FOUR-WEEK ORAL ADMINISTRATION OF BALOXAVIR MARBOXIL AS AN ANTI-INFLUENZA VIRUS DRUG SHOWS NO TOXICITY IN CHICKENS.

High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.

Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts.

BACKGROUND: Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018-2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase-polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed. RESULTS: A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out. CONCLUSIONS: Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.).

Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications. METHODS: We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011. FINDINGS: 2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (-7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus. INTERPRETATION: Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications. FUNDING: Shionogi.

Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models.

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.

Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric Influenza Patients.

Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight-based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.

Baloxavir Marboxil: The First Cap-Dependent Endonuclease Inhibitor for the Treatment of Influenza.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, and clinical implications of baloxavir marboxil. DATA SOURCES: A MEDLINE search was conducted using the terms baloxavir, baloxavir marboxil, cap-dependent endonuclease inhibitor, and polymerase acidic endonuclease inhibitor. Additional data were obtained from the prescribing information and relevant guidelines. STUDY SELECTION AND DATA EXTRACTION: All clinical trials were included. DATA SYNTHESIS: Baloxavir marboxil exploits a new mechanism of action of inhibiting cap-dependent endonuclease. Baloxavir was shown to be superior compared with placebo and noninferior compared with oseltamivir with regard to the primary end point. Baloxavir was well tolerated in the trials. A second phase III study investigating high-risk patients was completed with positive results. However, the full article is not yet published. Relevance to Patient Care and Clinical Practice: The small amount of literature limits baloxavir's use in certain patient populations. Baloxavir offers advantages such as single-dose regimen, eliminating adherence concerns and lack of cross-resistance, making it an alternative for resistant viruses. Several uncertainties remain. Baloxavir has not been studied in hospitalized patients, patients with symptoms for >48 hours, or in combination with other antiviral agents. Furthermore, resistance to baloxavir can develop after 1 dose. Clinical studies are ongoing to evaluate baloxavir in young pediatric patients, hospitalized patients, and in combination therapy with neuraminidase inhibitors to further elucidate baloxavir's place in therapy. CONCLUSION: Baloxavir is a new antiviral medication for the treatment of influenza. Given the new mechanism of action, baloxavir may be useful in treating patients with resistant viruses.

Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection.

OBJECTIVES: Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection. METHODS: The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection. RESULTS: Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung. CONCLUSIONS: Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial.

Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents.

BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. METHODS: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively. CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).

Baloxavir: First Global Approval.

Baloxavir marboxil (Xofluza™; baloxavir) is an oral cap-dependent endonuclease inhibitor that has been developed by Roche and Shionogi. The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In February 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication. This article summarized the milestones in the development of baloxavir leading to this first global approval for influenza A or B virus infections.