Cap-dependent Endonuclease Inhibitor Research Articles

1536. Population Pharmacokinetic Analysis of Baloxavir Morboxil, a Cap-Dependent Endonuclease Inhibitor, in Adult and Adolescent Healthy Subjects and Influenza Patients and Exposure-Response Relationships in the Patients at High-Risk of Influenza Complications

BackgroundBaloxavir marboxil is a prodrug of baloxavir acid which is a selective inhibitor of cap-dependent endonuclease. The global Phase 3 study conducted in the influenza patients at high-risk of influenza complications (CAPSTONE-2) enrolled adult and adolescent patients from 2016 to 2018. Baloxavir marboxil demonstrated significantly shorter time to improvement of influenza symptoms (TTIIS) than placebo. The aim of this study was to build a population pharmacokinetic (PK) model of baloxavir acid and to evaluate the exposure-response relationships in high-risk patients.MethodsThe population PK analysis was conducted on the pooled data from 13 clinical studies: 10 phase 1 studies, a phase 2 study, and 2 phase 3 studies. A total of 11846 plasma concentrations from 1827 subjects were used for this analysis. The influence of background characteristics including risk factors of influenza complications was assessed on the PK of baloxavir acid. The individual Cmax and AUC were estimated with an empirical Bayesian approach. Exposure-response analysis was conducted for TTIIS and virus titer in the high-risk patients.ResultsA 3-compartment model with first-order absorption and lag time was selected as a structural PK model, and well described the plasma concentrations. The population PK analysis suggested that (1) AUC in non-Asians was 30.7% lower than that in Asians, (2) body weight significantly affected the exposures to baloxavir acid, (3) the exposures in high-risk patients were similar to those in otherwise healthy patients, and (4) no PK differences were identified regarding the risk factors for influenza complications. The exposure-response analyses showed that the body weight-based dose regimen (40 mg for the patients weighing <80 kg and 80 mg for the patients weighing ≥80 kg) shortened TTIIS and reduced virus titer for both type A and B influenza, across the entire range of baloxavir acid exposures observed in CAPSTONE-2 although subject number in the lowest exposure group was limited and it was difficult to discuss the magnitude of the responses accurately.ConclusionThe results of the population PK analysis and exposure-response analyses provide useful information for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil. Disclosures All authors: No reported disclosures.

2644. Evaluation of Clinical Course and Heath-Related Quality-of-Life Following Treatment with Oseltamivir, Laninamivir, and Baloxavir Marboxil in Adult Patients with Seasonal Influenza: Prospective Observational Study

BackgroundInfluenza is currently being treated in Japan with 4 types of neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir marboxil. Among these, baloxavir marboxil is the newest agent and currently available in limited countries, while the clinical efficacy of this drug in the real world remains to be determined.MethodsAdult patients with seasonal influenza during the 2018–2019 winter season, who received either oseltamivir (75 mg twice daily for 5 days), laninamivir (40 mg once), or baloxavir marboxil (40 or 80 mg once) at their physician’s discretion in one hospital, were enrolled. The course of the symptoms including fever were surveyed by questionnaire. Health-related quality-of-life (HRQOL) was also examined by using Short Form-8 before and 7 days after admission. The main study endpoints were the time to defervescence and the extent of improvement of HRQOL after treatment initiation. Welch’s t-test and Fisher exact test were used for statistical analysis.ResultsForty-two patients (oseltamivir group; n = 12, laninamivir group; n = 16, baloxavir group; n = 14) could be followed up. There were no significant differences in clinical backgrounds of all groups. Although there were no significant differences between the oseltamivir and each other groups with the time of defervescence, the average time to defervescence in the baloxavir group was shorter than that in the oseltamivir group (average ± standard deviation; 1.57 ± 0.76 vs. 2.33 ± 1.23 days, P = 0.0853). There were significant differences between the baloxavir and laninamivir groups (2.50 ± 1.26 days, P = 0.0231). There were no significant differences between each group with respect to the change of HRQOL and the time of clearing of other symptoms.ConclusionRegarding the antipyretic effect, baloxavir marboxil is clinically superior to laninamivir. Although there was no significant difference between the baloxavir group and the oseltamivir group with respect to the time to defervescence, baloxiavir marboxil also might be clinically superior to oseltamivir because baloxavir marboxil has an advantage over oseltamivir with respect to medication adherence.Disclosures All authors: No reported disclosures.

Cold Weather Viruses.

1. Asif Noor, MD* 2. Theresa Fiorito, MD* 3. Leonard R. Krilov, MD*,† 1. *Department of Pediatrics, Children's Medical Center, NYU Winthrop Hospital, Mineola, NY 2. †Department of Pediatrics, State University of New York, Stony Brook School of Medicine, Stony Brook, NY * Abbreviations: AAP: : American Academy of Pediatrics Adv: : adenovirus CDC: : Centers for Disease Control and Prevention FDA: : Food and Drug Administration hMPV: : human metapneumovirus PCR: : polymerase chain reaction PIV: : parainfluenza virus RSV: : respiratory syncytial virus RV: : rhinovirus Clinicians must learn to identify viral infections in children during the winter months and must practice caution with the use of unnecessary medications in such cases. Recognition of the clinical pattern of viral infection (eg, bronchiolitis) in conjunction with judicious use of viral tests (either office-based immunoassays or newer molecular tests) may assist in epidemiological monitoring, cohorting patients in the hospital, withholding unnecessary therapies, and providing a definitive diagnosis. After completing this article, readers should be able to: 1. Review the epidemiological aspects and clinical signs and symptoms of common cold weather viruses. 2. Recognize situations in which viral testing is indicated. 3. Recognize situations in which treatment is indicated. In early November you are evaluating a 9-month-old boy born at 33 weeks of gestation. The infant presents with 2 days of fevers (101°F–102°F [38.3°C–38.8°C]), copious rhinorrhea, and 1 day of coughing with difficulty breathing. He is otherwise feeding well and has had adequate urination. His 4-year-older sister has an upper respiratory tract infection. On physical examination, the infant has a respiratory rate of 45 breaths/min without chest wall retractions. On auscultation there is good air entry with scattered rhonchi bilaterally. What is the most appropriate next step in management? 1. Obtain respiratory syncytial virus (RSV) and influenza antigen testing. 2. Obtain a chest radiograph to look for focal infiltrate. 3. Provide supportive care with nasal …

Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.

The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.

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.

PIN7 A NETWORK META-ANALYSIS OF THE EFFICACY AND SAFETY OF BALOXAVIR MARBOXIL VERSUS NEURAMINIDASE INHIBITORS IN THE TREATMENT OF INFLUENZA VIRUS INFECTION IN HIGH-RISK PATIENTS

Baloxavir marboxil (BXM) is the first cap-dependent endonuclease inhibitor being studied for the treatment of influenza using a one-time oral dosing regimen. The relative efficacy and safety of BXM compared to other antiviral treatments for influenza in high-risk patients was evaluated with a network meta-analysis (NMA). A systematic literature review was performed in Medline, Embase, CENTRAL and ICHUSHI up to August 8th, 2018 to identify randomized controlled trials assessing antivirals in high-risk influenza. A Bayesian NMA was performed to compare BXM with antivirals (oseltamivir 75 mg BID for 5 days, zanamivir 10 mg BID for 5 days, laninamivir 40 mg single administration, peramivir 600 mg single or repeated administration) on efficacy (time to alleviation of all symptoms (TTAS), change in virus titer from baseline to 24h, rate of total complications) and drug-related adverse events (AEs). Ten trials were included in the NMA. The fixed effect model was selected based on the deviance information criterion for all outcomes. BXM was associated with a shorter TTAS compared with zanamivir, laninamivir, oseltamivir and peramivir; however the difference did not reach statistical significance. Mean decline in virus titer from baseline to 24h was significantly greater for BXM when compared with oseltamivir (difference in mean [95% credibility interval]: 1.60 [1.27; 1.93] log10TCID50/mL), and peramivir (1.46 [0.65; 2.26] log10TCID50/mL). The risk of total complications for BXM did not differ significantly from zanamivir, oseltamivir and laninamivir. The risk of drug-related AEs was comparable between BXM and zanamivir, peramivir, and laninamivir. BXM led to a significant decrease in virus titer at 24h versus oseltamivir and peramivir and non-significant decrease in TTAS versus all assessed antivirals. These findings are consistent with a previously conducted NMA on otherwise healthy patients. No significant differences were shown between BXM and other antivirals regarding the safety profile.

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.

A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors for the treatment of influenza in otherwise healthy patients

Objective: Baloxavir marboxil (baloxavir) is the first cap-dependent endonuclease inhibitor being studied for the treatment of influenza in single oral dosing regimen. This network meta-analysis (NMA) evaluated the efficacy and safety of baloxavir compared to other antivirals for influenza in otherwise healthy patients.Methods: A systematic literature review was performed on 14 November 2016 in Medline, Embase, CENTRAL, and ICHUSHI to identify randomized controlled trials assessing antivirals for influenza. A NMA including 22 trials was performed to compare the efficacy and safety of baloxavir with other antivirals.Results: The time to alleviation of all symptoms was significantly shorter for baloxavir compared to zanamivir (difference in median time 19.96 h; 95% CrI [3.23, 39.07]). The time to cessation of viral shedding was significantly shorter for baloxavir than zanamivir and oseltamivir (47.00 h; 95% CrI [28.18, 73.86] and 56.03 h [33.74, 87.86], respectively). The mean decline in virus titer from baseline to 24 h was significantly greater for baloxavir than for the other drugs. Other differences in efficacy outcomes were not significant. No significant differences were found between baloxavir and the other antivirals for safety, except total drug-related adverse events where baloxavir demonstrated a decrease compared to oseltamivir and laninamivir.Conclusions: The NMA suggests that baloxavir demonstrated better or similar efficacy results compared to other antivirals with a comparable safety profile. Baloxavir led to a significant decrease in viral titer versus zanamivir, oseltamivir and peramivir and decreased viral shedding versus zanamivir and oseltamivir.

Baloxavir: A Novel Single-Dose Oral Antiviral for the Treatment of Influenza

OBJECTIVE: To review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosing, and administration of baloxavir marboxil (BXM), as well as its place in the treatment of influenza.<br/> DATA SOURCES: A search of PubMed and Google Scholar using the terms "baloxavir" and "S-033188" was performed. The manufacturer's website was also reviewed to further identify relevant information.<br/> STUDY SELECTION/DATA EXTRACTION: All Englishlanguage articles from January 2008 to December 2018 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches.<br/> DATA SYNTHESIS: BXM is a selective cap-dependent endonuclease inhibitor approved by the Food and Drug Administration for the treatment of acute uncomplicated influenza in adults and adolescents 12 years of age and older who weigh at least 40 kg. Clinical trials demonstrated that BXM was associated with a significantly shorter time to alleviation of influenza symptoms compared with placebo when taken within 48 hours of symptom onset. The time to alleviation of symptoms was similar with BXM and oseltamivir. The most common adverse reactions associated with BXM were diarrhea, bronchitis, nausea, nasopharyngitis, and headache. BXM is administered orally as a single-dose of 40 mg or 80 mg, depending on body weight. No dosage adjustment is needed in patients with mild-to-moderate hepatic or renal impairment.<br/> CONCLUSION: BXM has been proven safe and effective in the treatment of acute uncomplicated influenza in patients 12 years of age and older when administered within 48 hours of symptom onset.

Baloxavir: A Novel Single-Dose Oral Antiviral for the Treatment of Influenza.

OBJECTIVE: To review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosing, and administration of baloxavir marboxil (BXM), as well as its place in the treatment of influenza.<br/> DATA SOURCES: A search of PubMed and Google Scholar using the terms "baloxavir" and "S-033188" was performed. The manufacturer's website was also reviewed to further identify relevant information.<br/> STUDY SELECTION/DATA EXTRACTION: All Englishlanguage articles from January 2008 to December 2018 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches.<br/> DATA SYNTHESIS: BXM is a selective cap-dependent endonuclease inhibitor approved by the Food and Drug Administration for the treatment of acute uncomplicated influenza in adults and adolescents 12 years of age and older who weigh at least 40 kg. Clinical trials demonstrated that BXM was associated with a significantly shorter time to alleviation of influenza symptoms compared with placebo when taken within 48 hours of symptom onset. The time to alleviation of symptoms was similar with BXM and oseltamivir. The most common adverse reactions associated with BXM were diarrhea, bronchitis, nausea, nasopharyngitis, and headache. BXM is administered orally as a single-dose of 40 mg or 80 mg, depending on body weight. No dosage adjustment is needed in patients with mild-to-moderate hepatic or renal impairment.<br/> CONCLUSION: BXM has been proven safe and effective in the treatment of acute uncomplicated influenza in patients 12 years of age and older when administered within 48 hours of symptom onset.

Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil

Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug baloxavir marboxil (BXM), a first-in-class cap-dependent endonuclease inhibitor, against A(H7N9), in vitro and in vivo. In cell culture, BXA at four nanomolar concentration achieved a 1.5–2.8 log reduction in virus titers of A(H7N9), including the NA-R292K mutant virus and highly pathogenic avian influenza viruses, whereas NA inhibitors or favipiravir required approximately 20-fold or higher concentrations to achieve the same levels of reduction. A(H7N9)-specific amino acid polymorphism at position 37, implicated in BXA binding to the PA endonuclease domain, did not impact on BXA susceptibility. In mice, oral administration of BXM at 5 and 50 mg/kg twice a day for 5 days completely protected from a lethal A/Anhui/1/2013 (H7N9) challenge, and reduced virus titers more than 2–3 log in the lungs. Furthermore, the potent therapeutic effects of BXM in mice were still observed when a higher virus dose was administered or treatment was delayed up to 48 hours post infection. These findings support further investigation of BXM for A(H7N9) treatment in humans.

Influenza virus polymerase inhibitors in clinical development.

Purpose of reviewWe review antivirals inhibiting subunits of the influenza polymerase complex that are advancing in clinical development.Recent findingsFavipiravir, pimodivir, and baloxavir are inhibitory in preclinical models for influenza A viruses, including pandemic threat viruses and those resistant to currently approved antivirals, and two (favipiravir and baloxavir) also inhibit influenza B viruses. All are orally administered, although the dosing regimens vary. The polymerase basic protein 1 transcriptase inhibitor favipiravir has shown inconsistent clinical effects in uncomplicated influenza, and is teratogenic effects in multiple species, contraindicating its use in pregnancy. The polymerase basic protein 2 cap-binding inhibitor pimodivir displays antiviral effects alone and in combination with oseltamivir in uncomplicated influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Single doses of the polymerase acidic protein cap-dependent endonuclease inhibitor baloxavir are effective in alleviating symptoms and rapidly inhibiting viral replication in otherwise healthy and higher risk patients with acute influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Combinations of newer polymerase inhibitors with neuraminidase inhibitors show synergy in preclinical models and are currently undergoing clinical testing in hospitalized patients.SummaryThese new polymerase inhibitors promise to add to the clinical management options and overall control strategies for influenza virus infections.

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

To review the pharmacology, pharmacokinetics, clinical trials, and clinical implications of baloxavir marboxil. 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. All clinical trials were included. 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. 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.

Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.

Flupyranochromene, a novel inhibitor of influenza virus cap-dependent endonuclease, from Penicillium sp. f28743.

Influenza virus RNA polymerase has cap-dependent endonuclease activity that produces capped RNA fragments for priming viral mRNA synthesis. This enzymatic activity is essential for viral propagation, but it is not present in any host cellular enzyme, making it an attractive target for the development of anti-influenza drugs. Here, we isolated a novel inhibitor of cap-dependent endonuclease, named flupyranochromene, from the fermentation broth of the fungus Penicillium sp. f28743. Structural analysis revealed that this compound bears a putative pharmacophore that chelates divalent metal ion(s) present in the endonuclease active site in the PA subunit of the polymerase. Consistently, in vitro endonuclease assays showed that flupyranochromene exerts its inhibitory effects by blocking endonucleolytic cleavage by the PA subunit of viral RNA polymerase complex.

Baloxavir marboxil: a novel cap-dependent endonuclease (CEN) inhibitor for the treatment of acute uncomplicated influenza.

Baloxavir marboxil is a newly approved antiviral agent with activity against influenza via a novel mechanism of action of inhibition of cap-dependent endonuclease (CEN). The novel agent was approved in October of 2018 in the United States for the treatment of acute uncomplicated influenza A and B in patients aged 12 years or older. Baloxavir is given as a single weight-based dose of 40 mg orally once for patients weighing less than 80 kg and 80 mg orally once for those weighing 80 kg or more within 48 hours of symptom onset. In comparison with current therapy, baloxavir is as effective in decreasing time to symptom alleviation as the drug of choice, oseltamivir, and significantly reduces viral load 1 day after treatment compared with placebo and oseltamivir. In safety analyses baloxavir was well tolerated with only mild adverse events reported (nausea, headache, diarrhea, bronchitis, nasopharyngitis), thus providing a safe and reliable alternative option to current therapy for acute uncomplicated influenza. Further studies are being conducted to evaluate the use of baloxavir in additional patient populations including pediatric patients less than 12 years of age and patients who are at high risk of complications related to influenza.

Susceptibility of Influenza Viruses to the Novel Cap-Dependent Endonuclease Inhibitor Baloxavir Marboxil.

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza A and B virus infections in February 2018 in Japan. Because of the need to monitor influenza viruses for reduced susceptibility to this drug, we used two cell-based screening systems – a conventional plaque reduction assay and a focus reduction assay – to evaluate the susceptibility of influenza viruses to baloxavir. First, we generated a reference virus possessing an I38T substitution in the polymerase acidic subunit (PA), which is known to be associated with reduced susceptibility to baloxavir, and demonstrated the validity of our systems using this reference virus. We then determined the susceptibility of a panel of neuraminidase (NA) inhibitor-resistant viruses and their sensitive counterparts to baloxavir. No significant differences in baloxavir susceptibilities were found between the NA inhibitor-resistant and -sensitive viruses. We also examined seasonal influenza viruses isolated during the 2017–2018 influenza season in Japan and found that no currently circulating A(H1N1)pdm09, A(H3N2), or B viruses had significantly reduced susceptibility to baloxavir and none of the viruses possessed an amino acid substitution at PA residue 38. Use of a combination of methods to analyze antiviral susceptibility and detect amino acid substitutions is valuable for monitoring the emergence of baloxavir-resistant viruses.

1343. Prophylactic Dosing of Baloxavir Acid Eliminates Mortality in Mice Lethal Influenza A Virus Infection Model

BackgroundBaloxavir acid (BXA), an active form of orally available prodrug baloxavir marboxil (BXM, formerly S-033188), is a novel small molecule inhibitor of cap-dependent endonuclease (CEN) of influenza A and B virus, and was recently launched for the treatment of acute and uncomplicated influenza with single dosing of BXM (the trade name XOFLUZA™) in Japan in March 2018. Here, we evaluated the prophylactic efficacy of BXA in mice lethally infected with influenza A virus.MethodsT1/2 of BXA in human is more than 10 times longer than that in mice. Therefore, suspension of BXA was subcutaneously administered at 0.8 or 1.6 mg/kg in mice to maintain the plasma concentration of BXA as seen in humans, and then mice were intranasally inoculated with a lethal dose of A/PR/8/34 strain at 48, 72, or 96 hours after the administration of BXA. Survival time and body weight change were then monitored through a 28-day period after virus infection. Mice were euthanized and regarded as dead if their body weights were lower than 70% of the initial body weights according to humane endpoints.ResultsSingle dosing of BXA (1.6 mg/kg) completely eliminated mortality in mice, when the mice were administrated the drug at 48, 72, or 96 hours before virus infection (Figure 1). BXA treatment also significantly prevented body weight loss, consistent with the prolonged survival.ConclusionProphylactic dosing of BXA exhibited significant protective efficacy against mortality and body weight loss in mice following a lethal infection with influenza A virus. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of BXM for the prophylaxis of influenza in human. Disclosures S. Shano, Shionogi & Co., Ltd.: Employee, Salary. K. Fukao, Shionogi & Co., Ltd.: Employee, Salary. T. Noshi, Shionogi & Co., Ltd.: Employee, Salary. K. Sato, Shionogi & Co., Ltd.: Employee, Salary. M. Sakuramoto, Shionogi & Co., Ltd.: Employee, Salary. K. Baba, Shionogi TechnoAdvance Research & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. A. Naito, Shionogi & Co., Ltd.: Employee, Salary.

1350. Therapeutic Effects of Baloxavir Marboxil against Influenza A Virus Infection in Ferrets

BackgroundBaloxavir marboxil (BXM) is a novel small molecule inhibitor of cap-dependent endonuclease that is essential for influenza virus transcription and replication. In this study, pharmacokinetic profiles of BXM and baloxavir acid (BXA), an active form of BXM, were first examined in ferrets, and then the therapeutic effects of BXM against influenza A virus infection were compared with that of oseltamivir phosphate in ferrets.MethodsThe plasma exposure of BXA and BXM was examined after a single oral administration of BXM at doses of 10 and 30 mg/kg. The concentrations in plasma were determined by liquid chromatography-tandem mass spectrometry(LC/MS/MS). For efficacy study, ferrets infected intranasally with A/Kadoma/2006 (H1N1) were administrated 10 or 30 mg/kg of BXM orally twice daily for 1 day, starting at 1 day post-infection (p.i.) or administrated 10 mg/kg of BXM orally twice daily for 1 day, starting at 2 days p.i.. Oseltamivir phosphate was administered at doses of 5 mg/kg orally twice daily for 2 days as a comparison. The virus titer in the nasal washes and body temperature change were monitored during infection.ResultsBXA was detected in ferret plasma after a single oral administration of BXM at 10 and 30 mg/kg, in more than a dose-proportional manner. When the treatment was initiated at 1 day p.i., BXM at 10 and 30 mg/kg showed reduction of virus titer to an undetectable level on day 2 p.i. and statistically significant reduction in virus titer over time from day 2 to 3 p.i. compared with vehicle and oseltamivir phosphate. Moreover, the change of body temperature over time from 8 hours after the first administration to 3 days p.i. was significantly lower in BXM at 10 and 30 mg/kg than vehicle and oseltamivir phosphate. These effects were also observed in ferrets treated with BXM at 10 mg/kg even when administered at 2 day p.i. where ferret exhibit fever that is more than 1 degree higher than on 1 day p.i..ConclusionSingle-day oral administration of BXM had beneficial effects on viral titer and symptoms in ferrets infected with influenza A virus, which were superior to those observed with oseltamivir phosphate and vehicle.Disclosures M. Kitano, Shionogi & Co., Ltd.: Employee, Salary. T. Matsuzaki, Shionogi & Co., Ltd.: Employee, Salary. R. Oka, Shionogi & Co., Ltd.: Employee, Salary. K. Baba, Shionogi TechnoAdvance Research & Co., Ltd.: Employee, Salary. T. Noda, Shionogi TechnoAdvance Research & Co., Ltd.: Employee, Salary. Y. Yoshida, Shionogi & Co., Ltd.: Employee, Salary. K. Sato, Shionogi & Co., Ltd.: Employee, Salary. R. Yoshida, Shionogi & Co., Ltd.: Employee, Salary. A. Sato, Shionogi & Co., Ltd.: Employee, Salary. H. Kamimori, Shionogi & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. A. Naito, Shionogi & Co., Ltd.: Employee, Salary.

LB16. Phase 3 Trial of Baloxavir Marboxil in High-Risk Influenza Patients (CAPSTONE-2 Study)

BackgroundBaloxavir marboxil (BXM), an oral selective cap-dependent endonuclease inhibitor, is effective and safe for treating acute influenza in otherwise healthy patients.MethodWe conducted an international, randomized, double-blind, placebo (PLC)- and oseltamivir (Os)-controlled treatment study in patients at higher risk (HR) of influenza complications. Inclusion criteria included age ≥12 years, fever + influenza symptoms of ≤48 hours duration, and presence of at least 1 HR factor adapted from CDC criteria. Patients were randomized (1:1:1) to a single oral dose of BXM (40/80 mg for BW </≥80 kg), PLC, or 75 mg Os BID for 5 days. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in those with RT-PCR confirmed influenza (ITTI population). Secondary endpoints included infectious virus detection in serial nasopharyngeal swabs, prescription of antibiotics, and influenza-related complications.ResultAmong 2,184 randomized patients, 1,163(53%) comprised the ITTI population (47.9% A/H3N2, 6.9% A/H1N1, 41.6% B). The most common risk factors were asthma or chronic lung disease (39.2%) and age ≥65 years (27.4%). TTIIS was significantly shorter in BXM than PLC (median 73.2 hours vs. 102.3 hours, P < 0.0001) and numerically shorter than Os (81.0 hours, P = 0.8347). TTIIS in BXM patients with A/H3N2 virus (median: 75.4 hours) was significantly shorter than in PLC (100.4 hours; P =0.0141) and was significantly shorter in patients with influenza B (74.6 hours) than in either PLC (100.6 hours; P = 0.0138) or Os (101.6 hours; P = 0.0251). Median time to cessation of viral shedding in BXM patients was 48 hours, significantly less than 96 hours in both PLC and Os patients. Systemic antibiotic use and influenza-related complications were significantly fewer in BXM (3.4% and 2.8%, resp.) than PLC (7.5% and 10.4%; P = 0.0112, and P < 0.0001). The incidence of any (25.1–29.7%) or serious adverse events (0.7–1.2%) did not differ significantly across the groups.ConclusionBXM was well-tolerated and associated with faster recovery and reduced risk of complications in HR influenza patients compared with PLC. It proved superior to Os in shortening the duration of virus replication and in resolving influenza B illness. Oral BXM is a promising treatment option for patients with risk factors for influenza complications.Disclosures M. G. Ison, Romark: Investigator, Research support. Shionogi: Scientific Advisor, Paid DSMB Member. Emergent BioScience: Investigator, Research support. Janssen: Investigator and Scientific Advisor, Consulting fee and Research support. GlaxoSmithKlein: Scientific Advisor, Paid DSMB Member. VirBio: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. S. Portsmouth, Shionogi Inc.: Employee, Salary. Y. Yoshida, Shionogi & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. F. Hayden, Shionogi & Co., Ltd.: Scientific Advisor, Consulting fee (donated) and travel support for attending 6th ESWI meeting, 10–13 September 2017, Latvia, to present phase 3 OWH results. .T. Uehara, Shionogi & Co., Ltd.: Employee, Salary.