Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers. METHODS: This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections. RESULTS: There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80-125%). Geometric mean Cmax and AUClast following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants. CONCLUSIONS: After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals. TRIAL REGISTRATION: ClinicalTrials.Gov: NCT04988152.

Immunogenicity and safety of the diphtheria, pertussis, tetanus and inactivated poliovirus vaccine when co-administered with the human rotavirus vaccine (Rotarix) in healthy Japanese infants: a phase IV randomized study.

Rotavirus infections have been reported to account for 40-50% of all hospitalized acute gastroenteritis cases in young children (<5 years) in Japan. Since 2011, Rotarix containing the live attenuated human rotavirus RIX4414 strain (HRV) has been licensed in Japan for infants. Vaccination against rotavirus is optional in Japan whereas administration of diphtheria, pertussis, tetanus, and inactivated poliovirus (DPT-IPV) vaccine is part of the national routine immunization program. In this open-label, randomized, controlled, multicenter study, we evaluated the immunogenicity and safety of the DPT-IPV vaccine (Squarekids) administered concomitantly or staggered with the liquid HRV (Rotarix) vaccine in healthy Japanese infants. A total of 292 infants aged 6-12 weeks were randomly assigned to receive DPT-IPV vaccine and HRV vaccine co-administered (n = 147) or staggered (n = 145). Immune responses to DPT-IPV vaccine were evaluated by measuring the post-vaccination serum antibody titers/concentrations to each antigen at one month following the third dose of DPT-IPV vaccine. Seroprotection/seropositivity against each of the diphtheria, pertussis (pertussis toxin and filamentous hemagglutinin), tetanus, and poliovirus type 1, 2 and 3 antigens was 92.8% or higher in both groups. In terms of immunogenicity, DPT-IPV vaccine co-administered with HRV vaccine was shown to be non-inferior to DPT-IPV vaccine with a staggered administration. The safety profile was comparable in the two vaccine groups with no vaccine-related serious adverse events, no deaths and no cases of intussusception. These results support co-administration of HRV vaccine with DPT-IPV vaccine in Japan. ClinicalTrials.gov NCT02907216.

Efficacy and safety of mepolizumab in Japanese patients with severe eosinophilic asthma.

BACKGROUND: The MENSA trial assessed the efficacy and safety of mepolizumab in patients with severe eosinophilic asthma. This report describes the efficacy and safety of mepolizumab in Japanese patients from MENSA. METHODS: A post hoc analysis of the Japanese subgroup from the randomized, double-blind, placebo-controlled, double-dummy, Phase III MENSA trial (NCT01691521). Patients ≥12 years with severe eosinophilic asthma received mepolizumab 75 mg intravenously (IV), 100 mg subcutaneously (SC), or placebo, every 4 weeks for 32 weeks. The primary endpoint was the annualized rate of exacerbations. Secondary and other endpoints included annualized rate of exacerbations requiring emergency department (ED) visit/hospitalization, morning peak expiratory flow (PEF), St George's Respiratory Questionnaire (SGRQ) score and eosinophil counts. Adverse events (AEs) were monitored. RESULTS: In the Japanese subgroup (N = 50), the rate of clinically significant exacerbations was reduced by 90% (rate ratio [RR]: 0.10; 95% confidence interval [CI]: 0.02-0.57; P = 0.010) with mepolizumab IV and 62% (RR: 0.38; 95% CI: 0.12-1.18; P = 0.094) with mepolizumab SC, versus placebo. No exacerbations requiring ED visit/hospitalization were reported with mepolizumab IV; exacerbations were reduced by 73% (RR: 0.27; 95% CI: 0.06-1.29; P = 0.102) with mepolizumab SC versus placebo. Compared with placebo, mepolizumab IV and SC numerically increased morning PEF from baseline by 40 L/min and 13 L/min, improved quality of life by greater than the minimal clinically important difference (SGRQ: 9.5 [P = 0.083] and 7.9 [P = 0.171] points) and reduced eosinophil counts. AE incidence was similar between treatments. Results were broadly consistent with the overall population. CONCLUSIONS: Mepolizumab was efficacious and well tolerated in Japanese patients with severe eosinophilic asthma, producing similar responses to the overall MENSA population.

Safety and efficacy of fluticasone furoate nasal spray in Japanese children 2 to <15 years of age with perennial allergic rhinitis: a multicentre, open-label trial.

BACKGROUND: Fluticasone furoate nasal spray (FFNS) is a glucocorticoid developed for the treatment of allergic rhinitis (AR). This study aimed to assess the safety, efficacy, and systemic exposure of FFNS in Japanese children with perennial AR (PAR). METHODS: In this multicentre, open-label, phase 3 study, 61 children aged 2 to <15 years were treated with FFNS 55 µg, once daily for 12 weeks. Nasal and ocular symptoms were scored by parents/guardians/patients and recorded in a patient's daily diary. In addition, rhinoscopy findings, including mucosal swelling, were scored by the investigators as an efficacy measure. As a safety measure, adverse events and clinical laboratory data were evaluated. RESULTS: An adverse event was reported by 67% of patients during the treatment and follow-up period, all of which were mild in intensity. The most commonly reported adverse events were nasopharyngitis and acute sinusitis (acute rhinosinusitis). There were no serious adverse events. FFNS 55 µg improved nasal symptom scores and rhinoscopy findings compared with the baseline. Ocular symptom scores were also improved compared with the baseline in FFNS 55 µg in a sub-group of patients with any ocular symptoms at baseline. FFNS 55 µg was shown to be well tolerated over the 12-week treatment period. Majority of patients receiving FFNS 55 µg had unquantifiable plasma levels of fluticasone furoate (FF). CONCLUSIONS: Twelve-week treatment with FFNS 55 µg, once daily, is well tolerated and effective with low systemic exposure in Japanese children aged 2 to <15 years with PAR.

Efficacy and safety of fluticasone furoate nasal spray in Japanese children with perennial allergic rhinitis: a multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fluticasone furoate nasal spray (FFNS) is a glucocorticoid developed for the treatment of allergic rhinitis (AR). This is the first randomized clinical trial to assess the efficacy and safety of FFNS in Japanese children with perennial AR (PAR). METHODS: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study, 261 children aged 6 to <15 years were treated with FFNS 55µg, once daily or placebo for two weeks. Nasal and ocular symptoms were rated by parents/guardians/patients in the patient daily diary. The primary endpoint was the mean change from baseline in the three total nasal symptom score (3TNSS). In addition, rhinoscopic findings were rated by the investigators as an efficacy measure. As a safety measure, adverse events and clinical chemistry and hematology were evaluated. RESULTS: Mean change from baseline over the entire treatment period in 3TNSS was greater in the FFNS 55µg group compared with placebo, and the difference was statistically significant (p < 0.001). Significant improvements in rhinoscopic findings of swelling of inferior turbinate mucosa and quantity of nasal discharge were also observed. The total ocular symptom score (TOSS) was reduced significantly in the FFNS 55µg group, compared with placebo, in the second week in a subgroup of patients with baseline TOSS > 0. The incidence of adverse events was similar between FFNS 55µg(18%) and placebo (19%). CONCLUSIONS: Two-week treatment with FFNS 55µg, once daily is effective and tolerable in Japanese children aged 6 to <15 years with PAR.