RESUMEN
Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent episodes of swelling of the skin, larynx, gastrointestinal tract, genitals, and extremities that can be disruptive to patient quality of life. Dysregulation of plasma kallikrein activity leads to increased production and accumulation of bradykinin in HAE and causes attacks of angioedema. Plasma kallikrein is a serine protease essential for the formation of bradykinin. Berotralstat is a potent, highly selective, orally bioavailable small-molecule plasma kallikrein inhibitor that has been approved to prevent attacks of HAE in adults and children 12 years of age and older. Population pharmacokinetic (PK) analyses were conducted to describe the PK of berotralstat (BCX7353; Orladeyo™ ) and to evaluate the covariates that may explain variability in PK. The PK of berotralstat were characterized by population PK modeling of data from 13 clinical studies and a total of 771 healthy subjects and patients with HAE. The PK profile was well described by a three-compartment model with first-order absorption including an absorption lag time and linear elimination. Among the covariates tested, the effects of bilirubin and food were found not to be clinically significant and were removed from the model. Covariate analysis indicated significant effects of dose on bioavailability and weight on berotralstat clearance and volume. Despite the covariate effect of weight, simulations in adolescents and adults who were underweight, low weight, and overweight demonstrated similar predicted exposures to those observed at therapeutic doses in a clinical trial. Therefore, no dose adjustment is required in these HAE patient subpopulations.
Asunto(s)
Angioedemas Hereditarios , Adolescente , Adulto , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/prevención & control , Bradiquinina , Niño , Humanos , Calicreína Plasmática , Pirazoles , Calidad de VidaRESUMEN
Galidesivir (BCX4430) is an adenosine nucleoside analog broadly active in cell culture against multiple RNA virus families, and active in animal models of viral diseases associated with Ebola, Marburg, yellow fever, Zika, and Rift Valley fever. Current studies demonstrated the pharmacokinetics and safety of the first-in-human evaluations of galidesivir as intramuscular (IM) and intravenous (IV) formulations. Two double-blind, placebo-controlled, dose-ranging studies were conducted enrolling 126 healthy subjects. Study 1 evaluated the safety and tolerability of IM galidesivir over single day dosing, single day dosing ± lidocaine, and 7-day dosing with lidocaine. Study 2 evaluated the safety and tolerability of single ascending doses of IV galidesivir. Safety and tolerability were evaluated via clinical and laboratory monitoring. The plasma concentration-time profile of galidesivir at doses 0.3 to 10 mg/kg IM was characterized by rapid absorption, an initial rapid distribution and clearance phase, and an extended terminal elimination phase. The initial rapid distribution and extended terminal elimination were mimicked in the profile of galidesivir at doses 5 to 20 mg/kg IV. No fatal events or related serious adverse events were reported. No clinically significant dose-related trends in laboratory values, vital signs, electrocardiograms, or echocardiograms were noted. Galidesivir was safe and generally well tolerated.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Adenina/análogos & derivados , Adenosina/efectos adversos , Adenosina/análogos & derivados , Animales , Antivirales/efectos adversos , Voluntarios Sanos , Humanos , Nucleósidos , Pirrolidinas , Infección por el Virus Zika/tratamiento farmacológicoRESUMEN
BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).
RESUMEN
BACKGROUND: Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile. OBJECTIVE: Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks. METHODS: APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability. RESULTS: One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (±standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (±0.25) and 1.06 (±0.25) in the berotralstat 150mg 48-week group and 2.97 (±0.21) and 1.35 (±0.33) in the berotralstat 110mg 48-week group. CONCLUSIONS: The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment.
Asunto(s)
Angioedemas Hereditarios , Angioedemas Hereditarios/tratamiento farmacológico , Método Doble Ciego , Humanos , Pirazoles , Resultado del TratamientoRESUMEN
BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
Asunto(s)
Angioedemas Hereditarios/tratamiento farmacológico , Pirazoles/administración & dosificación , Administración Oral , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Calicreína Plasmática/administración & dosificación , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients. METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period. RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%). CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.
Asunto(s)
Angioedemas Hereditarios , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/epidemiología , Proteína Inhibidora del Complemento C1/efectos adversos , Humanos , Japón/epidemiología , Estudios Prospectivos , PirazolesRESUMEN
Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection against Zika virus infection. Galidesivir exhibited favorable pharmacokinetics with no observed teratogenic effects in rats or rabbits at any dose tested. The antiviral efficacy of galidesivir observed in the blood and central nervous system of infected animals warrants continued evaluation of this compound for the treatment of flaviviral infections.
Asunto(s)
Hepatitis C Crónica , Infección por el Virus Zika , Virus Zika , Animales , Antivirales/uso terapéutico , Macaca mulatta , Conejos , Ratas , Viremia/tratamiento farmacológico , Infección por el Virus Zika/tratamiento farmacológicoRESUMEN
Rift Valley fever virus (RVFV) is a mosquito-borne pathogen endemic to sub-Saharan Africa and the Arabian Peninsula. There are no approved antiviral therapies or vaccines available to treat or prevent severe disease associated with RVFV infection in humans. The adenosine analog, galidesivir (BCX4430), is a broad-spectrum antiviral drug candidate with in vitro antiviral potency (EC50 of less than 50⯵M) in more than 20 different viruses across eight different virus families. Here we report on the activity of galidesivir in the hamster model of peracute RVFV infection. Intramuscular and intraperitoneal treatments effectively limited systemic RVFV (strain ZH501) infection as demonstrated by significantly improved survival outcomes and the absence of infectious virus in the spleen and the majority of the serum, brain, and liver samples collected from infected animals. Our findings support the further development of galidesivir as an antiviral therapy for use in treating severe RVFV infection, and possibly other related phleboviral diseases.
Asunto(s)
Antivirales/administración & dosificación , Nucleósidos de Purina/administración & dosificación , Fiebre del Valle del Rift/tratamiento farmacológico , Virus de la Fiebre del Valle del Rift/efectos de los fármacos , Adenina/análogos & derivados , Adenosina/análogos & derivados , Animales , Modelos Animales de Enfermedad , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Hígado/virología , Mesocricetus , Pirrolidinas , Bazo/virología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses. We tested this compound against African and Asian lineage ZIKV in cytopathic effect inhibition and virus yield reduction assays in various cell lines. To further evaluate the efficacy in a relevant animal model, we developed a mouse model of severe ZIKV infection, which recapitulates various human disease manifestations including peripheral virus replication, conjunctivitis, encephalitis and myelitis. Time-course quantification of viral RNA accumulation demonstrated robust viral replication in several relevant tissues, including high and persistent viral loads observed in the brain and testis. The presence of viral RNA in various tissues was confirmed by an infectious culture assay as well as immunohistochemical staining of tissue sections. Treatment of ZIKV-infected mice with BCX4430 significantly improved outcome even when treatment was initiated during the peak of viremia. The demonstration of potent activity of BCX4430 against ZIKV in a lethal mouse model warrant its continued clinical development.
Asunto(s)
Antivirales/farmacología , Antivirales/uso terapéutico , Nucleósidos de Purina/farmacología , Nucleósidos de Purina/uso terapéutico , Infección por el Virus Zika/tratamiento farmacológico , Virus Zika/efectos de los fármacos , Adenina/análogos & derivados , Adenosina/análogos & derivados , Animales , Antivirales/administración & dosificación , Encéfalo/virología , Línea Celular , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Nucleósidos de Purina/administración & dosificación , Pirrolidinas , ARN Viral , Testículo/virología , Carga Viral/efectos de los fármacos , Viremia , Replicación Viral/efectos de los fármacos , Infección por el Virus Zika/virologíaAsunto(s)
Angioedemas Hereditarios/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Calicreína Plasmática/antagonistas & inhibidores , Prolina/análogos & derivados , Adulto , Angioedemas Hereditarios/metabolismo , Proteína Inhibidora del Complemento C1/metabolismo , Estudios Cruzados , Femenino , Humanos , Masculino , Prolina/uso terapéuticoRESUMEN
The adenosine nucleoside analog BCX4430 is a direct-acting antiviral drug under investigation for the treatment of serious and life-threatening infections from highly pathogenic viruses, such as the Ebola virus. Cellular kinases phosphorylate BCX4430 to a triphosphate that mimics ATP; viral RNA polymerases incorporate the drug's monophosphate nucleotide into the growing RNA chain, causing premature chain termination. BCX4430 is active in vitro against many RNA viral pathogens, including the filoviruses and emerging infectious agents such as MERS-CoV and SARS-CoV. In vivo, BCX4430 is active after intramuscular, intraperitoneal, and oral administration in a variety of experimental infections. In nonclinical studies involving lethal infections with Ebola virus, Marburg virus, Rift Valley fever virus, and Yellow Fever virus, BCX4430 has demonstrated pronounced efficacy. In experiments conducted in several models, both a reduction in the viral load and an improvement in survival were found to be related to the dose of BCX4430. A Phase 1 clinical trial of intramuscular administration of BCX4430 in healthy subjects is currently ongoing.
Asunto(s)
Antivirales/farmacología , Antivirales/uso terapéutico , Nucleósidos de Purina/farmacología , Nucleósidos de Purina/uso terapéutico , Infecciones por Virus ARN/tratamiento farmacológico , Virus ARN/efectos de los fármacos , Adenina/análogos & derivados , Adenosina/análogos & derivados , Administración Oral , Animales , Ensayos Clínicos Fase I como Asunto , Modelos Animales de Enfermedad , Descubrimiento de Drogas/tendencias , Humanos , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Pirrolidinas , Infecciones por Virus ARN/virología , Virus ARN/fisiología , Resultado del Tratamiento , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Current influenza treatment options include oral or inhaled antiviral agents. There is an unmet need for parenteral antiviral treatments. METHODS: Peramivir, a parenteral influenza neuraminidase inhibitor (NAI), was administered by single-dose intramuscular (IM) injection in two placebo-controlled studies in adult outpatients with acute, uncomplicated influenza during two consecutive influenza seasons. RESULTS: In a Phase II study, peramivir treatment significantly shortened duration of fever and reduced viral load in nasopharyngeal secretions. A subsequent Phase III study was not fully enrolled; however, in both studies, the magnitude of the treatment effect favouring peramivir was consistent with that reported for other NAIs. A post-hoc analysis was conducted by integrating efficacy and safety results of 427 subjects from both studies. The median time to alleviation of symptoms (TTAS) in subjects receiving peramivir 300 mg (113.2 h) was shorter than for placebo (134.8 h; P=0.161 adjusted for smoking behaviour, influenza season and virus type; unadjusted P=0.047). The median time to resolution of fever was reduced by 24 h after treatment with peramivir 300 mg compared with placebo (P=0.004). The proportion of subjects shedding influenza virus was significantly decreased over 48 h following peramivir treatment (P=0.009). Detection of post-treatment viruses with decreased susceptibility to NAIs was uncommon. Peramivir was generally safe and well-tolerated with types and rates of adverse event similar to placebo. CONCLUSIONS: The results of these studies are consistent with previous reports of peramivir administered by intravenous infusion, and demonstrate a positive risk-benefit profile for peramivir in patients with acute uncomplicated influenza.
Asunto(s)
Antivirales/administración & dosificación , Ciclopentanos/administración & dosificación , Guanidinas/administración & dosificación , Gripe Humana/tratamiento farmacológico , Ácidos Carbocíclicos , Enfermedad Aguda , Adulto , Antivirales/efectos adversos , Ensayos Clínicos Controlados como Asunto , Ciclopentanos/efectos adversos , Femenino , Guanidinas/efectos adversos , Humanos , Virus de la Influenza A/clasificación , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/virología , Concentración 50 Inhibidora , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estaciones del Año , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: Seasonal influenza causes >200 000 annual hospitalizations in the United States. Current antiviral treatment options are limited to oral or inhaled agents. There is an urgent unmet need for intravenous antiviral treatments. METHODS: Patients hospitalized with suspected influenza were randomized to 5-day treatment with intravenous peramivir (600 mg once daily) or placebo; all received the institution's standard of care (SOC) treatment. Time to clinical resolution and change in viral shedding in nasopharyngeal specimens were the primary and key secondary end points. RESULTS: Influenza infection was confirmed in 338 of 405 enrolled patients. At the time of a preplanned interim analysis, the primary efficacy analysis population comprised 121 patients who did not receive a concurrent neuraminidase inhibitor as part of the SOC. The median (95% confidence interval) time to clinical resolution was 42.5 (34.0-57.9) hours for peramivir versus 49.5 (40.0-61.9) hours for placebo (P = .97). A larger treatment effect was observed in patients with history of symptoms <48 hours or admitted to an intensive care unit. Greater reductions in viral shedding, based on median tissue culture infective dose, were observed in patients who received peramivir than in placebo recipients, although this difference was not statistically significant. The incidence and severity of adverse events and laboratory abnormalities were similar between the 2 treatment groups. The study was terminated for futility after a preplanned interim analysis. CONCLUSIONS: A significant clinical benefit was not demonstrated for peramivir plus SOC compared with placebo plus SOC. Peramivir was generally safe and well tolerated. These findings highlight the challenges in designing studies to evaluate influenza antiviral agents in a hospitalized setting. Clinical Trials Registration. NCT00958776.
Asunto(s)
Antivirales/uso terapéutico , Ciclopentanos/uso terapéutico , Guanidinas/uso terapéutico , Gripe Humana/diagnóstico , Ácidos Carbocíclicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
No effective antiviral therapies are currently available to treat disease after infection with yellow fever virus (YFV). A Syrian golden hamster model of yellow fever (YF) was used to characterize the effect of treatment with BCX4430, a novel adenosine nucleoside analog. Significant improvement in survival was observed after treatment with BCX4430 at 4 mg/kg of body weight per day dosed intraperitoneally (i.p.) twice daily (BID). Treatment with BCX4430 at 12.5 mg/kg/day administered i.p. BID for 7 days offered complete protection from mortality and also resulted in significant improvement of other YF disease parameters, including weight loss, serum alanine aminotransferase levels (6 days postinfection [dpi]), and viremia (4 dpi). In uninfected hamsters, BCX4430 at 200 mg/kg/day administered i.p. BID for 7 days was well tolerated and did not result in mortality or weight loss, suggesting a potentially wide therapeutic index. Treatment with BCX4430 at 12 mg/kg/day i.p. remained effective when administered once daily and for only 4 days. Moreover, BCX4430 dosed at 200 mg/kg/day i.p. BID for 7 days effectively treated YF, even when treatment was delayed up to 4 days after virus challenge, corresponding with peak viral titers in the liver and serum. BCX4430 treatment did not preclude a protective antibody response, as higher neutralizing antibody (nAb) concentrations corresponded with increasing delays of treatment initiation, and greater nAb responses resulted in the protection of animals from a secondary challenge with YFV. In summary, BCX4430 is highly active in a hamster model of YF, even when treatment is initiated at the peak of viral replication.
Asunto(s)
Antivirales/uso terapéutico , Nucleósidos de Purina/uso terapéutico , Fiebre Amarilla/tratamiento farmacológico , Virus de la Fiebre Amarilla/efectos de los fármacos , Virus de la Fiebre Amarilla/inmunología , Adenina/análogos & derivados , Adenosina/análogos & derivados , Adenosina/uso terapéutico , Alanina Transaminasa/sangre , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Células Cultivadas , Cricetinae , Modelos Animales de Enfermedad , Femenino , Mesocricetus , Pirrolidinas , Resultado del Tratamiento , Ensayo de Placa Viral , Viremia/tratamiento farmacológico , Viremia/virología , Fiebre Amarilla/mortalidad , Fiebre Amarilla/virologíaRESUMEN
Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/farmacología , Infecciones por Filoviridae/prevención & control , Infecciones por Filoviridae/virología , Filoviridae/efectos de los fármacos , Nucleósidos de Purina/farmacología , Adenina/análogos & derivados , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/química , Antivirales/farmacocinética , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/metabolismo , Modelos Animales de Enfermedad , Ebolavirus/efectos de los fármacos , Filoviridae/enzimología , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/virología , Humanos , Inyecciones Intramusculares , Macaca fascicularis/virología , Enfermedad del Virus de Marburg/prevención & control , Enfermedad del Virus de Marburg/virología , Marburgvirus/efectos de los fármacos , Nucleósidos de Purina/administración & dosificación , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacocinética , Pirrolidinas , ARN/biosíntesis , Factores de TiempoRESUMEN
BACKGROUND: Influenza causes over 200,000 hospitalizations a year in the United States, but few antiviral treatment studies have focused on patients hospitalized with influenza. This open-label, randomized study was initiated during the 2009 H1N1 pandemic to help assess the antiviral activity, safety and tolerability of 5-10 days treatment with two different dosing regimens of the intravenous neuraminidase inhibitor, peramivir, in hospitalized subjects with influenza. METHODS: Quantitative virology was done on nasopharyngeal swab specimens from subjects ≥6 years of age to measure change from baseline in tissue culture infective dose (primary end point) and quantitative viral RNA levels by real-time PCR. Clinical end points included time to clinical resolution, a composite end point of four vital signs and oxygen saturation. RESULTS: A total of 234 hospitalized patients were randomized to peramivir 300 mg twice daily or 600 mg once daily; 127 had laboratory confirmed influenza. In those with detectable virus at baseline, viral titres declined without differences between regimens. There were no significant differences in clinical or virological end points between treatment arms, and apparent differences were explained by baseline disease severity differences in the groups. Peramivir was generally safe and well tolerated for treated patients hospitalized with pandemic influenza with outcomes similar to those described in the literature. CONCLUSIONS: This open-label trial of intravenous peramivir in subjects hospitalized predominantly with 2009 influenza A (H1N1) demonstrated that once- or twice-daily administration was associated with decreases in viral shedding and clinical improvement. ClinicalTrials.gov number NCT00957996.
Asunto(s)
Antivirales/uso terapéutico , Ciclopentanos/uso terapéutico , Guanidinas/uso terapéutico , Hospitalización , Gripe Humana/tratamiento farmacológico , Ácidos Carbocíclicos , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/administración & dosificación , Antivirales/efectos adversos , Ciclopentanos/administración & dosificación , Ciclopentanos/efectos adversos , Femenino , Guanidinas/administración & dosificación , Guanidinas/efectos adversos , Humanos , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/diagnóstico , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Carga Viral , Esparcimiento de Virus , Adulto JovenAsunto(s)
Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/uso terapéutico , Ciclopentanos/administración & dosificación , Ciclopentanos/efectos adversos , Ciclopentanos/uso terapéutico , Drogas en Investigación/administración & dosificación , Tratamiento de Urgencia , Guanidinas/administración & dosificación , Guanidinas/efectos adversos , Guanidinas/uso terapéutico , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Femenino , Humanos , Masculino , EmbarazoRESUMEN
Analysis of a US hospitalization database demonstrated that more influenza patients were hospitalized and the age distribution of hospitalizations was younger during the 2009 (H1N1) influenza A pandemic compared with the three previous influenza seasons. The duration of hospital stay remained stable in all four seasons. A higher proportion of patients was treated with antivirals (P < 0·0001), comprised almost entirely of neuraminidase inhibitors, and the proportion was highest in those with influenza confirmed by diagnostic testing (P < 0·0001). Approximately one-third remained untreated. Young children had the lowest rate of neuraminidase-inhibitor treatment during the 2009 pandemic (P < 0·05).