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Clinical Infectious Diseases : An... Apr 2019Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study.
BACKGROUND
Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.
METHODS
Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).
RESULTS
From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57-75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.
CONCLUSIONS
Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.
CLINICAL TRIALS REGISTRATION
NCT01611974.
Topics: Adolescent; Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Viral; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Male; Ribonucleosides; Transplant Recipients; Young Adult
PubMed: 30329038
DOI: 10.1093/cid/ciy706 -
Current Opinion in Investigational... Aug 2004ViroPharma, under license from GlaxoSmithKline, is developing maribavir, a DNA synthesis inhibitor for the potential prevention and treatment of human cytomegalovirus... (Review)
Review
ViroPharma, under license from GlaxoSmithKline, is developing maribavir, a DNA synthesis inhibitor for the potential prevention and treatment of human cytomegalovirus infections related to transplants (including solid organ and hematopoietic stem cells), congenital transmission, and in patients with HIV infection. In July 2004, a phase II trial was initiated.
Topics: Animals; Antiviral Agents; Benzimidazoles; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytomegalovirus Infections; Humans; Nucleic Acid Synthesis Inhibitors; Patents as Topic; Randomized Controlled Trials as Topic; Ribonucleosides; Structure-Activity Relationship
PubMed: 15600248
DOI: No ID Found -
The Journal of Infectious Diseases Feb 2024This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56%... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This drug resistance analysis of a randomized trial includes 234 patients receiving maribavir and 116 receiving investigator-assigned standard therapy (IAT), where 56% and 24%, respectively, cleared cytomegalovirus DNA at week 8 (treatment responders).
METHODS
Baseline and posttreatment plasma samples were tested for mutations conferring drug resistance in viral genes UL97, UL54, and UL27.
RESULTS
At baseline, genotypic testing revealed resistance to ganciclovir, foscarnet, or cidofovir in 56% of patients receiving maribavir and 68% receiving IAT, including 9 newly phenotyped mutations. Among them, 63% (maribavir) and 21% (IAT) were treatment responders. Detected baseline maribavir resistance mutations were UL27 L193F (n = 1) and UL97 F342Y (n = 3). Posttreatment, emergent maribavir resistance mutations were detected in 60 (26%) of those randomized to maribavir, including 49 (48%) of 103 nonresponders and 25 (86%) of the 29 nonresponders where viral DNA initially cleared then rebounded while on maribavir. The most common maribavir resistance mutations were UL97 T409M (n = 34), H411Y (n = 26), and C480F (n = 21), first detected 26 to 130 (median 56) days after starting maribavir.
CONCLUSIONS
Baseline maribavir resistance was rare. Drug resistance to standard cytomegalovirus antivirals did not preclude treatment response to maribavir. Rebound in plasma cytomegalovirus DNA while on maribavir strongly suggests emerging drug resistance.
CLINICAL TRIALS REGISTRATION
NCT02931539.
Topics: Humans; Antiviral Agents; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; DNA; Drug Resistance, Viral; Ganciclovir; Mutation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Transplant Recipients
PubMed: 37506264
DOI: 10.1093/infdis/jiad293 -
Clinical Infectious Diseases : An... Mar 2024Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated... (Randomized Controlled Trial)
Randomized Controlled Trial
Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.
BACKGROUND
Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir.
METHODS
In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed.
RESULTS
Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%).
CONCLUSIONS
Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].
Topics: Humans; Antiviral Agents; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole; Hematopoietic Stem Cell Transplantation; Neutropenia; Valganciclovir; Viremia
PubMed: 38036487
DOI: 10.1093/cid/ciad709 -
Transplant Infectious Disease : An... Jun 2023
Topics: Humans; Cytomegalovirus Infections; Antiviral Agents
PubMed: 37053091
DOI: 10.1111/tid.14063 -
The Medical Letter on Drugs and... Nov 2022
Topics: Humans; Cytomegalovirus Infections; Dichlororibofuranosylbenzimidazole
PubMed: 36397194
DOI: No ID Found -
The Annals of Pharmacotherapy Oct 2008To review the pharmacology, pharmacokinetics, efficacy, and safety of maribavir, a novel antiviral agent in the benzimidazole drug class. (Comparative Study)
Comparative Study Review
OBJECTIVE
To review the pharmacology, pharmacokinetics, efficacy, and safety of maribavir, a novel antiviral agent in the benzimidazole drug class.
DATA SOURCES
Articles were identified through searches of MEDLINE (January 1998-July 2008). Abstracts from recent scientific meetings and the manufacturer were also included.
STUDY SELECTION AND DATA EXTRACTION
All English-language in vitro and in vivo studies and abstracts evaluating maribavir were reviewed and considered for inclusion. All human studies were included.
DATA SYNTHESIS
Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses. Unlike ganciclovir, which needs to be phosphorylated by UL 97 kinase to become an active inhibitor of DNA polymerase, maribavir directly inhibits UL 97 kinase. UL 97 kinase is an early viral gene product involved in viral DNA elongation, DNA packaging, and egress or shedding of capsids from viral nuclei. Maribavir has also been found to be effective against ganciclovir-resistant CMV strains. Maribavir differs from current CMV antiviral agents in its adverse event profile. Maribavir is not associated with nephrotoxicity or hematologic toxicities, but has been associated with taste disturbances. In February 2007, maribavir was granted Food and Drug Administration orphan drug status for prevention of CMV viremia and diseases in at-risk populations. Maribavir Phase 2 trials in stem-cell transplant recipients have been completed, and there are ongoing Phase 3 trials in stem-cell and organ transplant recipients.
CONCLUSIONS
Maribavir may be an option for treatment of ganciclovir-resistant CMV infections. Its bioavailability is greater than that of oral ganciclovir, but less than that of valganciclovir. No differences in pharmacokinetics were seen in renally impaired patients, although dialysis-dependent patients were not evaluated. Maribavir is not associated with hematologic toxicities; however, the high prevalence of taste disturbances may limit its tolerability.
Topics: Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; Drug Resistance, Viral; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides
PubMed: 18698013
DOI: 10.1345/aph.1L065 -
Drugs in R&D 2007Maribavir is a novel benzimidazole riboside compound that is currently in clinical development with ViroPharma for the prevention of cytomegalovirus (CMV) infections in... (Review)
Review
Maribavir is a novel benzimidazole riboside compound that is currently in clinical development with ViroPharma for the prevention of cytomegalovirus (CMV) infections in transplant patients. Maribavir is thought to inhibit viral DNA assembly and inhibit egress of viral capsids from infected cell nuclei. This mechanism is different to other available CMV treatments that inhibit CMV DNA polymerase. Maribavir, originally developed by GlaxoSmithKline, was licensed to ViroPharma in August 2003. Glaxo was conducting phase I/II clinical studies in the EU and the US in 2001, but discontinued development because the company felt that there was no longer a significant clinical need for maribavir as advances in the treatment of HIV have lead to improved immune systems in patients, resulting in a reduction in the incidence of CMV and CMV retinitis. In August 2003, ViroPharma acquired exclusive worldwide rights (excluding Japan) to develop and commercialise maribavir for the prevention and treatment of CMV infections related to transplant and congenital transmission and in patients with HIV infection. ViroPharma paid GlaxoSmithKline a $US3.5 million upfront licensing fee and will pay additional milestones based on defined clinical development and regulatory events. The company will also pay royalties on product sales in the US and the rest of the world, excluding Japan.A phase III study with maribavir as a prophylactic agent in patients undergoing allogeneic stem cell transplant who are CMV seropositive has been initiated and another phase III trial in solid organ transplant patients is planned. The stem cell transplant trial will take approximately 18 months to complete enrolment and the solid organ transplant trial, which won't be as large as the stem cell transplant trial, will be completed within this time-frame also. ViroPharma hopes to file an NDA for maribavir in 2009. Maribavir was granted fast-track status by the US FDA in February 2006 for the prevention of CMV infection in allogeneic bone marrow and solid organ transplant patients. Maribavir has received orphan drug status in the US for the prevention of CMV viraemia and disease in at-risk populations. ViroPharma has conducted a dose-ranging phase II clinical study designed to evaluate the antiviral activity, safety and pharmacokinetic profile of maribavir for the prevention of CMV infection in patients who have undergone allogeneic stem cell transplantation. The randomised, double-blind, placebo-controlled, dose-ranging study was conducted at 13 transplant centres across the US. Patients (n = 111) were randomised 3 : 1 to receive maribavir in three ascending dose groups (100mg bid, 400mg qd, 400mg bid) or placebo for up to 12 weeks. Enrolment in the phase II trial was completed in November 2005. Preliminary results have been reported. In February 2004, ViroPharma announced the initiation of a clinical programme to develop maribavir for prevention of CMV infection in transplant patients. A phase I drug-drug interaction and safety study in healthy volunteers, designed to evaluate the potential for maribavir to affect the blood levels of various other drugs that are metabolised by the liver, was conducted in the US. Results of this study were reported in March 2005. A second phase I study was initiated in March 2004 to evaluate the pharmacokinetic profile of a single 400mg dose of maribavir in patients with varying levels of renal functional impairment, compared with subjects with normal renal function. Maribavir has been tested in several phase I studies by GlaxoSmithKline, in which the drug demonstrated antiviral activity, oral bioavailability and an acceptable safety and tolerability profile.The patents covering maribavir held by GlaxoSmithKline expire in 2015.
Topics: Animals; Antiviral Agents; Benzimidazoles; Clinical Trials as Topic; Cytomegalovirus; Cytomegalovirus Infections; HIV Infections; Humans; Ribonucleosides
PubMed: 17472414
DOI: 10.2165/00126839-200708030-00006