WO2023280911A1

WO2023280911A1 - P38-inhibitors for the treatment of coronavirus infections and/or covid-19 cytokine storm

Info

Publication number: WO2023280911A1
Application number: PCT/EP2022/068724
Authority: WO
Inventors: Stephan Ludwig; Ursula RESCHER; Linda BRUNOTTE; Aileen FAIST; Sebastian Maximilian SCHLOER
Original assignee: Westfälische Wilhelms-Universität Münster
Priority date: 2021-07-06
Filing date: 2022-07-06
Publication date: 2023-01-12

Abstract

The present invention relates to p38 inhibitors for use in a method for the treatment of a coronavirus infection and/or the treatment or prevention of COVID-19 cytokine storm. Also provided are compositions comprising such inhibitors for use in the treatment of a corona virus infection, such as COVID-19.

Description

P38- INHIBITORS FOR THE TREATMENT OF CORONAVIRUS INFECTIONS

AND/OR COVID-19 CYTOKINE STORM

FIELD OF THE INVENTION

The present invention relates to the use of p38-inhibitors for the treatment of coronavirus infections and/or the treatment or prevention of COVID-19 cytokine storm.

BACKGROUND

The newly emerged pandemic SARS-CoV-2 virus is the etiological agent of COVID-19, a severe respiratory disease accompanied by pneumonia and systemic inflammation. So far, SARS-CoV-2 has infected almost 180 million individuals world wide and caused more than 3,9 million deaths (WHO, June 2021). Despite the recent availability of efficient SARS-CoV-2 vaccines, the number of viral infections and individuals requiring intensive clinical care remains high, which leads to an extraordinary burden of the national health care systems. Risk groups for COVID-19 include people of high age (+70 Years) and individuals with comorbidities such as cancer, diabetes, chronic kidney, heart and lung diseases as well as autoimmune diseases. However, also healthy younger individuals as well as children can develop COVID-19. Due to the severe tissue damage of the lungs caused by the overshooting immune response to SARS-CoV-2, COVID-19 patients often require submission to rare intensive care units (ICU) and extra corporal membrane oxygenation (ECMO) to stabilize the blood oxygen levels. Such intensive care treatments require high numbers of specifically educated personel, are very cost intensive and represent a strongly limited resource of the health care system. The current pharmacological treatments for COVID-19 are limited to the clinical emergency use of the antiviral drug Remdesivir, a nucleoside analogue targeting the viral polymerase, and the immunomodulatory corticosteroid Dexamethasone. The development of new therapeutic options and identification of repurposed drugs that reduce the disease burden and high lethality of COVID-19 by inhibiting viral replication and rebalancing of the dysregulated immune response is of highest priority.

Development of COVID-19 is facilitated by an early, virus-mediated inhibition of the innate immune response at the site of infection, the upper respiratory tract. Absence of induction of type I interferons (type I IFN) allows robust viral replication and further dissemination to the lungs without restriction by interferon-induced antiviral restriction factors and delays the onset of the protective inflammatory response. Later stages of the disease are characterized by massive recruitment of activated immune cells that produce disproportional amounts of pro-inflammatory cytokines (IL-6, IL- 8, IL-lb, TNF-a) leading to severe tissue damage in diverse organs including the lung, heart, kidneys and others (1,2). Treatments for this unique biphasic disease model of COVID-19 are therefore required to achieve reduction of viral replication and the rebalancing of the uncontrolled inflammation.

In addition, it is known that coronaviruses undergo frequent recombination. SARS-CoV-2 is a member of the subgenus Sarbecovirus (beta-CoV lineage B). There are many thousands of variants of SARS- CoV-2, several of which are considered to be increasingly dominant in different regions, such as the British variant B.l.1.7 (Alpha), the South African variant B.1.351 (Beta), the Brazilian variants P.l and P.2 (Gamma) or the Indian variant B.1.617 (Delta).

In the case of COVID-19, the clinical spectrum of SARS-CoV-2 infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and even death, with many patients being hospitalized. The use of a 3-stage classification system is widely accepted, recognizing that COVID-19 illness exhibits three grades of increasing severity which correspond with distinct clinical findings, response to therapy and clinical outcome. Despite high numbers of infections with the original Sars-CoV-2 virus, 80% of all positively tested patients experienced mild symptoms only, 20% showed signs of hypoxemia leading to hospitalization and only 5% required treatment in intensive care units (ICU). However, these statistics do not necessarily apply to the emerging virus variants, in particular the Indian variant seems to lead to higher numbers of symptomatic patients with severe hypoxemia requiring hospitalization and intensive care.

In early May 2020, an emergency authorization was provided by the US FDA for the use of the antiviral Remdesivir in the treatment of hospitalized COVID-19 patients. Remdesivir is an RNA polymerase inhibitor that was originally developed for the treatment of Ebola, where it was found to be ineffective. Remdesivir was only approved to treat patients in a hospital setting showing severe symptoms which we would classify as stage III COVID-19. However, while Remdesivir was found to decrease the length of hospitalization of the patients in trials, there was no significant effect on mortality. Other ribonucleoside analogs, such as favipiravir and molnupiravir are currently being investigated for their usefulness in treating COVID-19 (Borbone et al.; Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV2 and other Coronaviruses; Molecules 2021, 26, 986).

In view of the prior art and the multitude of ongoing studies, it is clear that there is the need of new compounds and compositions effective in the treatment and prevention of COVID-19. SUMMARY OF THE INVENTION

The solution to the above problem provided herein is the provision of a p38 inhibitor for the treatment of COVID-19, which is administered in combination with a ribonucleoside analog, preferably selected from the group consisting of Remdesivir (GS-5734), GS-441524 monophosphate, GS-441524 triphosphate, Sofosbuvir, Ribavirin, Favipiravir or Molnupiravir. Surprisingly, it was found that the combination of the p38 inhibitors with Remdesivir reduced SARS-CoV-2 viral titers 100-fold more efficiently in vitro compared to the treatment with Remdesivir alone. This was unexpected as p38 inhibitors alone do not significantly reduce the viral load.

Remdesivir is a prodrug that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase. While currently only Remdesivir is used as a prodrug, it is likely that the active metabolites GS-441524 monophosphate and triphosphate would also be effective.

The Mitogen activated protein kinase (MAPK) p38 is a central factor in the signaling pathways and feedback mechanisms governing the expression of proinflammatory cytokines in response to stress and viral infections. Pharmacological inhibition of p38 has therefore been widely investigated for the treatment of chronic and auto-immune diseases. Suitable p38 inhibitors are PH-797804, VX-702, Losmapimod (GW856553), SB202190, Pamapimod, Dilmapimod (SB681323), SB239063,

Doramapimod (BIRB 796), BMS-582949, ARRY-797, Adezamapimod (SB203580), and SCIO-469. In particularly preferred embodiments, the p38 inhibitor is PH-797804, Losmapimod or VX-702 and the antiviral compound is Remdesivir.

Specifically, the p38 inhibitor or a pharmaceutically acceptable salt thereof as mentioned above can be used in combination with the ribonucleoside analog to treat COVID-19 Stage I, Stage II or Stage III or COVID-19 cytokine storm. In addition, treatment of COVID-19 caused by a SARS-CoV-2 variant, such as D614G, B.l.1.7, B.1.351, PI, P2, B.1.617, B.1.427, B.1.429, B.1.525, B.1.526 or a new variant is also encompassed.

For treatment of COVID-19, the p38 inhibitor or a pharmaceutically acceptable salt thereof can be administered contemporaneously, previously or subsequently to the ribonucleoside analog.

In one aspect, a pharmaceutical composition comprising a p38 inhibitor or a pharmaceutically acceptable salt thereof and ribonucleoside analog selected from the group consisting of Remdesivir (GS-5734), GS-441524 monophosphate or GS-441524 triphosphate can be administered. This pharmaceutical composition is useful as a medicament in the prophylaxis and/or treatment of a viral disease, specifically COVID-19. The COVID-19 can be is Stage I, Stage II or Stage III COVID-19 or COVID-19 cytokine storm.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Cytokine response and MAPK p38 signaling is activated during SARS-CoV-2 infection

Figure 2: Inhibition of MAPK p38 reduced the expression of pro-inflammatory cytokines during SARS- CoV-2 infection in vitro.

Figure 3: p38 inhibition can affect SARS-CoV-2 replication at high concentrations

Figure 4: Antiviral activity of the single and combination treatments with the p38 inhibitors and remdesivir.

Figure 5: Table summarizing clinical studies

Figure 6: p38 Inhibitors

DETAILED DESCRIPTION

The above being said, the present invention relates to p38 inhibitors for use in combination with a ribonucleoside analog such as Remdesivir in a method of treatment of COVID-19. In the examples, the inventors showed that surprisingly the combination of the p38 inhibitors with Remdesivir reduced SARS-CoV-2 viral titers 100-fold more efficiently compared to the treatment with Remdesivir alone. Remdesivir alone achieved a 10-fold reduction of viral replication compared to solvent-treated cells (DMSO). In contrast, combination with 5 mM of PH-707804 or VX-702 reduced viral titers by 10.000- and 1000-fold compared to the solvent-treated control or treatment with 5 mM of the p38 inhibitors alone, respectively.

Specifically, as demonstrated in the appended Example 1, the inventors were originally interested in finding out whether cytokine response and MAPK p38 signaling is activated during SARS-CoV-2 infection. First experimental evidence for the importance of p38 MAPK signaling for SARS-CoV-2 hyperinflammation was provided by Bouhaddou et al. (2020;The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell 182, 685-712) demonstrating that inhibition of p38 reduced the production of disease-relevant cytokines in infected cells. This was confirmed by the inventors, showing a strong induction of pro-inflammatory cytokines and p38 MAPK activation upon SARS-CoV- 2 infection in cultured human airway cells (Calu-3) as shown in Figure 1. As can be seen from Figure 1A and IB, the SARS-CoV-2 was able to replicate in the Calu-3 cells and pro-inflammatory cytokines were increased after infection. Further, Figure 1C is a Volcano plot summarizing significantly increased host response factors upon infection with SARS-CoV-2 compared to non-infected cells (mock). Finally, Figure 1 D shows MAPK p38 phosphorylation and activation after infection with SARS- CoV-2.

Next, the inventors wanted to see if inhibition of MAPK p38 reduced the expression of pro- inflammatory cytokines during SARS-CoV-2 infection in vitro. To achieve a reduction of cytokine expression by SARS-CoV-2, three pre-clinically evaluated p38 inhibitors VX-702 (Vertex), PH-797804 (Pfizer) and GW856553X (GlaxoSmithKline) were tested as described in Example 2 to analyze their therapeutic potential for the treatment of COVID-19 in a repurposing approach. The results shown in Figure 2 demonstrated that all three p38 inhibitors reduced the mRNA-expression of the COVID-19 relevant cytokines IFN-b, IL-6, IP-10 and TNF-a in a concentration-dependent manner (Figure 2A). In parallel, western blot analysis demonstrated efficient and concentration-dependent reduction of the p38 kinase activity following inhibitor treatment as evidenced by the lack of MSK-1 phosphorylation, which is a direct downstream target of p38. Specifically, it was found that all three inhibitors block p38 signaling in a concentration-dependent manner as demonstrated by the reduction of MSK-1 phosphorylation (Figure 2B). Further experiments showed that all three inhibitors are non-toxic over a wide range of concentrations (Figure 2C).

In a next step, the inventors investigated whether p38 inhibition can affect SARS-CoV-2 replication at high concentrations as described in Example 3. To determine a potential antiviral effect on SARS- CoV-2 replication by the p38 inhibitors in addition to the observed immunomodulatory properties, supernatants of p38 inhibitor PH-797804 or VX-702 treated infected cells were analyzed. A reduction in viral titers was observed for inhibitor PH-797804 at 20 and 40 mM, which represent 4- and 10-fold higher concentration compared to the previous assays (Figure 3A). For VX-702 no antiviral effect could be observed at any tested concentration (Figure 3B). None of the inhibitors affected viral replication at a concentration of 5 pM.

Finally, the inventors tested the antiviral activity of the single and combination treatments with the p38 inhibitors and Remdesivir as described in Example 4. Immunomodulatory and antiviral drugs are often combined to increase therapeutic effects, which can facilitate faster recovery of diseased patients and further reduce lethality. Therefore the effect of a combined treatment of the p38 inhibitors PH-797804 and VX-702 with the only clinically used antiviral drug Remdesivir was analyzed. Specifically, viral replication was analysed after 48 h of infection. As can be seen from Figure 4, the combination of the p38 inhibitors with Remdesivir reduced SARS-CoV-2 viral titers 100-fold more efficiently compared to the treatment with Remdesivir alone. Remdesivir alone achieved a 10-fold reduction of viral replication compared to solvent-treated cells (DMSO). In contrast, combination with PH-707804 or VX-702 reduced viral titers by 10.000- and 1000-fold compared to the solvent- treated control or treatment with 5 pM of the p38 inhibitors alone, respectively. To assess the degree of drug synergism between PH-797804 and Remdesivir to reduce viral titers of SARS-CoV-2, a titration matrix using the drug concentrations shown in Figure 4A (lpM Remdesivir (Rem), 5pM PH- 797804 (PH), 5pM VX-702 (VX) and a combination of lpM Remdesivir (Rem) with 5pM PH-797804 (PH) or 5pM VX-702 (VX)) was performed and titers were determined by plaque assay. This demonstrates that the combination of the p38 inhibitor PH-797804 or VX-702 with Remdesivir resulted in 1000-10000 reductions of viral titer, though combinations of Remdesivir with PH-797804 were 10 fold more effective and showed the strongest response. Figure 4B shows a drug combination matrix used to assess the synergy score of PH-797804 with Remdesivir to inhibit replication of SARS-CoV-2. Synergy scores were calculated using the Bliss, HSA, and ZIP synergy models (5-7). All three models report a high synergistic action of 17.078, 13.288 and 17.811, respectively for the combination of PH-797894 with Remdesivir to reduce viral replication of SARS- CoV-2. Results from the analysis of the drug synergy score was calculated using the algorithms "Bliss", "HAS" and "ZIP" are shown in Figure 4C. The "Bliss" Model quantifies the excess effect (using a multiplicative model) of the response as if the drugs would act independently. The "HAS" Model quantifies excess over the highest single drug effect. The "ZIP" (zero interaction potency) Model quantifies the deviation from the additive effect of the drugs as if they don't interact.

As described above, the combination of p38 inhibitors with Remdesivir showed a strong unexpected synergistic antiviral effect. In addition, there is evidence from the Examples that p38 inhibitors are able to decrease inflammatory cytokine expression, which plays a significant role in the COVID-19 cytokine storm and the transition from Stage II to Stage III COVID-19. The stages of COVID-19 have been summarized by Hasan et al., in a paper entitled "COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal" ((2020). J Heart Lung Transplant. 2020 Mar 20) summarized below.

The initial stage, termed Stage I, is a mild infection and occurs at the time of inoculation and early establishment of disease. For most people, this involves an incubation period associated with mild and often non-specific symptoms for some days such as malaise, fever, and a dry cough. In patients who can keep the virus limited to this stage of COVID-19, prognosis and recovery is excellent. Treatment at this stage is primarily targeted towards symptomatic relief. Should an antiviral therapy be proven beneficial, targeting selected patients during this stage may reduce duration of symptoms, minimize contagiousness, and prevent progression of severity.

In the second stage, termed Stage II, of an established pulmonary disease, viral multiplication and localized inflammation in the lung is the norm. Stage II includes pulmonary involvement, termed Stage lla, without and Stage Mb with hypoxia. During this stage, patients develop a viral pneumonia, with cough, fever and possibly hypoxia. Over the course of the disease, dyspnea occurs after a median of 13 days after the first onset of symptoms (range 9-16.5 days). Dyspnea is a sign of serious disease of the airway, lungs, or heart and is characterized by difficult or labored breathing and shortness of breath. In the case of COVID-19, imaging with chest X-ray or computerized tomography reveals bilateral infiltrates or ground glass opacities. It is at this stage that most patients with COVID- 19 need to be hospitalized for close observation and management. Treatment primarily consists of supportive measures and antiviral therapies, once available. It is possible that patients will nevertheless progress to Stage III to require mechanical ventilation in an intensive care unit (ICU). In Stage II COVID-19, markers of systemic inflammation may be elevated, but not remarkably so. In early studies performed on the first group of patients in Wuhan, China, it was found that upon entry into the hospital, plasma Iίΐb, I LIRA, IL7, IL8, IL9, IL10, basic FGF, GCSF, GMCSF, IFNy, IP10, MCP1, MIRIa, MIRIb, PDGF, TNF-a, and VEGF concentrations were higher than in healthy adults. In addition, it was found that patients in ICU had plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIPla, and TNF-a that were higher than in patients upon admission to the hospital (Fluang et al.; The Lancet; Vol 395; pp.: 497-506 February 15, 2020), indicating that an increase in these cytokines marks the transition from COVID-19 stage II to stage III. This transition marked by sudden and rapidly progressing clinical deterioration that is called the "COVID-19 cytokine storm" (also termed "cytokine storm" herein). As described in detail in Jamilloux et al. (Autoimmunity Reviews 2020), here markers of systemic inflammation are elevated, such as IL-Ib, IL-Ra, IL-6, TNF-a and slL2Ra. This corresponds to what was shown by Huang et al. discussed above.

A minority of COVID-19 patients will experience a COVID-19 cytokine storm and transition into the third and most severe stage of illness, termed Stage III, which manifests as an extra-pulmonary systemic hyperinflammation syndrome. Overall, the prognosis and recovery from this critical stage of illness is poor.

For this reason, the dual mechanism provided by p38 inhibition and viral inhibition through the synergistic effect with Remdesivir or the active metabolites thereof would be critical to prevent progressing into Stage III and therefore decrease mortality.

The p38 inhibitors of the present invention can be used in combination with Remdesivir or the active metabolites thereof in a method for treating. As such the term "treating" or "treatment" includes administration of a p38 inhibitor and an antiviral preferably in the form of one or two pharmaceutical compositions, to a subject suffering from a coronavirus infection for the purpose of ameliorating or improving symptoms. Similarly included is the administration of a p38 inhibitor preferably in the form of a pharmaceutical, to a subject suffering from a COVID-19 cytokine storm for the purpose of ameliorating or improving symptoms.

Furthermore, the term "prevent" as used herein, refers to a medical procedure whose purpose is to prevent a disease. As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given condition in a patient diagnosed with a coronavirus infection, such as a COVID-19 cytokine storm. Also meant by "prevention" is the reduction or inhibition of markers of systemic hyperinflammation, such as TNF-a, IL-1R, IP-10, IL-8, MCP-1, and/or MIR-Ib, in a subject diagnosed with a coronavirus infection, such as SARS-CoV-2 to reduce the risk of systemic hyperinflammation, such as a COVID-19 cytokine storm, in a subject.

"p38 inhibitors" are molecules that inhibit p38 mitogen-activated protein kinases (MAPK) and are being investigated for therapeutic effects on autoimmune diseases and inflammatory processes. While p38 inhibitors are known and used for research purposes, so far no p38 inhibitor has been approved for therapeutic use. However, clinical studies are in progress for several p38 inhibitors, summarized in Figure 5.

A "p38 MAP kinase inhibitor" is well known in the art. The terms "p38 inhibitor," "p38 kinase inhibitor," and "p38 MAP kinase inhibitor" are used interchangeably herein. In the context of the present invention a p38 MAP kinase inhibitor inhibits p38 MAP kinase. Preferably, the p38 MAP kinase inhibitor inhibits one of the isoforms of p38 MAP kinase, preferably one of the four isoforms (a, b, y or d) of p38 MAP kinase with the a-isoform being preferred, more preferably it inhibits any combination of two isoforms of p38 MAP kinase, even more preferably it inhibits any combination of three isoforms of p38 MAP kinase and most preferably, it inhibits all isoforms or the a, b, y and d isoform of p38 MAP kinase. In some embodiments, the p38 MAP kinase inhibitor inhibits the isoform of p38 that is involved in inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, viral diseases or neurodegenerative diseases. It is reported that the a-isoform of p38 MAP kinase is involved in inflammation, proliferation, differentiation and apoptosis, whereas the biological functions of p38 b, p38 d and p38 y are not yet understood completely. Accordingly, it is preferred herein that the p38 MAP kinase inhibitor inhibits the a-isoform.

A p38 MAP kinase inhibitor can be a small molecule, large molecule, peptide, oligonucleotide, and the like. The p38 MAP kinase inhibitor may be a protein or fragment thereof or a nucleic acid molecule. Also included by the term p38 inhibitor is a pharmaceutically acceptable salt of the p38 inhibitor. The determination of whether or not a compound is a p38 kinase inhibitor is within the skill of one of ordinary skill in the art.

There are many examples of p38 inhibitors in the art. U.S. Pat. Nos. 5,965,583, 6,040,320, 6,147,096, 6,214,830, 6,469,174, 6,521,655 disclose compounds that are p38 inhibitors. U.S. Pat. Nos. 6,410,540, 6,476,031 and 6,448,257 also disclose compounds that are p38 inhibitors. Similarly, U.S. Pat. Nos. 6,410,540, 6,479,507 and 6,509,361 disclose compounds that are asserted to be p38 inhibitors. U.S. Published Application Nos. 20020198214 and 20020132843 disclose compounds that are said to be p38 inhibitors. Another p38 MAP kinase inhibitor is BIRB 796 BS (l-(5-tert-butyl-2-p- tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea); see Branger (2002), J. Immunol. 168:4070-4077 or US 6,319,921 for further p38 MAP kinase inhibitors.

Other p38 MAP kinase inhibitors are AMG 548 (Amgen), BIRB 796 (Boehringer Ingelheim), VX 702 (Vertex/Kissei), SCIO 469, SCIO 323 (Scios Inc.), SB 681323 (GlaxoSmithKline), PH-797804 (Pfizer) and Org-48762-O (Organon NV); see, for example, Lee and Dominguez in Curr Med Chem. 2005;12(25):2979-2994 and Dominguez in Curr Opin Drug Discov Devel. 2005 Jul;8(4):421-430.

According to the present invention, the inhibitor may exhibit its regulatory effect upstream or downstream of p38 MAP kinase or on p38 MAP kinase directly, with the latter mode of action being preferred. Examples of inhibitor regulated p38 MAP kinase activity include those where the inhibitor may decrease transcription and/or translation of p38 MAP kinase, may decrease or inhibit post- translational modification and/or cellular trafficking of p38 MAP kinase, or may shorten the half-life of p38 MAP kinase. The inhibitor may also reversibly or irreversibly bind p38 MAP kinase, inhibit its activation, inactivate its enzymatic activity, or otherwise interfere with its interaction with downstream substrates.

The four isoforms of the p38 MAP kinase share a high level of sequence homology. The alpha and beta isoforms of the p38 MAP kinase are closely related while the gamma and delta isoforms are more divergent. Given the high degree of structural similarity, it is not surprising that certain compounds with the ability to inhibit one p38 MAP kinase isoform can often inhibit other isoforms of the MAP kinase. Accordingly, in some embodiments, an inhibitor of p38 MAP kinase that is specific for the a-isoform of the kinase possesses at least three categories of structural features that are theorized to permit isoform specific inhibition.

Selective binding of a candidate p38 MAP kinase inhibitor can be determined by a variety of methods. The genes for the various isoforms of p38 MAP kinase are known in the art. One of ordinary skill in the art could readily clone and express the various isoforms of the kinase, purify them, and then perform binding studies with candidate compounds to determine isoform binding characteristics. This series of experiments was performed for the a-isoform of p38 MAP kinase and provided in U.S. Pat. No. 6,617,324 Bl.

Another kinase selectivity assay is described in Mihara (2008), Br. J. Pharmacol. 154(1):153-164. In some embodiments herein, a p38 MAP kinase inhibitor inhibits one of the four isoforms of p38 MAP kinase, more preferably it inhibits any combination of two isoforms of p38 MAP kinase, even more preferably it inhibits any combination of three isoforms of p38 MAP kinase, e.g., p38- a(MARK14), -b(MARKII), -y (MAPK12 or ERK6). Alternatively, but also preferred, it inhibits all four isoforms of p38 MAP kinase.

In one embodiment, the p38 inhibitor is selected from the group consisting of the inhibitors listed in Table 2 (Fig. 6). In the context of the invention, preferred p38 inhibitors are losmapimod, VX-702 and PH797804. In another embodiment, the p38 inhibitor is selected from the group consisting of SB202190, LY2228820, CAY10571, SB 203580, Tie2 Kinase Inhibitor, 2-(4-Chlorophenyl)-4- (fluorophenyl)-5-pyridin-4-yl-l,2-dihydropyrazol-3-one, CGH 2466, SB220025, Antibiotic LL Z1640-2, TAK 715, SB202190 hydrochloride, SKF 86002, AMG548, CMPD-1, EO 1428, JX 401, ML 3403, RWJ 67657, SB 202190, SB 203580, SB 203580 hydrochloride, SB 239063, SCIO 469, SX Oil, TAK 715, Pamapimod, Losmapimod (GW856553), Dilmapimod (SB681323), VX 702, VX 745, Doramapimod (BIRB 796), BMS-582949, ARRY-797, PH797804, SCIO-469, preferably VX-702, SB202190,

Pamapimod, Losmapimod (GW856553), Dilmapimod (SB681323), Doramapimod (BIRB 796), BMS- 582949, ARRY-797, PH797804 and SCIO-469.

More information on some of these inhibitors can also be obtained from Arthur and Ley (2013) Mitogen-activated protein kinases in innate immunity; Nature Reviews Immunology 13,679- 692(2013).

The "subject", which may be treated by the inhibitors, in particular p38 inhibitors of the present invention, is a human subject that has been diagnosed with a coronavirus infection. In one embodiment, the subject is hospitalized. The subject may be of any age and may be a child between 0 to 10 years, a teenager between 10 and 18 years or an adult of 18 years and above. The subject may optionally be between the ages of 50 and 65, between the ages of 18 or 50, or older than 65 years of age. In other embodiments the subject is selected from the group consisting of subjects who are at least 60 years old, subjects who reside in chronic care facilities, subjects who have chronic disorders of the pulmonary or cardiovascular system, subjects who required regular medical follow up or hospitalization during the preceding year because of chronic metabolic diseases, renal dysfunction, hemoglobinopathies, or immunosuppression.

In one specific aspect, the subject may be treated with the p38 inhibitor in order to prevent or treat a "COVID-19 cytokine storm". As mentioned above, this term is used within its regular meaning as used in the art (see, in this respect, Jamilloux et al, 2020) to mean a cytokine storm that may occur in subjects that have been infected with a human-pathogenic coronavirus, in particular SARS-CoV-2. Such a cytokine storm is marked by rapid clinical deterioration and an increase in pro-inflammatory cytokines marks the transition from Stage II to Stage III COVID-19. Specifically, both Huang et al. and Jamilloux et al. note that a sudden increase in IL-Ib and/or TNF-a was observed, possibly together with an increase in two or more, three or more, four or more, five or more or all six of TNF-a, IL-1R, IP-10, IL-8, MCP-1, and MIP-Ib. In one aspect, the MEK inhibitor is used to reduce the level of IL-Ib and/or TNF-a in the subject, preferably reducing the level of one or more, two or more, three or more, four or more, five or more or all six of TNF-a, IL-1R, IP-10, IL-6, IL-8, MCP-1, MIP-la and MIR-1b in a subject.

The inflammatory cytokines and chemokines cited above are well known in the art. Specifically, the terms TNF-a, IL-1R, IP-10, IL-8, MCP-1, and MIP-Ib refer to the human protein sequences known in UNIPROT and GENEBANK under the following accession numbers:

Gene GeneBank accession Uniprot accession species

TNF-a NM_000594 P01375

IL-Ib NM_000576 P01584

IP-10 NM 001565 P02778

- Fluman

IL-8 NM_000584 P10145

MCP-1 NM_002982 P13500

MIP-Ib NM_002984 P13236

In the method of the invention, the p38 inhibitor and the antiviral may be administered orally, intravenously, intrapleurally, intramuscularly, topically or via inhalation. Preferably, the compounds are administered via inhalation or orally. In preferred embodiment, PH-797804 is administered once daily in an oral dosage between lOOmg and lOOOmg, preferably 300mg, 600mg or 900mg, for on 1 to 21 consecutive days, preferably 5 to 18 or 7 to 14 consecutive days after hospitalization.

Specifically, as summarized in Figure 5, in studies Losmapimod was administered at doses of 2.5 mg, 7.5 mg, 15 mg, 20 mg or 30 mg as oral tablets. Different dosages were tested. Specifically, for the treatment of COVID-19, 30mg daily in two doses as oral tablets were administered for 14 days. Results of this study are not yet available. Different dosage schemes are summarized in Figure 5, however any dosage between at least 0.5 mg to 30 mg daily is considered to be feasible. PH-797804 was administered at 0.5 mg, 3 mg, 6 mg or 10 mg once daily as oral tablets for 28 days, 6 or 12 weeks. Again, dosage between 0.5 mg and 30 mg is envisioned.

VX-702 was administered at 5 and 10 mg daily for 12 weeks. However, for the treatment of COVID- 19, dosages between 0.5 mg and 30 mg daily are envisaged.

The ribonucleoside analog can be selected from the group comprising Favipiravir, Molnupiravir, Sofosbuvir, Ribavirin, Remdesivir or GS-441524 monophosphate or triphosphate. The preferred ribonucleoside analog is Remdesivir, however, as mentioned above, other ribonucleoside analogs are currently being examined for their usefulness in treating Coronaviruses (Borbone et al.; Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV2 and other Coronaviruses; Molecules 2021, 26, 986). It is likely that a synergistic effect will be observed between Sofosbuvir, Ribavirin, Favipiravir or Molnupiravir in combination with p38 inhibitors in the treatment of COVID- 19 and follow-up studies are planned.

Remdesivir is a prodrug that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase. Remdesivir has the Chemical structure below:

Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID-19 pandemic, Remdesivir was approved or authorized for emergency use to treat COVID-19 in around 50 countries. Updated guidelines from the World Health Organization in November 2020 include a conditional recommendation against the use of remdesivir for the treatment of COVID-19. Remdesivir was originally developed to treat hepatitis C, and was subsequently investigated for Ebola virus disease and Marburg virus infections before being studied as a post-infection treatment for COVID-19. As can be seen from Figure 5, Remdesivir is administered at a dosage of 200 mg on day 1 and 100 mg per day fur up to 9 days intravenously. Therefore, a physical combination of the generally orally administered p38 inhibitor with Remdesivir, which is administered intravenously, would be difficult unless the p38 inhibitor was formulated for intravenous use, however simultaneous or sequential administration would be conceivable.

As mentioned above, the composition comprising the p38 inhibitor or an antiviral compound may be a pharmaceutical composition. Preferably, such compositions further comprise a carrier, preferably a pharmaceutically acceptable carrier. The composition can be in the form of orally administrable suspensions or tablets, nasal sprays, preparations for inhalation devices, sterile injectable preparations (intravenously, intrapleurally, intramuscularly), for example, as sterile injectable aqueous or oleaginous suspensions or suppositories.

The p38 inhibitor and the antiviral agent are preferably administered in a therapeutically effective amount. The "therapeutically effective amount" for each active compound/inhibitor can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the compound by the body, the age and sensitivity of the patient to be treated, adverse events, and the like, as will be apparent to a skilled artisan. The amount of administration can be adjusted as the various factors change over time.

The inhibitors, methods and uses described herein are applicable to human therapy. The compounds described herein, in particular, PH-797804 and Remdesivir, may be administered in a physiologically acceptable carrier to a subject, as described herein. Depending upon the manner of introduction, the compounds may be formulated in a variety of ways as discussed below. The concentration of therapeutically active compound in the formulation may vary from about 0.1-100 wt. %. The agents may be administered alone or in combination with other treatments.

The pharmaceutical compounds in the method of present invention can be administered in any suitable unit dosage form. Suitable oral formulations can be in the form of tablets, capsules, suspension, syrup, chewing gum, wafer, elixir, and the like. Pharmaceutically acceptable carriers such as binders, excipients, lubricants, and sweetening or flavoring agents can be included in the oral pharmaceutical compositions. If desired, conventional agents for modifying tastes, colors, and shapes of the special forms can also be included. For injectable formulations, the pharmaceutical compositions can be in lyophilized powder in admixture with suitable excipients in a suitable vial or tube. Before use in the clinic, the drugs may be reconstituted by dissolving the lyophilized powder in a suitable solvent system for form a composition suitable for intravenous or intramuscular injection.

In one embodiment, the reduction of the viral infection is a reduction in plaque forming units (PFU)/ml. The "plaque forming units" is a measure of the number of particles capable of forming plaques per unit volume, such as virus particles. It is a functional measurement rather than a measurement of the absolute quantity of particles: viral particles that are defective or which fail to infect their target cell will not produce a plaque and thus will not be counted. For example, a solution of coronavirus with a concentration of 1,000 PFU/mI indicates that 1 mI of the solution carries enough virus particles to produce 1000 infectious plaques in a cell monolayer. In the case of the present invention, a cell culture treated with an inhibitor shows a reduced number of plaque forming units in a culture after the treatment, when compared to a culture before the treatment with a p38 inhibitor, such as PFI-797804, or an antiviral agent such as Remdesivir.

For the purpose of the invention the active compound as defined above also includes the pharmaceutically acceptable salt(s) thereof. The phrase "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds of the invention that are safe and effective for the desired administration form. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

It must be noted that as used herein, the singular forms "a", "an", and "the", include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a reagent" includes one or more of such different reagents and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.

All publications and patents cited in this disclosure are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term "comprising" can be substituted with the term "containing" or sometimes when used herein with the term "having".

When used herein "consisting of" excludes any element, step, or ingredient not specified in the claim element. When used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

EXAMPLES

The following examples illustrate the invention. These examples should not be construed as to limit the scope of the invention. The examples are included for purposes of illustration and the present invention is limited only by the claims.

MATERIALS:

1. CELL LINES

2. VIRUS

Example 1: Cytokine response and MAPK p38 signaling is activated during SARS-CoV-2 infection

First experimental evidence for the importance of p38 MAPK signaling for SARS-CoV-2 hyperinflammation was provided by Bouhaddou et al. (2020;The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell 182, 685-712) demonstrating that inhibition of p38 reduced the production of disease-relevant cytokines in infected cells. This was confirmed in the experiment below, showing a strong induction of pro-inflammatory cytokines and p38 MAPK activation upon SARS-CoV-2 infection in cultured human airway cells (Calu-3). The human bronchioepithelial cell line Calu-3 was cultivated in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% standardized foetal bovine serum (FBS Advance; Capricorne), 2 mM L-glutamine, 100 U/mL penicillin, and 0.1 mg/mL streptomycin. All cells were cultured in a humidified incubator at 37°C and 5% C02. Calu-3 cells were infected with three SARS-CoV-2 isolates FI, NK and LP in infection-PBS (containing 0.2% BSA, 1% CaCI2, 1% MgCI2, 100 U/mL penicillin and 0.1 mg/mL streptomycin) at a MOI of 2 or Mock infected. Titers of newly produced SARS-CoV-2 virus particles and supernatants were analyzed over 72 h.p.i. Figure 1A shows the results of three independent experiments indicating that all three SARS-CoV-2 isolates could replicate in Calu-3 cells. Figure IB shows mRNA induction of COVID-19 relevant pro-inflammatory cytokines IL-6, IP-10 and TNF during SARS-CoV-2 infection in Calu-3 cells determined by RT-PCR analysis.

As can be seen from Figure 1A and IB, the SARS-CoV-2 was able to replicate in the Calu-3 cells and pro-inflammatory cytokines were increased after infection. Figure 1 C is a Volcano plot summarizing significantly increased host response factors upon infection with SARS-CoV-2 compared to non- infected cells (mock). Data are derived from mRNA hybridization using the NanoString host response panel. Figure 1 D shows a Western blot analysis of phosphorylated active MAPK p38 at 24 h.p.i. with

SARS-CoV-2.

To achieve a reduction of cytokine expression by SARS-CoV-2 we employed the three pre-clinical evaluated p38 inhibitors VX-702 (Vertex), PH-797804 (Pfizer) and GW856553X (GlaxoSmithKline) to analyze their therapeutic potential for the treatment of COVID-19 in a repurposing approach. Calu-3 cells were pretreated with 0.5, 1 and 5 mM concentrations of each inhibitor or DMSO, respectively, for one hour before infection with SARS-CoV-2 at MOI 0,001. The mRNA expression levels of IFN-b, IL-6, IP-10 and TNF-a were determined by RT-PCR analysis on total RNA isolated after 48 h.p.i. and compared to the mRNA levels in infected cells that where not treated with inhibitor. The results demonstrated that all three p38 inhibitors reduced the mRNA-expression of the COVID-19 relevant cytokines IFN-b, IL-6, IP-10 and TNF-a in a concentration-dependent manner (Figure 2A). In parallel, western blot analysis demonstrated efficient and concentration-dependent reduction of the p38 kinase activity following inhibitor treatment as evidenced by the lack of MSK-1 phosphorylation, which is a direct downstream target of p38. Specifically it was found that all three inhibitors block p38 signaling in a concentration-dependent manner as demonstrated by the reduction of MSK-1 phosphorylation. Calu-3 cells were treated with the inhibitors for lh and then infected with SARS- CoV-2 at MOI 0,01 or left untreated (mock). Cells were lysed and proteins separated by SDS-Page and transferred to nitrocellulose membrane. Phosphorylation of p38 (p-p38) and its downstream target MSK-1 (p-MSK-1) was detected using phospho-specific antibodies. Viral infection is verified by staining of the viral N protein. Tubulin levels are used as loading control. (Figure 2B). Further experiments showed that all three inhibitors are non-toxic over a wide range of concentrations. Calu- 3 cells were treated for 24h with the indicated inhibitors at the indicated concentrations and the release of Lactose-Dehydrogenase (LDH) was measured. Treatment with Triton X-100 or H₂0 was used as positive control (pos. Ctrl.) or negative control (ng. Ctrl.), respectively. All three inhibitors demonstrated absence of cytotoxicity upon treatment with up to 60 mM (Figure 2C).

Example 3: p38 inhibition can affect SARS-CoV-2 replication at high concentrations.

To determine a potential antiviral effect on SARS-CoV-2 replication by the p38 inhibitors in addition the observed immunomodulatory properties, supernatants of inhibitor-treated infected cells were analyzed by standard plaque assay. Calu-3 cells were treated for lh with the indicated concentrations of p38 inhibitor PH-797804 or VX-702 before infection with SARS-CoV-2 at MOI 0,001. Viral titers were determined after 48h by plaque titration. A reduction in viral titers was observed for inhibitor PH-797804 at 20 and 40 pM, which represent 4- and 10-fold higher concentration compared to the previous assays (Figure 3A). For VX-702 no antiviral effect could be observed at any tested concentration (Figure 3B). None of the inhibitors affected viral replication at a concentration of 5 pM.

Example 4: Antiviral activity of the single and combination treatments with the p38 inhibitors and Remdesivir.

Immunomodulatory and antiviral drugs are often combined to increase therapeutic effects, which can facilitate faster recovery of diseased patients and further reduce lethality. We therefore analyzed the effect of a combined treatment of the p38 inhibitors PH-797804 and VX-702 with the only clinically used antiviral drug Remdesivir and analyzed viral replication after 48h of infection.

Specifically, Calu-3 cells were treated with DMSO, the p38 inhibitors VX-702 (5 pM) or PH-797804 (5 pM) for lh before infections with SARS-CoV-2 variant FI at MOI 0.01 for 48h. Supernatants were collected and titrated by plaque assay. The results are shown in Figure 4A. Each symbol represents plaque-forming units (PFU) per mL detected in a single experimental sample; n = 4 per treatment. For statistical analysis, significant differences were evaluated using one-way ANOVA followed by Dunnett's multiple comparison test. **p < .01, ***p < .001. Unexpectedly, the combination of the p38 inhibitors with Remdesivir reduced SARS-CoV-2 viral titers 100-fold more efficiently compared to the treatment with Remdesivir alone. While Remdesivir alone achieved a 10-fold reduction of viral replication compared to solvent-treated cells (DMSO). In contrast, combination with 5 pM of PH- 707804 or VX-702 reduced viral titers by 10.000- and 1000-fold compared to the solvent-treated control or treatment with 5 mM of the p38 inhibitors alone, respectively. To assess the degree of drug synergism between PH-797804 and Remdesivir to reduce viral titers of SARS-CoV-2 a titration matrix using the drug concentrations shown in Figure 4A (ImM Remdesivir (Rem), 5mM PH-797804 (PH), 5mM VX-702 (VX) and a combination of ImM Remdesivir (Rem) with 5mM PH-797804 (PH) or 5mM VX- 702 (VX)) was performed and titers were determined by plaque assay. This demonstrates that the combination of 5 mM of the p38 inhibitor PH-797804 or VX-702 with 1 mM of Remdesivir resulted in reductions of viral titer, though combinations of Remdesivir with PH-797804 were 10 fold more effective and showed the strongest response. Figure 4B shows a drug combination matrix used to assess the synergy score of PH-797804 with Remdesivir to inhibit replication of SARS-CoV-2. Calu-3 cells were treated with the indicated amounts of PH-797804 or Remdesivir and plaque titers were determined and synergy scores were calculated. The results were used to calculate the drug synergy scores using the Bliss, HSA, and ZIP synergy models (5-7). All three models report a high synergistic action of 17.078, 13.288 and 17.811, respectively for the combination of PH-797894 with Remdesivir to reduce viral replication of SARS-CoV-2. Results from the analysis of the drug synergy score was calculated using the algorithms "Bliss", "HAS" and "ZIP" are shown in Figure 4C. The "Bliss" Model quantifies the excess effect (using a multiplicative model) of the response as if the drugs would act independently. The "HAS" Model quantifies excess over the highest single drug effect. The "ZIP" (zero interaction potency) Model quantifies the deviation from the additive effect of the drugs as if they don't interact.

REFERENCES

1. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo, L, Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., and Cao, B. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497-506

2. Moore, J. B., and June, C. H. (2020) Cytokine release syndrome in severe COVID-19. Science 368, 473-474

3. Borgeling, Y., Schmolke, M., Viemann, D., Nordhoff, C., Roth, J., and Ludwig, S. (2014) Inhibition of p38 mitogen-activated protein kinase impairs influenza virus-induced primary and secondary host gene responses and protects mice from lethal H5N1 infection. J Biol Chem 289, 13-27

4. Bouhaddou, M., Memon, D., Meyer, B., White, K. M., Rezelj, V. V., Correa Marrero, M., Polacco, B. J., Melnyk, J. E., Ulferts, S., Kaake, R. M., Batra, J., Richards, A. L., Stevenson, E., Gordon, D. E., Rojc, A., Obernier, K., Fabius, J. M., Soucheray, M., Miorin, L., Moreno, E., Koh, C., Tran, Q. D., Hardy, A., Robinot, R., Vallet, T., Nilsson-Payant, B. E., Hernandez-Armenta, C., Dunham, A., Weigang, S., Knerr, J., Modak, M., Quintero, D., Zhou, Y., Dugourd, A., Valdeolivas, A., Patil, T., Li, Q., Huttenhain, R., Cakir, M., Muralidharan, M., Kim, M., Jang, G., Tutuncuoglu, B., Hiatt, J., Guo, J. Z., Xu, J., Bouhaddou, S., Mathy, C. J. P., Gaulton, A., Manners, E. J., Felix, E., Shi, Y., Goff, M., Lim, J. K., McBride, T., O'Neal, M. C., Cai, Y., Chang, J. C. J., Broadhurst, D. J., Klippsten, S., De Wit, E., Leach, A. R., Kortemme, T., Shoichet, B., Ott, M., Saez-Rodriguez, J., tenOever, B. R., Mullins, R. D., Fischer, E. R., Kochs, G., Grosse, R., Garcia-Sastre, A., Vignuzzi, M., Johnson, J. R., Shokat, K. M., Swaney, D. L., Beltrao, P., and Krogan, N. J. (2020) The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell 182, 685-712 e619

5. Yadav, B., Wennerberg, K., Aittokallio, T., and Tang, J. (2015) Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model. Comput Struct BiotechnolJ 13, 504-513

6. Bliss, C. I. (1939) The Toxicity of Poisons applied jointly. Anna I of Applied Biology Berenbaum, M. C. (1989) What is synergy? Pharmacol Rev 41, 93-141

Claims

1. A p38 inhibitor or a pharmaceutically acceptable salt thereof for use in a method for the treatment of COVID-19, and wherein the p38 inhibitor is administered in combination with a ribonucleoside analog, preferably selected from the group consisting of Remdesivir (GS-5734), GS-441524 monophosphate, GS-441524 triphosphate, Sofosbuvir, Ribavirin, Favipiravir or Molnupiravir.

2. The p38 inhibitor or a pharmaceutically acceptable salt thereof for the use according to claim 1 wherein the p38 inhibitor is selected from the group consisting of PH-797804, VX-702, Losmapimod (GW856553), SB202190, Pamapimod, Dilmapimod (SB681323), SB239063, Doramapimod (BIRB 796), B MS-582949, ARRY-797, Adezamapimod (SB203580), and SCIO-469.

3. The p38 inhibitor or pharmaceutically acceptable salt thereof for the use according to claim 1 or 2, wherein the p38 inhibitor is PH-797804, Losmapimod or VX-702 and the ribonucleoside analog is Remdesivir.

4. The p38 inhibitor or a pharmaceutically acceptable salt thereof for the use according to any one of the preceding claims, wherein the COVID-19 is Stage I, Stage II or Stage III COVID-19, or COVID-19 cytokine storm.

5. The p38 inhibitor for the use of claim 4, wherein the COVID-19 is caused by a SARS-CoV-2 variant, preferably selected from the group consisting of D614G, B.1.1.7, B.1.351, PI, P2, B.1.617, B.1.427, B.1.429, B.1.525 or B.1.526.

6. The p38 inhibitor or a pharmaceutically acceptable salt thereof for the use according to any one of claims 1 to 5, wherein the p38 inhibitor or a pharmaceutically acceptable salt thereof is administered contemporaneously, previously or subsequently to the ribonucleoside analog.

7. A pharmaceutical composition comprising a p38 inhibitor or a pharmaceutically acceptable salt thereof and a ribonucleoside analog selected from the group consisting of Remdesivir (GS- 5734), GS-441524 monophosphate or GS-441524 triphosphate.

8. A pharmaceutical composition comprising a p38 inhibitor, and a ribonucleoside analog selected from the group consisting of Remdesivir (GS-5734), GS-441524 monophosphate or GS-441524 triphosphate for use as a medicament.

9. The pharmaceutical composition of claim 7 or 8 wherein the p38 inhibitor is selected from the group consisting of PH-797804, VX-702, Losmapimod (GW856553), SB202190, Pamapimod, Dilmapimod (SB681323), SB239063, Doramapimod (BIRB 796), BMS-582949, ARRY-797, Adezamapimod (SB203580), and SCIO-469.

10. The pharmaceutical composition as defined in any one of claims 7 to 9 for use in the prophylaxis and/or treatment of a viral disease.

11. The pharmaceutical composition for the use according to claim 10, wherein the viral disease is COVID-19.

12. The pharmaceutical composition for the use according to claim 11, wherein the COVID-19 is Stage I, Stage II or Stage III COVID-19 or COVID-19 cytokine storm.