WO2021251792A1

WO2021251792A1 - Pharmaceutical composition for the treatment of covid-19 respiratory syndrome

Info

Publication number: WO2021251792A1
Application number: PCT/KR2021/007328
Authority: WO
Inventors: Sei Eun KIM; Yu Kyung Kwon; Jong Lae Lim
Original assignee: Chong Kun Dang Pharmaceutical Corp.
Priority date: 2020-06-12
Filing date: 2021-06-11
Publication date: 2021-12-16
Also published as: TW202207913A; KR20210154771A

Abstract

The present invention relates to a pharmaceutical composition for treating human COVID-19 respiratory syndrome containing nafamostat or a pharmaceutically acceptable salt thereof as an active ingredient. Moreover, the present invention relates to a dosage regimen and a dose, which are useful when nafamostat or a pharmaceutically acceptable salt thereof is administered to humans for the purpose of treating COVID-19 respiratory syndrome. Furthermore, the present invention relates to a pharmaceutical composition for treating particularly patients belonging to a high risk group, among patients suffering from COVID-19 respiratory syndrome, the pharmaceutical composition containing, as an active ingredient, nafamostat or a pharmaceutical salt thereof, in which the pharmaceutical composition is used to improve or recover from COVID-19 respiratory syndrome in COVID-19 respiratory syndrome patients with a National Early Warning Score (NEWS) of 7 or more, COVID-19 respiratory syndrome patients 65 years of age or older, or COVID-19 respiratory syndrome patients with an oxygen saturation of less than 90%.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF COVID-19 RESPIRATORY SYNDROME

In 2019, an outbreak of novel coronavirus infection occurred in Wuhan City, Hubei Province, China. The disease has been officially named COVID-19 (coronavirus infectious disease-19) by the WHO, and defined as a respiratory syndrome caused by SARS-CoV-2 infection. In Korea, the disease has been designated as a first-class infectious disease which is a legally infectious disease of new infectious disease syndrome. SARS-CoV-2, an RNA virus belonging to the coronavirus, has been identified as a pathogen, and was reported to spread through saliva droplets generated when coughing or sneezing, or spread by touching objects contaminated with the COVID-19 virus and then touching the eyes, nose, and mouth. The incubation period for the COVID-19 virus is 1 to 14 days (average incubation period: 4 to 7 days), and the diagnosis of the COVID-19 virus is performed by isolating the virus from a sample collected from a patient or by detecting a specific gene in the sample.

It has been reported that symptoms of COVID-19 respiratory syndrome include a variety of respiratory symptoms, ranging from mild symptoms, such as fever, boredom, and cough, to severe symptoms such as difficulty in breathing and pneumonia, as well as phlegm, sore throat, headache, hemoptysis, nausea, and diarrhea. The mortality of COVID-19 infection is about 3.4% (based on WHO 3.5), and older patients, patients with reduced immune function, and patients with underlying diseases mainly show severe signs and lead to death in severe cases. Researchers around the world have spurred the development of a treatment or vaccine for Covid-19 respiratory syndrome, and the main drugs mentioned as candidates for the treatment of COVID-19 respiratory syndrome are as follows.

There is a prediction that chloroquine and hydroxychloroquine, known as drugs used for the prevention and treatment of malaria, may partially block the proliferation of the COVID-19 virus by inhibiting autophagy. As a result of testing 24 patients with confirmed COVID-19 virus infection, it was shown that, after 6 days, 75% of the patients were converted to negative, while only 10% of control patients for whom any treatment was not selected were converted to negative. Based on this result, chloroquine and hydroxychloroquine are considered therapeutic candidates with therapeutic utility. It is predicted that remdesivir, known as a therapeutic agent for Ebola virus, may be useful for the treatment of COVID-19 virus infection, based on its ability to block viral RNA synthesis by RNA polymerase. Remdesivir was found to shorten the recovery time of inpatients by about 30% in a clinical study led by the National Institute of Health (NIH). Specifically, as a result of administering remdesivir and placebo to 1,063 COVID-19 patients, it was shown that the recovery period was shortened from 15 days to 11 days in the remdesivir-administered group compared to the placebo group. In addition, the mortality rates 2 weeks after remdesivir administration were 7.1% and 11.9% in the remdesivir-administered group and the placebo group, respectively, which show a more favorable clinical result for remdesivir than the previous mortality rates of 8% and 11.6%. However, an expert panel of the World Health Organization (WHO) Guideline Development Group (GDG) has revealed that it does not recommend the use of remdesivir for the treatment of COVID-19 respiratory syndrome patients, and thus questions have also been raised about the actual therapeutic effect of remdesivir.

Kaletra, known as an antiretroviral agent for adults infected with HIV-1, contains lopinavir and ritonavir as active ingredients. Lopinavir has an antiviral effect, and ritonavir acts to increase the plasma concentration of lopinavir by inhibiting the cytochrome 3A4 enzyme. In an in vitro test, lopinavir exhibited antiviral activity against SARS-CoV-1, and the EC₅₀ thereof was 4.1 μg/mL. The EC₅₀ of lopinavir against the coronavirus (MERS-CoV) causing Middle East Respiratory Syndrome (MERS) is 10.8 μg/mL, and the EC₅₀ of lopinavir against the SARS-CoV-2 virus causing COVID-19 respiratory syndrome is 16.4 μg/mL. Based on these study results, there have been attempts to use Kaletra as a treatment for COVID-19 respiratory syndrome. However, although the lopinavir concentrations in samples from COVIDd-19 respiratory syndrome patients are two times higher than those in samples from HIV patients, about 60 to 120 times higher lopinavir concentrations are required to reach the EC₅₀. Thus, there are also negative reports that it is not possible to treat COVID-19 respiratory syndrome with currently approved doses of lopinavir.

There is a report that, in cell experiments, niclosamide, known as an anthelmintic ingredient, showed 40 times higher antiviral activity than remdesivir and 26 times higher antiviral activity than chloroquine against COVID-19. However, when niclosamide was administered orally to humans, the blood level thereof showing antiviral activity was not maintained. Thus, it is unclear whether it can actually be used as a treatment for COVID-19 respiratory syndrome.

There is a report that nafamostat, which is used as a therapeutic agent for disseminated intravascular coagulation (DIC), showed an antiviral effect against COVID-19 in in vitro tests performed using Vero cells and Calu-2 cells. According to this report, nafamostat showed 600 times stronger antiviral activity than remdesivir in a test performed using Calu-3 cells, and considering that one of complications of COVID-19 respiratory syndrome is blood clotting, nafamostat, which has anticoagulant effects, may help improve the pneumonia symptoms of COVID-19 respiratory syndrome.

However, despite such various reports, there have not been reports of drugs that have been confirmed to show a distinct therapeutic effect in COVID-19 respiratory syndrome patients in actual clinical settings. In particular, although several drugs have been reported as promising candidates for the treatment of COVID-19 respiratory syndrome in in vitro tests or animal studies, the therapeutic effects thereof have been repeatedly denied in actual clinical trials conducted on humans. Considering this fact, it is unpredictable whether or not which drugs are actually useful for treating COVID-19 respiratory syndrome in humans.

That is, at present, in relation to the treatment of COVID-19 respiratory syndrome in humans, there are no drugs whose therapeutic effect has been confirmed through clinical testing on humans, and there are no reports on the dose and dosage regimen of a specific drug which exhibits a therapeutic effect when being administered to humans. Furthermore, there is no report on means capable of improving or recovering from symptoms of COVID-19 respiratory syndrome, particularly in patients belonging to a high-risk group, among COVID-19 respiratory syndrome patients.

[Prior Art Documents]

[Non-Patent Documents]

Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells: Nafamostat is the most potent antiviral drug candidate (Meehyun Ko et al., bioRxiv, https://doi.org/10.1101/2020.05.12.090035).

Objects of the present invention are summarized into three objects as follows.

A first object of the present invention is to provide a pharmaceutical composition for treating COVID-19 respiratory syndrome patients, which may achieve actual therapeutic effects when administered to humans. As mentioned above, with the worldwide spread of COVID-19 respiratory syndrome, various research institutes have developed antibody therapeutics as candidates for treatment of COVID-19 respiratory syndrome and repositioned previously known drugs. However, despite the fact that specific drugs exhibited specific effects in in vitro tests or animal tests, there are reports that the drugs have no clinical significance in actual clinical settings. Therefore, a first object of the present invention is to provide a pharmaceutical composition for treating COVID-19 respiratory syndrome patients, which may achieve therapeutic effects in actual clinical settings by administration to humans, not in vitro tests or animal models.

In order to effectively treat COVID-19 respiratory syndrome in clinical settings, it is necessary to appropriately set a dosage regimen, such as the administration cycle, administration site or administration route, and a dose for administered to a patient, and such a dosage regimen and dose have significance as factors that allow the pharmaceutical drug to fully exert its efficacy in addition to a target disease, for which the pharmaceutical drug is used, or the medicinal effect of the drug. In this sense, a second object of the present invention is to provide the dosage regimen and dose of nafamostat or a pharmaceutically acceptable salt thereof for the purpose of treating COVID-19 respiratory syndrome patients.

A third object of the present invention is to provide a pharmaceutical composition for treating particularly patients belonging to a high risk group, among patients suffering from COVID-19 respiratory syndrome, the pharmaceutical composition containing, as an active ingredient, nafamostat or a pharmaceutical salt thereof. Specifically, it has been reported that, in the case of mild patients among COVID-19 respiratory syndrome patients, the transition of the disease to the severe stage may be partially prevented by a certain therapeutic antibody or standard of care (SOC), but there has been no report of a means that exerts a special therapeutic effect on COVID-19 respiratory syndrome patients with a national early warning score (NEWS) of 7 or more, COVID-19 respiratory syndrome patients over 65 years of age, or COVID-19 respiratory syndrome patients with an oxygen saturation of less than 90%. Therefore, a third object of the present invention is to provide a pharmaceutical composition for treating COVID-19 respiratory syndrome patients belonging to a high risk group.

To achieve the first object, the present invention provides a pharmaceutical composition containing nafamostat or a pharmaceutically acceptable salt thereof. As described below, it was confirmed that the pharmaceutical composition of the present invention exhibited a therapeutic effect against COVID-19 respiratory syndrome in clinical testing on humans, not an in vitro test or an animal model.

To achieve the second object, the present invention provides a pharmaceutical composition for treating COVID-19 respiratory syndrome, which is used to administer nafamostat or a pharmaceutically acceptable salt thereof by intravenous infusion at a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) as nafamostat mesylate or 0.064 to 0.129 mg/kg/hr as nafamostat for 5 to 10 days. The present inventors confirmed that, when the pharmaceutical composition of the present invention was administered to COVID-19 respiratory syndrome patients using the above-described dosage regimen and dose, it exhibited a therapeutic effect.

To achieve the third object, the present invention provides a pharmaceutical composition which is used to administer nafamostat or a pharmaceutically acceptable salt thereof to COVID-19 respiratory syndrome patients with a national early warning score (NEWS) of 7 or more, COVID-19 respiratory syndrome patients 65 years of age or older, or COVID-19 respiratory syndrome patients with an oxygen saturation of less than 90%. The present inventors confirmed through clinical testing that, when the pharmaceutical composition of the present invention was administered to the patient group specified as described above, the time taken for clinical improvement and/or recovery was significantly shortened.

The pharmaceutical composition of the present invention, which contains nafamostat or a pharmaceutically acceptable salt thereof as an active ingredient, may treat COVID-19 respiratory syndrome patients when administered to the patients. In addition, the present invention discloses a dosage regimen and dose useful for exhibiting the above-described therapeutic effect. Furthermore, the pharmaceutical composition of the present invention may achieve clinical improvement and/or recovery, particularly in COVID-19 respiratory syndrome patients belonging to a high risk group.

FIG. 1 shows the changes in NEWS depending on the administration period when the pharmaceutical composition of the present invention was administered to all clinical test patients.

FIG. 2 shows the changes in NEWS depending on the administration period when the pharmaceutical composition of the present invention was administered to patients showing a NEWS of 7 or more among clinical test patients.

FIG. 3 shows the changes in NEWS depending on the administration period when the pharmaceutical composition of the present invention was administered to patients showing an oxygen saturation of less than 90% among clinical test patients.

COVID-19 respiratory syndrome, which occurred in Wuhan, China in December 2019, has spread worldwide over the past six months, and the number of COVID-19 respiratory syndrome patients in Korea has increased sharply since February 2020. As of January 2021, the number of COVID-19 pneumonia patients worldwide is more than 92 million, of which about 2 million have died.

Since there is no proven therapeutic agent for COVID-19 respiratory syndrome, medical teams have performed standard symptomatic therapy depending on individual symptoms, such as administration of antiviral drugs, or treatment with medical fluids, antibiotics, anti-inflammatory drugs, or oxygen, according to empirical judgment. The World Health Organization (WHO) has warned that COVID-19 respiratory syndrome could go beyond pandemic and become endemic, and it is believed that the only way to break through this unprecedented situation is the development of therapeutic agents and vaccines. To this end, hundreds of clinical trials of therapeutic agents and vaccines are in progress worldwide, and dozens of clinical trials (including researcher trials) have been approved in Korea. Among the ways to develop therapeutic agents in global emergencies, the most effective will be the so-called drug repositioning, which expands the indications of existing approved drugs, which have proven, to COVID-19 respiratory syndrome. The present invention relates to: a pharmaceutical composition for treating COVID-19 respiratory syndrome containing nafamostat, which has proven safety and efficacy as a therapeutic agent for pancreatitis, or a pharmaceutically acceptable salt thereof as an active ingredient; a dosage regimen and a dose, which are useful when nafamostat or a pharmaceutically acceptable salt thereof is administered to humans for the purpose of treating COVID-19 respiratory syndrome; and a pharmaceutical composition for treating COVID-19 respiratory syndrome, which is used to administer nafamostat or a pharmaceutically acceptable salt thereof to patients suffering from COVID-19 respiratory syndrome, particularly patients belonging to a high risk group, that is, COVID-19 respiratory syndrome patients with a national early warning score (NEWS) of 7 or more, COVID-19 respiratory syndrome patients 65 years of age or older, or COVID-19 respiratory syndrome patients with an oxygen saturation of less than 90%, thereby shortening the time taken for clinical improvement and/or recovery.

Nafamostat is a compound represented by the following formula, and is a serine protease inhibitor.

Nafamostat is characterized in that it has a very short half-life of 5 to 8 minutes, and may be easily excreted from the body through extracorporeal circulation due to its small molecular weight. Nafamostat is known to exhibit anticoagulant effects by acting on blood coagulators IX, X, XIIa and VIIa, and thus is widely used as a therapeutic agent for thrombosis or as an anticoagulant. The pharmaceutically acceptable salt of nafamostat, which is referred to in the present invention, is preferably in the form of mesylate, but is not limited thereto (hereinafter, the term “nafamostat” as used in the present specification refers to nafamostat or a pharmaceutically acceptable salt thereof unless otherwise specified.)

In order to treat COVID-19 respiratory syndrome patients more efficiently, it may be necessary to classify the patients according to symptoms and provide detailed treatment strategies for patients who fall into a specific classification. For example, for more efficient treatment of COVID-19 respiratory syndrome, patients confirmed to be positive for SARS-CoV-2 by RT-PCR may be classified as follows.

Stage 1: Patients who do not need hospitalization and are capable of normal activities

Stage 2: Patients who do not need hospitalization, but have difficulty in normal activities

Stage 3: Inpatients who do not need oxygen supplementation

Stage 4: Inpatients who need oxygen supplementation

Stage 5: Inpatients who use a non-invasive breathing device or a high-flow oxygen device

Stage 6: Inpatients who use invasive mechanical ventilation or extracorporeal oxygen supply (ECMO)

One aspect of the present invention is intended to achieve clinical improvement and/or recovery by administering the pharmaceutical composition of the present invention containing nafamostat to a COVID-19 respiratory syndrome patient. The term "clinical improvement" as used herein means obtaining an effect of improving symptoms by two or more stages based on the above-described patient classification stages. In addition, the term "recovery" as used herein refers to the case in which the patient has left the hospital or is well enough to leave the hospital (for example, the case in which the patient has not been given permission to leave the hospital by the doctor for reasons such as prognosis confirmation, but has no need for further medical treatment). For example, the case in which symptoms of COVID-19 respiratory syndrome are clearly improved by administering the pharmaceutical composition of the present invention to an inpatient who needs oxygen supplementation (stage 4 above) may be judged as recovery or clinical improvement, and this case corresponds to the case in which the patient has left the hospital and is capable of normal activities (stage 1), or the patient has difficulty in normal activities, but does not need hospitalization (stage 2).

Another aspect of the present invention is intended to provide a pharmaceutical composition capable of clinical improvement and/or recovery by administering nafamostat to an impatient who needs oxygen supplementation and/or an inpatient who uses a non-invasive breathing device or a high-flow oxygen device, by 24-hour intravenous infusion at a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) as nafamostat mesylate or 0.064 to 0.129 mg/kg/hr as nafamostat for 5 to 10 days. Since there has not been any report of the dosage regimen and dose which are used when nafamostat is administered to humans for the purpose of treating COVID-19 respiratory syndrome, the above-described dosage regimen and dose form part of the technical spirit of the present invention.

Still another aspect of the present invention is intended to provide a pharmaceutical composition that achieves remarkable clinical improvement and/or recovery by administration, particularly to patients belonging to a high risk group among COVID-19 respiratory syndrome patients. As used herein, the expression “patients belonging to a high risk group” refers to (1) COVID-19 respiratory syndrome patients with a national early warning score (NEWS) of 7 or more, (2) COVID-19 respiratory syndrome patients 65 years of age or older, or (3) COVID-19 respiratory syndrome patients with an oxygen saturation of less than 90%.

It has been reported that about 15 to 20% of COVID-19 respiratory syndrome patients are developed into a serious condition (death or ICU treatment), and severe pneumonia with acute respiratory syndrome (ARDS), sepsis, septic shock or multiple organ failure occurs in the patients. Therefore, it is important to early recognize and manage the risk of death and the risk of intensive care.

The national early warning score (NEWS) is a strong marker that can predict post-mortems including mortality in inpatients, and is a score obtained by scoring respiration/pulse/systolic blood pressure/consciousness/oxygen saturation, and is used internationally. COVID-19 respiratory syndrome patients are generally classified as follows according to the NEWS. A NEWS of 7 or more: high risk group; a NEWS of 5 to 6: a moderate risk group; a NEWS of 0 to 4: low risk group. There is a report that the mortality rate of the COVID-19 respiratory syndrome patients of the high risk group with a NEWS of 7 or more is 18 times higher than that of the COVID-19 respiratory syndrome patients of the low risk group with a NEWS of 0 to 4 (see Ref. European Journal of Internal Medicine, 21 Dec 2020).

The present inventors confirmed that, when nafamostat was administered to patients with a NEWS score of 7 or more, that is, patients with an extremely high risk of death, the mortality rate of the patients dramatically decreased, the time taken to reach improvement or recovery was significantly shortened. In addition, the present inventors confirmed that, when nafamostat was administered to COVID-19 respiratory syndrome patients of the high risk group, such as COVID-19 respiratory syndrome patients 65 years of age or older, or COVID-19 respiratory syndrome patients with an oxygen saturation of less than 90%, the time taken to reach improvement of or recovery from COVID-19 respiratory syndrome dramatically decreased, thereby completing the present invention.

The pharmaceutical composition of the present invention may be a pharmaceutical composition for intravenous infusion, which contains nafamostat (e.g., nafamostat mesylate) as an active ingredient, and also contains a pharmaceutically acceptable carrier, excipient and additive which is generally used in compositions for intravenous infusion.

Administration of the pharmaceutical composition of the present invention to a COVID-19 respiratory syndrome patient may be performed in combination with standard of care (SOC). That is, in the case of a COVID-19 respiratory syndrome patient who has previously been administered an antiviral/anti-inflammatory drug, the pharmaceutical composition of the present invention may be administered to the patient while the administration of the antiviral/anti-inflammatory drug is maintained. That is, the pharmaceutical composition of the present invention may be administered to a COVID-19 respiratory syndrome patient who has previously or has not administered another drug. Currently, for the treatment of COVID-19 respiratory syndrome, co-administration with other drugs whose therapeutic effect has not been confirmed is being experimentally tried, and the other drugs include antiviral drugs such as lopinavir/ritonavir, and drugs such as hydroxychloroquine.

Hereinafter, clinical testing and results confirming the therapeutic effect of the present invention will be disclosed as examples. It should be particularly noted that the following examples show the technical spirit of the present invention through the effect of improving symptoms of a specific individual patient or by statistical analysis, and the scope of the present invention is limited only by the matters described in the claims, and is not limited by a detailed clinical testing protocol or the results thereof.

Examples

Clinical Testing Design

Clinical testing was conducted on inpatients aged 18 years or older who were positive for SARS-COV by PCR and diagnosed with COVID-19 pneumonia by CT/X-ray and who were within 72 hours after being confirmed with COVID-19 respiratory syndrome. As the inpatients, 104 patients who required oxygen supplementation and/or used a non-invasive breathing device or a high flow oxygen device were divided into a nafamostat-administered group (53 patients; a patient group to whom the pharmaceutical composition of the present invention was administered and who received standard of care; referred to as the “test group” in the following examples) and a non-nafamostat-administered group (51 patients; a patient group who received only standard of care; referred to as the “control group” in the following examples). In the clinical testing, efficacy was compared and evaluated. The following patients were excluded from the clinical testing: patients with a history of immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS); patients who have been using invasive mechanical breathing or ECMO; female patients who were pregnant within 6 months before the date of informed consent or who were breastfeeding within 3 months before the date, or who would become pregnant or lactating within 1 month after the end of the study; patients with a high probability of death within 3 days after randomization, as judged by the investigator; liver cirrhosis patients with a Child-Pugh score of B or C; and liver disease patients who had abnormalities in laboratory test results related to liver levels, etc. In consideration of the patient's severity and underlying disease, a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) as nafamostat mesylate was administered. The assigned dose was mixed with 1,000 ml of 5% DW medical fluid and infused intravenously over 24 hours (continuous infusion). Administration to each patient was conducted for 10 days in consideration of the patient's severity and underlying disease, but when symptoms were improved and the patient left the hospital before 10 days, administration was conducted only until hospital discharge. Thus, the actual administration period was 5 to 10 days. After the treatment period of 5-10 days, follow-up observations were conducted on day 14 (±2) and day 28 (±3), and the shorter of the period taken for symptoms to be improved by two stages or more among the following classification stages and the period from the time of randomization to hospital discharge was evaluated.

Stage 3: Inpatients who do not need oxygen supplementation

Stage 4: Inpatients who need oxygen supplementation

It was confirmed that, when the pharmaceutical composition according to the present invention was administered through the above-described clinical testing, it could treat COVID-19 respiratory syndrome.

Confirmation of Therapeutic Effect on Individual Patients

Before the final analysis of the clinical testing results was performed, the clinical results for individual patients, which indicate the effect of the pharmaceutical composition of the present invention, were classified into the test group (a patient group to whom the pharmaceutical composition of the present invention was administered and who received standard of care) and the control group (a patient group who received only standard of care), and the results are shown in Table 1 below.

[Table 1]

(In Table 1 above, CRP: inflammatory marker, normal range 0 to 5 U/L; Ferritin: inflammatory marker, normal range 20 to 250 μg/L; LDH: inflammatory marker, normal range 140 to 280 U/L)

Referring to Table 1 above, it could be seen that, in the case of the test group to whom nafamostat was administered, the time taken to reach clinical improvement was 7 to 8 days, whereas, in the case of the control group who received only standard of care, the time taken to reach clinical improvement was 14 to 20 days or longer. Accordingly, it is demonstrated that administration of nafamostat at a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) for 5 to 10 days is effective for the treatment of a COVID-19 respiratory syndrome patient.

Final Analysis Results 1 for Clinical Testing (Time Taken to Reach Improvement of Symptoms of COVID-19 Respiratory Syndrome)

For the 102 finally analyzed clinical testing patients, the time taken to reach improvement of symptoms of COVID-19 respiratory syndrome was evaluated. The results are shown in Table 2 below.

[Table 2]

(The abbreviations used in Table 2 above indicate the following: N (%): the number (%) of patients who reached improvement; CI: confidence interval; median: median time (days) taken to reach clinical improvement; HR: hazard ratio; p-value; NEWS: national early warning score; Age; SpO2: oxygen saturation)

Referring to Table 2 above, it was confirmed that, in the case of particularly patients with a national early warning score (NEWS) of 7 or more, patients 65 years of age or older, and patients with an oxygen saturation of less than 90%, among the 102 finally analyzed patients, the administration of nafamostat achieved better effects than standard of care alone (control group) in all terms, including the number (N) of patients who reached clinical improvement, the median time and the hazard ratio (HR).

With respect to the final results shown in Table 2 above, the results obtained on

day

4, 7, 11, 14 and 28 are shown in Table 3 below.

[Table 3]

(The abbreviations used in Table 3 above are as indicated with respect to Table 2 above.)

As shown in Table 3 above, referring to, for example, the values measured on day 11, it was confirmed that, in the case of particularly patients with a national early warning score (NEWS) of 7 or more, patients 65 years of age or older, and patients with an oxygen saturation of less than 90%, the administration of nafamostat achieved better effects than standard of care alone (control group) in term of the number (N) of patients who reached clinical improvement.

Final Analysis Results 2 for Clinical Testing (Time Taken to Reach Recovery from COVID-19 Respiratory Syndrome)

For the 102 finally analyzed clinical testing patients, the time taken to reach recovery from COVID-19 respiratory syndrome was evaluated. The results are shown in Table 4 below.

[Table 4]

(The abbreviations used in Table 4 above are as indicated with respect to Table 2 above.)

Referring to Table 4 above, it was confirmed that, in the case of particularly patients with a national early warning score (NEWS) of 7 or more, patients 65 years of age or older, and patients with an oxygen saturation of less than 90%, among the 102 finally analyzed patients, the administration of nafamostat achieved better effects than standard of care alone (control group) in all terms, including the number (N) of patients who reached clinical improvement, the median time and the hazard ratio (HR). With respect to the final results shown in Table 4 above, the results obtained on

days

4, 7, 11, 14 and 28 are shown in Table 5 below.

[Table 5]

(The abbreviations used in Table 5 above are as indicated with respect to Table 2 above.)

Referring to Table 5 above, it was confirmed that, in the case of particularly patients with a national early warning score (NEWS) of 7 or more, patients 65 years of age or older, and patients with an oxygen saturation of less than 90%, the administration of nafamostat achieved better effects than standard of care alone (control group) in term of the number (N) of patients who reached recovery.

Final Analysis Results 3 for Clinical Testing (Decrease in NEWS by Administration of Nafamostat)

FIGS. 1 to 3 show the changes in NEWS depending on the administration period in the test group to whom nafamostat was administered and the control group who received only standard of care. FIG. 1 is a graph showing the results obtained for all the patients, FIG. 2 is a graph showing the results obtained for the patients with a NEWS of 7 or more, and FIG. 3 is a graph showing the results obtained for the patients with an oxygen saturation of less than 90%. As shown in FIGS. 1 to 3, it could be confirmed that nafamostat was particularly effective for the treatment of patients with a national early warning score (NEWS) of 7 or more or patients with an oxygen saturation of less than 90%, among COVID-19 respiratory syndrome patients.

Final Analysis Results 4 for Clinical Testing (Decrease in Mortality)

A total of 5 patients died during this clinical testing. One patient in the nafamostat-administered group (test group) and four patients in the control group who received only standard of care died. The processes leading to death are summarized in Table 6 below.

Test group (N=1)					Control group (N=4)
Patient No.	Age/ gender	NEWS	Comorbidity	Description	Patient No.	Age/ gender	NEWS	Comorbidity	Description
25-006	56/M	6	Pneumonia, HIV (diagnosed after random)	D2: right cubital vein affection G1 G2: pneumothorax G4 D6: hyperthermia G3(early termination) D9: Respiratory failure D22: multiple organ failure → death	04-003	51/M	3	Pulmonary arterial hypertension	D4: Pulmonary embolism → death
					30-005	81/M	4	Diabetes, hypertension, Brain/peripheral neuropathy, cardiac failure (NYAH class II)	D3: 1^st degree atrioventricular block (G1)D6: anabasis of type 2 DM (G2) (D7: Early termination by researcher's judgment) Cerebral edema (G4) after exclusion Acute cardiopulmonary failure Day 20 → death
					31-001	69/M	7	Coronary heart disease, obesity, arterial hypertension	D10: thromboembolism (G5) → death
					31-007	72/F	8		D6: worsening respiratory failure (early termination) →death after exclusion

(The abbreviations used in Table 6 above are as indicated with respect to Table 2 above.)

As can be seen in Table 6 above, in the case of the control group, four deaths occurred in the patient group with a NEWS of 3 to 8. There was one death in the test group to whom nafamostat was administered, but as shown in Table 6 above, this death was due to vascular injury that occurred during treatment, and was not due to worsening symptoms of COVID-19 respiratory syndrome.

According to the present invention, it is possible to provide a therapeutic agent for treating COVID-19 respiratory syndrome patients, which is actually useful for humans.

Claims

A pharmaceutical composition for treating COVID-19 respiratory syndrome containing, as an active ingredient, a nafamostat or a pharmaceutically acceptable salt thereof, which is administered to a human COVID-19 respiratory syndrome patient to shorten the time taken for clinical improvement of or recovery from COVID-19 respiratory syndrome.
The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of the nafamostat is nafamostat mesylate.
The pharmaceutical composition of claim 2, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered by intravenous infusion at a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) as nafamostat mesylate or 0.064 to 0.129 mg/kg/hr as nafamostat.
The pharmaceutical composition of claim 3, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 10 days.
The pharmaceutical composition of claim 3, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 9 days.
The pharmaceutical composition of claim 3, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 8 days.
The pharmaceutical composition of claim 3, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 7 days.
The pharmaceutical composition of claim 3, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 6 days.
The pharmaceutical composition of claim 3, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 5 days.
A pharmaceutical composition for treating COVID-19 respiratory syndrome containing, as an active ingredient, a nafamostat or a pharmaceutically acceptable salt thereof, which is administered to a human COVID-19 respiratory syndrome patient to shorten the time taken for clinical improvement of or recovery from COVID-19 respiratory syndrome,

wherein the COVID-19 respiratory syndrome patient is selected from the group consisting of inpatients who need oxygen supplementation, and inpatients who use a non-invasive breathing device or a high-flow oxygen device, and

the nafamostat or pharmaceutically acceptable salt thereof is administered by intravenous infusion at a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) as nafamostat mesylate or 0.064 to 0.129 mg/kg/hr as nafamostat.
The pharmaceutical composition of claim 10, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 10 days.
The pharmaceutical composition of claim 10, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 9 days.
The pharmaceutical composition of claim 10, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 8 days.
The pharmaceutical composition of claim 10, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 7 days.
The pharmaceutical composition of claim 10, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 6 days.
The pharmaceutical composition of claim 10, wherein the nafamostat or pharmaceutically acceptable salt thereof is administered for 5 days.
A pharmaceutical composition for treating COVID-19 respiratory syndrome containing, as an active ingredient, a nafamostat or a pharmaceutically acceptable salt thereof, which is administered to a high risk patient to shorten the time taken for clinical improvement of or recovery from COVID-19 respiratory syndrome.
The pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable salt of the nafamostat is nafamostat mesylate.
The pharmaceutical composition of claim 17, wherein the high risk patient is selected from the group consisting of a COVID-19 respiratory syndrome patient with a national early warning score (NEWS) of 7 or more, a COVID-19 respiratory syndrome patient 65 years of age or older, or a COVID-19 respiratory syndrome patient with an oxygen saturation of less than 90%.
The pharmaceutical composition of claim 19, wherein the high risk patient is the COVID-19 respiratory syndrome patient with a national early warning score (NEWS) of 7 or more.
The pharmaceutical composition of claim 19, wherein the high risk patient is the COVID-19 respiratory syndrome patient 65 years of age or older.
The pharmaceutical composition of claim 19, wherein the high risk patient is the COVID-19 respiratory syndrome patient with an oxygen saturation of less than 90%.
A pharmaceutical composition for treating COVID-19 respiratory syndrome containing, as an active ingredient, a nafamostat or a pharmaceutically acceptable salt thereof, which is administered to a human high-risk COVID-19 respiratory syndrome patient to shorten the time taken for clinical improvement of or recovery from COVID-19 respiratory syndrome,

wherein the high-risk COVID-19 respiratory syndrome patient is a national early warning score (NEWS) of 7 or more, a COVID-19 respiratory syndrome patient 65 years of age or older, or a COVID-19 respiratory syndrome patient with an oxygen saturation of less than 90%, who is selected from the group consisting of inpatients who need oxygen supplementation, and inpatients who use a non-invasive breathing device or a high-flow oxygen device, and

the nafamostat or pharmaceutically acceptable salt thereof is administered at a dose of 0.1 to 0.2 mg/kg/hr (2.4 to 4.8 mg/kg/day) as nafamostat mesylate or 0.064 to 0.129 mg/kg/hr as nafamostat for 5 to 10 days.