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Aim: To evaluate the efficacy and safety of an oral, once‐daily, 14‐day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD). Methods: This multicenter, randomized, double‐blind, placebo‐controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment‐period), followed by two 6‐week follow‐up periods. The primary endpoint was change from baseline in the 17‐item Hamilton Depression Rating Scale (HAMD‐17) total score on Day 15. Results: Overall, 250 patients (enrolled: 07/07/2020–05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD‐17 total score on Day 15 was −6.22 (0.62), −8.14 (0.62), and − 8.31 (0.63) in the placebo, zuranolone 20‐mg, and zuranolone 30‐mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (−1.92; [−3.65, −0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (−2.09; [−3.83, −0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug‐placebo separation was observed during follow‐up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone. Conclusion: Oral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD‐17 total score change from baseline over 14 days in Japanese patients with MDD. [ABSTRACT FROM AUTHOR]

Drug‐drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C‐like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P‐gp and BCRP and inhibits P‐gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug‐drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P‐gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P‐gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment‐emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration–time curve were, respectively, 2.17 (1.72‐2.73) and 1.31 (1.13‐1.52) for digoxin, 1.97 (1.73‐2.25) and 1.65 (1.47‐1.84) for rosuvastatin, and 1.03 (0.91‐1.16) and 1.02 (0.94‐1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P‐gp, BCRP, OATP1B1, and OATP1B3 substrates. [ABSTRACT FROM AUTHOR]

Background This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic. Methods Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events. Results A total of 341 patients (ensitrelvir 125-mg group: 114; ensitrelvir 250-mg group: 116; and placebo group: 111; male: 53.5–64.9%; mean age: 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in SARS-CoV-2 titer on day 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: −0.41 log10 50% tissue-culture infectious dose/mL; P <.0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity. Conclusions Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile. Clinical Trials Registration Japan Registry of Clinical Trials: jRCT2031210350 (https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350) [ABSTRACT FROM AUTHOR]

• S-268019-a is a recombinant spike protein vaccine adjuvanted with agatolimod sodium. • S-268019-a elicited immunogenicity and efficacy against SARS-CoV-2 in mice. • S-268019-a was safe but insufficiently immunogenic in humans. • Translating preclinical data to clinical studies is innately challenging. • S-268019-b formulation with a squalene-based adjuvant is in Phase 3 clinical trials. In early 2020, developing vaccines was an urgent need for preventing COVID-19 from a contingency perspective. S-268019-a is a recombinant protein-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a modified recombinant spike protein antigen adjuvanted with agatolimod sodium, a Toll-like receptor-9 agonist. In the preclinical phase, it was administered intramuscularly twice at a 2-week interval in 7-week-old mice. Immunogenicity was assessed, and the mice were challenged intranasally with mouse-adapted SARS-CoV-2 at 2 and 8 weeks, respectively, after the second immunization. After confirming the preclinical effect, a Phase 1/2, randomized, parallel-group clinical study was conducted in healthy adults (aged 20–64 years). All participants received 2 intramuscular injections at various combinations of the antigen and the adjuvant (S-910823/agatolimod sodium, in μg: 12.5/250, 25/250, 50/250, 25/500, 50/500, 100/500, 10/500, 100/100, 200/1000) or placebo (saline) in an equivalent volume at a 3-week interval and were followed up until Day 50 in this interim analysis. In the preclinical studies, S-268019-a was safe and elicited robust immunoglobulin G (IgG) and neutralizing antibody responses in mice. When challenged with SARS-CoV-2, all S-268019-a-treated mice survived and maintained weight until 10 days, whereas all placebo- or adjuvant-treated (without antigen) mice died within 6 days. In the Phase 1/2 trial, although S-268019-a was well tolerated in adult participants, was safe up to Day 50, and elicited robust anti-spike protein IgG antibodies, it did not elicit sufficient neutralizing antibody levels. The S-268019-a vaccine was not sufficiently immunogenic in Japanese adults despite robust immunogenicity and efficacy in mice. Our results exemplify the innate challenges in translating preclinical data in animals to clinical trials, and highlight the need for continued research to overcome such barriers. (jRCT2051200092) [ABSTRACT FROM AUTHOR]

Lusutrombopag is a thrombopoietin receptor agonist approved to treat thrombocytopenia in patients with chronic liver disease (CLD). This post hoc analysis of the Japanese L-PLUS 1 and global L-PLUS 2 trials aimed to clarify factors related to platelet count increase after lusutrombopag treatment. In L-PLUS 1, Pearson's correlation coefficients were used to evaluate correlations between platelet count and spleen index, thrombopoietin concentration, white blood cell (WBC) counts, and red blood cell counts (intent-to-treat [ITT] population). Associations between platelet count increase after lusutrombopag treatment and each parameter were assessed by regression analysis and mixed-effect model for repeated measures (MMRM). Associations between time-dependent changes in platelet count increase and each parameter were also examined in the L-PLUS 2 lusutrombopag ITT population by MMRM. In L-PLUS 1, the baseline platelet count was correlated with pretreatment spleen index (r = −0.23, 95% confidence interval [CI] −0.41 to −0.03) and WBC count (r = 0.26, 95% CI 0.06 to 0.43). No selected parameters were associated with the maximum platelet count increase from baseline. Patients with WBC counts below the normal range showed smaller platelet count increases after lusutrombopag treatment than patients with WBC counts within the normal range (p =.0028). In L-PLUS 2 (p =.0533), findings were similar and confirmed by larger pooled data of L-PLUS 1/L-PLUS 2 (p =.0021). This post hoc analysis revealed a possible association between baseline WBC count and platelet count increase after lusutrombopag treatment. WBC count could be a relevant factor for lusutrombopag efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Ensitrelvir fumaric acid (ensitrelvir) is an orally active 3C-like protease inhibitor used to treat severe acute respiratory syndrome coronavirus 2 infection. Ensitrelvir was granted an emergency use authorization in Japan in 2022, but reports on the effectiveness and safety of ensitrelvir in actual clinical settings are limited., Methods: Here, we report a case series of 9 patients with laboratory-confirmed symptomatic coronavirus disease of 2019 (COVID-19) who completed a 5-day course of ensitrelvir at Tomita Hospital from November 2022 to April 2023. Data on clinical symptoms, oxygen saturation, and food intake were collected for 14 days, beginning on the first day of ensitrelvir administration. The outcome of COVID-19 in each patient was also evaluated during this period., Results: All patients were female, 80 years old or older, and the mean age was 90.2 ± 5.5 years. All patients received ensitrelvir within 2 days after the onset of COVID-19. At baseline, 7 among the 9 patients had their body temperature above 37.5 °C and all of them had oxygen saturation levels of 94% or higher. All patients recovered without worsening of COVID-19, and none received oxygen or additional antiviral drugs during the observation period; no deaths were reported within 14 days. After receiving ensitrelvir for 5 days, all patients had resolution of fever (<37 °C). There was no significant decrease in food intake of patients due to COVID-19. All patients maintained oxygen saturation above 93%., Conclusion: Our results provide information on the real-world usage of ensitrelvir in elderly, hospitalized patients with COVID-19, and suggests that ensitrelvir is an option for treatment of COVID-19 in these population., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)