WO2021233484A1

WO2021233484A1 - Pharmaceutical composition for the treatment of respiratory diseases of viral origin

Info

Publication number: WO2021233484A1
Application number: PCT/CU2021/050003
Authority: WO
Inventors: Iraldo Bello Rivero; Yaquelin DUNCAN ROBERTS; Dania Marcia VÁZQUEZ BLOMQUIST; Claudia MARTÍNEZ SUÁREZ; Iván CAMPA LEGRÁ; Gerardo Enrique Guillen Nieto
Original assignee: Centro De Ingenieria Genetica Y Biotecnologia
Priority date: 2020-05-20
Filing date: 2021-05-19
Publication date: 2021-11-25
Also published as: CU20200029A7

Abstract

A pharmaceutical composition for the treatment of acute respiratory diseases of viral origin, comprising interferon (IFN) type I and IFN gamma where the amount of IFN type I (IU) is between 5 and 13 times higher than the amount of IFN gamma (IU). Said pharmaceutical composition is useful for the treatment of patients with persistence of a virus that causes acute respiratory diseases, and comprises IFN type I and IFN gamma where the amount of IFN type I (IU) is between 5 and 13 times higher than the amount of IFN gamma (IU). The invention contemplates the use of IFN type I and IFN gamma for the manufacture of a drug for the treatment of acute respiratory diseases of viral origin, as well as methods for treating patients with these diseases.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF RESPIRATORY DISEASES OF VIRAL ORIGIN

Technical field The present invention relates to biotechnology and medical sciences, particularly with a composition for the treatment of patients with acute respiratory infections of viral origin. Said composition comprises interferon (IFN) alpha and IFN gamma in a synergistic ratio.

Prior State of the Art Emerging and re-emerging virus infections represent a serious threat to global health. The absence of vaccines for emerging virus infections, and the unavailability of sufficient vaccines for reemerging virus infections, creates an obvious need for direct antivirals to be implemented during a pandemic. On the other hand, viruses mutate to become resistant to specific antivirals (Daczkowski CM., Et al. (2017). J Mol Biol, 429 (11): 1661-83), which requires the development of broad pleiotropic antivirals. spectrum. Viruses develop mechanisms to evade the functions of the IFN system, simulating proteins that intervene in the synthesis mechanisms of IFNs (Yoshikawa T., et al. (2010). PLoS One; 5 (1): e8729; Yang Y., et al. (2015). Sci Rep, 5: 17554) and intracellular signaling, to establish the protection mechanisms by these (IFN receptor, and other signaling cascade proteins (Frieman M., et al. (2007 ). J Virol, 81 (18): 9812-24; Strayer D., et al. (2014). Infect Disord - Drug Targets, 14 (1): 37-43). The severe acute respiratory syndrome virus (SARS ) -CoV, which emerged in 2003 and caused considerable mortality in humans, encodes at least five proteins that function as IFN antagonists (Devaraj SG., Et al. (2007) J Biol Chem, 282: 32208-32221; Kamitani W „et al. (2006) Proc Nati Acad Sci USA 103, 12885-12890; Sarah A., et al. (2007). J Virol, 81 (2): 548-557; Xiaojuan Chen., Et al ( 2014). Protein Cell, 5 (5): 369-381), deleting the components of signage and its production. These proteins are believed to be responsible for the pathogenesis of SARS-CoV.

Type I IFNs are broad spectrum antiviral candidates, specifically due to their rapid induction in response to each and every infection viruses, the pleiotropic nature of their effects on the inhibition of different stages of the viral replication cycles, and their effects on the activation of immune cells to eliminate virus infections (Qiong Zhou et al. (2020). Front. Immunol, 2020. https://doi.org/10.3389/fimmu.2020.01061). The induction of IFNs plays a fundamental role in defending the body against SARS-CoV infections.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) coronavirus, similar to SARS and Middle East respiratory syndrome (MERS). This type of virus is susceptible to the antiviral action of IFNs, but variations have developed to interfere with this activity (Daczkowski CM „et al (2017). J Mol Biol, 429 (11): 1661-83).

The clinical course of SARS-CoV-2 infection can last up to 70 days (Zhou F, et al. (2020). Lancet, S0140-6736 (20) 30566-3). It is described that there are a large number of patients in whom the infection can last for several months. (Yang, JR et al. (2020). J Med Virol, doi.org/10.1002/jmv.25940; Li N. J Med Virol, doi.org/10.1002/jmv.25952). The persistence of SARS-CoV-2 in elderly patients could be a triggering factor that causes organ damage, persistent inflammation in the alveoli, and disease progression. The persistence of this virus may be the reason for the high level of lethality in the population of patients over 60 years of age (Xinwei Du X et al (2020). Journal of

Infection, www.elsevier.com/locate/jinf).

The susceptibility of SARS-CoV to IFN has been evaluated in cell culture, in animals and in the clinic. IFN alpha is relatively ineffective in cultured cells, it is suggested that it achieves some efficacy in monkeys and SARS patients, but this was not widely supported in controlled experiments (Haagmans, BL., Et al. (2004). Nat. Med. , 10: 290-293; Loutfy MR., Et al. (2003). JAMA 290: 3222-3228). Against this virus, IFN beta is more potent as an antiviral than IFN alpha. However, in experiments carried out in vitro, at IFN beta concentrations above 1000 U / mL, this exerts only a marginal effect in reducing the virus titer (Cinatl J., et al. (2003). Lancet, 362: 293-294; Hensley LE., Et al.

(2004). Emerg. Infect. Dis, 10: 317-319; Stroher, U., et al. (2004). J. Infect. Dis,

189: 1164-1167. Both IFN alpha and IFN gamma have been ineffective against SARS-CoV in cell culture experiments (Spiegel M., et al. (2004). J. Clin. Virol, 30: 211-213). Type I IFNs have had limited clinical use for the treatment of acute and chronic infections in patients. In a study of 349 patients with MERS, 144 (41.3%) received the combination of ribavirin and IFN (IFN alpha 2a, IFN-alpha 2b, or IFN-beta 1a). Treatment with ribavirin and IFN was started 2 days (median) from admission to the intensive care unit. The combined use of these two drugs was not associated with changes in mortality at 90 days, or with a rapid elimination of this virus (Yaseen M., et al. (2020). Clinical Infectious Diseases, 70 (9): 1837 ^ f4).

The combination of IFN type I (IFN alpha, IFN beta) and IFN type II (IFN gamma) has antiviral effect on a variety of viruses (human cytomegalovirus, Herpes simplex virus (HSV-1), vesicular stomatitis virus (VSV ), Virus Lassa et al. (Asper M., et al. (2004). J. Virol, 78: 3162-3169; Sainz B., et al. (2002). J. Virol, 76: 11541-11550; Sainz B., et al. (2005). Virol. J, 2:14) However, all this evidence has been obtained at the level of cell culture and in vitro experimentation, without having been translated into the clinical setting or medical practice.

Anti-coronavirus therapy is difficult to develop. Coronaviruses are biologically diverse and rapidly mutate. Therefore, the effective agent for one strain, especially those that target replicative mechanisms, may be useless in another strain. Animal studies are logistically difficult, from a technical point of view, since the number of available animal models is limited and only found in designated biosafety level 3 laboratories (Zumla A., et al. (2016). Nat Rev Drug Discov, 15: 327-47). These challenges result in a lack of novel and effective treatment modalities, and a paucity of clinical trials. Most of the therapeutic options for MERS are extrapolated from the 2003 SARS outbreak. On the other hand, a problem that must be solved, due to its negative impact on the morbidity and mortality caused by SARS-CoV-2, is the prolonged viral persistence observed in patients.

For this reason, it is necessary to obtain new drugs for the treatment of patients with viral respiratory infections, which have superior clinical efficacy, and which manage to eliminate prolonged viral persistence.

Explanation of the invention

This invention contributes to solving the aforementioned problem, by providing a pharmaceutical composition for the treatment of respiratory diseases. acute of viral origin comprising interferon (IFN) type I and IFN gamma where the amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma (Ul), trehalose at 50.0 mg / mL and succinic acid at 2.36 mg / L. In one embodiment of the invention, the composition has an amount of IFN type I (Ul) that is 6 times higher than the amount of IFN gamma (Ul).

To define the characteristic that distinguishes the composition of the invention from others, isobolograms were made in the Flep-2 cell line infected with Mengo virus and treated with a series of concentrations of both IFNs.

In one embodiment of the invention, the pharmaceutical composition comprises IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta as type I IFN. For the purposes of the invention, acute respiratory disease of viral origin is caused by coronavirus, influenza virus A and B, respiratory syncytial virus (RSV), parainfluenza or adenovirus. In a particular embodiment, the coronavirus is SARS-CoV, SARS-CoV-2, MERS-CoV. In another aspect, the invention provides a pharmaceutical composition for the treatment of patients with persistence of a virus that causes acute respiratory diseases that comprises IFN type I and IFN gamma, where the amount of IFN type I (Ul) is between 5 and 13 times greater than the amount of IFN gamma (Ul). In a particular embodiment, the pharmaceutical composition contains an amount of IFN type I (Ul) that is 6 times higher than the amount of IFN gamma (Ul). In the invention, without limiting its scope, type I IFN may be IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta.

In one embodiment of the invention, the acute respiratory disease of viral origin that is treated with the IFNs composition is caused by coronavirus, influenza A and B virus, respiratory syncytial virus (RSV), parainfluenza or adenovirus. In a preferred embodiment, the coronavirus is SARSCoV, SARSCoV-2, MERSCoV.

Another object of the invention is the use of IFN type I and IFN gamma for the manufacture of a drug for the treatment of acute respiratory diseases of viral origin where the amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma (Ul). In a particular embodiment, the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul). Without limiting the scope, the type I IFN present in the composition is IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta. In one embodiment of the invention, the drug comprising IFN type I and IFN gamma is administered parenterally or mucosally. Parenteral administration can be carried out, for example, subcutaneously, intramuscularly, intravenously. In one embodiment, the drug is administered by the nasal route.

In another aspect, the invention contemplates the use of IFN type I and IFN gamma for the manufacture of a drug for the treatment of patients with persistence of a virus that causes acute respiratory diseases, where the amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma (Ul). In a particular embodiment, the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul). Type I IFN can be IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta. Acute respiratory disease of viral origin can be caused by coronavirus, influenza A and B viruses, respiratory syncytial virus (RSV), parainfluenza, or adenovirus. Said use contemplates that the drug is administered parenterally or mucosally.

Another object of the invention is a method for the treatment of patients with acute respiratory diseases of viral origin characterized in that an effective amount of a pharmaceutical composition comprising IFN type I and IFN gamma is administered to an individual in need, where the The amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma (Ul). In a particular embodiment, the drug is administered parenterally, twice a week for two consecutive weeks.

In one embodiment of the invention, the patient who is treated with the pharmaceutical composition comprising IFN type I and IFN gamma is a patient with viral persistence after antiviral treatment.

Unexpectedly, SARS-CoV-2 positive subjects treated with the combination of IFNs of the invention make the virus negative, very quickly, in more than 70% of positive patients from 96 hours after starting treatment. Patients with viral persistence for more than 21 days and up to at least 40 days enter this group. It is shown that the combination of IFNs alpha 2b and gamma (in total 3.5 MIU) achieved that 75% of patients eliminated the virus after 4 days of treatment, while in the group that was treated with IFN alpha 2b (3.5 MIU), only 41.6% cleared the virus after 4 days of treatment. A result like this has not been described in the literature. There is no study of the combination of type I and type II IFNs in patients with respiratory diseases. The concentrations of IFNs used in in vitro studies cannot be extrapolated to in vivo studies, since the effect being evaluated is direct on infected cells. There is no method in the state of the art that can define, induce or suggest the treatment of patients with acute respiratory infections with the combination of alpha and gamma IFNs. The invention does not exclude that the combination of interferons is administered simultaneously with antivirals used in therapy.

Brief description of the figures

Figure 1. Isobologram for the identification of the optimal combination of IFN alpha and gamma. The isobologram analysis defines the concentration range with which a 50% inhibition of the cytopathic effect of Mengo virus is obtained.

Figure 2. Percentage of patients who were negative for SARS-CoV-2 after starting treatment with the combination of IFNs.

Figure 3. RNA levels of 2'-5 'OAS after nasal administration of the IFNs under study at different times.

Detailed discussion of embodiments / Examples of embodiments Example 1. Inhibition of the cytopathic effect of Mengo virus on the Hep-2 cell line by the combination of IFN alpha and IFN gamma.

The antiviral activity of combinations of IFN alpha and IFN gamma was evaluated by the inhibition of the cytopathic effect produced by Mengo virus in Flep-2 cells (ATCC No. CCL23). Culturing cells in monolayers it was incubated in 96 - well plates for 24 hours at 37 ^Q C in atmosphere of 3% CO2 and 95% humidity, with serial dilutions of IFN alpha 2b and IFN gamma in minimal essential medium with 2% fetal bovine serum and 40 pg / mL of gentamicin. The virus (10 ⁷ TCID50, from the English Median Tissue Culture Infectious Dose) was added to each well and incubated under the same conditions, until the cytopathic effect (90% cell lysis) was evident in the wells of the virus control (without the presence of IFNs). This happened between 6:00 p.m. and 8:00 p.m. The degree of cell lysis was measured by crystal violet staining.

Figure 1 shows the isobologram resulting from plotting the concentrations of IFN alpha 2b (120 Ul, 100 Ul, 300 Ul, 600 Ul, 2000 Ul) and IFN gamma (1000 Ul, 500 Ul, 200 Ul, 100 Ul, 150 Ul) that showed a 50% inhibition of the effect cytopathic (IC: 50) of Mengo virus on infected Hep-2 cells. Concentrations were found in proportions (5: 1, 6: 1 13: 1) that enhance the antiviral effect, according to the concave behavior of the resulting curve, and that were surprising, according to what was reported in the specialized literature. Taking into account the therapeutic doses of IFNs in humans, the combination of 3.0 MIU of IFN alpha 2b and 0.5 MIU of IFN gamma (ratio 6: 1) was taken as the dose for the treatment of patients. The literature describes the synergistic antiviral effect, against VSV, of the combination of a consensual interferon alpha (IFN alphacon-1) and IFN gamma, in proportions 1: 120 and 1: 60 (IFN alpha: IFN gamma) (Tan H, et al. (2005). Journal of Interferon & Cytokine Research, 25: 632-649), or against FISV in a 1: 1 ratio (Peng T et al. (2008). Journal of Virology 1934-1945) . These combinations of IFNs, which are reported in the specialized literature, contain equal amounts of both IFNs or a greater amount of IFN gamma than IFN type I. Therefore, the findings of a combination with evident antiviral activity where IFN alpha it is found in a higher proportion than gamma interferon.

Example 2. Demonstration of the effectiveness of the combination of alpha 2b and gamma interferons in SARS-CoV-2 positive patients.

A prospective study was conducted, where SARS-CoV-2 positive patients were studied (with a confirmed diagnosis between 2 and 3 days before starting treatment). Patients were treated twice a week, for two weeks, with one of the following two variants: a) IFN alpha 2b (3.5 MIU) b) a composition comprising IFN alpha 2b (3.0 MIU) and IFN gamma (0.5 MIU) (6: 1 ratio, total IFN dose: 3.5 MIU) c) trehalose at 50.0 mg / mL and succinic acid at 2.36 mg / L

The above compositions were administered subcutaneously. Tables 1 and 2 show the data of the patients treated with said compositions, which comprise IFNs, and the results of the determination of the presence of SARS-CoV-2 by qPCR, 4 days after starting treatment. Table 1. Characteristics of patients treated with the combination of IFN alpha 2b and IFN gamma and qPCR results.

Table 2. Characteristics of patients treated with IFN alpha 2b and qPCR results.

As can be seen in Tables 1 and 2, in the group of patients treated with the IFNs combination, there were 75.0% of patients who shed the virus when only 4 days had elapsed since the start of treatment. In contrast, in the In the group that was treated with IFN alpha 2b, only 41.6% cleared the virus 4 days after starting treatment.

Example 3. Treatment of SARS-CoV-2 positive patients with the composition comprising IFN alpha 2b and IFN gamma. A retrospective study was carried out in which patients with positivity for SARS-CoV-2 infection were studied. The patients were treated twice a week, for two weeks, with the composition comprising IFN alpha 2b (3.0 MIU) and IFN gamma (0.5 MIU) (ratio 6: 1, total dose of IFNs: 3.5 MUI). The administrations were made subcutaneously. Table 3 shows the data of the patients treated with the combination of IFNs, as well as the results of the determination of the presence of SARS-CoV-2 using qPCR, 7 days after starting treatment. As can be seen in said table, surprisingly, 7 days after starting treatment with the combination of IFN alpha 2b and IFN gamma, SARS-CoV-2 had cleared in 100% of the treated patients.

Table 3. Characteristics of the patients treated with the combination of alpha 2b and gamma interferons and qPCR results at 7 days.

Example 4. Determination of the presence of SARS-CoV-2 in the pharyngeal exudate of patients treated with the combination of IFNs alpha 2b and gamma.

The pharyngeal exudates of the patients were taken before treatment with IFNs, and 48 hours, 72 hours and 96 hours after it started. The patients were treated twice a week, for two weeks, with the composition comprising IFN alpha 2b (3.0 MIU) and IFN gamma (0.5 MIU) (ratio 6: 1, total dose of IFNs: 3.5 MUI). In this study, for the amplification of the SARS-CoV-2 virus, the Genesig real-time PCR detection reagent set for 2019-nCoV, from Primer Design Ltd, was used, targeting the viral RdRp polymerase. The ABI 7500 platform was used.

In Figure 2 it can be seen that 41.7% of the patients treated with IFN alpha 2b and IFN gamma already had negative CRP 48 hours after starting treatment. The percentage of negatives increased to 62.5% at 72 hours; while 75% were negative by PCR 96 hours after starting the treatment. This result is very encouraging, considering that the long persistence of the virus is a problem associated with infections caused by the SARS-CoV-2 virus. Example 5. Stimulation of ^{2-5 '} oligoadenylate synthase levels in the blood of SARS CoV-2 positive patients treated with the combination of alpha 2b and gamma interferons.

The determinations of ^2'-5 ^' OAS were made by relative quantification of the enzyme in the serum of the treated patients. For these evaluations, a sandwich-type immunoenzymatic assay was used for the in vitro quantification of isoform 1 of the human OAS enzyme in serum, marketed by USNCK Life Science inc., Which has a minimum detectable amount of <1.5 ng / ml. Table 4 shows the serum levels of ^2'-5 ^' OAS, a marker of response to IFNs. The mean concentration of this enzyme in serum, before treatment, was 166 ± 42.1 ng / ml. After combined treatment with IFN alpha 2b and gamma, the concentration of this enzyme in serum rose to 459 ± 92.4 ng / ml. These concentrations are higher than those found when individuals received IFN alpha or IFN gamma separately. Table 4. Serum concentration of the enzyme ^2'-5 ^' OAS after the administration of the combination of IFNs alpha 2b and gamma.

Example 6. Clearance of the persistent SARS-CoV-2 virus in patients for more than 15 days as a result of the administration of the combination of IFN alpha 2b and IFN gamma.

It is known that patients with COVID-19, positive for the diagnosis of the SARS-CoV-2 virus, can remain with the virus after 15 days, even up to more than 30 days, despite the antiviral treatments that are applied to them. Patients with COVID-19, with viral persistence after receiving antiviral treatments, were treated with different combinations of IFN alpha 2b and IFN gamma, taken from the results of the isobologram shown in Figure 1.

Of 21 patients with viral persistence who were treated with the composition comprising IFN alpha 2b (3.0 MIU) and IFN gamma (0.5 MIU) (ratio 6: 1, total dose of IFNs: 3.5 MIU), for Subcutaneously, 16 were negative for the virus after receiving only two doses of the combination, in the same week, for 76.2% viral clearance in the patients. At the time of initiating treatment with the IFNs combination, those 16 patients with prolonged viral persistence of SARS-CoV-2 had the following distribution: 10 patients with two consecutive positive qPCR assays; 5 patients with three consecutive positive qPCR assays and 1 patient with five consecutive positive qPCR assays.

This surprising result is very valuable, since a large number of patients are described with prolonged viral persistence, which can lead to aggravation and death due to complications derived from this permanence of the virus (Xinwei Du X et al (2020). Journal of Infection, www.elsevier.com/locate/jinf). There is no method described in the state of the art that can eliminate the virus in a short time, in patients with prolonged viral persistence of SARS-CoV-2.

Example 7. Nasal administration of the combination of IFN alpha 2b and IFN gamma promotes the stimulation of 2'-5 'OAS at the level of messenger RNA in healthy subjects.

An exploratory clinical trial was carried out in healthy volunteers, without decompensated or autoimmune chronic diseases. The included subjects were randomized into two groups to receive nasal treatment. The first group received a composition (in nasal drops) comprising IFN alpha 2b (250,000 IU) and IFN gamma (50,000 IU), applied 3 times a day, for 3 days. The second group received a placebo formulation in the form of nasal drops. The treatment was completed in a hospital admission regime, and consisted of two drops (40 pL) in each nostril, every 3 hours, for 24 hours.

Blood samples were taken for clinical laboratory examinations (hematology and clinical biochemistry), which also included analysis of RNA expression of ^2' -5 ^' OAS, a marker of IFN response. These determinations were made at 0 hours, 6 hours, 12 hours, 18 hours and 24 hours and 48 hours.

RNA purification was performed from human peripheral blood in collecting tubes with RNA stabilizer product ("PAXgene Blood tube ^® "). The method is based on obtaining total RNA from lymphocytes, from whole blood, using the “PAXgene RNA Blood ^® ” Reagent Pack (PreAnalytix RNase Free DNase set ^® / Quiagen). Complementary deoxyribonucleic acid (cDNA) was obtained using the RT SuperScriptlITM ^® kit (Invitrogen) according to the manufacturer's procedure.

The reaction was carried out in a volume of 25 pL, of which 12.5 pL correspond to a mixture containing all the components of the reaction, while 0.5 pL are from the oligonucleotide mixture at 5 pmol / pL, 1 pL is from cDNA from each time point, per individual, and 11 pL is from water.

Real-time PCR is carried out using the ABsolute QPCR SYBR Green Mix ^® Reagent Pack (Termo scientific, ABgene, UK), in a set suitable for qPCR. The reactions were developed in a total volume of 20 pL, of which 10 pL corresponded to SYBR Green 2X ^® ; 0.6 pL to the oligonucleotide mixture at 10 pmol / pL (300 nM final); 5.4 pL of water and 4 pL of each cDNA to be amplified at the selected dilution. In addition to performing the runs for the quantification of ^2'-5 ^' OAS, the runs were performed in real time PCR with the oligonucleotides for the enzyme glyceraldehyde3-phosphate dehydrogenase (GAPDH) and hydroxymethyl bilane synthetase (HMBS). The use of these oligonucleotides allows the quantification of two internal control genes, whose expression rate in the cell does not vary and the data was normalized with respect to them.

As can be seen in Figure 3, the nasal administration of the composition comprising IFN alpha 2b and IFN gamma stimulates the expression of ^2'-5 ^' OAS, measured at the messenger RNA level, in healthy volunteers. In the group treated with IFNs, this enzyme is produced at levels much higher than those found in individuals who received a placebo formulation, by the same route.

Claims

1. A pharmaceutical composition for the treatment of acute respiratory diseases of viral origin comprising interferon (IFN) type I and IFN gamma where the amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma ( Ul).

2. The pharmaceutical composition according to claim 1 wherein the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul).

3. The pharmaceutical composition according to claim 1 wherein the type I IFN is IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta.

4. The pharmaceutical composition according to claim 1 wherein the acute respiratory disease of viral origin is caused by coronavirus, influenza virus A and B, respiratory syncytial virus (RSV), parainfluenza or adenovirus.

5. The pharmaceutical composition according to claim 4 wherein the coronavirus is SARS-CoV, SARS-CoV-2, MERS-CoV.

6. A pharmaceutical composition for the treatment of patients with persistence of a virus that causes acute respiratory diseases comprising interferon (IFN) type I and IFN gamma where the amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma (Ul).

7. The pharmaceutical composition according to claim 6 wherein the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul).

8. The pharmaceutical composition according to claim 6 wherein the IFN type I is IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta.

9. The pharmaceutical composition according to claim 6 wherein the acute respiratory disease of viral origin is caused by coronavirus, influenza A and B virus, respiratory syncytial virus (RSV), parainfluenza or adenovirus.

10. The pharmaceutical composition according to claim 9 wherein the coronavirus is SARSCoV, SARSCoV-2, MERSCoV.

11. Use of type I interferon (IFN) and IFN gamma for the manufacture of a medicinal product for the treatment of acute respiratory diseases of viral origin where the amount of IFN type I (Ul) is between 5 and 13 times higher than the amount of IFN gamma (Ul).

12. The use according to claim 11 where the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul).

The use according to claim 11 where the type I IFN is IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta.

14. The use according to claim 11 where the acute respiratory disease of viral origin is caused by coronavirus, influenza virus A and B, respiratory syncytial virus (RSV), parainfluenza or adenovirus.

15. The use according to claim 11 where the drug is administered parenterally or mucosally.

16. The use according to claim 15 where the drug is administered subcutaneously, intramuscularly, intravenously or nasal.

17. The use according to claim 15 wherein the drug administered parenterally is administered twice a week for two consecutive weeks.

18. Use of interferon (IFN) type I and IFN gamma for the manufacture of a drug for the treatment of patients with persistence of a virus that causes acute respiratory diseases where the drug comprises an amount of IFN type I (Ul) that is between 5 and 13 times higher than the amount of IFN gamma (Ul).

19. The use according to claim 18 wherein the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul).

20. The use according to claim 18 wherein the type I IFN is IFN alpha, preferably IFN alpha 2a, IFN alpha 2b, IFN alpha 2c, or IFN beta.

21. The use according to claim 18 wherein the acute respiratory disease of viral origin is caused by coronavirus, influenza A and B virus, respiratory syncytial virus (RSV), parainfluenza or adenovirus.

22. The use according to claim 18 wherein the drug is administered parenterally or mucosally.

23. A method for the treatment of patients with acute respiratory diseases of viral origin characterized in that an effective amount of a pharmaceutical composition that It comprises type I interferon (IFN) and gamma IFN where the amount of type I IFN (Ul) is between 5 and 13 times higher than the amount of gamma IFN (Ul).

24. The method according to claim 23 wherein the amount of IFN type I (Ul) is 6 times higher than the amount of IFN gamma (Ul).

25. The method according to claim 23 wherein the patient who is treated with the pharmaceutical composition comprising interferon (IFN) type I and IFN gamma is a patient with viral persistence after antiviral treatment.