Safety and Anti-coronavirus Response of Suppression of Host Nucleotide Synthesis in Patients With COVID-19

Inclusion Criteria:

1. Willing and able to provide informed consent for the trial, written, electronic, verbal or other method deemed acceptable by the institution and IRB.

2. 18 years of age or older.

3. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study drug-related adverse event, willing to go to an outpatient laboratory for a laboratory sample as well as a contact (phone call or other digital media) on Study Days 7 and 15 and contact only on Day 29.

4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or public health assay.

5. Hospitalized (in patient with expected duration ≥ 24 hours)

6. The effects of brequinar on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and for 90 days after completion of brequinar administration.

7. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of brequinar.

8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician.

9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea), moderate (any symptom of mild illness or shortness of breath with exertion), or severe (any symptom of moderate illness or shortness of breath at rest, or respiratory distress).

10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, heart rate ≥ 90 beats per minute) or severe (respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300)

Exclusion Criteria:

1. Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient

2. Active malignancy other than squamous cell carcinoma; anticancer treatment such as chemotherapy or radiation therapy within the past month.

3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.

4. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide), tacrolimus, sirolimus.

5. Platelets ≤150,000 cell/mm3.

6. Hemoglobin < 12 gm/dL

7. Absolute neutrophil count < 1500 cells/mm3

8. Renal dysfunction, i.e., creatinine clearance < 50 mL/min

9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN

10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment

11. Concomitant use of agents known to cause bone marrow suppression leading to thrombocytopenia

12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding.

13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis.

14. Heart failure, current uncontrolled cardiovascular disease, including unstable angina, uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g. stroke, myocardial infarction, hospitalization due to heart failure, or revascularization procedure).

15. Baseline COVID-19 severity characterized as "Critical" based on the FDA Guidance "COVID-19: Developing Drugs and Biological Products for the Treatment or Prevention" (https://www.fda.gov/media/137926/download). Evidence of critical illness defined by at least one of the following:

1. Respiratory failure based on resource utilization requiring at least one of the following:

2. Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies may not be able to be administered in setting of resource limitation)

3. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg or requiring vasopressors)

16. Multi-organ dysfunction/failure.