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WO2022166885A1 - Interféron supercomposé recombinant (rsifn-co) pour le traitement de patients atteints de la covid-19 avec ou sans symptômes - Google Patents

Interféron supercomposé recombinant (rsifn-co) pour le traitement de patients atteints de la covid-19 avec ou sans symptômes Download PDF

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WO2022166885A1
WO2022166885A1 PCT/CN2022/074977 CN2022074977W WO2022166885A1 WO 2022166885 A1 WO2022166885 A1 WO 2022166885A1 CN 2022074977 W CN2022074977 W CN 2022074977W WO 2022166885 A1 WO2022166885 A1 WO 2022166885A1
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rsifn
covid
subject
spray
days
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Guangwen Wei
Rongbing Guo
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Sichuan Huiyang Life Science & Technology Corp.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to recombinant super-compound interferon (rSIFN-co) and its use to treat COVID-19 patients with or without symptoms.
  • COVID-19 Common symptoms of COVID-19 include fever (83–99%) , cough (59–82%) , fatigue (44–70%) , anorexia (40–84%) , shortness of breath (31–40%) , and myalgias (11–35%) [3] . Other reported symptoms have included, but are not limited to, sore throat, nasal congestion, headache, diarrhea, nausea and vomiting, anosmia, and ageusia [3] . The mortality of COVID-19 varies by geographical area. According to a recent analysis conducted by the Centers for Disease Control and Prevention (CDC) of the United States, more than 1.3 million laboratory-confirmed cases were reported between January and May 2020.
  • CDC Centers for Disease Control and Prevention
  • COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , a newly discovered virus in the family of Coronaviridae (beta) , which has 89%nucleotide identity with bat SARS-like-CoVZXC21 and 82%with human SARS-CoV [6] .
  • SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Virus entry is achieved through binding of viral spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2) , on the host cell [7] .
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • ACE2 angiotensin-converting enzyme 2
  • the present invention discloses a method that prevents and/or treats COVID-19 (SARS-Cov-2) coronavirus infection, including mild COVID-19 infection and asymptomatic infection, in a subject suffering from diseases in digestive system, liver, heart and/or kidney.
  • the method comprises administering to the subject therapeutically effective doses, e.g., from 5 to 100 ⁇ g per day, of recombinant super-compound interferon (rSIFN-co) for a period of at least 3 days and up to 30 days.
  • the administration can be by nasal spray or intravenous injection.
  • Figure 1 is an illustration of the study schema.
  • Figure 2 compares structure of rSIFN-co and IFN- ⁇ 2b
  • Figure 3 compares structure of rSIFN-co and Infergen of Amgen
  • Figure 4 shows vector diagram of rSIFN-co in Plasmid pHY-5.
  • Figure 5 shows a manufacturing flowchart for rSIFN-co drug product.
  • interferons have long been used as antiviral treatments.
  • the preclinical studies of rSIFN-co have demonstrated its superiority of anti-SARS-CoV-2 capacity than conventional IFNs.
  • dysregulated IFNs was found in COVID-19 patients, implicating the role of IFN in COVID-19 pathogenesis [18] .
  • the potential of rSIFN-co as a protective and therapeutic agent against SARS-CoV-2 infection is suggested.
  • Impairment of type I interferon (IFN) response was discovered in severe and critical COVID-19 patients. No IFN- ⁇ and low IFN- ⁇ production/activity were observed and was associated with a persistent blood viral load and an exacerbated inflammatory response [17] .
  • IFNs type I interferon
  • IFN ⁇ -1a the efficacy and safety of IFN ⁇ -1a were evaluated in patients with severe COVID-19.
  • the patients in the IFN group received subcutaneous injection of 12 million IU/mL of IFN ⁇ -1a three times per week for two weeks [22] .
  • time to reach clinical response was not significantly improved, the proportions of subjects discharged on Day 14 were significantly higher in the IFN group [22] .
  • Recombinant super-compound interferon is a product of patented technological research developed by Sichuan Huiyang Life Science and Technology Corporation. It is a recombinant form of the naturally occurring cytokine interferon-alpha (IFN- ⁇ ) which has a modified spatial configuration.
  • rSIFN-co has the same amino acid sequence as the Amgen product (Interferon Alfacon-1) consisting of 167 amino acids (MCDLPQTHSLGNRRALILLAQMRRISPFSCLKDRHDFGFPQEEFDGNQFQKAQAISVLHEMIQQTFNLFSTKDSSAAWDESLLEKFYTELYQQLNDLEACVIQEVGVEETPLMNVDSILAVKKYFQRITLYLTEKKYSPCAWEVVRAEIMRSFSLSTNLQERLRRKE, SEQ ID NO: 1) .
  • the amino acid homology of and rSIFN-co are naturally occurring interferon ⁇ -2a and interferon ⁇ -2b, with only a difference of 18 and 19 amino acids, respectively.
  • rSIFN-co This amino acid difference results in rSIFN-co having 10 times greater affinity for IFN-specific cell surface receptors IFNAR1 compared to interferon ⁇ -2a and interferon ⁇ -2b [15] .
  • rSIFN-co binds to IFN-specific cell surface receptors, resulting in the transcription and translation of genes whose protein products have antiviral, antiproliferative, anticancer, and immune-modulating effects.
  • the 3-dimensional conformational change improves efficacy and causes fewer side effects compared to IFN-a.
  • the nucleic acid sequence encoding the amino acid sequence of SEQ ID NO. 1 is as follows (SEQ ID NO: 2) .
  • the rSIFN-co can be produced by the method comprising the following steps: introducing a nucleotide sequence comprising SEQ ID NO: 2 that encodes the recombinant interferon into an isolated host cell; culturing the host cell under appropriate condition for expression of the recombinant interferon; and harvesting the recombinant interferon, wherein the recombinant interferon has an amino acid sequence of SEQ ID NO: 1, and the recombinant interferon inhibits secretion of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) of Hepatitis B Virus.
  • the host cell is Escherichia coli.
  • the nucleotide sequence comprising SEQ ID NO: 2 is under the control of the promoter PBAD.
  • the harvesting step comprises extraction of the interferon from the fermentation broth, collection of the inclusion bodies, denaturation and renaturation of the harvested interferon. Still further, the harvesting step also comprises separation and purification of the recombinant interferon. Met at the N-terminus of SEQ ID NO: 1 is resected in mature protein.
  • the study used reagents including DMEM (Gibco) , fetal calf serum (Gibco) , DMSO (sigma) , double-antibody, pancreatine, etc., kits including Cell Counting Kit-8 (CCK-8) (B34304, bimake) , QIAamp viral RNA mini kit (52906, Qiagen) , Novel Coronavirus (2019-nCoV) Real Time RT-PCR kit (by Wuhan Institute of Virology) , and main instruments such as Varioskan Flash (by Thermo Fisher Scientific) , QIAcube HT 9001793 (by Qiagen) and CFX96 Touch Real-Time PCR Detection System (by Bio-rad) .
  • DMEM Gibco
  • Gibco fetal calf serum
  • DMSO double-antibody
  • pancreatine pancreatine, etc.
  • kits including Cell Counting Kit-8 (CCK-8) (B34304, bimake)
  • the final set of concentrations of rSIFN-co was 6 ⁇ 10 8 , 3 ⁇ 10 8 , 1.5 ⁇ 10 8 , 7.5 ⁇ 10 7 , 3.75 ⁇ 10 7 , 1.875 ⁇ 10 7 and 0 pg/ml
  • the final set of concentrations of recombinant human Interferon ⁇ -2b injection was 2 ⁇ 10 7 , 1 ⁇ 10 7 , 5 ⁇ 10 6 , 2.5 ⁇ 10 6 , 1.25 ⁇ 10 6 , 6.25 ⁇ 10 5 and 0 pg/ml
  • the final set of concentrations of Remdesivir was 320, 160, 80, 40, 20, 10 and 0 ⁇ M;
  • a) Grow Vero-E6 cells in a 24-well plate, 8 ⁇ 10 4 cells per well. Put the plate into 37 °Cincubator with 5%CO 2 . When the confluence reaches 70%-80%, using DMEN with 2%FBS for 2 times gradient dilution of rSIFN-co, recombinant human Interferon ⁇ -2b injection (pseudomonas) and Remdesivir, respectively.
  • qRT-PCR real time RT-PCR
  • RNA quantitative detection on collected virus. Take 20 ⁇ L collected supernatant after infection and extract RNA following instructions of QIAamp viral RNA mini kit. Conduct the qRT-PCR by using Novel Coronavirus (2019-nCoV) Real Time RT-PCR kit (TaqMan probe method) ;
  • Inhibition rate (%) 1 -Viral RNA Copies in test groups /Viral RNA Copies in drug free group ⁇ 100%. Analyze the half effective concentration of drugs (EC 50 ) by GraphPad PrisM6.0; and
  • Therapeutic Index (TI) half cytotoxicity concentration (CC 50 ) /half effective concentration (EC 50 ) .
  • the study showed that the EC 50 and CC 50 of rSIFN-co were 14.6 pg/mL and 7.12 ⁇ 10 8 pg/mL, respectively, whereas the EC 50 and CC 50 of IFN ⁇ -2b were 162 pg/mL and 1.37 ⁇ 10 7 pg/mL, respectively.
  • the results suggested that rSIFN-co exhibited a higher efficacy against SARS-CoV-2 and a lower cytotoxicity as compared with IFN ⁇ -2b.
  • PK pharmacokinetic
  • rSIFN-co induces more 2′-5′-oligoadenylate synthetase (2′, 5′-OAS; a specific marker triggered by interferon) over a longer time period, when compared to 2′, 5′-OAS induced by
  • the incidence of adverse events in the rSIFN-co group was lower than that in the group.
  • Type I interferons are known to play an important role in first-line defense against viruses by stimulating the expression of proteins such as ribonucleic acid (RNA) -dependent protein kinase, 2′, 5′-OAS, RNase L, and RNA-specific adenosine deaminase [16] .
  • RNA ribonucleic acid
  • 2′, 5′-OAS ribonucleic acid
  • RNase L RNA-specific adenosine deaminase
  • rSIFN-co severe acute respiratory syndrome
  • Sichuan aprovince in China
  • rSIFN-co spray was allocated to 3,000 users, including doctors and nurses in hospitals, populated areas with a high risk for SARS, and the National research group.
  • the highest dose was 16 million international unit (IU) and the longest treatment duration was over two months. No side effects connected to the use of the spray was reported, and none of users administered with rSIFN-co spray has been infected by SARS.
  • the present invention provides a method of preventing or treating Covid-19 (SARS-Cov-2) coronavirus infection in a subject.
  • the method comprises administering to the subject a therapeutically effective dose of recombinant super-compound interferon (rSIFN-co) for a period of at least 3 days.
  • rSIFN-co recombinant super-compound interferon
  • the rSIFN-co is administered to said subject by nasal spray, pharynx spray or intravenous injection.
  • the therapeutically effective dose ranges from 5 ⁇ g to 100 ⁇ g per day.
  • the therapeutically effective dose is selected from the group consisting of 8 ⁇ g, 16 ⁇ g, 32 ⁇ g, 64 ⁇ g and 96 ⁇ g per day.
  • the period is 5 to 30 days.
  • the subject suffers from one or more diseases in one or more of the digestive system, liver, heart, and kidney.
  • the subject receives one or more additional treatments selected from the group consisting of Remdesivir, hydroxychloroquine, and dexamethasone.
  • the subject is healthy or has an asymptomatic infection of Covid-19 coronavirus, and said subject receives 2 sprays per nostril and 4 sprays through pharynx once daily, each spray comprising 0.2-5.0 ⁇ g of said rSIFN-co.
  • the subject shows mild covid-19 infection and receives 2 sprays per nostril and 4 sprays through pharynx twice daily, each spray comprising 0.2-5.0 ⁇ g of said rSIFN-co.
  • the rSIFN-co has a specific activity greater than 5.0 x 10 8 IU/mg protein.
  • the nasal spray, pharynx spray or intravenous injection comprises one or more of stabilizer, bacteriostat, surfactant, metal complex, isosmotic adjusting agent, buffering agent, and viscosity modifier.
  • the stabilizer is human serum albumin.
  • the metal complex is disodium edetate.
  • the surfactant is Tween 80.
  • the buffering agent is citric acid.
  • the viscosity modifier is glycerol.
  • the isosmotic adjusting agent is sodium chloride.
  • the bacteriostat is benzyl alcohol.
  • the nasal spray, pharynx spray or intravenous injection has a pH value of about 5.0.
  • the nasal spray or pharynx spray is stable under 4-8°C for 3 months, at 25°C for 2 months and at 37°C for 2 weeks.
  • the present provides a method of preventing or treating Covid-19 (SARS-Cov-2) coronavirus infection in a subject.
  • the method comprises administering to the subject a composition comprising a therapeutically effective dose of recombinant super-compound interferon (rSIFN-co) for a period of at least 3 days
  • the present provides a method of preventing or treating Covid-19 (SARS-Cov-2) coronavirus infection in a subject by administering a composition consisting of a therapeutically effective dose of rSIFN-co for a period of at least 3 days.
  • SARS-Cov-2 Covid-19 coronavirus
  • the primary objective is to assess the safety and tolerability of rSIFN-co in healthy subjects in close contact with confirmed COVID-19 case (s) and patients with mild COVID-19 or asymptomatic infection.
  • the secondary objective is to assess the efficacy of rSIFN-co in healthy subjects in close contact with confirmed COVID-19 case (s) and patients with mild COVID-19 or asymptomatic infection.
  • the primary endpoint is the safety and tolerability profiles of rSIFN-co.
  • the secondary endpoint for Healthy subjects in close contact with confirmed COVID-19 case (s) is:
  • the secondary endpoint for patients with mild COVID-19 or asymptomatic infection is:
  • the exploratory endpoint for Healthy subjects in close contact with confirmed COVID-19 case (s) is the subjects’ evaluation on ease of use, discomfort using the study product, and overall satisfaction.
  • the exploratory endpoint for patients with mild COVID-19 or asymptomatic infection is:
  • the study is designed as a randomized, double-blind, placebo-controlled study to minimize the potential for subjective bias.
  • the inclusion of placebo arms will provide a control for comparison of efficacy endpoints between the treatment groups.
  • the study will be conducted at multiple study centers to facilitate subject enrollment and to increase the generalizability of the study results.
  • the doses evaluated for this study 8 and 16 million IU, are based on the totality of the data from previous trials in adults.
  • An eligible subject must fulfill ALL of the following inclusion criteria:
  • RT-PCR Negative reverse transcriptase polymerase chain reaction
  • Healthy subjects in close contact with confirmed COVID-19 case (s) Subjects with exposure to confirmed COVID-19 case (s) within 96 hours and belong to one of the following exposure situations per health department directives:
  • ICU intensive care unit
  • First responders i.e., first aid personnel, paramedics
  • Level 2 protection refers to wearing a disposable cap, medical protective mask (N95 or higher level medical protective mask) , goggles (anti-fog type) or protective mask (anti-fog type) , medical protective suit or overalls (white gown) , disposable gloves and disposable shoe covers.
  • Asymptomatic or presymptomatic infection Individuals who test positive for SARS-CoV-2 by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or antigen test, but have no symptoms.
  • a molecular diagnostic e.g., polymerase chain reaction
  • antigen test e.g., antigen test, but have no symptoms.
  • rSIFN-co or placebo, for a maximum of 10 to 28 days.
  • rSIFN-co will be administered with one or more other agents, wherein the control group will receive said one or more other agents only.
  • rSIFN-co The dose of rSIFN-co given by nebulization or injection is equivalent to 8 to 16 million IU (32 ⁇ g) per day. Other agents will be given in their usual dosages.
  • Randomize eligible subjects into one of the two treatment arms i.e., placebo or rSIFN-co
  • Vital sign measurements include blood pressures (systolic blood pressure [SBP] and diastolic blood pressure [DBP] ) , pulse rate, respiratory rate, body temperature, and SpO 2 . Vital signs will be assessed at each visit. Results will be documented in the CRF. Measurements of all vital signs shall be completed in the during the visit within a time frame of 2 hours. Measurements should be taken in a seated position after resting for approximately 10 minutes. The same thermometer should be used consistently throughout the study. Subjects in Group B will be provided with an oximeter to help monitor their oxygen level. The subjects will be instructed to document daily oxygen level on the diary card.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • Fever is defined as rectal, ear, or forehead temperature greater than 38 °C. Site personnel should measure ear temperature of subject if possible. If other methods are used, the same method should be used consistently throughout the study.
  • a complete physical examination will be conducted by the Investigator or designee at screening.
  • Complete physical examination items include general appearance, HEENT (head, eyes, ears, nose, and throat) , mouth, skin, neck (including thyroid) , lymph nodes, spine, cardiovascular system, respiratory system, gastro-intestinal system, nervous system, musculoskeletal system, blood and blood forming organs, mental status, and other body systems if applicable for describing the status of subject’s health.
  • HEENT head, eyes, ears, nose, and throat
  • mouth skin, neck (including thyroid)
  • lymph nodes spine
  • cardiovascular system respiratory system
  • gastro-intestinal system gastro-intestinal system
  • nervous system musculoskeletal system
  • blood and blood forming organs forming organs, mental status, and other body systems if applicable for describing the status of subject’s health.
  • an abbreviated physical examination comprising a brief medical history and targeted physical examination will be performed at the discretion of the Investigator to evaluate possible adverse events.
  • Electrocardiogram ECG
  • Single 12-lead ECG will be obtained at screening using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc (either Bazette or Fridericia formulas) intervals.
  • the assessment will follow the current SOPs at each participating study center. Throughout the study, additional ECGs may be obtained if clinically indicated.
  • the Investigators will compare ECGs to the screening ECG and document overall interpretation of specific ECGs as either normal, abnormal with clinical significance, or abnormal without clinical significance. An AE will be recorded if clinically significant.
  • Laboratory tests (including hematology, biochemistry, and coagulation) will be performed at screening, Days 5, 10, 15, 21, 28, and 60. All samples will be analyzed by the study center’s local laboratory per the standard operating procedures (SOPs) of the laboratory.
  • the examination items will include analytes in the following table:
  • Additional tests may be conducted at any time during the study as determined necessary by the Investigator. A clinically significant change from baseline will be recorded as an AE.
  • nasopharyngeal swabs are preferred [26] , but if these are not obtainable or additional samples are required by local regulations, oropharyngeal or nasal swabs may be obtained if necessary.
  • Samples will be delivered to the laboratories selected by the Sponsor to quantitatively and qualitatively detect viral RNA via RT-PCR assays approved by local regulatory authorities. Preparation, handling, storage, shipment, and examinations of specimens will follow the lab SOPs.
  • Thoracic CT-scan or chest X-ray will be performed at Screening, Day 5 (only for mild COVID-19 patients or asymptomatic infection) , and End of Treatment (Day 10) .
  • a standardized framework will be used to assess the chest imaging at each study site.
  • Clinical improvement will be defined as a decrease of at least one point on the 11-point scale compared to the baseline value (e.g., from 2 to 1; from 2 to 0) .
  • COVID-19 disease severity and symptoms will be assessed and documented at screening and throughout the entire study. Typical symptoms for patients with mild disease include fever, cough, fatigue, anorexia, shortness of breath, myalgias, sore throat, nasal congestion, headache, gastrointestinal symptoms, loss of smell (anosmia) , loss of taste (ageusia) , and without evidence of viral pneumonia or hypoxia.
  • Asymptomatic or presymptomatic infection Individuals who test positive for SARS-CoV-2 by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or antigen test, but have no symptoms;
  • Mild disease Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain) and a SpO2 ⁇ 94%on room air at sea level, without shortness of breath, dyspnea, or abnormal chest imaging;
  • COVID-19 e.g., fever, cough, sore throat, malaise, headache, muscle pain
  • SpO2 ⁇ 94%on room air at sea level, without shortness of breath, dyspnea, or abnormal chest imaging
  • Moderate disease Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and SpO2 ⁇ 94%on room air at sea level;
  • Severe disease Individuals who have respiratory frequency >30 breaths per minute, SpO2 ⁇ 94%on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) ⁇ 300 mmHg, or lung infiltrates >50%; and
  • ⁇ Critical disease Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.
  • the Master Cell Bank (MCB) and Working Cell Bank (WCB) for rSIFN-co are manufactured under cGMP.
  • the DS manufacture process involves bioproduction and harvest then purification of rSIFN-co from the E. coli inclusion bodies using upstream and downstream manufacturing processing typical for this type of production.
  • the rSIFN-co cDNA was cloned into the E. coli high expression vector pHY-4 plasmid to yield the final recombinant plasmid pHY-5 ( Figure 4) .
  • Typical production and purification can be found in US Patent No. 8,415,151 and Patent No. 8,846,025.
  • ⁇ PBAD promoter which derived from bacterial arabinose operon (araBAD operon) and was mainly regulated by CAP-cAMP and L-arabinose binding protein AraC i.e. product of ara Cgene
  • ⁇ ⁇ -Lactamase coded by Bla gene could provide ampicillin resistance.
  • ⁇ ColE1 replicon determined the copy number and replication of plasmid in bacteria.
  • Animal-based ingredients, tryptone and acid hydrolyzed casein, are used in upstream manufacture and are of GMP quality and certified that they are sourced in a controlled and validated way as to reduce the risk of contamination or exposure to any diseases, especially Bovine Spongiform Encephalopathy.
  • the release testing specifications for the DS include protein content, biological activity, specific activity, purity, molecular weight, exogenous DNA, host protein, antibiotic residue, endotoxin and a number of characterization assays.
  • the biological activity of rSIFN-co was determined based on the effect of rSIFN-co to protect cells against a viral cytopathic effect. It is quantified using a CPE potency assay, referenced against IFN ⁇ -2a reference standard, which has been tested and calibrated in International Units against the WHO reference standard.
  • the three-dimensional structure of the present recombinant interferon (SEQ ID NO: 3, without N-terminal M) is different from the three-dimensional structure of IFN ⁇ -2b (SEQ ID NO: 4) published in the art (see Figure 2) and the three-dimensional structure of based on computational modeling. There are obvious differences between the AB loops of the two, and their BC loops also cannot overlap completely (see Figure 3) .
  • Stability was tested according to ICH guideline for biological products Q1A and Q5C.
  • the stability of the rSIFN-co composition is tested under 4-8°C for 6 months, -80°C for 24 months, and accelerated condition at 25°C for 1 month. Repeated freeze/thaw cycle tests are done for 7 cycles. Stability data for 2 representative batches of drug substance 201801003, and 201801004 is shown in the following Tables 7-10.
  • a composition of rSIFN-co was prepared by obtaining a 80%of the total volume of water for injection, adding a prescribed amount of disodium edetate, polysorbate 80, citric acid, glycerol, sodium chloride and benzyl alcohol in turn while stirring. Add the next component after the former component is fully dissolved. After each component is added, stir for more than 60 minutes until well combined. Cool the solution to below 20°C and adjust pH value to about 5.0 with diluted hydrochloric acid. Stir the solution fully, add the prescribed amount of human serum albumin and rSIFN-co protein stock solution and then test pH value. If pH deviates, adjust pH value again to 5.0 and stir slightly. Dilute with water for injection cooled to below 20°C to volume, homogenizing by gently stirring for more than 30 minutes before filter and sterilize with a 0.22 ⁇ m filter to obtain the semi-finished rSIFN-co spray.
  • a typical workflow is shown in Figure 5.
  • composition (alternatively “drug product” ) is stable under 4-8°C for 3 months and the real time study is on-going. It is also stable under accelerated condition at 25°C for 2 months and at 37°C for 2 weeks.
  • the main components of the drug product are shown in the Table 11.
  • the product is a homogeneous colorless or light yellow with slightly sticky liquid spray.
  • the product is filled in high-density polyethylene bottles for pharmaceuticals with a mechanical nasal spray pump. Each bottle contains 8 ml and each pump is 0.1 ml.
  • a solution is prepared according to the formula followed by sterilization and filtering by a 0.22 ⁇ m filter.
  • the filtered liquid was transferred into a sterile container to obtain a semi-finished product.
  • the sterile filtered solution is packaged into 10 ml medicinal high-density polyethylene bottle for external use by filling machine and equip with medicinal spray pump.
  • the final product is stored at a controlled temperature of between 2-8°C, and the latest stability data showed that the drug product is stable under 4-8°C for 3 months and at accelerated condition of 25°C for 2 months and at 37°C for 2 weeks. Based on these test results at this time, the data supports a shelf life of 12 months and the stability program is on-going to support longer shelf life.
  • the drug product is supplied in spray bottle with mechanical pump.
  • the components of the container closure system are in conformance to the compendial requirements for spray bottle containers for pharmaceutical use.
  • the drug product is produced in GMP qualified facilities under ISO5, ISO7, and ISO8 clean room classification.
  • Stability was established according to ICH guideline for biological products Q1A and Q5C. Sponsor plans to test the drug product stability under 4-8°C for 36 months, at accelerated conditions 25°C for 6 months and 37°C for 1 month. Stability data for 3 representative batches of drug product 20200209, 20200210, and 20200311 is shown in the following Tables 14-17.
  • Example 3 Treatment by rSIFN-co of COVID-19 patients with symptoms
  • COVID-19 patients with symptoms such as mild pneumonia are treated by rSIFN-co or placebo for up to 10 to 28 days.
  • rSIFN-co is administered by nebulization or injection twice a day, 8 to 12 million International Units (IU) each time.
  • Clinical improvement is determined by assessing radiological improvement and/or virus nucleic acid negative conversion at the end of treatment period. The median time to reach clinical improvement is approximately 8 to 16 days, and an overall rate of clinical improvement at the end of treatment is approximately 80%to 90%.
  • Example 4 Treatment by rSIFN-co of COVID-19 patients without symptoms
  • COVID-19 patients without symptoms are treated by rSIFN-co or placebo for up to 10 to 28 days.
  • rSIFN-co is administered by nebulization or injection twice a day, 8 to 12 million International Units (IU) each time. Any COVID-19 symptoms are assessed during the course of treatment.
  • Patients treated with rSIFN-co are expected to show no symptom throughout the study, or significantly less treated patients show symptoms compared to patients receiving placebo.
  • Example 5 Treatment by rSIFN-co in combination with other agents of COVID-19 patients with symptoms
  • COVID-19 patients with symptoms such as mild pneumonia are treated by rSIFN-co in the presence of one or more agents for up to 10 to 28 days.
  • rSIFN-co is administered by nebulization or injection twice a day, 8 to 12 million International Units (IU) each time.
  • one or more of the following agents are also administered: (1) lopinavir (twice a day, 200 mg each time) , (2) ritonavir (twice a day, 50 mg each time) , (3) arbidol or umifenovir (three times a day, 200 mg each time) , (4) Remdesivir (100 mg per day) , (5) hydroxychloroquine (200 mg per day) , and (6) dexamethasone (4 mg per day) .
  • Clinical improvement is determined by assessing radiological improvement and/or virus nucleic acid negative conversion at the end of treatment period. The median time to reach clinical improvement and virus nucleic acid negative conversion is expected to be significantly shorter in patients receiving rSIFN-co than patients not receiving rSIFN-co.
  • Example 6 Safety and tolerability in healthy subjects receiving rSIFN-co
  • subjects receive rSIFN-co by nebulization or injection, or placebo for up to 10 to 28 days. Any symptoms or adverse events are assessed and recorded during the course of the study.
  • Example 7 Treatment by rSIFN-co of COVID-19 patients on respirators
  • COVID-19 patients on respirators are treated by rSIFN-co or placebo for up to 10 to 28 days.
  • rSIFN-co is administered by nebulization or injection twice a day, 8 to 12 million International Units (IU) each time.
  • Clinical improvement is determined by assessing blood oxygen level during and at the end of treatment period. The median time to reach clinical improvement is approximately 8 to 16 days, and an overall rate of clinical improvement at the end of treatment is approximately 80%to 90%.
  • Example 8 Treatment by rSIFN-co Spray
  • healthy subjects or patients with an asymptomatic infection of Covid-19 receive 2 sprays per nostril and 4 sprays through pharynx once daily. Each spray comprises 2 ⁇ g of rSIFN-co.
  • the period of treatment is approximately 5 days to 20 days.
  • Subjects treated with rSIFN-co are expected to show no symptom throughout the study, or significantly less treated patients show symptoms compared to patients receiving placebo.
  • each spray comprises 2 ⁇ g of rSIFN-co.
  • the period of treatment is approximately 10 days to 30 days.
  • the median time to reach clinical improvement and virus nucleic acid negative conversion is expected to be significantly shorter in patients receiving rSIFN-co than patients not receiving rSIFN-co.

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Abstract

La présente invention divulgue une méthode de prévention et/ou de traitement de l'infection par le coronavirus de la COVID-19 (SARS-Cov-2) par administration à un sujet qui en a besoin d'une dose thérapeutiquement efficace d'interféron supercomposé recombinant (rSIFN-co) pendant une certaine période. Dans un mode de réalisation, la dose varie de 1,0 à 100 μg par jour et la période peut s'étendre sur 3 à 30 jours. Dans un mode de réalisation, le rSIFN-co est administré par pulvérisation nasale, pulvérisation dans le pharynx ou injection intraveineuse.
PCT/CN2022/074977 2021-02-04 2022-01-29 Interféron supercomposé recombinant (rsifn-co) pour le traitement de patients atteints de la covid-19 avec ou sans symptômes WO2022166885A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2011202683A1 (en) * 2003-08-28 2011-06-30 Superlab Far East Limited Uses of interferons with altered spatial structure
CN111346219A (zh) * 2020-02-21 2020-06-30 上海甘翼生物医药科技有限公司 干扰素在制备预防冠状病毒感染或预防冠状病毒感染引发的疾病的药物中的用途
CN111658779A (zh) * 2020-06-22 2020-09-15 四川大学华西医院 治疗新型冠状病毒肺炎的联合用药物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2011202683A1 (en) * 2003-08-28 2011-06-30 Superlab Far East Limited Uses of interferons with altered spatial structure
CN111346219A (zh) * 2020-02-21 2020-06-30 上海甘翼生物医药科技有限公司 干扰素在制备预防冠状病毒感染或预防冠状病毒感染引发的疾病的药物中的用途
CN111658779A (zh) * 2020-06-22 2020-09-15 四川大学华西医院 治疗新型冠状病毒肺炎的联合用药物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FRAGKOU P.C., BELHADI D., PEIFFER-SMADJA N., MOSCHOPOULOS C.D., LESCURE F.-X., JANOCHA H., KAROFYLAKIS E., YAZDANPANAH Y., MENTRÉ : "Review of trials currently testing treatment and prevention of COVID-19", CLINICAL MICROBIOLOGY AND INFECTION., WILEY-BLACKWELL PUBLISHING LTD, UNITED KINGDOM, SWITZERLAND, vol. 26, no. 8, 1 August 2020 (2020-08-01), United Kingdom, Switzerland , pages 988 - 998, XP055955419, ISSN: 1198-743X, DOI: 10.1016/j.cmi.2020.05.019 *
PEREDA RICARDO, GONZÁLEZ D, RIVERO HB, RIVERO JC, PÉREZ A, LÓPEZ LR, MEZQUIA N, VENEGAS R, BETANCOURT JULIO RAUL, DOMÍNGUEZ RE: "Therapeutic effectiveness of interferon alpha 2b treatment for COVID-19 patient recovery", MEDRXIV, 4 August 2020 (2020-08-04), XP055955420, Retrieved from the Internet <URL:https://www.medrxiv.org/content/medrxiv/early/2020/08/04/2020.07.28.20157974.full.pdf> DOI: 10.1101/2020.07.28.20157974 *

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