Interim analysis concluded primary endpoint was not met

This is a phase 2 double-blind, randomized study of PBI-0451(Pomotrelvir) in nonhospitalized symptomatic adults with COVID-19. PBI-0451(Pomotrelvir) is a new chemical entity and inhibitor of the main protease of coronaviruses, including the SARS-CoV-2 that causes COVID-19 disease. This study is designed to evaluate the antiviral activity, safety, and efficacy of orally administered PBI-0451(Pomotrelvir) compared with placebo.

Following randomization on Day 1, subjects will complete baseline assessments prior to receiving their first dose of study drug (PBI-0451 or placebo).

Randomization will be stratified as follows:

• SARS-CoV-2 positive direct test diagnosis ≤ 3 days (target 30%) versus > 3 days from first onset of COVID-19 symptom(s) ≤ 5 days prior to randomization
• Received primary vaccination series, alone versus any booster shots
• PK substudy participation versus nonparticipation Study drug will be taken with food, approximately 12 hours between doses, at approximately the same time for each BID dose for the remainder of the 5 days of treatment.All subjects will have additional safety and efficacy assessments during the 28-day study period. A follow-up visit (eg, telephone visit, virtual visit, clinic visit, etc. as convenient) will be conducted at Week 24 (± 20 days) after the last dose of study drug for all subjects. Information regarding ongoing or recurrent COVID-19 symptoms, survival status, pregnancy status (for female subjects of childbearing potential and female partners of male subjects), and any hospitalizations or acute/critical care visits (eg, non-admitted hospital or other care facility)that have occurred since the last study visit will be collected. A team of medically qualified individuals, including but not limited to, the Sponsor and the CRO Medical Monitors, and the Drug Safety Consultant are responsible for ongoing review of all AEs, concomitant medications, laboratory values (including virology), and vital signs (including pulse oximetry), worsening of symptoms (COVID-19 symptom questionnaire, including dyspnea), acute/critical care visits (eg, nonadmitted hospital or other care facility), and study drug discontinuations, at a minimum monthly basis throughout the study, per the Safety Monitoring Plan. Subjects who experience severe COVID-19 illness (defined in this study as sustained pulse oximetry <94%, a respiratory rate of >30 breaths/min, or dyspnea that requires medical attention) should discontinue study drug and be immediately referred by the Investigator to emergency care or treated by the Investigator for standard of care treatment of symptoms including, but not limited to, other antivirals, supplemental oxygen, corticosteroids, Janus kinase inhibitors, or interleukin-6 blockers, in accordance with the NIH Treatment Guidelines (NIH 2022). The subject should continue participation in the study, with study drug discontinued, for safety follow-up and clinical outcome of the medically attended visit.

Inclusion Criteria:

1. Can understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of any study procedures.
2. Onset of COVID-19 symptoms ≤ 5 days prior to randomization with a positive SARS-CoV-2 test ≤ 24 hours prior to randomization. Authorized NAAT or antigen tests that detect viral RNA or protein, respectively, are allowed.
3. Received primary vaccination series as defined by Centers for Disease Control and Prevention (CDC). Subjects should be advised during informed consent that alternate therapies may be available outside of study participation.
4. ≥ 2 symptoms of acute COVID-19 infection as determined by the investigator from the symptoms listed on the COVID-19 symptoms questionnaire present at randomization
5. Male and nonpregnant, nonlactating female subjects 18 to < 65 years of age. Females must have a negative serum or urine pregnancy test at screening and prior to the first dose of study drug unless permanently sterile or in a postmenopausal state (see Appendix 3).
6. Male and female subjects and/or their heterosexual partners must either be of nonchildbearing potential or must use effective contraception from screening through 90 days after the last dose of study drug (see Appendix 3)
7. Female subjects must refrain from egg donation and in vitro fertilization during treatment and for ≥ 28 days after the last dose of study drug
8. Male subjects must refrain from sperm donation from screening through 90 days after the last dose of study drug
9. Normal 12-lead electrocardiogram (ECG) evaluation without clinically significant abnormalities
10. Able and willing to comply with all study requirements

Exclusion Criteria:

1. Considered at high-risk of developing severe illness from COVID-19 defined as ≥ 1 CDC underlying medical condition associated with an increased risk of developing severe illness from COVID-19 (see Appendix 5)
2. Unvaccinated against SARS-CoV-2 (defined as having not completed a primary vaccination series)
3. Any SARS-CoV-2 vaccination within 3 month prior to randomization or anticipated to receive a SARS-CoV-2 vaccination (including a booster) during the 28-day study period
4. Currently hospitalized or expected to require hospitalization for COVID-19 within 48 hours of randomization
5. Currently being treated or expected to be treated for COVID-19 with monoclonal antibodies, convalescent serum, or direct-acting antiviral agents (all potential subjects should be informed of evolving treatment options during informed consent that alternate therapies may or may not be available to them outside of study participation)
6. Any clinical condition or laboratory result considered by the investigator to indicate any unstable or poorly controlled underlying clinically significant medical condition(s), active disseminated infection (other than SARS-CoV-2), or other medical condition that could represent a risk to the subject, including increasing the likelihood of a safety event, affect subject compliance, or affect efficacy and/or safety data collected during the 28-day study period
7. Known active liver disease, including nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, primary biliary cirrhosis, Child-Pugh Class B or C, chronic alcoholic liver disease, or acute liver failure
8. Receiving dialysis or having known severe renal impairment (chronic kidney disease, Stage 4 or above)
9. Unable or unwilling to comply with the protocol procedures
10. Participating in another interventional study with an investigational compound or device, including those for COVID-19
11. Known prior participation in this study or another study involving PBI-0451(Pomotrelvir)
12. Females who are pregnant or breastfeeding
13. Oxygen saturation of < 94% on room air