable IFN-β in COPD patients treated with systemic corticosteroids and / or antibiotics for exacerbations (Group B) or untreated (Group A). ​​This suggests that inhalable IFN-β can enhance IFN signaling and antiviral responses even in the presence of systemic corticosteroids, and therefore has potential to treat COPD patients receiving systemic corticosteroids for virally induced exacerbations of the disease.

[0033] [Figure 3] Inhaled IFN-β significantly improved pulmonary function (PEFR) in COPD patients treated with systemic corticosteroids for virus-induced exacerbations. The difference in change from baseline PEFR over the treatment period (days 2–15) between patients treated with inhaled IFN-β and those treated with placebo was 25.5 L / min (95% CI 1.1, 49.9, p=0.04). These data demonstrate that IFN-β therapy is a viable treatment option for COPD patients receiving systemic corticosteroid therapy. [Modes for carrying out the invention]

[0034] 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.

[0035] 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.

[0036] The IFN-β is preferably 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.

[0037] For example, human recombinant IFN-β1a available from Rentschler Biopharma SE or Akron Biotechnology, LLC (Akron Biotech) is preferred.

[0038] 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.

[0039] 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.

[0040] 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 that retains IFN-β activity after aerosolization.

[0041] 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 lung, e.g., MX1 sputum cell gene expression, 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.

[0042] For nebulizer delivery of aqueous formulations containing IFN-β1a, the aqueous formulations considered above contain, but are not limited to, approximately 3 to 16 MIU / ml of IFN-β1a. Preferably, the concentration is 11 to 13 MIU / ml of IFN-β1a. More preferably, 11 to 12 MIU / ml may be found to be preferable.

[0043] A preferred once-daily administration schedule is achieved by delivering 0.5 ml or preferably about 0.25 to 1.3 ml of an aqueous formulation containing approximately 3 to 16 MIU / ml, preferably about 11 to 12 MIU / ml, more preferably 12 MIU / ml IFN-β1a, from an I-neb nebulizer (Phillips Respironics), and other nebulizers that provide similar efficiency of airway delivery may be suitable. When using alternative nebulizers, it may be necessary to adjust the concentration and dose or volume of IFN-β1a in the formulation to account for differences in the efficiency of drug delivery to the lungs. For example, the Ultra nebulizer (Aerogen) delivers a lower percentage of the release to the lungs. To illustrate this, a dose of 0.65 ml to 1.3 ml of 12 MIU / ml IFN-β1a aqueous solution is preferred. 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 days, in order to alleviate LRT disease and preferably to reduce score improvement back to a lower score.

[0044] Timing of administration IFN-β administration is recommended in COPD patients who are receiving systemic corticosteroid treatment for exacerbation of COPD symptoms and who have preferably been infected with the virus within two days of symptom exacerbation.

[0045] Therefore, according to the present invention, IFN-β, for example recombinant IFN-β1a, may be administered by inhalation to a patient with a viral infection, preferably within two days of symptom exacerbation. Use may also extend to patients more than two days after the onset of symptom exacerbation, for example, three, four, five, six, seven, eight, or nine days or more after the onset of symptoms of the viral infection.

[0046] The effectiveness of the treatment may be evaluated daily by assessing peak expiratory flow rate.

[0047] Combination therapy The data presented herein support the use of inhaled IFN-β as an add-on therapy to reduce the severity of virus-induced exacerbations in COPD patients receiving systemic corticosteroid therapy, although it should be understood that such administration of IFN-β is not excluded by one or more other therapeutic agents that may aid in the improvement of one or more symptoms in patients caused by viral infection. The use of inhaled IFN-β may be combined, for example, with the administration of antibiotics or antiviral therapies proposed to prevent or reduce the severity of LRT disease in COPD patients whose symptoms are exacerbated by viral infection. Such combination therapies may include, as necessary, simultaneous, sequential, or separate administrations of IFN-β and another therapeutic agent.

[0048] Treatment method In another embodiment, the present invention provides a method for reducing the severity of lower respiratory tract disease and / or improving one or more symptoms and / or outcomes in patients with COPD who are treated with systemic corticosteroids but are also infected with a virus capable of causing respiratory infections, the method comprising the step of administering IFN-β by inhalation. IFN-β may be administered alone or in combination with one or more further therapeutic agents as an add-on therapy to aid in the improvement of one or more symptoms resulting from the same viral infection, as discussed above. [Examples]

[0049] Outline of a protocol to investigate the efficacy of IFN-β in treating virus-induced exacerbations in COPD patients treated with systemic corticosteroids. The applicant has developed an inhaled formulation of IFN-β1a (SNG001) for use in treating viral exacerbations of COPD in patients receiving systemic corticosteroid therapy. The objectives of this study were to confirm the upregulation of IFN-β-driven antiviral biomarkers, to evaluate the clinical efficacy in COPD patients, regardless of the presence or absence of respiratory virus-induced exacerbations after administration of inhaled SNG001, and to investigate how the use of systemic corticosteroids affects the antiviral activity of inhaled IFN-β in the lungs.

[0050] SNG001 is a solution of IFN-β1a at a concentration of 12 MIU / mL. The active pharmaceutical ingredient, recombinant IFN-β1a, and final product are manufactured by either Rentschler Biotechnologie GmbH, Erwin-Rentschler-Strase 21, 88471 Laupheim, Germany, or Vetter Development Services USA Inc, 8025 Lamon Ave, Skokie, Illinois 60077, USA.

[0051] The test reagent is presented as a ready-to-use aqueous solution with a pH of 6.5.

[0052] Test design The study was divided into two parts. During Part 1, local tolerance and pulmonary antiviral biomarker responses to inhaled IFN-β (SNG001) were evaluated in COPD patients without symptoms of respiratory viral infection. In Part 2, the clinical efficacy and pulmonary antiviral biomarker responses to inhaled IFN-β were evaluated in COPD patients with confirmed respiratory viral infection.

[0053] Part 1: Ten patients with COPD (stable, asymptomatic respiratory viral infections) received either SNG001 (6MIU IFN-β1a) or placebo once daily for three days via a CE-marked respiratory nebulizer (I-neb Philips Respironics). Patients were randomized in a 4:1 ratio; therefore, eight patients were randomized to SNG001 and two to placebo. Evaluations, including pulmonary function tests, vital signs, blood and sputum sampling, adverse events (AEs), and concomitant medications, were performed during the study. Sputum samples were collected 24 hours after the first and third doses for biomarker evaluation. Sputum cell gene expression of IFN-β-dependent antiviral biomarkers, including MX1, was determined by reverse transcription quantitative PCR.

[0054] Part 2: Treatment of COPD patients with confirmed respiratory viral infections.

[0055] COPD patients who developed upper respiratory tract viral symptoms (cold symptoms) and / or whose COPD symptoms worsened were tested for the presence of common respiratory viruses. This test included obtaining nasopharyngeal swabs and / or sputum samples (optional) from the patients. Nasopharyngeal swabs were sufficient for testing. The presence of respiratory viruses was established using multiplex PCR techniques, such as the BioFire FilmArray system available from BioMerieux.

[0056] If the respiratory panel virus test was positive, patients were randomized to consider treatment and stratified into one of two groups according to whether they had an exacerbation of COPD symptoms without cold-like symptoms and / or a moderate COPD exacerbation (Group A), or a moderate COPD exacerbation with or without cold-like symptoms (Group B). For the purposes of this study, a moderate exacerbation was defined, in accordance with the GOLD2017 guidelines, as "an acute exacerbation of respiratory symptoms resulting in additional therapy treated with a short-acting bronchodilator (SABD) + antibiotics and / or oral corticosteroids."

[0057] Patients were classified into Group B only if their COPD symptoms exacerbated and required treatment with oral corticosteroids and / or antibiotics. Patients who did not require treatment with oral corticosteroids and / or antibiotics did not meet the criteria for moderate exacerbation and were stratified into Group A only.

[0058] Patients were randomized in a 1:1 ratio to receive either SNG001 (6MIU IFN-β1a) or placebo once daily for 14 days. Doses were delivered via CE-labeled respiratory nebulizers (I-neb Philips Respironics) in clinics and at home. The first dose of the study drug was administered within 48 hours of the onset of respiratory viral symptoms and / or exacerbation of COPD symptoms (Group A), or the onset of a moderate COPD exacerbation requiring treatment with systemic corticosteroids and / or antibiotics (Group B).

[0059] To evaluate the effectiveness of the treatment, peak expiratory flow rate (PEFR), a measure of lung function, was assessed daily throughout the treatment period.

[0060] To evaluate the pulmonary antiviral response to treatment, sputum samples were collected whenever possible during clinic visits. Sputum cell gene expression of IFN-β-dependent antiviral biomarkers (including Mx1) was determined by reverse transcription quantitative PCR.

[0061] 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 is supplied in ready-to-use syringes by Vetter Pharma, Catalent Inc., or Patheon NV.

[0062] SNG001 formulation: [Table 1]

[0063] Peak expiratory flow rate test PEFR is measured using a peak flow meter, a handheld device used to monitor a person's ability to exhale air. A suitable example of a PEFR monitor is the eMini-Wright Digital Peak Flow Meter (model 3210001) from Clement Clarke International.

[0064] Findings supporting the benefit of IFN-β administration in COPD patients experiencing viral exacerbations and taking corticosteroids. In Part 1 of a trial conducted in COPD patients without symptoms of respiratory viral infection and not treated with systemic corticosteroids, IFN-β was shown to be well-tolerated via the inhalation route. Gene expression of the IFN-β-dependent antiviral biomarker MX1 ​​was elevated and maintained in sputum cells 24 hours after the first and third doses, demonstrating that inhalable IFN-β can turn on and maintain antiviral protection in the lungs of COPD patients (Figure 1).

[0065] In Part 2 of a trial conducted in COPD patients with confirmed respiratory viral infections, inhaled IFN-β was shown to be well-tolerated via the inhalation route. As assessed by measuring statistically significant increases (p=<0.001) in IFN-β-dependent antiviral biomarkers, such as MX1, in lung (sputum) cells over the treatment period, IFN-β (compared to placebo) significantly enhanced patients' pulmonary antiviral response to viral infection. The biomarker responses were similar in patients in groups A and B, indicating that treatment with systemic corticosteroids did not suppress the pulmonary antiviral response to inhaled IFN-β. This was further demonstrated by the fact that patients in Group B, who required treatment with systemic corticosteroids and / or antibiotics at the start of the treatment period due to exacerbations, had significantly better lung function during the treatment period (the difference in the change from baseline in morning PEFR between patients administered IFN-β over days 2–15 and those administered placebo was 25.5 L / min [95% CI 1.1, 49.9], p=0.041, Figure 2). In summary, inhalable IFN-β enhances the pulmonary antiviral response and showed clinical benefit in COPD patients treated with systemic corticosteroids for virus-induced exacerbations. The present invention includes the following embodiments. <1> Interferon-beta (IFN-β) for use in the treatment of virus-induced COPD exacerbations in patients treated with systemic corticosteroids, wherein the IFN-β is administered by inhalation. <2> The patient is infected with rhinovirus, influenza, RSV, adenovirus, parainfluenza, human metapneumovirus, or coronavirus, and the coronavirus is not a highly pathogenic coronavirus that causes SARS, MERS, or COVID-19. <1> IFN-β for use as described above. <3> The aforementioned virus is either a rhinovirus or influenza virus. <2> IFN-β for use as described above. <4> The aforementioned IFN-β is recombinant human IFN-β1a. <1> from <3> IFN-β for use as described in any of the following. <5> 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 <4> IFN-β for use as described in any of the following. <6> The administration by inhalation is directed to the patient's airway and includes aerosolization of the liquid formulation of IFN-β. <1> from <5> IFN-β for use as described in any of the following. <7> The administration is done using a nebulizer. <6> IFN-β for use as described above. <8> The administration of IFN-β is as an inhalation dose once daily. <1> from <7> IFN-β for use as described in any of the following. <9> The aforementioned patient is receiving systemic treatment with a corticosteroid selected from prednisolone, hydrocortisone, dexamethasone, methylprednisolone, or prednisone, or a combination thereof. <1> from <8> IFN-β for use as described in any of the following. <10> 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 <9> IFN-β for use as described in any of the following.

Claims

1. A pharmaceutical formulation for use in the treatment of virus-induced COPD exacerbations in patients treated with systemic corticosteroids, The aforementioned pharmaceutical preparation contains interferon-beta (IFN-β), A pharmaceutical preparation in which the aforementioned IFN-β is administered by inhalation.

2. The pharmaceutical formulation according to claim 1, wherein the patient is infected with rhinovirus, influenza, RSV, adenovirus, parainfluenza, human metapneumovirus, or coronavirus, and the coronavirus is not a highly pathogenic coronavirus that causes SARS, MERS, or COVID-19.

3. The pharmaceutical preparation according to claim 2, wherein the virus is rhinovirus or influenza.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the IFN-β is recombinant human IFN-β1a.

5. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the IFN-β is formulated in an aqueous solution with a pH of approximately 6 to 7, for example, pH 6.5, and preferably excludes mannitol, human serum albumin, and arginine.

6. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the administration by inhalation is to the airway of the patient, and includes aerosolization of the liquid formulation of IFN-β.

7. The pharmaceutical preparation according to claim 6, wherein administration is by the use of a nebulizer.

8. The pharmaceutical preparation according to any one of claims 1 to 7, wherein the administration of IFN-β is as an inhalation dose once daily.

9. The pharmaceutical preparation according to any one of claims 1 to 8, wherein the patient is receiving systemic treatment with a corticosteroid selected from prednisolone, hydrocortisone, dexamethasone, methylprednisolone, or prednisone, or a combination thereof.

10. The pharmaceutical formulation 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.

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