Obeldesivir for the treatment of a coronavirus infection

Abstract

The present disclosure relates to methods for treating coronavirus infections.

Description

Attorney Docket No. 1571-WO-PCTMETHODS FOR TREATMENT OF VIRAL INFECTIONSCROSS REFERENCE

[0001] The application claims priority to the U.S. Provisional Application No. 63 / 693,534 filed September 11, 2024. The entire contents of which application are incorporated herein in their entity or all purposes.FIELD OF THE INVENTION

[0002] The present disclosure relates to methods for treating viral infections.BACKGROUND

[0003] Obeldesivir (ODV) is a mono-5 ’-isobutyryl ester prodrug of GS-441524. Following oral administration, ODV is extensively hydrolyzed presystemically to the parent nucleoside GS-441524, which can then enter cells where it is subsequently anabolized to the same active triphosphate metabolite (GS-443902) as remdesivir (RDV). ODV has been developed with the intent to deliver consistent and high systemic exposures to GS-441524 following oral administration. At targeted therapeutic exposures with ODV, GS-441524 exposures are anticipated to be approximately 14-fold higher as compared to exposures with RDV.

[0004] Availability of a highly effective oral treatment with a high bander to resistance, similar to that of RDV, with minimal drug-drug interactions and with fewer tablets to take (i.e., the dose of ODV selected for Phase 3 is one 350 mg tablet twice daily) has the potential to address a critical public health need in the ongoing COVID-19 pandemic.

[0005] ODV represents a promising oral option for the treatment of CO VID- 19 in nonhospitalized patients who are at increased risk of progressing to severe COVID-19, that is anticipated to fulfill an unmet medical need.SUMMARY

[0006] Provided herein is a method of treating a coronavirus infection in a patient in need thereof, wherein the method comprises administering to the patient obeldesivir, or a pharmaceutically acceptable salt thereof, wherein the patient has at least one risk factor for coronavirus infection.

[0007] Also provided herein is a method of treating a coronavirus infection in a patient in need thereof, wherein the method comprises administering to the patient obeldesivir, or a pharmaceutically acceptable salt thereof, wherein the patient does not have any risk factors for severe coronavirus infection.Attorney Docket No. 1571-WO-PCTBRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is a Kaplan-Meier estimate of time to Covid-19 symptom alleviation by day 15 (Full Analysis Positive Set).

[0009] FIG. 2 is a least-squares mean (95% CI) change from baseline in SARS-CoV-2 nasal swab viral RNA copy number using mixed-effects model repeated measures (MMRM).

[0010] FIG. 3 is least-squares mean (95% CI) change from baseline in SARS-CoV-2 nasal swab infectious viral titer using MMRM in participants with value >200 plaque-forming unit (PFU) per mL at baseline and tested on day 3 or day 5 (Virology Analysis Set).

[0011] FIG. 4 is a graph showing the Kaplan-Meier estimate of time to COVID- 19 symptom alleviation (full analysis positive set).

[0012] FIG. 5 is a graph showing the Kaplan-Meier estimate of time to COVID- 19 symptom resolution (full analysis positive set).

[0013] FIG. 6 is a graph showing the forest plot of time to COVID- 19 symptom alleviation for selected subgroups (full analysis positive set).

[0014] FIG. 7 is a graph showing the least squares mean (95% CI) change from baseline in SARS-CoV-2 nasal swab viral RNA copy number (logio copies / mL) using MMRM model (virology analysis set).

[0015] FIG. 8 is a graph showing the proportion of participants with negative SARS-CoV-2 nasal swab viral RNA copy number (virology analysis set).DETAILED DESCRIPTION

[0016] Obeldesivir (compound 1, ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate) is an antiviral agent,compound 1 and its methods of making it, as well as its salts and polymorph forms are described in WO 2022 / 047065 (Compound 15 of WO 2022 / 047065), which is incorporated herein by reference in its entirety.

[0017] Provided herein is a method of treating a coronavirus infection in a patient in need thereof, wherein the method comprises administering to the patient obeldesivir, or aAttorney Docket No. 1571-WO-PCT pharmaceutically acceptable salt thereof, wherein the patient has at least one risk factor for coronavirus infection.

[0018] In some embodiments, the at least one risk factor is for severe coronavirus infection.

[0019] In some embodiments, the patient demonstrates greater reduction in coronavirus viral load from baseline compared to an untreated patient. In some embodiments, the patient demonstrates greater reduction in coronavirus viral load from baseline by Day 5 comparted to an untreated patient.

[0020] In some embodiments, the patient demonstrates greater reduction in nasal swab coronavirus viral load from baseline compared to an untreated patient. In some embodiments, the patient demonstrates greater reduction in nasal swab coronavirus viral load from baseline by Day 5 compared to an untreated patient. In some embodiments, the patient achieves a reduction in nasal swab coronavirus viral load from baseline compared to an untreated patient.

[0021] In some embodiments, the patient demonstrates a greater proportion of negative infectious titer compared to an untreated patient. In some embodiments, the patient demonstrates a greater proportion of negative infectious titer at Day 5 compared to an untreated patient.

[0022] In some embodiments, the patient demonstrates a greater reduction in nasal swab coronavirus viral titer from baseline compared to untreated patient. In some embodiments, the patient demonstrates a greater reduction in nasal swab coronavirus viral titer from baseline to Day 5 compared to untreated patient. In some embodiments, the patient demonstrates a greater reduction in nasal swab coronavirus viral titer from baseline to Day 3 compared to untreated patient.

[0023] In some embodiments, the patient achieves improvement in time to symptom alleviation compared to an untreated patient. In some embodiments, the patient achieves about a two-day improvement in time to symptom alleviation compared to an untreated patient. In some embodiments, the patient achieves about a two-day improvement in time to symptom alleviation by Day 15 compared to an untreated patient.

[0024] In some embodiments, the at least one risk factor for coronavirus infection is: equal to or greater than age of 50 years, cancer, human immunodeficiency virus infection, prior splenectomy, prior solid organ, stem cell, or bone marrow transplant, systemic rheumatologic or dermatologic disorders, use of systemic immunosuppressive agents, cerebrovascular disease, cardiovascular disease, chronic kidney disease, chronic lung disease, chronic liver disease, cystic fibrosis, diabetes mellitus, type 1 diabetes, type 2 diabetes, neurodevelopmental conditions, neurodegenerative conditions, body mass index equal to or greater than 25 kg / m2, sickle cellAttorney Docket No. 1571-WO-PCT disease, primary immunodeficiencies, compensated cirrhosis, asthma, or smoking equal to or greater than 20 packs a year, or a combination thereof.

[0025] In some embodiments, the systemic immunosuppressive agent is high-dose corticosteroids, alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, or tumor necrosis factor blockers. In some embodiments, the cardiovascular disease is heart failure, coronary artery disease, cardiomyopathies, or hypertension. In some embodiments, the chronic lung disease is interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, or chronic obstructive pulmonary disease.

[0026] In some embodiments, the patient does not have anticipated access to and use of authorized or approved therapies against the viral infection, has not received any approved, authorized, or investigational direct-acting antiviral drug against the viral infection, does not have an anticipated need for hospitalization, does not requires oxygen, is not infected with influenza, does not have decompensated cirrhosis, does not have acute liver injury or failure, is not undergoing dialysis, does not have an alanine aminotransferase level greater than or equal to five times the upper limit of normal, does not have a bilirubin level greater than or equal to two times the upper limit of normal, is not pregnant, is not breastfeeding, is willing to use protocol- mandated birth control, is not hypersensitivities to obeldesivir or its metabolites, or has not received a vaccine against the viral infection within 120 days before the administration of obeldesivir.

[0027] In some embodiments, the approved, authorized, or investigational direct-acting antiviral drug is nirmatrelvir / ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir, or monoclonal antibodies.

[0028] In some embodiments, the patient meets all of the following criteria:Aged > 18 years;Willing and able to provide written informed consent, or with a legal representative who can provide informed consent;Viral infection confirmed by PCR or an approved alternative assay < 5 days before randomization;Initial onset of symptoms < 5 days before randomization with > 1 of the following targeted signs / symptoms present at randomization: stuffy or runny nose, sore throat, shortness of breath, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, and diarrhea;Not currently hospitalized or requiring hospitalization; andAttorney Docket No. 1571-WO-PCTPresence of > 1 risk factor if unvaccinated or > 2 risk factors if vaccinated.

[0029] Also provided herein is a method of treating a coronavirus infection in a patient in need thereof, wherein the method comprises administering to the patient obeldesivir, or a pharmaceutically acceptable salt thereof, wherein the patient does not have any risk factors for severe coronavirus infection.

[0030] In some embodiments, obeldesivir is administered within 3 to 1 days of symptom onset. In some embodiments, obeldesivir is administered within 3 days of symptom onset. In some embodiments, obeldesivir is administered within 2 days of symptom onset. In some embodiments, obeldesivir is administered within 1 day of symptom onset.

[0031] In some embodiments, obeldesivir is administered to the patient before symptom onset.

[0032] In some embodiments, the patient achieves an improvement in time to symptom alleviation compared to an untreated patient. In some embodiments, the patient achieves about a one-day improvement in time to symptom alleviation compared to an untreated patient.

[0033] In some embodiments, the patient demonstrates greater reduction in coronavirus viral RNA copy number from baseline compared to an untreated patient. In some embodiments, the patient demonstrates greater reduction in coronavirus viral RNA copy number from baseline compared to an untreated patient at Day 3. In some embodiments, the patient demonstrates greater reduction in coronavirus viral RNA copy number from baseline compared to an untreated patient at Day 5.

[0034] In some embodiments, the patient tests negative for coronavirus by Day 5. In some embodiments, the patient tests negative for coronavirus on Day 5.

[0035] In some embodiments, the patient is not planning to receive a direct acting antiviral or monoclonal antibody against SARS-CoV-2 for the treatment of CO VID- 19, has not received any approved, authorized, or investigational direct acting antiviral drug or monoclonal antibody against SARS-CoV-2 for the treatment of COVID-19 within 28 days or 5 half-lives before the administration of ODV, has not received any convalescent COVID- 19 plasma or other antibodybased anti-SARS-CoV-2 prophylaxis, has not received an approved, authorized, or investigational COVID-19 vaccine within 120 days before the administration of ODV, does not have a self-reported COVID-19 diagnosis within 120 days before the administration of ODV does not have anticipated need for hospitalization, does not have a new oxygen requirement, does not have influenza, does not have a history of chronic liver disease, is not undergoing dialysis, does not have a history of chronic kidney disease, does not have a history of any of alanine aminotransferase >5 x ULN, bilirubin >2 x ULN, or creatinine clearance (CLcr) <60Attorney Docket No. 1571-WO-PCT mL / min, does not have persistent symptoms from previous COVID- 19 illness, does not have a positive urine pregnancy test at screening, is not breastfeeding, is willing to use protocol- mandated contraception, is not hypersensitivity to the obeldesivir, or is not using nirmatrelvir / ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir, or monoclonal antibodies against COVID- 19.

[0036] In some embodiments, the patient meets all of the following criteria:Aged >18 to <65 years (at all sites), or aged >12 to <18 years weighing >40 kg;Willing and able to provide written informed consent or for participants > 12 and < 18 years of age, a parent or legal guardian willing and able to provide written informed consent prior;SARS-CoV-2 infection confirmed, <3 days before randomization, by polymerase chain reaction, rapid antigen test, or an approved alternative assay;Willing and able to complete the COVID-19 symptom questionnaire prior to first dose and daily throughout the study period;Initial onset of COVID-19 signs / symptoms <3 days before randomization with >2 of the following targeted symptoms, at moderate or higher severity, present at randomization: stuffy or runny nose, sore throat, shortness of breath (difficulty breathing), cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, and feeling hot or feverish; andNot currently hospitalized or requiring hospitalization.

[0037] In some embodiments, the risk factors are obesity, diabetes mellitus, type 1 diabetes, type 2 diabetes, heart failure, coronary artery disease, cardiomyopathies, chronic kidney disease, chronic liver disease, chronic lung diseases, current pulmonary embolism, moderate to severe asthma, active pulmonary tuberculosis, cerebrovascular disease, down syndrome, pregnancy, receiving chemotherapy or other therapies for cancer, or hematologic malignancy, or combination thereof.

[0038] In some embodiments, the administering comprising administering about 100-600 mg, about 150-550 mg, about 200-500 mg, about 250-450 mg, about 300-400 mg, about 350 mg of obeldesivir, or a pharmaceutically acceptable salt thereof, or a free base. In some embodiments, the administering is conducted twice per day. In some embodiments, the administering is comprising administering 350 mg of obeldesivir twice daily for five consecutive days. In some embodiments, the administering is oral administration.

[0039] In some embodiments, the viral infection is a coronavirus infection. As such, in some embodiments, provided herein is a method of treating a coronavirus infection in a human in needAttorney Docket No. 1571-WO-PCT thereof, wherein the method comprises administering to the human a compound described herein. In some embodiments, the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS-CoV) infection, Middle Eastern Respiratory Syndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections. In some embodiments, the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection. In some embodiments, the viral infection is a Middle Eastern Respiratory Syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection. In some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS- CoV-2 polymerase. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS- CoV polymerase and SARS-CoV-2 polymerase. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2 polymerase. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS- CoV-2 polymerase.

[0040] In some embodiments, the viral infection is caused by a variant of SARS-CoV-2, for example by the B.1.1.7 variant (the UK variant), B.1.351 variant (the South African variant), P. l variant (the Brazil variant), B.1.1.7 with E484K variant, B.1.1.207 variant, B.1.1.317 variant, B.1.1.318 variant, B.1.429 variant, B.1.525 variant, or P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P. 1 variant of SARS-CoV-2.

[0041] In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the coronavirus is an alpha coronavirus, a beta coronavirus, a gamma coronavirus, a delta coronavirus, an epsilon coronavirus, an eta coronavirus, an iota coronavirus, a kappa coronavirus, an omicron coronavirus, a zeta coronavirus, or a mu coronavirus.

[0042] In some embodiments, the coronavirus infection is an alpha coronavirus infection. In some embodiments, the alpha coronavirus is feline coronavirus (FCoV), FCoV-II, transmissible gastroenteritis virus (TGEV), porcine respiratory coronavirus (PRCV), canine coronavirus (CCoV), CCoV-II, CRCoV, human coronavirus229E (HCoV-229E), human coronavirus NL63Attorney Docket No. 1571-WO-PCT(HCoV-NL63), porcine epidemic diarrhea vims (PEDV), swine acute diarrhea syndromecoronavirus (SADS-CoV), bat coronaviruses (Bat CoV), or FRCoV.

[0043] In some embodiments, the coronavirus infection is a beta coronavirus infection. In some embodiments, the beta coronavirus is human coronavirus OC43 (HCoV-OC43), human coronavirus HKU-1 (HCoV-HKUl), human enteric coronavirus-4408 (HECoV-4408), bovine coronavirus (BCoV), BCoV-like CoVs, BCoV-like CoVs, canine respiratory coronavirus (CRCoV), equine coronavirus (ECoV), porcine hemagglutinating encephalomyelitis virus (PHEV), murine hepatitis virus (MHV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bat coronaviruses (Bat CoV), rabbit coronavirus (RbCoV), or bubaline coronavirus (BuCoV).

[0044] In some embodiments, the beta coronavirus is a sarbecovirus. In some embodiments, the sarbecovirus is Longquan 140, Pangolin-CoV, RmYN02, RaTG13, CoVZC45, CoVZXC21, GX-P4L, RshSTT182, RshSTT200, RacCS203, Rc-o319, RpYN06, or PrC31.

[0045] In some embodiments, the coronavirus infection is a gamma coronavirus infection. In some embodiments, the gamma coronavirus is infectious bronchitis virus (IBV), turkey coronavirus (TCoV), bottlenose whale coronavirus (BdCoV), beluga whale coronavirus (BWCoV), or PhCoV.

[0046] In some embodiments, the coronavirus infection is a delta coronavirus infection. In some embodiments, the delta coronavirus is a porcine deltacoronavirus (PDCoV).

[0047] In some embodiments, the coronavirus infection is an omicron coronavirus infection. In some embodiments, the omicron coronavirus is WAI (lineage A), BF.7, BQ.l , XBB.1.5, CH.1.1, XBF, XBB.1.16, or XBB.1.9.1.Definitions

[0048] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

[0049] As used herein “BL” is an abbreviation for baseline.

[0050] As used herein “CI” is an abbreviation for confidence interval.

[0051] As used herein, the term “Cmax” refers to the maximum observed concentration of drug.

[0052] As used herein “HR” is an abbreviation for hazard ratio.

[0053] As used herein “MMRM” is an abbreviation for mixed-effects model repeated measures.Attorney Docket No. 1571-WO-PCT

[0054] As used herein, the term “ AUCo - -24,” refers to the area under the concentration-time curve from 0 time to 24 hours. Unless specifically described, AUC0-24 can be calculated using standard methods.

[0055] Coronavirus viral RNA copy number can be determined using quantitative (reverse- transcriptase-polymerase-chain-reaction) RT-PCR testing.

[0056] Symptoms of coronavirus infections include stuffy or runny nose, sore throat, shortness of breath, difficulty breathing, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, or diarrhea or combinations thereof.

[0057] Cepheid’s Xpert Xpress CoV-2 / Flu / RSV plus (Multiplex), SARS-CoV-2 RT-qPCR test, or RT-PCR can be used to determine if a patient is positive or native for coronavirus. A patient can be considered positive for coronavirus if Cepheid’s Xpert Xpress CoV-2 / Flu / RSV plus (Multiplex) test result is positive for SARS-CoV-2 or if SARS-CoV-2 RT-qPCR test result is numerical viral load result or “<2228cp / mL SARSCoV2 detected”, regardless of if the sample was collected with less than specified volume of test solution. A patient can be considered negative for coronavirus if the result of RT-PCR testing is “target not detected”.

[0058] As used herein, patients are considered to have a severe coronavirus infection when they have SpCh <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaC / FiCh) <300 mm Hg, a respiratory rate >30 breaths / min, or lung infiltrates >50%. Symptoms of a severe coronavirus infection can include trouble breathing, persistent pain or pressure in the chest, new confusion, inability to wake or stay awake, and pale, gray, or blue-colored skin, lips, or nail beds, depending on skin tone.

[0059] As used herein, an “untreated patient” is a patient that receives the placebo.

[0060] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters, which can be changed or modified to yield essentially the same results.EXAMPLES

[0061] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.Example 1. Dose Selection of Obeldesivir (ODV)

[0062] ODV safety and PK were evaluated in a Phase 1 single and multiple ascending dose study (GS-US-611-6248) in healthy participants. Single ODV doses up to 1600 mg and multiple doses of ODV 500 mg twice daily and ODV 900 mg once daily for 5 days were generally safeAttorney Docket No. 1571-WO-PCT and well tolerated. A graded laboratory abnormality of decreased creatinine clearance (CLcr) was observed across all cohorts, although there was a disproportionately higher number of participants with decreased CLcrat the highest dose evaluated (single ODV 1600 mg dose).

[0063] Following oral administration of ODV, GS -441524 (parent nucleoside that can enter cells where it is anabolized to the active triphosphate metabolite GS-443902, see both structures below) was the only circulating species. The plasma half-life of this metabolite was approximately 6 hours, supporting twice daily dosing. The twice daily dosing regimen also provided higher daily exposure (AUCo-24h), higher Ctauconcentrations, and lower Cm;lxas compared with once daily dosing. ODV builds on the already proven mechanism of action of RDV that is inhibition of SARS-CoV-2 RNA polymerase by the active triphosphate metabolite, GS-443902. The major metabolic pathways leading to formation of the GS-443902 metabolite are different between RDV and ODV. For ODV, the major metabolic pathway is through phosphorylation of the GS-441524 metabolite by cellular kinases, a pathway that is believed to play a minor role in activation of RDV to GS-443902 metabolite. In order to overcome the less efficient conversion to GS-443902, the levels of GS-441524 need to be approximately 14-fold higher, as compared with what is observed after RDV, in order to result in the similar levels of intracellular active metabolite. Robust intracellular formation of active metabolite was observed in the GS-US-611-6248 clinical study in PBMCs (e.g., ODV 500 mg administered twice daily achieved GS-443902 levels comparable with IV RDV on Day 1 and exceeded those on later days by approximately 4-fold). The intracellular formation of GS-443902 was dose-proportional and significant accumulation was observed following twice daily dosing (approximately 6-fold accumulation by Day 5).Attorney Docket No. 1571-WO-PCT

[0064] ODV showed therapeutic efficacy in multiple SARS-CoV-2 animal models (i.e., mouse, ferret, and African green monkeys [AGMs]). Administration of ODV to SARS-CoV-2-infected mice (10 mg / kg twice daily; AUC0-24h = 10,500 h»ng / mL), ferrets (20 mg / kg once daily; AUCo-24h = 28,500 h»ng / mL) and AGM (60 mg / kg once daily; AUC0-2411 = 25,700 h»ng / mL) for 5 days resulted in a significant reduction of clinical signs of respiratory disease, infectious virus titers in lungs, and genomic RNA compared with vehicle-treated animals. Similarly, in the AGM model, IV delivery of parent nucleoside (20 mg / kg once daily; AUCo-24h = 42,800 h»ng / mL) and oral administration of GS-621763, a tri-isobutyryl ester tool prodrug of GS-441524 (60 mg / kg once daily; AUC0-2411 = 18,200 h*ng / niL); (120 mg / kg once daily; AUC0-2411 = 36,400 h»ng / mL) significantly reduced SARS-CoV-2 levels in the lower airways, as early as 1 to 2 days after infusion.

[0065] ODV 350 mg twice daily dose was selected for the treatment of COVID-19 in participants at high risk for disease progression. This dosing regimen allows for GS-441524 concentrations over the dosing interval to be predominantly maintained above the effective concentration (EC50) needed for SARS-CoV-2 viral inhibition in normal human bronchial epithelia cells (EC50 = 713 ng / mL). This dosing regimen also provides a substantial exposure (Cmax) margin relative to the 1600 mg dose (approximately 2- to 3-fold) where potential drug- related effects on CLcrwere observed.Example 2. Clinical Trial for High-Risk Patients

[0066] Oral ODV safety and efficacy was evaluated in a randomized, double-blind, placebo- controlled study in non-hospitalized participants with COVID-19 who are at high risk of progression to hospitalization. Overall, 465 participants were randomized and received >1 dose. Participants were randomized within 48 hours of screening. Eligible participants were stratified by duration of symptoms at enrollment (<3 days versus >3 days) and vaccination status (ever versus never) and randomized 1 :1 to receive oral obeldesivir 350 mg or placebo twice daily during the treatment period (days 1-5). 56% were female, 4% were Black, 9% were American Indian or Alaska native, and 12% were Asian. Median age was 56 years; 29% were >65 years of age. The most common risk factor was having a body mass index >25 mg / kg2(85% of all participants). 76% were randomized within 3 days of symptom onset, 42% had never been vaccinated, and 92% were SARS-CoV-2 seropositive. 90% were SARS-CoV-2 positive by nucleic acid amplification test at baseline for efficacy analyses.

[0067] Starting on Day 1, placebo or ODV 350 mg (1 x 350 mg tablet) was administered orally twice daily without regard to food with approximately 240 mL of water for 5 days. This doseAttorney Docket No. 1571-WO-PCT was selected based on the totality of available clinical and nonclinical data and with careful consideration of the overall risk-benefit profile. A screening was done within 48 hours prior to the Day 1 dose. Baseline measurements were taken just prior to administration of the Day 1 dose.Inclusion Criteria

[0068] Participants in the study were non-hospitalized participants with COVID-19 with at least 1 risk factor (if unvaccinated) and at least 2 risk factors (if vaccinated at any point) for disease progression. Participants needed to meet all the following inclusion criteria to be eligible for participation in the study:1) Aged > 18 years at screening.2) Willing and able to provide written informed consent, or with a legal representative who can provide informed consent (where locally and nationally approved).3) SARS-CoV-2 infection confirmed by PCR or an approved alternative assay (e.g., Rapid Antigen Test) < 5 days before randomization. Serologic tests will not be accepted.4) Initial onset of COVID-19 signs / symptoms < 5 days before randomization with > 1 of the following targeted signs / symptoms present at randomization: stuffy or runny nose, sore throat, shortness of breath (difficulty breathing), cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, and diarrhea.5) Not currently hospitalized or requiring hospitalization.6) Presence of > 1 risk factor (if unvaccinated) or > 2 risk factors (if vaccinated at any point) for progression to severe disease. Risk factors are the following: a) Aged > 50 years b) Current or recent (< 6 months prior to randomization) cancer (other than localized skin cancer). c) Have human immunodeficiency virus infection. d) Prior splenectomy. e) Prior solid organ, stem cell, or bone marrow transplant. f) Have systemic rheumatologic or dermatologic disorders. g) Use of systemic immunosuppressive agents, e.g., high-dose corticosteroids (i.e., > 20 mg of prednisone or equivalent per day administered for > 2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosisAttorney Docket No. 1571-WO-PCT factor blockers, other biologic agents that are immunosuppressive or immunomodulatory. h) Have cerebrovascular disease. i) Have cardiovascular disease, including heart failure, coronary artery disease, cardiomyopathies, and hypertension. j) Have chronic kidney disease (provided participant does not meet exclusion criterion 7). k) Have chronic lung disease (interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, or chronic obstructive pulmonary disease). l) Have chronic liver disease. m) Have cystic fibrosis. n) Have diabetes mellitus, type 1 and / or type 2. o) Have neurodevelopmental and / or neurodegenerative conditions. p) Have a body mass index > 25 kg / n . q) Have sickle cell disease. r) Have primary immunodeficiencies. s) Have compensated cirrhosis. t) Have asthma. u) Have > 20 pack-year smoking history and currently smoking or have quit within the past 15 years.Exclusion criteria

[0069] Participants meeting any of the following criteria are not eligible for includes in the study.1) Anticipated access to and use of authorized or approved COVID-19 therapies during the current COVID- 19 illness < 5 days after randomization (therapies include nirmatrelvir / ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir [RDV, Veklury®], monoclonal antibodies).2) Received any approved, authorized, or investigational direct-acting antiviral drug against SARS-CoV-2 for the treatment of COVID-19 < 28 days or < 5 half-lives, whichever is longer, before randomization.3) Anticipated need for hospitalization < 48 hours after randomization.4) New oxygen requirement < 24 hours before randomization.Attorney Docket No. 1571-WO-PCT5) Known influenza or any other suspected or confirmed concurrent active systemic infection other than COVID- 19 that may interfere with the evaluation of response to the study drug.6) Decompensated cirrhosis (Child-Pugh class B or class C) or acute liver injury / failure.7) Undergoing dialysis, or known history of moderate or severe renal impairment, or known CLa < 60 mL / min (as calculated by Cockroft- Gault) or eGFR < 60 mL / min / 1.73m2within the last 6 months. Potential participants meeting the laboratory criterion may be enrolled if test results available before dosing show that renal function no longer meets this criterion.8) Known history of any of the following abnormal laboratory results (< 6 months before randomization) unless confirmed as resolved to not meet criteria at screening. Alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN). Bilirubin > 2 x ULN (> 3 x ULN for participants with Gilbert’s syndrome).9) Positive urine pregnancy test at screening.10) Breastfeeding (nursing).11) Unwilling to use protocol-mandated birth control.12) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.13) Requirement for ongoing therapy with or prior use of any prohibited medications.14) Received an approved, authorized, or investigational COVID-19 vaccine (including booster dose) < 120 days before randomization.15) Any inability to take study drug or comply with study procedures that, in the opinion of the investigator, would make the participant unsuitable for the study.Objectives and Endpoints

[0070] The primary objective was to evaluate the efficacy of ODV in reducing the rate of COVID-19-related hospitalization or all-cause death.

[0071] The secondary objectives were:1) To evaluate the safety and tolerability of ODV administered in non-hospitalized participants with COVID-19.2) To evaluate the efficacy of ODV in reducing all-cause hospitalization.3) To evaluate the efficacy of ODV in reducing COVID- 19-related medically attended visits (MAVs) or all-cause death.4) To evaluate the efficacy of ODV in reducing C OVID- 19-related MAVs.5) To evaluate the efficacy of ODV in reducing all-cause death.Attorney Docket No. 1571-WO-PCT6) To evaluate the efficacy of ODV in reducing the duration and severity of COVID-19 symptoms.7) To evaluate the antiviral activity of ODV on SARS-CoV-2 nasal swab viral load at Day 5.8) To evaluate the plasma PK of GS-441524 (metabolite of ODV).

[0072] The primary endpoint was proportion of COVID-19-related hospitalization or all-cause death by Day 29.

[0073] The secondary endpoints were:1) Incidence of treatment-emergent adverse events (AEs) and laboratory abnormalities.2) Incidence of serious adverse events (SAEs) and AEs leading to study drug discontinuation.3) Proportion of participants with all-cause hospitalization by Day 29.4) Proportion of participants with COVID-19-related medically attended visits (MAVs) or all-cause death by Day 29.5) Proportion of participants with COVID-19-related MAVs by Day 29.6) Proportion of participants with all-cause death by Day 29.7) Time to COVID-19 symptom alleviation by Day 15.8) Change from baseline (Day 1) in SARS-CoV-2 nasal swab viral load at Day 5.9) Plasma concentrations and PK parameters AUCtau, Ctau, and Cmax of GS-441524, as available.Patient-Reported Outcomes

[0074] The Symptoms of Infection with Coronavirus-19 (SIC) instrument will assess patient reported outcomes in this study and scores will be completed daily from Day 1 through Day 15 and at Day 29. Patient reported outcomes will only be administered to participants after Day 1 if available at Day 1 for that participant. The participant should read and answer the questionnaire individually without external assistance.

[0075] The SIC was developed to assess the presence and severity of COVID- 19 symptoms in clinical and observational research with the goal of capturing changes in the incidence and / or severity of symptoms associated with COVID- 19. In the context of clinical trials, the SIC is intended to support the evaluation of both primary and key secondary endpoints related to the prevalence and severity of new cases (vaccine trials), as well as improvements in CO VID- 19 symptom severity (treatment trials).

[0076] The SIC includes 30 signs and symptoms associated with COVID- 19 infection. Of these, 25 items assess the presence or absence of a sign or symptom and if present, the respondent ratesAttorney Docket No. 1571-WO-PCT the severity using a 0 to 10 numeric rating scale. The presence or absence of 5 additional signs or symptoms are assessed without a severity rating. Highest daily body temperature (in relation to fever) is also captured. The recall period is "the last 24 hours" and the SIC requires approximately to 10 minutes to complete.

[0077] Symptom alleviation was defined as all targeted symptoms measured via the SIC questionnaire with a rating of 0, a >3-point decrease in rating from baseline, or an answer “No” to the question for >48 consecutive hours. The targeted symptoms for the measurement of symptom alleviation were nasal congestion, runny nose, sore throat, shortness of breath (difficulty breathing), cough, feeling generally unwell (run down), fatigue (tiredness), physical weakness, feeling faint, muscle aches / pains, joint aches / pains, headache, chills, uncontrollable body shaking / shivering, and fever.Virology Testing

[0078] Mid-turbinate nasal swab samples were used to assess SARS-CoV-2 viral load by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR).Safety Assessments

[0079] Safety was assessed by physical examinations and clinical laboratory assessments conducted at a central laboratory. Safety endpoints included incidence of treatment-emergent adverse events (AEs), laboratory abnormalities, serious AEs (SAEs), and AEs leading to study drug discontinuation. A treatment-emergent AE was defined as any AE that began on or after the first dose up to the date of the last dose of study drug plus 30 days, or any AE leading to premature discontinuation of study drug. All AEs and clinically significant laboratory abnormalities were followed until resolution or until the AE was stable, if possible.Statistical Analysis

[0080] Assuming the placebo group event rate was 2% based on the Covid-19 landscape prior to study initiation, a sample size of 2300 participants was determined to provide >90% power to detect a hazard ratio (HR) of 0.25 for Covid- 19-related hospitalization or all-cause death by day 29 in the comparison of obeldesivir with placebo, with a 2-sided significance level of 0.05.

[0081] Participants who were randomized and received >1 dose of study drug were grouped according to treatment received for the safety analysis set and according to treatment assigned for the full analysis set. The full analysis positive set included all participants in the full analysis set with central laboratory-positive SARS-CoV-2 RT-PCR at baseline. The virology analysis set included participants within the full analysis set with a baseline SARS-CoV-2 viral RNA copy number above the lower limit of quantification. Demographic data, baseline characteristics, and laboratory abnormalities were summarized with descriptive statistics.Attorney Docket No. 1571-WO-PCT

[0082] The primary and key secondary endpoints were estimated using a Cox proportional hazards model and the HR, P value, and 95% confidence intervals (Cis) reported. Additionally, Kaplan-Meier estimates were reported. For median time to Covid- 19 symptom alleviation by day 15, the Kaplan-Meier product-limit method was used to estimate, and a stratified log -rank test was used to compare the treatment groups. HR and 95% Cis from a Cox proportional hazards model with stratification factors as covariates were provided. Change from baseline in SARS-CoV-2 nasal swab viral RNA copy number at each visit and change from baseline in SARS-CoV-2 nasal swab infectious viral titer at each visit were compared between treatment groups using mixed-effects model repeated measures with baseline value and stratification factors as covariates. The proportion of participants with negative infectious viral titer was compared between treatment groups using Fisher’s exact test. Statistical analyses were performed using SAS® Software Version 9.4 (SAS Institute Inc., Cary, NC, USA).Participants

[0083] Enrollment was halted early due to a lower-than-expected event rate for the primary endpoint in the context of a dynamic Covid- 19 landscape. Of the 515 participants screened, 468 were randomized (obeldesivir, 233; placebo, 235). The full analysis set had 465 participants (obeldesivir, 233; placebo, 232).

[0084] The safety analysis set had 465 participants (obeldesivir, 234; placebo, 231), of whom 216 (92.3%) and 221 (95.7%) completed study drug, respectively. Fourteen (3.0%) participants prematurely discontinued the study, primarily due to withdrawal of consent (obeldesivir, 6 [2.6%]; placebo, 2 [0.9%]). One participant randomized to placebo received obeldesivir, accounting for the 1 -participant discrepancy between the safety and full analysis sets. Demographic and baseline characteristics were generally similar between groups (Table 1). Table 1. Baseline Characteristics and Demographics (Safety Analysis Set)Attorney Docket No. 1571-WO-PCTAttorney Docket No. 1571-WO-PCTAttorney Docket No. 1571-WO-PCTCovid- 19, coronavirus disease 2019; QI, first quartile; Q3, third quartile; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SD, standard deviation. aFor race category, “Other” includes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, Other, and not permitted. bDuration of Covid- 19 symptoms was defined as the first dosing date minus the Covid-19 symptom onset date (day 0). cDuration from first positive SARS-CoV-2 diagnostic test to first dose of study drug was defined as the first dosing date minus the first positive SARS-CoV-2 test date (day 0). dRisk factors were defined in the inclusion criteria of the protocol. eSerostatus was defined as positive when antispike antibody or antinucleocapsid antibody was positive and negative when both were negative. Serostatus percentages do not include those with missing values. fResult of “No SARS-CoV-2 Detected” was imputed as 746.5 copies / mL (2.87 logic copies / mL); “<2228 copies / mL” was imputed as 1114 copies / mL (3.05 logio copies / mL).

[0085] Overall, the median age was 56 years, 262 (56.3%) participants were assigned female at birth, 343 (73.8%) were White, 78 (16.8%) were Hispanic or Latino, and the median body mass index was 28.2 kg / m2. A greater proportion of participants in the obeldesivir group were female compared to the placebo group (62.8% vs 49.8%). Most participants (352 [75.7%]) had a duration of symptoms <3 days prior to the first treatment dose, and 196 (42.2%) had never received a Covid-19 vaccination prior to screening. Seropositivity for SARS-CoV-2 antibodies was 91.8% overall. The median (QI, Q3) duration of Covid-19 symptoms prior to the first treatment dose was 2 (2, 3) days in both treatment groups. The mean (standard deviation [SD]) number of baseline risk factors was 3 (1.1) in the obeldesivir group, versus 2 (1.0) in the placebo group. However, except for the proportion of participants aged >50 years (75.2% forAttorney Docket No. 1571-WO-PCT obeldesivir; 64.1% for placebo), individual baseline risk factors associated with progression to severe Covid-19 were generally balanced (Table 2).Table 2. Baseline Risk Factors (Safety Analysis Set)Attorney Docket No. 1571-WO-PCTResults

[0086] The primary endpoint was reported in 0% for ODV (0 / 211 participants) and 0.5% for placebo (1 / 207 participants; P = 0.3161).

[0087] Among the 162 participants who completed a symptom questionnaire, ODV showed a 2- day improvement in time to symptom alleviation by Day 15 (ODV: 7.3 days; placebo: 9.3 days; P = 0.0859). The median (95% CI) time to Covid- 19 symptom alleviation by day 15 was 7.3 (5.4 to 9.4) days with ODV and 9.3 (6.5 to not estimable) days with placebo (FIG. 1). Symptom alleviation was evaluated via the Symptoms of Infection with Coronavirus- 19 (SIC) questionnaire, which was only collected for participants enrolled under the original protocol. Hazard ratio (HR) and 2-sided 95% confidence interval (CI) for HR were estimated using a Cox proportional hazards model with stratification factors as covariates. P value was based on stratified log-rank test with stratification factors as the strata. If a participant prematurely discontinued from the study prior to day 15 or the alleviation status was missing, the participant was censored at the last date / time at which the symptom was assessed or day 14, whichever occurred first. The last known symptom alleviation occurred on day 14.

[0088] ODV demonstrated greater reductions in SARS-CoV-2 nasal swab viral load from baseline to Day 5 (-0.58 logio copies / mL; P < 0.0001) compared to placebo in the subset of participants who had evaluable SARS-CoV-2 nasal swab viral load. ODV also demonstrated a greater proportion with negative infectious titer at Day 5 (ODV: 100%; placebo: 81%).

[0089] ODV demonstrated greater reductions in SARS-CoV-2 nasal swab infectious viral titer from baseline to Day 3 (-0.54 logic PFU / mL; P = 0.0003) and Day 5 (-0.17 logic PFU / mL; P = 0.0014) compared to placebo in the subset of participants who had evaluable SARS-CoV-2 nasal swab infectious viral titer. There were more participants who had negative SARS-CoV-2 nasal swab infectious viral titer in the ODV group versus the placebo group at Day 3 (80.4% versus 50.0%; P = 0.0011) and Day 5 (100% versus 76%; P < 0.0001).

[0090] Currently, no established relationship exists between the magnitude and timing of infectious titer reductions and the degree of clinical benefit. However, an analysis of 16 clinical trials assessing 17 COVID-19 interventions in outpatients, including a study in which nirmatrelvir / ritonavir reduced viral load by an adjusted mean difference of -0.87 logic copies / mL versus placebo, found that treatments achieving >0.41 logic reductions in nasopharyngeal SARS-CoV-2 viral load relative to placebo at Days 5 to 7 were moderately associated with a reduction in the risk of hospitalization or death (R2=0.53). Overall, the potential for rapid clearance of SARS-CoV-2 viral RNA is of particular importance for high-risk patients, such as those on immunosuppressive therapy due to hematologic malignancies.Attorney Docket No. 1571-WO-PCT

[0091] The virology analysis set had 193 and 192 participants in the obeldesivir and placebo groups, respectively. At day 5, the least-squares mean (standard error) change from baseline in SARS-CoV-2 nasal swab viral RNA copy number was -2.80 (0.092) logic copies / mL for the obeldesivir group and -2.22 (0.092) logic copies / mL for the placebo group (treatment difference, -0.58 logic copies / mL [95% CI, -0.83 to -0.33 logic copies / mL]; FIG. 2), demonstrating a treatment difference favoring obeldesivir. In the subset of participants with SARS-CoV-2 nasal swab infectious viral titer >200 plaque- forming units (PFU) / mL at baseline, there was a treatment difference in SARS-CoV-2 nasal swab infectious viral titer least-squares mean (95% CI) for obeldesivir versus placebo at day 3 of -0.58 (-0.90 to -0.26) logic PFU / mL and at day 5 of -0.13 (-0.22 to -0.05) logic PFU / mL (FIG. 3; Table 3). Least-squares mean analysis in FIG. 2 included participants in the full analysis set who had a quantifiable baseline SARS-CoV-2 viral RNA copy number. Least-squares mean and 95% CI were from MMRM with baseline viral RNA copy number and stratification factors as covariates. Postbaseline result of “No SARS-CoV-2 Detected” was imputed as 746.5 copies / mL (2.87 logic copies / mL);“<2228 copies / mL” was imputed as 1114 copies / mL (3.05 logic copies / mL). Least-squares mean and 95% CI in FIG. 3 were from MMRM with baseline infectious viral titer and stratification factors as covariates. Infectious viral titer was assessed on SARS-CoV-2 nasal swab samples with viral RNA copy number >106copies / mL. In participants with a positive infectious viral status at baseline, additional testing was conducted on postbaseline samples if day 3 or day 5 swab samples were available, independent of viral RNA copy number value. If day 3 or day 5 samples were available, day 10 sample was also tested, if available. This analysis included participants with baseline infectious viral titer >200 PFU / mL at baseline.

[0092] Additionally, in those participants with baseline infectious titer >200 PFU / mL, a greater proportion in the obeldesivir group versus placebo group had negative SARS-CoV-2 nasal swab infectious viral titer at day 3 (obeldesivir, 35 / 44 [79.5%]; placebo, 18 / 37 [48.6%]) and at day 5 (obeldesivir, 67 / 67 [100.0%]; placebo, 56 / 69 [81.2%]; Table 4).Table 3. Change from Baseline in SARS-CoV-2 Nasal Swab Infectious Viral Titer Using MMRM in Participants with Value >200 PFU / mL at Baseline and Tested on Day 3 or Day 5 (Virology Analysis Set)Attorney Docket No. 1571-WO-PCTCI, confidence interval; MMRM, mixed-effects model repeated measures; PFU, plaqueforming unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, standard error.Least-squares mean (SE), 95% CI and P value were from MMRM with baseline infectious viral titer and stratification factors as covariates.Baseline was the last available value recorded on or prior to first dosing date of study drug. Infectious viral titer was assessed on SARS-CoV-2 nasal swab samples with viral RNA copy number >106copies / mL. In participants with a positive infectious viral status at baseline, additional testing was conducted on postbaseline samples if day 3 or day 5 swab samples were available, independent of viral RNA copy number value. If day 3 or day 5 samples were available, day 10 sample was also tested, if available.Table 4. Proportion of Participants with Negative SARS-CoV-2 Nasal Swab Infectious Viral Titer by Visit with Value >200 PFU / mL at Baseline and Tested on Day 3 or Day 5 (Virology Analysis Set)Attorney Docket No. 1571-WO-PCTN / A, not applicable; PFU, plaque-forming unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.P value was from Fisher’ s exact test.Baseline was the last available value recorded on or prior to first dosing date of study drug. Infectious viral titer was assessed on SARS-CoV-2 nasal swab samples with viral RNA copy number >106copies / mL. In participants with a positive infectious viral status at baseline, additional testing was conducted on postbaseline samples if day 3 or day 5 swab samples were available, independent of viral RNA copy number value. If day 3 or day 5 samples were available, day 10 sample was also tested, if available.

[0093] The safety profiles of ODV and placebo were comparable, with similar rates of AEs, serious AEs, and AEs leading to discontinuation of study drug. ODV resulted in greater decreases in viral load and infectious titer, and a trend in faster time to symptom alleviation. In this population of participants with comorbidities, ODV was generally safe and well tolerated.Example 3. Clinical Trial for Patients Without Risk Factors

[0094] Non-hospitalized adults and adolescents without specified risk factors for severe COVID-19 were enrolled <3 days from COVID-19 symptom onset and randomized 1 : 1 to receive ODV 350 mg or placebo twice daily starting on Day 1 for 5 days. Randomization was stratified by completion of primary COVID-19 vaccination series. A screening was done within 24 hours prior to the Day 1 dose. Baseline measurements were taken just prior to administration of the Day 1 dose.Attorney Docket No. 1571-WO-PCTInclusion Criteria

[0095] Eligible participants were aged >12 to <65 years and had SARS-CoV-2 infection confirmed by rapid antigen or reverse transcriptase-polymerase chain reaction (RT-PCR) test with initial onset of >2 targeted COVID-19 signs or symptoms (stuffy or runny nose; sore throat; shortness of breath; cough; low energy or tiredness; muscle or body aches; headache; chills or shivering; or feeling hot or feverish) <3 days before randomization. Participants must have met all the following inclusion criteria to be eligible for participation in this study1) Aged >18 to <65 years (at all sites), or aged >12 to <18 years weighing >40 kg (US sites only, after the first data monitoring committee meeting occurred) at screening.2) Willing and able to provide written informed consent (and assent as applicable). For participants > 12 and < 18 years of age, a parent or legal guardian willing and able to provide written informed consent prior to performing study procedures.3) SARS-CoV-2 infection confirmed, <3 days before randomization, by polymerase chain reaction, rapid antigen test, or an approved alternative assay. Serologic tests were not accepted.4) Willing and able to complete the COVID-19 symptom questionnaire prior to first dose and daily throughout the study period.5) Initial onset of COVID- 19 signs / symptoms <3 days before randomization with >2 of the following targeted symptoms, at moderate or higher severity, present at randomization: a) Stuffy or runny nose. b) Sore throat. c) Shortness of breath (difficulty breathing). d) Cough. e) Low energy or tiredness. f) Muscle or body aches. g) Headache. h) Chills or shivering. i) Feeling hot or feverish.6) Not currently hospitalized or requiring hospitalization.Exclusion Criteria

[0096] Participants were ineligible if they had specified risk factors for progression to severe disease, had a COVID-19 diagnosis or received a COVID-19 vaccine <120 days before randomization, or had an anticipated need for hospitalization <48 hours after randomization.Attorney Docket No. 1571-WO-PCT1) Any risk factors for progression to severe disease, including: a) Obesity (body mass index >30 kg / nr for those >18 years or >95"' percentile in those >12 but <18 years of age). b) Diabetes mellitus, type 1 and type 2. c) Heart failure, coronary artery disease, or cardiomyopathies. d) Chronic kidney disease or undergoing dialysis. e) Chronic liver disease, limited to cirrhosis, nonalcoholic steatohepatitis, alcoholic liver disease, and autoimmune hepatitis. f) Chronic lung diseases limited to:Chronic obstructive pulmonary disease.Interstitial lung disease.Cystic fibrosis.Pulmonary hypertension.Bronchiectasis. g) Current pulmonary embolism. h) Moderate to severe asthma (or asthma of any severity participants >12 and <18 years of age). i) Active pulmonary tuberculosis. j) Cerebrovascular disease. k) Down syndrome. l) Pregnancy. m) One or more of the following immunocompromising conditions or immunosuppressive treatments:Receiving chemotherapy or other therapies for cancer.Hematologic malignancy (active or in remission).2) Planning to receive a direct acting antiviral or monoclonal antibody against SARS- CoV-2 for the treatment of COVID-19.3) Received any approved, authorized, or investigational direct acting antiviral drug or monoclonal antibody against SARS-CoV-2 for the treatment of COVID-19 <28 days or <5 half- lives, whichever is longer, before randomization.4) Received any convalescent COVID-19 plasma or other antibody-based anti-SARS- CoV-2 prophylaxis at any time prior to study entry.5) Received an approved, authorized, or investigational COVID- 19 vaccine (including booster dose) <120 days before randomization.Attorney Docket No. 1571-WO-PCT6) Self-reported COVID-19 diagnosis <120 days before randomization.7) Anticipated need for hospitalization <48 hours after randomization.8) New oxygen requirement <24 hours before randomization.9) Known influenza, or any other suspected or confirmed concurrent active systemic infection other than COVID-19 that may interfere with the evaluation of response to the study drug.10) Known history of chronic liver disease, limited to cirrhosis, nonalcoholic steatohepatitis, alcoholic liver disease, and autoimmune hepatitis.11) Undergoing dialysis, or known history of chronic kidney disease12) Known history of any of the following abnormal laboratory results <6 months before randomization, unless confirmed as not meeting the exclusion criteria below, at screening: a) Alanine aminotransferase >5 x ULN. b) Bilirubin >2 x ULN (>3 x ULN for participants with Gilbert’s syndrome). c) Creatinine clearance (CLcr) <60 mL / min or estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2.13) Persistent symptoms from previous COVID-19 illness that may interfere with the evaluation of response to the study drug.14) Positive urine pregnancy test at screening.15) Breastfeeding (nursing).16) Unwilling to use protocol-mandated contraception.17) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.18) Requirement for ongoing therapy with or prior use of any prohibited medications (nirmatrelvir / ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir, monoclonal antibodies against COVID- 19).19) Any other factor, including inability to complete the patient-reported outcome questionnaire for the primary endpoint, making the participant, in the opinion of the investigator, unsuitable to participate in the study.20) Concurrent participation / enrollment in a separate therapeutic clinical study.Objectives and Endpoints

[0097] The primary efficacy endpoint was time to COVID-19 symptom alleviation by Day 29.Symptom alleviation was defined as follows: all targeted symptoms scored moderate or severe at baseline were scored as mild or none for >48 consecutive hours and all targeted symptoms scored mild or none at baseline were scored as none for >48 consecutive hours; the first day ofAttorney Docket No. 1571-WO-PCT the 48 consecutive hours was considered the symptom alleviation date. Key secondary efficacy endpoints included time to CO VID- 19 symptom resolution by Day 29 and proportions of participants with moderate relapse of COVID-19 symptoms, COVID-19-related medically attended visits (MAVs) or all-cause death, and COVID-19-related hospitalization or all-cause death by Day 29. Symptom resolution was defined as follows: all targeted symptoms scored as none for >48 consecutive hours; the first day of the 48 consecutive hours was considered the date of symptom resolution. Additional endpoints included change from baseline in SARS-CoV- 2 nasal swab viral RNA copy number and proportion of participants with negative SARS-CoV-2 nasal swab at Days 3, 5, 10, 15, 20, and 29.

[0098] Safety was assessed by physical examinations and centrally analyzed clinical laboratory assessments. The safety endpoints included incidence of treatment-emergent AEs, laboratory abnormalities, SAEs, and AEs leading to study drug discontinuation. Treatment-emergent AEs were defined as any AE that began on or after the date of first dose of study drug up to the date of last dose of study drug plus 30 days or any AE leading to premature discontinuation of study drug. All AEs and clinically significant laboratory abnormalities were followed until the AE was resolved or stable, if possible.Patient-Reported Outcomes

[0099] The Efficacy and safety assessments were performed through Day 90. Assessments included physical examinations, laboratory testing of blood and mid-turbinate nasal swabs, and adverse event (AE) reporting. Patient-reported outcomes were collected through a COVID- 19 symptom questionnaire adapted from US Food and Drug Administration guidance. Questionnaires were completed daily through Day 29 and then at Days 60 and 90; during the first 5 days, questionnaires were completed predose.Participants

[0100] Of the 2253 participants screened, 1955 were included in the full analysis set. Overall, 979 participants received >1 dose of ODV and 976 participants received >1 dose of placebo and were included in the full analysis set and the safety analysis set, of which 969 (99.0%) and 955 (97.8%) completed study drug, respectively. Forty-five (2.3%) participants prematurely discontinued the study, primarily due to withdrawal of consent (ODV, 7 [0.7%]; placebo, 13 [1.3%]) and loss to follow-up (ODV, 5 [0.5%]; placebo, 13 [1.3%]).

[0101] Demographic and baseline characteristics were comparable between treatment groups (Table 5).Attorney Docket No. 1571-WO-PCTTable 5. Baseline characteristics and demographics (safety analysis set)Attorney Docket No. 1571-WO-PCTAttorney Docket No. 1571-WO-PCTCO VID- 19=corona virus disease 2019. IQR=interquartile range. LLOD=lower limit of detection.LLOQ=lower limit of quantitation. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. Ql=first quartile. Q3=third quartile. SD=standard deviation.*For race category, “Other” includes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, Other, and not permitted.^Randomisation was stratified by completion of a primary vaccination series.^Duration of COVID-19 symptoms was defined as the first dosing date minus the COVID-19 symptom onset date (day 0).§Total of targeted COVID-19 symptom scores was defined as the total scores of 9 targeted COVID-19 symptoms with score 0 = none, 1 = mild, 2 = moderate, and 3 = severe.^Serostatus was defined as positive when either antispike antibody or antinucleocapsid antibody was positive and negative when both were negative. Serostatus percentages do not include those with missing values.Attorney Docket No. 1571-WO-PCTIIAnti-SARS-CoV-2 antibodies were evaluated in the full analysis positive set using independent assays; results from each assay should be interpreted individually. Percentages do not include those with missing values.**The LLOD and LLOQ for SARS-CoV-2 viral RNA were 1493 and 2228 copies / mL, respectively. The result of “No SARS-CoV-2 detected” was imputed as half of the LLOD (746-5 copies / mL; 2- 87 logw copies / mL); the result of “<2228 copies / mL” was imputed as half of the LLOQ (1114 copies / mL; 3-05 logio copies / mL).

[0102] The median (range; IQR) age was 41 (12 to 64; 21 ) years, 1 155 (59.1 %) were female, 1698 (86.9%) were White, and 1819 (93.0%) were Hispanic or Latino. The median (QI, Q3) duration of COVID-19 symptoms prior to the first dose of study drug was 2 (2, 2) days for both treatment groups. The median (QI, Q3) baseline SARS-CoV-2 viral RNA copy number was 5.22 (3.97, 6.15) and 5.27 (3.80, 6.22) logic copies / mL for the ODV and placebo groups, respectively. Most participants had completed a primary COVID-19 vaccination series (1368 [70.0%]) and were seropositive for anti-spike or anti-nucleocapsid antibodies (1938 [99.6%]). The full analysis positive set had 1768 participants (884 participants per group), of whom 1738 (99.4%) and 1511 (86.0%) were positive for SARS-CoV-2 spike and nucleocapsid protein antibodies, respectively.Efficacy

[0103] In participants in the full analysis positive set with COVID- 19 symptom data, median time to CO VID- 19 symptom alleviation by Day 29 was similar for those receiving ODV (5.9 [95% CI, 5.4 to 6.1] days) versus placebo (6.0 [95% CI, 5.8 to 6.3] days; P=0.07; FIG. 4). The P value was calculated from stratified log-rank test with randomization stratification factor as the strata. Hazard ratio and 2-sided 95% CI for hazard ratio were estimated using the Cox regression with randomization stratification factor as a covariate. Participants who prematurely discontinued from the study prior to Day 29 or whose alleviation status was missing were censored at last date / time on which the symptom were assessed or Day 28, whichever occurred first. Data only includes participants with COVID- 19 symptom data. Median time to symptom resolution by Day 29 was 9.2 (95% CI, 8.9 to 10.0) days for the ODV group compared with 9.3 (95% CI, 8.9 to 10.1) days for the placebo group (FIG 5). Moderate relapse of COVID-19 symptoms (as defined in the protocol) by Day 29 occurred in 63 (8.3%; 95% CI, 6.4% to 10.5%) participants in the ODV group and 67 (9.0%; 95% CI, 7.1% to 11.3%) participants in the placebo group. COVID-19-related MAVs by Day 29 were reported in 1 (0.1%) participant in the ODV group and 2 (0.2%) participants in the placebo group (HR, 0.50; 95% CI, 0.05 to 5.46, p=0- 56), with no deaths in either group. No COVID-19-related hospitalizations occurred byAttorney Docket No. 1571-WO-PCTDay 29 in either group. Subgroup analysis showed that time to COVID-19 symptom alleviation was generally similar between treatment groups regardless of sex, race, ethnicity, region, baseline SARS-CoV-2 viral RNA copy number, or body mass index (FIG. 6). In a post-hoc subgroup analysis, median time to COVID-19 symptom alleviation in those enrolled within 1 day of symptom onset was shorter with ODV (6.1 [95% CI, 5-4 to 7 0] days) than placebo (7.2 [95% CI, 6-2 to 8-0] days), but was similar between groups in those enrolled 2 days or 3 days after symptom onset (p>0-05) (Table 6).Table S2. Median time to COVID-19 symptom alleviation by duration of symptom onset

[0104] The virology analysis set had 751 and 727 participants in the ODV and placebo groups, respectively. Nasal swab viral RNA copy number measured from nasal swab samples decreased rapidly from baseline to Day 5 in both groups (FIG. 7). Result of “No SARS-CoV-2 detected” was imputed as 746.5 copies / mL (2.87 logic copies / mL); “< 2228 copies / mL” was imputed as 1114 copies / mL (3.05 logw copies / mL). At Day 3, the least squares mean (SE) change from baseline in viral RNA copy number was -1.30 (0.05) logw copies / mL for the ODV group and -0.99 (0.05) logic copies / mL for the placebo group, with a least squares mean treatment difference (95% CI) of -0.31 (-0.46 to -0.16) logw copies / mL. At Day 5, the least squares mean (SE) change from baseline in viral RNA copy number was -2.13 (0.04) and -1.95 (0.04) logw copies / mL for the ODV and placebo groups, respectively, with a least squares mean treatment difference (95% CI) of -0.18 (-0.30 to -0.06) logw copies / mL. At Day 5, the proportion of participants with negative SARS-CoV-2 nasal swab was 50.0% in the ODV group and 40.8% in the placebo group (difference [95% CI] of 9-2% [3-5% to 14-6%]; nominal P=0.001 ; FIG. 8).Attorney Docket No. 1571-WO-PCTSafety

[0105] Of those in the safety analysis set, 53 of 979 (5.4%) and 56 of 976 (5.7%) participants in the ODV and placebo groups, respectively, experienced >1 treatment-emergent AE (Table 7). Table 7. Incidence of treatment-emergent AEs, treatment-emergent SAEs, and most common (>4 participants) treatment-emergent AEs by preferred term* (safety analysis set)AE leading to premature discontinuation of study 1 (0- 1) 0 1 (<0 1) drugAE=adverse event. SAE=serious adverse event.Attorney Docket No. 1571-WO-PCT*AEs were coded using Medical Dictionary for Regulatory Activities Version 26.1. Severity grades were defined using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 2.1, dated July 2017.

[0106] Grade 3 AEs were reported in 2 (0.2%) participants in the ODV group and 3 (0.3%) in the placebo group. No Grade 4 or 5 AEs were reported. AEs related to study treatment were reported in 5 (0.5%) participants in the ODV group (none of which were Grade >3) and in 13 (1.3%) participants in the placebo group (1 [0.1 %] of which was Grade >3), with SAEs reported in 2 (0.2%) and 4 (0.4%) participants in the ODV and placebo groups, respectively. No participant reported an SAE related to study treatment in the ODV group; 1 (0.1%) was reported in the placebo group. One (0.1 %) participant had an AE that led to premature study drug discontinuation (Grade 1 diarrhea in the ODV group). The most common treatment-emergent AEs were diarrhea (7 [0.7%]), headache (6 [0.6%]), and nausea (4 [0.4%]) in the ODV group and dysgeusia (5 [0.5%]), diarrhea (4 [0.4%]), and dizziness (4 [0.4%]) in the placebo group.

[0107] There were similar proportions of participants with >1 graded laboratory abnormality (ODV, 753 [77.5%]; placebo, 757 [78.5%]), most of which were Grade 1 or 2. The frequencies of Grade >3 laboratory abnormalities were also similar in both groups (ODV, 59 [6.1% |; placebo, 82 [8.5%]). There were no clinically relevant changes from baseline for hematology, chemistry, and coagulation parameters.

[0108] All references, including publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims

Attorney Docket No. 1571-WO-PCTCLAIMS1 . A method of treating a coronavirus infection in a patient in need thereof, wherein the method comprises administering to the patient obeldesivir, or a pharmaceutically acceptable salt thereof, wherein the patient has at least one risk factor for coronavirus infection.

2. The method of claim 1, wherein the at least one risk factor is for severe coronavirus infection.

3. The method of claim 1 or 2, wherein the patient demonstrates greater reduction in coronavirus viral load from baseline compared to an untreated patient.

4. The method of any one of claims 1-3, wherein the patient demonstrates greater reduction in coronavirus viral load from baseline by Day 5 comparted to an untreated patient.

5. The method of any one of claims 1-4, wherein the patient demonstrates greater reduction in nasal swab coronavirus viral load from baseline compared to an untreated patient.

6. The method of any one of claims 1-5, wherein the patient demonstrates greater reduction in nasal swab coronavirus viral load from baseline by Day 5 compared to an untreated patient.

7. The method of any one of claims 1-6, wherein the patient achieves a reduction in nasal swab coronavirus viral load from baseline compared to an untreated patient.

8. The method of any one of claims 1-7, wherein the patient demonstrates a greater proportion of negative infectious titer compared to an untreated patient.

9. The method of any one of claims 1-8, wherein the patient demonstrates a greater proportion of negative infectious titer at Day 5 compared to an untreated patient.

10. The method of any one of claims 1-9, wherein the patient demonstrates a greater reduction in nasal swab coronavirus viral titer from baseline compared to untreated patient.

11. The method of any one of claims 1-10, wherein the patient demonstrates a greater reduction in nasal swab coronavirus viral titer from baseline to Day 5 compared to untreated patient.

12. The method of any one of claims 1-11, wherein the patient demonstrates a greater reduction in nasal swab coronavirus viral titer from baseline to Day 3 compared to untreated patient.

13. The method of any one of claims 1-12, wherein the patient achieves improvement in time to symptom alleviation compared to an untreated patient.

14. The method of any one of claims 1-13, wherein the patient achieves about a two-day improvement in time to symptom alleviation compared to an untreated patient.Attorney Docket No. 1571-WO-PCT15. The method of any one of claims 1-14, wherein the patient achieves about a two-day improvement in time to symptom alleviation by Day 15 compared to an untreated patient.

16. The method of any one of claims 1-15, wherein the at least one risk factor for coronavirus infection is: equal to or greater than age of 50 years, cancer, human immunodeficiency virus infection, prior splenectomy, prior solid organ, stem cell, or bone marrow transplant, systemic rheumatologic or dermatologic disorders, use of systemic immunosuppressive agents, cerebrovascular disease, cardiovascular disease, chronic kidney disease, chronic lung disease, chronic liver disease, cystic fibrosis, diabetes mellitus, type 1 diabetes, type 2 diabetes, neurodevelopmental conditions, neurodegenerative conditions, body mass index equal to or greater than 25 kg / m2, sickle cell disease, primary immunodeficiencies, compensated cirrhosis, asthma, or smoking equal to or greater than 20 packs a year, or a combination thereof.

17. The method of claim 16, wherein the systemic immunosuppressive agent is high-dose corticosteroids, alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, or tumor necrosis factor blockers.

18. The method of claim 16, wherein the cardiovascular disease is heart failure, coronary artery disease, cardiomyopathies, or hypertension.

19. The method of claim 16, wherein the chronic lung disease is interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, or chronic obstructive pulmonary disease.

20. The method of any one of claims 1-19, wherein the patient does not have anticipated access to and use of authorized or approved therapies against the viral infection, has not received any approved, authorized, or investigational direct-acting antiviral drug against the viral infection, does not have an anticipated need for hospitalization, does not requires oxygen, is not infected with influenza, does not have decompensated cirrhosis, does not have acute liver injury or failure, is not undergoing dialysis, does not have an alanine aminotransferase level greater than or equal to five times the upper limit of normal, does not have a bilirubin level greater than or equal to two times the upper limit of normal, is not pregnant, is not breastfeeding, is willing to use protocol-mandated birth control, is not hypersensitivities to obeldesivir or its metabolites, or has not received a vaccine against the viral infection within 120 days before the administration of obeldesivir.Attorney Docket No. 1571-WO-PCT21. The method of claim 20, wherein the approved, authorized, or investigational direct- acting antiviral drug is nirmatrelvir / ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir, or monoclonal antibodies.

22. The method of any one of claims 1-21 , wherein the patient meets all of the following criteria:Aged > 18 years;Willing and able to provide written informed consent, or with a legal representative who can provide informed consent;Viral infection confirmed by PCR or an approved alternative assay < 5 days before randomization;Initial onset of symptoms < 5 days before randomization with > 1 of the following targeted signs / symptoms present at randomization: stuffy or runny nose, sore throat, shortness of breath, cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, feeling hot or feverish, nausea, vomiting, and diarrhea;Not currently hospitalized or requiring hospitalization; andPresence of > 1 risk factor if unvaccinated or > 2 risk factors if vaccinated.

23. A method of treating a coronavirus infection in a patient in need thereof, wherein the method comprises administering to the patient obeldesivir, or a pharmaceutically acceptable salt thereof, wherein the patient does not have any risk factors for severe coronavirus infection.

24. The method of claim 23, wherein obeldesivir is administered within 3 to 1 days of symptom onset.

25. The method of claim 23, wherein obeldesivir is administered to the patient before symptom onset.

26. The method of any one claims 23-25, wherein the patient achieves an improvement in time to symptom alleviation compared to an untreated patient.

27. The method of any one of claims 23-26, wherein the patient achieves about a one-day improvement in time to symptom alleviation compared to an untreated patient.

28. The method of any one of claims 23-27, wherein the patient demonstrates greater reduction in coronavirus viral RNA copy number from baseline compared to an untreated patient.

29. The method of any one of claims 23-27, wherein the patient demonstrates greater reduction in coronavirus viral RNA copy number from baseline compared to an untreated patient at Day 3.Attorney Docket No. 1571-WO-PCT30. The method of any one of claims 23-27, wherein the patient demonstrates greater reduction in coronavirus viral RNA copy number from baseline compared to an untreated patient at Day 5.

31. The method of any one of claims 23-30, wherein the patient tests negative for coronavirus by Day 5.

32. The method of any one of claims 23-30, wherein the patient tests negative for coronavirus on Day 5.

33. The method of any one of claims 23-32, wherein the patient is not planning to receive a direct acting antiviral or monoclonal antibody against SARS-CoV-2 for the treatment ofCO VID- 19, has not received any approved, authorized, or investigational direct acting antiviral drug or monoclonal antibody against SARS-CoV-2 for the treatment of CO VID-19 within 28 days or 5 half-lives before the administration of ODV, has not received any convalescent CO VID- 19 plasma or other antibody-based anti-SARS-CoV-2 prophylaxis, has not received an approved, authorized, or investigational COVID-19 vaccine within 120 days before the administration of ODV, does not have a self-reported COVID-19 diagnosis within 120 days before the administration of ODV does not have anticipated need for hospitalization, does not have a new oxygen requirement, does not have influenza, does not have a history of chronic liver disease, is not undergoing dialysis, does not have a history of chronic kidney disease, does not have a history of any of alanine aminotransferase >5 x ULN, bilirubin >2 x ULN, or creatinine clearance (CLcr) <60 mL / min, does not have persistent symptoms from previous COVID- 19 illness, does not have a positive urine pregnancy test at screening, is not breastfeeding, is willing to use protocol-mandated contraception, is not hypersensitivity to the obeldesivir, or is not using nirmatrelvir / ritonavir, molnupiravir, ensitrelvir, intravenous remdesivir, or monoclonal antibodies against COVID- 19.

34. The method of any one of claims 23-33, wherein the patient meets all of the following criteria:Aged >18 to <65 years (at all sites), or aged >12 to <18 years weighing >40 kg;Willing and able to provide written informed consent or for participants > 12 and < 18 years of age, a parent or legal guardian willing and able to provide written informed consent prior;SARS-CoV-2 infection confirmed, <3 days before randomization, by polymerase chain reaction, rapid antigen test, or an approved alternative assay;Willing and able to complete the COVID-19 symptom questionnaire prior to first dose and daily throughout the study period;Attorney Docket No. 1571-WO-PCTInitial onset of COVID- 19 signs / symptoms <3 days before randomization with >2 of the following targeted symptoms, at moderate or higher severity, present at randomization: stuffy or runny nose, sore throat, shortness of breath (difficulty breathing), cough, low energy or tiredness, muscle or body aches, headache, chills or shivering, and feeling hot or feverish; and Not currently hospitalized or requiring hospitalization.

35. The method of any one of claims 23-34, wherein the risk factor is obesity, diabetes mellitus, type 1 diabetes, type 2 diabetes, heart failure, coronary artery disease, cardiomyopathies, chronic kidney disease, chronic liver disease, chronic lung diseases, current pulmonary embolism, moderate to severe asthma, active pulmonary tuberculosis, cerebrovascular disease, down syndrome, pregnancy, receiving chemotherapy or other therapies for cancer, or hematologic malignancy, or combination thereof.

36. The method of claim any one of claims 1-35, wherein the coronavirus infection is an alpha coronavirus, a beta coronavirus, a gamma coronavirus, a delta coronavirus, an epsilon coronavirus, an eta coronavirus, an iota coronavirus, a kappa coronavirus, an omicron coronavirus, a zeta coronavirus, or a mu coronavirus.

37. The method of any one of claims 1-35, wherein the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS-CoV) infection, a Middle Eastern Respiratory Syndrome (MERS) infection, or a SARS-CoV-2 infection.

38. The method of any one of claims 1-35, wherein the coronavirus infection is a SARS- CoV-2 infection.

39. The method of any one of claims 1-35, wherein the coronavirus infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.

40. The method of any one of claims 1-35, wherein the coronavirus infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.

41. The method of any one of claims 1-35, wherein the coronavirus infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2 polymerase.

42. The method of any one of claims 1-35, wherein the coronavirus infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2 polymerase.

43. The method of any one of claims 1-35, wherein the coronavirus infection is caused by a variant of SARS-CoV-2.Attorney Docket No. 1571-WO-PCT44. The method of claim 43, wherein the variant of SARS-CoV-2 is the B.1.1.7 variant (the UK variant), the B.1.351 variant (the South African variant), the P. l variant (the Brazil variant), the B.l.1.7 with the E484K variant, the B. 1.1.207 variant, the B.1.

1. 17 variant, the B. 1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant.

45. The method of any one of claims 1-44, wherein the administering comprising administering about 100-600 mg, about 150-550 mg, about 200-500 mg, about 250-450 mg, about 300-400 mg, about 350 mg of obeldesivir, or a pharmaceutically acceptable salt thereof, or a free base.

46. The method of any one of claims 1-45, wherein the administering is conducted twice per day.

47. The method of any one of claims 1-46, wherein the administering is comprising administering 350 mg of obeldesivir twice daily for five consecutive days.

48. The method of any one of claims 1-47, wherein the administering is oral administration.

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