Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results (original) (raw)
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The Journal of antimicrobial chemotherapy, 2018
Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-c...
Pharmacologic Advances in the Treatment and Prevention of Respiratory Syncytial Virus
Clinical Infectious Diseases, 2010
Currently, only 2 drugs have been approved for the treatment of respiratory syncytial virus (RSV). Palivizumab is a monoclonal antibody for the prevention of RSV in high-risk children. Ribavirin is approved for treatment of severe RSV disease; however, its effectiveness in improving outcomes is questionable. During the past 40 years, many obstacles have delayed the development of safe and effective vaccines and treatment regimens. This article reviews these obstacles and presents the novel development strategies used to overcome many of them. Also discussed are promising new antiviral treatment candidates and their associated mechanism of action, the significant advances made in vaccine development, and exciting, new studies directed at improving outcomes through pharmacologic manipulation of the host response to RSV disease. Respiratory syncytial virus (RSV) is the leading cause of pediatric viral respiratory tract infections. The World Health Organization estimates an annual mortality rate of ∼160,000 deaths worldwide [1]; more inclusive all-cause mortality rates related to RSV approach 600,000 deaths [2]. RSV is also the second leading cause of viral death in elderly individuals [3]. By 18 months of age, 87% of children have developed RSVspecific antibodies [4]; by 3 years of age, virtually all children have been infected. In the United States alone, RSV infection results in 1120,000 childhood hospitalizations and up to 500 deaths [5]. Compared with influenza, RSV accounts for 19 times more deaths in children younger than 1 year [6-11]. Only 2 US Food and Drug Administration (FDA)-approved drugs are currently available for RSV disease. Palivizumab is indicated for RSV prevention in high-risk infants, including those with chronic lung disease, those with congenital heart disease, and those born prematurely [12]. This indication is based on hospitalization rates that are ∼5 times greater in highrisk versus non-high-risk infants. However, among all infants hospitalized with severe RSV disease, ∼70% are term infants
Influenza and other respiratory viruses, 2015
As the most important viral cause of severe respiratory disease in infants and increasing recognition as important in the elderly and immunocompromised, respiratory syncytial virus (RSV) is responsible for a massive health burden worldwide. Prophylactic antibodies were successfully developed against RSV. However, their use is restricted to a small group of infants considered at high risk of severe RSV disease. There is still no specific therapeutics or vaccines to combat RSV. As such, it remains a major unmet medical need for most individuals. The World Health Organisations International Clinical Trials Registry Platform (WHO ICTRP) and PubMed were used to identify and review all RSV vaccine, prophylactic and therapeutic candidates currently in clinical trials. To perform an expert commentary on all RSV-specific prophylactic and therapeutic candidates that have entered clinical trials since 2008. This article is protected by copyright. All rights reserved.
Clinical Infectious Diseases, 2020
Background This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)–specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to ≤24 months. Methods Patients categorized by age (cohort 1: ≥6 to ≤24 months; cohort 2: ≥3 to < 6 months; cohort 3: > 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain ...
Recent Trends in RSV Immunoprophylaxis: Clinical Implications for the Infant
American Journal of Perinatology, 2019
Respiratory syncytial virus (RSV) remains the leading cause for hospitalizations in infants worldwide, resulting in significant health and financial burden. Since 1998, the humanized monoclonal antibody palivizumab remains the only available option licensed for the prevention of severe RSV disease in high-risk children, namely premature infants and those with chronic lung disease and congenital heart disease. In 2014, the American Academy of Pediatrics modified the recommendations on the use of RSV prophylaxis in these high-risk children, and limited its use to premature infants born at < 28 weeks' gestational age (wGA). Following this last guidance update, studies have confirmed that premature infants of 29 to 34 wGA remain at high risk for severe RSV disease, especially those of younger chronologic age. New and more cost-effective strategies are being developed that would help alleviate both the health and financial burden associated with severe RSV disease.
Antimicrobial agents and chemotherapy, 1999
We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (</=35 weeks' gestation) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SB 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura (n = 3) and thrombocytosis (n = 1). No subject developed a detectable level of anti-SB 209763 antibody. Approximately 1 week after administration of the second dose of SB 209763 at 10 mg/kg, the mean plasma concentration (n = 9) was 68.5 micrograms/ml. The terminal half-life (T1/2) determined by noncompartmental analysis ran...
Ongoing developments in RSV prophylaxis: a clinician’s analysis
Current Opinion in Virology, 2017
Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. Lower respiratory tract infection due to RSV is one of the most common causes of hospitalization for infants, especially those born premature or with chronic lung or heart disease. Furthermore, RSV infection is an important cause of morbidity in adults, particularly in the elderly and immunocompromised individuals. The acute phase of this infection is often followed by episodes of wheezing that recur for months or years and usually lead to a physician diagnosis of asthma. RSV was discovered more than 50 years ago, and despite extensive research to identify pharmacological therapies, the most effective management of this infection remains supportive care. The trial of a formalin-inactivated RSV vaccine in the 1960s resulted in priming the severe illness upon natural infection. Currently, Palivizumab is the only available option for RSV prophylaxis, and because of restricted clinical benefits and high costs, it has been limited to a group of high-risk infants. There are several ongoing trials in preclinical, Phase-I,-II, or-III clinical stages for RSV vaccine development based on various strategies. Here we review the existing available prophylactic options, the current stages of RSV vaccine clinical trials, different strategies, and major hurdles in the development of an effective RSV vaccine.