Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial.

PURPOSE: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. METHODS: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. RESULTS: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. CONCLUSION: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. GOV REGISTRATION NUMBER: NCT04575597.

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.

BACKGROUND: NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America. METHODS: We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed. RESULTS: Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose. CONCLUSIONS: NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).

Janus Kinase inhibitors for the treatment of hospitalized patients with COVID-19.

PURPOSE OF REVIEW: Janus Kinase (JAK) inhibitors have been successfully utilized in the clinical treatment of several rheumatologic (e.g. rheumatoid arthritis) and inflammatory diseases (e.g. hemophagocytic lymphohistiocytosis). Based on the growing evidence that moderate and severe COVID-19 infections are associated with a dysregulated inflammatory state, this class of medications has been repurposed as a potential therapy for COVID-19, an infection caused by Severe Acute Respiratory Syndrome Coronavirus 2. RECENT FINDINGS: Three JAK inhibitors have been evaluated in human studies of COVID-19: Baricitinib, Tofacitinib, and Ruxolitinib. Most published studies are observational, but three randomized placebo-controlled double-blind trials have been completed: two large trials (N = 2,558 patients) with baricitinb demonstrated significant faster improvement in clinical status and reduction in the recovery time, as well as, significant reduction in the progression to invasive mechanical ventilation and mortality. One smaller randomized trial (N = 289) involving tofacitinib showed significant reduction in the progression to invasive ventilation or death. Notably, these three randomized placebo-controlled trials with close to 3,000 patients did not reveal any safety concerns associated with JAK inhibitors in terms of secondary infections or venous thromboembolism. Based on this high-quality evidence, both the Infectious Diseases Society of America and the National Institutes of Health guidelines recommend using baricitinib as part of the treatment approach for hospitalized patients with COVID-19. SUMMARY: JAK inhibitors are novel treatment agents in the field of infectious diseases. One JAK inhibitor, baricitinib has demonstrated significant clinical and survival benefits in hospitalized patients with COVID-19 in phase III randomized placebo-controlled trials. Baricitinib is already recommended for clinical practice by multiple guidelines.