DESC:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition of anti-tumour necrosis factor (anti-TNF) agent for management of infectious diseases caused by coronaviruses. In particular, the present invention provides a pharmaceutical composition or kit comprising etanercept which is an anti-TNF agent either alone or in combination with other therapeutic agents(s) for use in the management of COVID-19. The invention also relates to their dosing regimens.

BACKGROUND OF THE INVENTION
Coronaviruses are large family of viruses that cause diseases like common cold, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). In 2019, a new coronavirus was identified which was named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease caused by it as coronavirus disease 2019 (COVID-19). Intensive research for vaccines and therapeutic agents for the prevention and treatment of COVID-19 is underway across the world. One practical approach as a rapid response to an emerging pandemic is to repurpose existing therapeutic agents, since most of these agents have already been tested for their safety. The present disclosure satisfies the need of re-purposing existing therapeutics in managing infection caused by coronaviruses.

COVID-19 infection is accompanied by an aggressive inflammatory response with the release of a large amount of pro-inflammatory cytokines in an event known as “cytokine storm.” Pro-inflammatory cytokines involved in COVID-19 are TNF- a, IL-6 and IL-1. Pro-inflammatory cytokines are involved in the up-regulation of inflammatory reactions. Lung injury is one consequence of high levels of these cytokines, that can progress into more severe form like acute respiratory distress syndrome (ARDS). ARDS is a type of respiratory failure characterized by low oxygen saturation levels, which is a major cause of mortality in COVID-19. Effectively suppressing the cytokine storm is an important way to prevent the deterioration of patients with COVID-19 infection and save the patients' lives. TNF is by far the most well-characterized pro-inflammatory cytokine and it is also known to play a central role in other viral diseases, including those caused by influenza virus, dengue virus, and Ebola virus. TNF-a was one of the cytokines whose overproduction was related to a poor prognosis in patients with SARS and MERS. In patients with SARS-CoV-2 infection, TNF-a levels increase early in the infection and remain elevated throughout the infection. Importantly, TNF-a in the lungs of COVID-19 patients induces HA-synthase-2 (HAS2) in EpCAM+ lung alveolar epithelium and CD31+ lung alveolar endothelium and fibroblasts. HA (hyaluronan) is a key culprit for the fluid influx in the lung alveoli, a leading cause of deoxygenation and ventilator admission. Also, TNF is expressed by a variety of immune cells, and its primary receptor, TNFR1, appears to be expressed by all cell types causing excess TNF to act as an amplifier of inflammation. Therefore, anti-TNF therapies that block effects of TNF, presents a highly specific therapeutic approach to prevent cytokine storm or its complications. TNF blockade leads to downregulation of pro-inflammatory mediators, including IL-1, IL-6, and granulocyte-macrophage colony stimulating factor within 24 hours. Clotting biomarkers are also rapidly downregulated, with significant reductions in D-dimer and pro-thrombin fragments seen within 1 hour of anti-TNF therapy. Accordingly, therapeutics that can control the production of certain cytokines, especially TNF, may be useful in the management of diseases caused by coronaviruses and hence, anti-TNF agents are potential treatment option that deserves high priority in the management of COVID-19.

Etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75-kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1, inhibits TNF-a, and to some extent TNF-ß, by blocking its interaction with cell-surface TNF receptors, thereby modulating the biological responses induced or regulated by TNF. Etanercept is most popular anti-TNF with well characterized safety profile in treatment of various auto-immune and inflammatory disorders.

In summary, anti-TNF agent like etanercept, either alone or in combination with other therapeutic agent(s), can be used for treating, managing, or preventing infectious diseases caused by coronaviruses.

SUMMARY OF THE INVENTION
It is therefore among the objects of the present invention to provide in certain of its preferred aspects and preferred embodiments each and all of the following.

The present invention accordingly, provides a composition comprising anti-TNF agent for management of infectious disease caused by coronaviruses.

In another embodiment the invention provides a composition comprising anti-TNF agent etanercept for management of infectious disease caused by coronaviruses.

In yet another embodiment the invention provides a composition comprising anti-TNF agent for management of infectious disease COVID-19.

In a further embodiment the invention provides a composition comprising anti-TNF agent etanercept for management of infectious disease COVID-19.

Another embodiment of the invention is to provide composition for management of infectious disease caused by coronaviruses comprising etanercept and other pharmaceutically acceptable excipients.

A further embodiment of the invention encompasses methods of treating, managing, or preventing infectious disease caused by coronaviruses which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an anti-TNF agent.

Another embodiment of the invention encompasses methods of treating, managing, or preventing infectious disease COVID-19 which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an anti-TNF agent.

Yet another embodiment of the invention encompasses methods of treating, managing, or preventing infectious disease caused by coronaviruses which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an anti-TNF agent etanercept.

Another embodiment of the invention encompasses methods of treating, managing, or preventing infectious disease COVID-19 which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an anti-TNF agent etanercept.

Yet other embodiment of the invention encompasses methods of treating, managing, or preventing infectious disease caused by coronaviruses which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an anti-TNF agent in combination with another therapeutic agent(s).

A further embodiment of the invention encompasses methods of treating, managing, or preventing infectious disease COVID-19 which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an anti-TNF agent, etanercept in combination with another therapeutic agent(s).

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent and instructions for administration to a patient in need thereof, for the treatment, management, or prevention of infectious disease caused by coronaviruses.

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent and instructions administration of the dosage forms to a patient in need thereof, for the treatment, management, or prevention of infectious disease COVID-19.

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent etanercept and instructions for administration to a patient in need thereof, for the treatment, management, or prevention of infectious disease caused by coronaviruses.

In yet another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent etanercept and instructions for administration of the dosage forms to a patient in need thereof, for the treatment, management, or prevention of infectious disease COVID-19.

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent and a pharmaceutically acceptable dosage form of another therapeutic agent(s) and instructions for mixing or simultaneous or sequential administration of the dosage forms to a patient in need thereof, for the treatment, management, or prevention of infectious disease caused by coronaviruses.

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent and a pharmaceutically acceptable dosage form of another therapeutic agent(s) and instructions for mixing or simultaneous or sequential administration of the dosage forms to a patient in need thereof, for the treatment, management, or prevention of COVID-19.

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage forms of anti-TNF agent etanercept and a pharmaceutically acceptable dosage form of another therapeutic agent(s) and instructions for mixing or simultaneous or sequential administration of the dosage forms to a patient in need thereof, for the treatment, management, or prevention of infectious disease caused by coronaviruses.

In another embodiment, the invention provides a kit comprising a pharmaceutically acceptable dosage form of anti-TNF agent etanercept and a pharmaceutically acceptable dosage form of another therapeutic agent(s) and instructions for mixing or simultaneous or sequential administration of the dosage forms to a patient in need thereof, for the treatment, management, or prevention of COVID-19.

In other embodiment of the invention, anti-TNF agent is administered in combination with standard of care protocol used to treat, prevent or manage infectious diseases or disorders caused by coronaviruses. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In yet other embodiment of the invention, anti-TNF agent etanercept is administered in combination with standard of care protocol used to treat, prevent or manage infectious diseases or disorders caused by coronaviruses. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In another embodiment of the invention, anti-TNF agent is administered in combination with standard of care protocol used to treat, prevent or manage infectious disease COVID-19. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In another embodiment of the invention, anti-TNF agent etanercept is administered in combination with standard of care protocol used to treat, prevent or manage infectious disease COVID-19. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In other embodiment of the invention, anti-TNF agent is administered in combination with another therapeutic agent(s) and standard of care protocol used to treat, prevent or manage infectious diseases or disorders caused by coronaviruses. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In other embodiment of the invention, anti-TNF agent etanercept is administered in combination with another therapeutic agent(s) and standard of care protocol used to treat, prevent or manage infectious diseases or disorders caused by coronaviruses. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In another embodiment of the invention, anti-TNF agent is administered in combination with another therapeutic agent(s) and standard of care protocol used to treat, prevent or manage infectious disease COVID-19. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In another embodiment of the invention, anti-TNF agent etanercept is administered in combination with another therapeutic agent(s) and standard of care protocol used to treat, prevent or manage infectious disease COVID-19. Examples of such standard of care protocol includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood transfusions and other non-drug based therapies.

In another embodiment of the invention, the anti-TNF agent is selected from the group comprising anti-TNF fusion proteins or anti-TNF monoclonal, chimeric, humanized, resurfaced and recombinant antibodies and fragments thereof that are capable of inhibiting TNFa activity, whether fully or partially.

In a preferred embodiment of the invention the anti-TNF agent is Etanercept.

In a further embodiment of the present invention, the dose of etanercept is in the range of about 1 to 100 mg and dose range is 0.1 to 20 mg/kg, and preferably is 1-10 mg/kg.

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent for the treatment, management, or prevention of infectious diseases or disorders caused by coronaviruses wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved.

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent for the treatment, management, or prevention of infectious disease COVID-19 wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved.

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent etanercept for the treatment, management, or prevention of infectious diseases or disorders caused by coronaviruses wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved.

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent etanercept for the treatment, management, or prevention of infectious disease COVID-19 wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved.

In one of the embodiments, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of infectious diseases or disorders caused by coronaviruses wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer additional doses till desired outcome is achieved.

In another embodiment, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of COVID-19 wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer additional doses till desired outcome is achieved.

In yet another embodiment, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of infectious diseases caused by coronaviruses wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer 25 mg to 50 mg of etanercept every 3 to 4 days till desired outcome is achieved.

In a further embodiment, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of COVID-19 wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4 with or without combination with other therapeutic agent(s), with an option to administer 25 mg to 50 mg of etanercept every 3 to 4 days till desired outcome is achieved.

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent for the treatment, management, or prevention of infectious diseases or disorders caused by coronaviruses wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved, in combination with another therapeutic agent(s).

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent for the treatment, management, or prevention of infectious disease COVID-19 wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved, in combination with another therapeutic agent(s).

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent etanercept for the treatment, management, or prevention of infectious diseases or disorders caused by coronaviruses wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved, in combination with another therapeutic agent(s).

In another embodiment, the present invention provides a dosing regimen for administration of anti-TNF agent etanercept for the treatment, management, or prevention of infectious disease COVID-19 wherein first dose of anti-TNF agent is administered on Day 1, and the second dose of anti-TNF agent is administered on Day 4, with an option to administer additional doses till desired outcome is achieved, in combination with another therapeutic agent(s).

In one of the embodiments, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of infectious diseases or disorders caused by coronaviruses wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer additional doses till desired outcome is achieved, in combination with another therapeutic agent(s).

In yet another embodiment, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of COVID-19 wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer additional doses till desired outcome is achieved, in combination with another therapeutic agent(s).

In another embodiment, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of infectious diseases caused by coronaviruses wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer 25 mg to 50 mg of etanercept every 3 to 4 days till desired outcome is achieved, in combination with another therapeutic agent(s).

In a further embodiment, the present invention provides a dosing regimen for administration of etanercept for the treatment, management, or prevention of COVID-19 wherein first dose of etanercept 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer 25 mg to 50 mg of etanercept every 3 to 4 days till desired outcome is achieved, in combination with another therapeutic agent(s).

The details of one or more embodiments of the invention set forth below are illustrative only and not intended to limit to the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims.

DETAIL DESCRIPTION OF INVENTION
Coronaviruses are enveloped, positive single stranded large RNA viruses. COVID-19 is caused by a novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accumulating evidence suggests that the severity of COVID-19 is associated with an increased level of inflammatory mediators including cytokines and chemokines like TNF- a, IL-6 and IL-1.

It is believed that TNF is a major component of the cytokine storm. TNF-a levels increase early in the infection and remain elevated throughout the infection. Anti-TNF drugs inhibits the hyper-inflammatory response of the immune system which is a major reason for mortality in Covid-19 patients. Etanercept has shown to decrease clotting biomarker like D-dimer and pro-thrombin fragments seen within 1 h of therapy.

Anti-TNF agents, alone or in combination with other therapeutic agent(s), are useful in autoimmune and inflammatory conditions and also for treating bacterial, viral, fungal or protozoal infections, and complications resulting therefrom. Accordingly, the present invention relates to administration of anti-TNF agents like etanercept for management of infectious disease caused by coronaviruses.

For purposes of the present invention as disclosed and described herein, the following terms are defined as follows.

The term “about” means ± 20% preferably ±10%.

The term treatment/treating, management/managing, prevention/preventing of infectious disease caused by coronaviruses or COVID-19 as used herein comprises prophylaxis and/or treatment, reduction in markers, reduction in lung injury caused by cytokine storm, reduced risk of ARDS, reduction in rate of morbidity and/or mortality caused by low oxygen saturation levels in COVID-19 patients. Treat, treating, or treatment are used broadly in relation to the invention and each such term encompasses, among others, preventing, ameliorating, inhibiting, or curing a deficiency, dysfunction, disease, or other deleterious process, including those that interfere with and/or result from a therapy.

In accord with this invention, "administered” or “administering” means that the patient is treated with the agent in an amount and for a time sufficient to induce a sustained improvement in at least one indicator that reflects the severity of the disorder. The degree of improvement is determined based on changes/reduction of biomarker level, signs or symptoms, and determinations may also employ questionnaires that are administered to the patient, such as quality-of-life questionnaires.

Various indicators that reflect the extent of the patient's illness may be assessed for determining whether the amount and time of the treatment is sufficient. The baseline value for the chosen indicator or indicators is established by examination of the patient prior to administration of the first dose of the anti-TNF agent with or without another therapeutic agent(s). Preferably, the next examination of the indicators may be done within Day 4, 7 and 14 after administering the first dose. The first dose is administered as soon as practically possible after the disease is diagnosed or symptoms start appearing.

Improvement is expected by administering anti-TNF agent with or without another therapeutic agent(s) until the patient manifests an improvement over baseline for the chosen indicator or indicators. A period of 4 to 7 days, one to eight weeks, or even a single dose, often is sufficient for treating the diseases/disorders as mentioned in the present invention.

Although the extent of the patient's illness after treatment may appear improved according to one or more indicators, treatment may be continued indefinitely at the same level or at a reduced dose or frequency. Once treatment has been reduced or discontinued, it later may be resumed at the original level if symptoms should reappear.

In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and anti-TNF agent. Pharmaceutical compositions disclosed herein typically comprise anti-TNF agent and pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

Depending upon the manner of introduction, the compounds described herein may be formulated in a variety of ways. The term pharmaceutical composition/dosage form as used herein comprises various pharmaceutically acceptable dosage forms including oral solid as well as liquid dosage forms, such as but not limited to, tablets, soft gelatin capsule, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles microspheres and multi-particulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles microspheres and multi-particulates) and sprinkles, liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on) and the like; parenteral dosage forms such as liquids, liquid dispersions, suspensions, solutions, emulsions, (rods, capsules, rings), lyophilized formulation for reconstitution or freeze-dried powder, ready-to-use-liquid and the like; topical dosage forms, such as but not limited to, sprays, solutions, suspensions, ointments, drops, in-situ gel, aerosols, ointments, microspheres, creams, gels, patches, films etc. These dosage forms will usually include one or more pharmaceutically acceptable ingredients or excipients which refers to non-API or inactive substances which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.

US Patent No US 10058589; US 7,648,702; US application US 2018236030 and WO 2014064637 discloses pharmaceutical compositions comprising aqueous composition of TNF-binding protein comprising a TNF-binding protein, the contents of which are hereby incorporated herein by reference in their entirety.

As will be understood by those skilled in the art, the most appropriate method of administering the therapeutic agent(s) is dependent on a number of factors. The pharmaceutical composition can be administered orally, intravenously, or through the lungs. However, in general, subcutaneous route of administration for anti-TNF agent is preferred, whilst oral or parenteral administration of other therapeutic agent(s) is preferred.

The term “administration” as used herein refers to single agent administration or when given in combination it refers to simultaneous administration either by mixing or sequential administration without mixing i.e. in any order, one immediately after the other.

Administration of the anti-TNF agent and the other therapeutic agent(s) to a patient can occur simultaneously or sequentially by the same or different routes of administration.

Typically, active ingredients of the invention may not be administered to a patient at the same time or by the same route of administration. This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a dosage form of an anti-TNF agent, etanercept. Kits encompassed by this invention can further comprise additional therapeutic agent(s) comprising but not limited to antivirals, antibiotics, analgesics, corticosteroids, antagonists of inflammatory cytokines, DMARDs and non-steroidal anti-inflammatories, biologicals, antimetabolites, analgesics, anticoagulants etc. or a combination thereof.

Kits of the invention can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, pre-filled syringes, dual chambered syringe, drip bags, patches, and inhalers.

Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Standard of care treatment (SOC) includes, but are not limited to, supplemental oxygen therapy, vitamins and other minerals, mechanical ventilation, surgery, blood or plasma transfusions and other non-drug based therapies may additionally be administered as per physician’s discretion or as per latest guidelines and protocols by drug regulatory authorities or health agencies.

As used herein, “anti-TNF agents” comprises any small or large molecule that inhibits TNF. For the purpose of the present invention anti-TNF agent is etanercept.
In one embodiment of the invention, anti-TNF agent is administered one time per week to treat the various diseases/disorders disclosed herein, in another embodiment is administered at least two times per week, and in another embodiment is administered at least three times per week. An adult patient is a person who is 18 years of age or older. If injected, the effective amount of anti-TNF agent per adult dose ranges from 1-20 mg/m2, and preferably is about 5-12 mg/m2. Alternatively, a flat dose may be administered, whose amount may range from 5-100 mg/dose. Exemplary dose ranges for a flat dose to be administered by subcutaneous injection are 5-25 mg/dose, 25-50 mg/dose and 50-100 mg/dose.

In one embodiment of the invention, the various indications described are treated by administering a preparation acceptable for injection containing anti-TNF agent at 25 mg/dose, or alternatively, containing 50 mg per dose. The 25 mg or 50 mg dose may be administered repeatedly.

If a route of administration other than injection is used, the dose is appropriately adjusted in accord with standard medical practices. In many instances, an improvement in a patient's condition will be obtained by injecting a dose of about 25 mg of anti-TNF agent one to three times per week over a period of at least three weeks, or a dose of 50 mg of anti-TNF agent one or two times per week for at least three weeks, though treatment for longer periods may be necessary to induce the desired degree of improvement. The regimen may be continued indefinitely, with adjustments being made to dose and frequency if such are deemed necessary by the patient's physician.

Preferably, anti-TNF agent may be administered in adult or juvenile subject, wherein the dose of the etanercept may range from about 1 to 100 mg and preferred dose range is 0.1 to 20 mg/kg, and preferably is 1-10 mg/kg.

For paediatric patients (age 4-17), a suitable regimen involves the subcutaneous injection of 0.4 mg/kg, up to a maximum dose of 25 mg of etanercept, administered by subcutaneous injection one or more times per week.

In general, the dose and the treatment regimen or the duration of treatment may be appropriately carried out by a physician. For the management of infectious disease COVID-19 caused by SARS-CoV-2 and for the purpose of the present invention etanercept at a dose of 50 mg is administered on Day 1, and the second dose of etanercept 25 mg is administered on Day 4, with an option to administer additional doses till desired outcome is achieved. The additional doses comprise 25 to 50 mg of etanercept every 3 to 4 days till desired outcome is achieved.

The invention further includes the administration of anti-TNF agent concurrently with one or more other therapeutic agent(s). "Concurrent administration" encompasses simultaneous or sequential treatment with the components of the combination, as well as regimens in which the therapeutic agents are alternated, or wherein one component is administered long-term and the other(s) are administered intermittently. Examples of other therapeutic agents to be administered concurrently include but are not limited to antivirals, antibiotics, analgesics, corticosteroids, antagonists of inflammatory cytokines, DMARDs and non-steroidal anti-inflammatories, biologicals, antimetabolites, analgesics, anticoagulants etc. or a combination thereof.

According to one of the aspects of the present invention, there is provided a method of treating, managing, or preventing infectious disease caused by coronaviruses which comprises administering to the patient a. first dose of etanercept 50 mg on Day 1 b. second dose of etanercept 25 mg on Day 4 c. single loading dose of remdesivir 200 mg on Day 1 followed by once-daily maintenance doses of 100 mg from Day 2 to Day 5, in a five days cycle. The dose and the treatment regimen or the duration of treatment may be appropriately carried out by a physician.

According to one of the aspects of the present invention, there is provided a method of treating, managing, or preventing infectious disease caused by coronaviruses which comprises administering to the patient a. etanercept at a dose of about 50 mg and methotrexate at a dose of about 16 mg on Day 1, followed by a determination of marker level on day 4 and if there is no significant reduction in the markers on day 4, administering etanercept at a dose of 50 mg along with reduced dose of methotrexate which is preferably about 8 mg on Day 5 followed by a determination of marker level on Day 8 and continuing this cycle until there is a significant reduction in the marker level. The dose and the treatment regimen or the duration of treatment may be appropriately carried out by a physician.

The term markers as used in refers to biomarkers comprising but not limited to TNF-alpha, D-dimer, C-reactive protein (CRP), lactic acid dehydrogenase (LDH), IL-6 or serum ferritin. The biochemical or other methods used to determine the levels of these markers is known to a person skilled in this art.

“Desired outcome” as mentioned herein refers to improvement in atleast one of the below mentioned criteria/indicators:
1. Defined as =2 points reduction on WHO Ordinal Scale: Improvement in clinical status assessed using WHO Ordinal Scale is considered an appropriate endpoint to evaluate the effect of the drugs for treatment or prevention of COVID-19. The same has been used in multiple clinical trials on COVID-19.
2. Clinically significant reduction or change in levels of biomarkers: D-dimer, CRP, IL-6, ferritin, TNF
3. Reduction in duration of hospitalization
4. Time to clinical improvement measured using WHO Ordinal Scale (defined as =2 points improvement)
5. Proportion of patients with clinical improvement (defined as =2 points reduction on WHO Ordinal Scale)
6. Time to clinical recovery: Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Uninfected, No clinical or virological evidence of infection; 2) Ambulatory, no limitation of activities; 3) Ambulatory, limitation of activities
7. Proportion of patients requiring mechanical ventilation
8. All cause mortality

The invention will be supported by pre-clinical and clinical study in COVID-19 patients and healthy subjects.

EXAMPLES:
Certain embodiments of the invention are illustrated by the following non-limiting examples:

CLINICAL STUDIES IN PATIENTS:
Study Protocol:
A phase II, multi-centre, double blind, randomized, comparative study is designed to evaluate efficacy and safety of composition of etanercept as an add-on therapy to remdesivir in moderate COVID-19 patients.

Moderate COVID-19 patients will be categorized as defined by the most recent version of ‘Clinical management protocol: COVID-19' released by Ministry of health and family welfare, Government of India. Patients who meet the eligibility criteria will be randomly assigned to any of the following treatment arms:
Treatment Arm 1 (Investigational arm): Etanercept (50/25 mg) + Remdesivir Injection
Etanercept dose: First dose of Etanercept 50 mg will be administered subcutaneously on Day 1, and the second dose of Etanercept 25 mg will be administered subcutaneously on Day 4.
Remdesivir dose*: Single loading dose of 200 mg on Day 1 followed by once-daily maintenance doses of 100 mg from Day 2 infused intravenously over 30 to 120 minutes to be given for 5 days.
Treatment Arm 2 (Comparator arm): Remdesivir injection + Placebo
Remdesivir dose*: Single loading dose of 200 mg on Day 1 followed by once-daily maintenance doses of 100 mg from Day 2 infused intravenously over 30 to 120 minutes to be given for 5 days.
Placebo: Placebo injection will be administered subcutaneously on Day 1 and Day 4 (injection volume will be similar to that of Etanercept in Treatment Arm 1)

[*Investigator should follow the most recent COVID-19 clinical management protocol for up-to-date dosing recommendations for Remdesivir]
Standard of care treatment (SOC): SOC such as corticosteroids/anti-virals/anti-biotics/ vitamins etc. will be administered as per investigator’s discretion or institutional protocol or guideline released by Ministry of health and family welfare, Govt. of India. Modification in the SOC treatment will be allowed as per investigator’s discretion.

Following assessments may be performed which includes but are not limited to vital signs assessment, physical & systemic examination, 12-lead ECG, RT-PCR, clinical laboratory assessment including biomarkers level, serum/urine pregnancy test in females of childbearing potential only and concomitant medication/ treatment assessment. Patients will be evaluated for Adverse Events (if any).

Study Endpoints:
Primary efficacy endpoint
• Proportion of patients with clinical improvement (defined as =2 points reduction on WHO Ordinal Scale) [Time frame: Day 14]
• Secondary efficacy endpoints
• Proportion of patients with clinically significant reduction in biomarkers: D-dimer, CRP, IL-6, ferritin, TNF. [Time frame: Day 4, 7 and 14 from baseline]
• [Responders will be defined as patients who demonstrate clinically significant reduction (=30%) or normalization of biomarkers elevated at baseline]
• Change in levels of biomarkers (D-dimer, C-reactive protein, IL-6, ferritin, TNF)
• [Time frame: Day 4, 7 and 14]
• Duration of hospitalization
• Time to clinical improvement measured using WHO Ordinal Scale (defined as =2 points improvement) [Time Frame: Day 14]
• Proportion of patients with clinical improvement (defined as =2 points reduction on WHO Ordinal Scale) [Time Frame: Day 7]
• Time to clinical recovery [Time Frame: Day 14]
[Note: Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the WHO Ordinal Scale: 1) Uninfected, No clinical or virological evidence of infection; 2) Ambulatory, no limitation of activities; 3) Ambulatory, limitation of activities]
• Proportion of patients requiring mechanical ventilation [Time frame: Day 14]
• All-cause mortality
• Safety endpoints:
• Proportion of patients experiencing Treatment-Emergent Adverse Events [Time Frame: Day 14]
• Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) including secondary bacterial infection [Time Frame: Day 14]

Our results would be in close conformity with the interpretations described above.
Results from phase II, multicenter, double blind, randomized clinical study to assess the safety and efficacy of Etanercept in moderate Covid-19 patients (COVETA study):

The study enrolled 50 patients grouped to receive the investigational drugs as:
Treatment Arm 1 (Investigational arm; 25 patients) [Etanercept group]: Lupin’s etanercept (50/25 mg) + Remdesivir Injection.
Etanercept dose: First dose of etanercept 50 mg was administered subcutaneously on day 1 followed by the second dose of etanercept 25 mg administered subcutaneously on day 4.
Remdesivir dose: Single loading dose of remdesivir 200 mg was administered on day 1 followed by once-daily maintenance doses of remdesivir 100 mg was infused intravenously over 30 to 120 minutes from day 2 for 5 days.
Treatment Arm 2 (Comparator arm; 25 patients) [Placebo group]: Placebo + Remdesivir injection
Remdesivir dose: Single loading dose of remdesivir 200 mg was administered on day 1 followed by once daily maintenance doses of remdesivir 100 mg was infused intravenously over 30 to 120 minutes from day 2 to be given for 5 days.

Standard of care (SOC) treatment such as corticosteroids/anti-viral/antibiotics/ vitamins etc. were administered as per investigator’s discretion.

Study Results:
Clinical Improvement (= 2 points reduction on WHO ordinal scale):
The proportion of patients with clinical improvement up to day 14 was higher (96%) in Etanercept group compared to placebo group (92%).
Primary Efficacy Endpoints - ITT Population
Parameter Statistics Etanercept
(N=25) Placebo
(N=25) Prop Difference p-value

Patients with clinical improvement up to Day 14 n (%) 24 (96.0) 23 (92.0) 0.04
0.999
95% CI (79.65, 99.90) (73.97, 99.02) (-0.09, 0.17)

Primary Efficacy Endpoints (Sensitivity Analysis) - PP Population
Parameter Statistics Etanercept
(N=25) Placebo
(N=25) Odds Ratio (95% CI) p-value
Sensitivity Analysis for the Logistic Regression of patients with clinical improvement Day 14
Patients with clinical improvement up to day 14 n (%) 24 ( 96.0) 23 ( 92.0) 2.31 0.517
95% CI (79.65, 99.90) (73.97, 99.02) (0.18, 28.83)

From above table, it can be inferred that the proportion of patients with clinical improvement was more in the etanercept group (96%) versus the placebo group (92%), indicating higher odds of improvement with etanercept. Similarly, clinical recovery rate was higher (96%) in Etanercept group compared to placebo group (92%).

Reduction in inflammatory markers:
Clinically desirable reduction was observed in inflammatory markers such as CRP, IL-6, Ferritin in both the groups with a dramatic fall in D-dimer levels in the etanercept group after the first dose.

Safety profile:
The safety profile was found to be comparable between both the treatment groups with none of the patients discontinuing the study due to adverse events.

The overall safety and tolerability of etanercept was found to be acceptable and in line with its known safety profile. No deaths, serious adverse events, discontinuations due to adverse events, or adverse events of special interest were reported during the study.

To summarize, Etanercept provided higher efficacy compared to placebo in terms of clinical improvement and reduction in inflammatory markers with acceptable safety profile for the treatment of hospitalized COVID-19 patients.

Clinical Improvement (= 2 points reduction on WHO ordinal scale) in Patients on Oxygen Support
It was also observed that in a sub-set of patients on oxygen support (baseline WHO ordinal scale score of 4), the proportion of patients with clinical improvement and clinical recovery was 100% in the etanercept group versus 80% in the placebo group indicating treatment difference of 20% in favor of etanercept by day 14. Thus, it can be concluded that the patients on oxygen support will also derive maximum benefit with etanercept treatment.

Also, in the same sub-set of patients, the median time to clinical improvement and clinical recovery was 8 days in the etanercept group versus 11 days in the placebo group, indicating faster improvement and earlier recovery by 3 days with etanercept compared to placebo in patients on oxygen support.

Reduction in inflammatory markers:
Clinically desirable reduction was observed in inflammatory markers such as CRP, IL-6, Ferritin in both the groups with a dramatic fall in D-dimer levels in the etanercept group after the first dose.

While examples of certain particular embodiments are provided herein, it will be apparent to those skilled in the art that various changes and modifications may be made. Such modifications are also intended to fall within the scope of the appended claims.

Both the foregoing summary and the detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the detailed description of the invention.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.

The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.
,CLAIMS:1. A pharmaceutical composition for use in the management of infectious diseases caused by coronaviruses wherein the composition comprises an anti-TNF agent and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the composition comprises pharmaceutically acceptable excipients selected from one or more of adjuvants, carriers, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants and preservatives.
3. The pharmaceutical composition according to claim 1, wherein the composition comprises an anti-TNF agent selected from a group consisting of anti-TNF fusion proteins, anti-TNF monoclonal, chimeric, humanized, resurfaced and recombinant antibodies or fragments thereof that are capable of inhibiting TNFa activity, whether fully or partially.
4. The pharmaceutical composition according to claim 2, wherein the anti-TNF agent is etanercept.
5. The pharmaceutical composition according to claim 3, wherein the composition contains about 1 to 100 mg etanercept.
6. The pharmaceutical composition according to claim 4, wherein the composition is administered in an amount of from about 25 mg to about 100 mg per administration.
7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is administered alone or in combination with therapeutically effective amount of one or more other therapeutic agent(s) or a supportive care therapy.
8. A pharmaceutical composition comprising about 1 to 100 mg of anti-TNF agent for use in the management of infectious diseases caused by coronaviruses, wherein first dose of the anti-TNF agent is administered on Day 1 and second dose of the anti-TNF agent is administered on Day 4 of the treatment cycle with an option to administer additional doses every 3 to 4 days till desired outcome is achieved, alone or in combination with one or more other therapeutic agent(s).
9. A pharmaceutical composition comprising about 25mg/ml or 50mg/ml of etanercept for use in the management of infectious diseases caused by coronaviruses, wherein about 50 mg of etanercept is administered on Day 1 and about 25 mg of etanercept is administered on Day 4 of the treatment cycle with an option to administer additional doses every 3 to 4 days till desired outcome is achieved, alone or in combination with one or more other therapeutic agent(s).
10. A kit comprising the pharmaceutical composition of anti-TNF agent alone or in combination with one or more other therapeutic agent(s) and instructions for administration of the anti-TNF composition alone or in combination with one or more other therapeutic agent(s) to a patient in need thereof for the management of infectious disease caused by coronaviruses.
11. A method of management of infectious disease caused by coronaviruses in a subject, wherein the method comprises administering therapeutically or prophylactically effective amount of an anti-TNF agent to a subject in need thereof.
12. The method of claim 11, wherein first dose of the anti-TNF agent is administered on Day 1 and second dose of the anti-TNF agent is administered on Day 4 of the treatment cycle with an option to administer additional doses every 3 to 4 days till desired outcome is achieved, alone or in combination with one or more other therapeutic agent(s).
13. The method of claim 11 or 12, wherein the anti-TNF agent is selected from a group consisting of anti-TNF fusion proteins, anti-TNF monoclonal, chimeric, humanized, resurfaced and recombinant antibodies or fragments thereof that are capable of inhibiting TNFa activity, whether fully or partially.
14. The method of claim 11 to 13, wherein the anti-TNF agent is etanercept.
15. The method of claim 14, wherein about 50 mg of etanercept is administered on Day 1 and about 25 mg of etanercept is administered on Day 4 of the treatment cycle with an option to administer additional doses every 3 to 4 days till desired outcome is achieved, alone or in combination with one or more other therapeutic agent(s).
16. The method of any one of claims 11 to 15, further comprising administering a therapeutically effective amount of one or more another therapeutic agent(s) or a supportive care therapy.
17. The method of claim 11, wherein the infectious disease caused by coronaviruses is SARS, MERS or COVID-19.