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Blood Jun 2008The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized,... (Randomized Controlled Trial)
Randomized Controlled Trial
Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.
The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression.
Topics: Adult; Antiviral Agents; Benzimidazoles; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Ribonucleosides; Stem Cell Transplantation; Taste Disorders; Transplantation, Homologous; Vomiting
PubMed: 18285548
DOI: 10.1182/blood-2007-11-121558 -
Reviews in Medical Virology Jul 2009The serine/threonine kinase expressed by human cytomegalovirus from gene UL97 phosphorylates the antiviral drug ganciclovir, but its biological function is the... (Review)
Review
The serine/threonine kinase expressed by human cytomegalovirus from gene UL97 phosphorylates the antiviral drug ganciclovir, but its biological function is the phosphorylation of its natural viral and cellular protein substrates which affect viral replication at many levels. The UL97 kinase null phenotype is therefore complex, as is the mechanism of action of maribavir, a highly specific inhibitor of its enzymatic activity. Studies that utilise the drug corroborate results from genetic approaches and together have elucidated many functions of the UL97 kinase that are critical for viral replication. The kinase phosphorylates eukaryotic elongation factor 1delta, the carboxyl terminal domain of the large subunit of RNA polymerase II, the retinoblastoma tumour suppressor and lamins A and C. Each of these is also phosphorylated and regulated by cdc2/cyclin-dependent kinase 1, suggesting that the viral kinase may perform a similar function. These and other activities of the UL97 kinase appear to stimulate the cell cycle to support viral DNA synthesis, enhance the expression of viral genes, promote virion morphogenesis and facilitate the egress of mature capsids from the nucleus. In the absence of UL97 kinase activity, viral DNA synthesis is inefficient and structural proteins are sequestered in nuclear aggresomes, reducing the efficiency of virion morphogenesis. Mature capsids that do form fail to egress the nucleus as the nuclear lamina are not dispersed by the kinase. The critical functions performed by the UL97 kinase illustrate its importance in viral replication and confirm that the kinase is a target for the development of antiviral therapies.
Topics: Amino Acid Sequence; Benzimidazoles; Cytomegalovirus; Cytomegalovirus Infections; DNA Replication; DNA, Viral; Humans; Molecular Sequence Data; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Viral Proteins; Virus Replication
PubMed: 19434630
DOI: 10.1002/rmv.615 -
Antiviral Research Feb 2024Therapeutic use of maribavir for human cytomegalovirus infection has renewed attention to the extent of cross-resistance with ganciclovir as the existing standard...
Therapeutic use of maribavir for human cytomegalovirus infection has renewed attention to the extent of cross-resistance with ganciclovir as the existing standard therapy. Each drug selects in vivo for a characteristic set of resistance mutations in the viral UL97 kinase gene. To improve the calibration of relative susceptibilities to each drug, genetic variants at relevant UL97 codons were extensively phenotyped using the same baseline viral clone, cell culture conditions and growth readout. Ganciclovir-selected mutations at codons 460, 520, 592, 594, 595 and 603 conferred 2.8-fold (C603Y) to 12-fold (M460I) increases in ganciclovir 50% inhibitory concentrations (EC50) over wild type baseline, while conferring maribavir EC50 fold changes ranging from 0.21-fold (M460I) to 1.9-fold (A594V). Maribavir-selected mutations at codons 409, 411 and 480 conferred maribavir EC50 fold changes ranging from 17 (H411Y) to 210 (C480F), while conferring ganciclovir EC50 fold changes ranging from 0.7 (H411Y) to 2.3 (C480F). The P-loop substitution F342Y, selected by either drug, is confirmed to confer 4.7-fold and 6-fold increases in maribavir and ganciclovir EC50s respectively, and suggests this part of the ATP-binding domain of UL97 to be involved in moderate resistance to both drugs. The maribavir hypersensitivity of M460I and M460V may be advantageous.
Topics: Humans; Ganciclovir; Cytomegalovirus; Antiviral Agents; Mutation; Codon; Drug Resistance, Viral; Phosphotransferases (Alcohol Group Acceptor); Dichlororibofuranosylbenzimidazole
PubMed: 38163624
DOI: 10.1016/j.antiviral.2023.105792 -
Retinal Cases & Brief Reports Mar 2024To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
PURPOSE
To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis.
METHODS
Retrospective case report of a lung-transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs.
RESULTS
A 72-year-old lung-transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the uninjected eye.
CONCLUSION
This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.
Topics: Humans; Aged; Cytomegalovirus Retinitis; Valganciclovir; Foscarnet; Retrospective Studies; Ganciclovir; Antiviral Agents; Dichlororibofuranosylbenzimidazole
PubMed: 36730596
DOI: 10.1097/ICB.0000000000001372 -
Clinical and Translational Science Nov 2020Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation....
Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline-adjusted and placebo-adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo-controlled, four-period crossover study in healthy participants (men and women ages 18-50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study's ability to detect QT prolongation. Digital 12-lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia's, and Bazett's QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100-mg and 1200-mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two-sided 90% confidence interval was below the 10-ms threshold at all time points. The concentration-effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.
Topics: Administration, Oral; Adolescent; Adult; Antiviral Agents; Benzimidazoles; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Dysgeusia; Electrocardiography; Female; Healthy Volunteers; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Moxifloxacin; Ribonucleosides; Young Adult
PubMed: 32506738
DOI: 10.1111/cts.12814 -
Current Opinion in Infectious Diseases Dec 2014To consider new treatment options for cytomegalovirus (CMV) infection, review recent trials, and anticipate their use in clinical practice, focussing on bone marrow... (Review)
Review
PURPOSE OF REVIEW
To consider new treatment options for cytomegalovirus (CMV) infection, review recent trials, and anticipate their use in clinical practice, focussing on bone marrow transplantation, congenital infection, and intervention during pregnancy.
RECENT FINDINGS
Three double-blind randomized placebo-controlled phase 2 proof-of-concept studies have each identified a novel antiviral drug with activity against CMV infection in bone marrow transplant patients. One of these (brincidofovir) inhibits the DNA polymerase that is the target of the currently licensed drug ganciclovir. Another new drug (maribavir) inhibits a protein kinase which, coincidentally, is the enzyme responsible for activating ganciclovir through phosphorylation. The third drug (letermovir) inhibits the terminase enzyme complex responsible for packaging unit length DNA into assembling virions.In addition, in a double-blind randomized placebo-controlled trial in neonates with symptomatic congenital CMV infection, a 6-month course of valganciclovir was superior to the standard 6-week course of the same drug. In pregnant women with primary CMV infection, administration of hyperimmune immunoglobulin did not significantly reduce transmission of CMV across the placenta.
SUMMARY
The ability to diagnose CMV infections reliably in different clinical settings through application of molecular laboratory methods has ushered in new ways of evaluating potential new treatments for CMV. Several of these may help control the diseases caused by this important human pathogen.
Topics: Acetates; Antiviral Agents; Benzimidazoles; Bone Marrow Transplantation; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Disease Transmission, Infectious; Double-Blind Method; Female; Ganciclovir; Humans; Male; Organ Transplantation; Organophosphonates; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Infectious; Quinazolines; Randomized Controlled Trials as Topic; Ribonucleosides
PubMed: 25304390
DOI: 10.1097/QCO.0000000000000107 -
Antiviral Therapy Oct 2023Cytomegalovirus (CMV) infection is a frequent complication in haematopoietic cell/solid organ transplant (HCT/SOT) recipients. Previous studies report all-cause...
Retrospective chart review of transplant recipients with cytomegalovirus infection who received maribavir in the Phase 3 SOLSTICE trial: Data at 52 weeks post-maribavir treatment initiation.
BACKGROUND
Cytomegalovirus (CMV) infection is a frequent complication in haematopoietic cell/solid organ transplant (HCT/SOT) recipients. Previous studies report all-cause mortality rates of 31% and 50% in HCT/SOT recipients post-treatment initiation with conventional anti-CMV therapies for refractory or resistant CMV.
METHODS
This was a multi-country, retrospective medical chart review study of HCT/SOT recipients with refractory CMV infection with or without resistance (R/R) who were randomized to the maribavir arm in the open-label Phase 3 SOLSTICE trial. Patients came from 21 SOLSTICE sites across 6 countries; each site randomized ≥3 patients to the maribavir arm. Patients were followed for 52 weeks (SOLSTICE trial period: 20 weeks; follow-up chart review period: 32 weeks). The primary outcomes were mortality and graft status.
RESULTS
Of 234 patients who were randomized and received maribavir in SOLSTICE, chart abstraction was completed for all 109 patients enrolled across 21 trial sites (SOT, 68/142; HCT, 41/92). At 52 weeks, overall mortality was 15.6% (17/109) and survival probability was 0.84. Among SOT recipients, survival probability was 0.96, and 3 (4.4%) deaths occurred during the chart review period. For the HCT recipients, survival probability was 0.65 with 14 (34.1%) deaths; 8 occurred during SOLSTICE and 6 during the chart review period. No new graft loss or re-transplantation occurred during the chart review period.
CONCLUSIONS
Overall mortality at 52 weeks post-maribavir treatment initiation in this sub-cohort of patients from the SOLSTICE trial was lower than that previously reported for similar populations treated with conventional therapies for R/R cytomegalovirus infection.
PubMed: 37657421
DOI: 10.1177/13596535231195431 -
Clinical Infectious Diseases : An... Feb 2023
PubMed: 36617223
DOI: 10.1093/cid/ciac970 -
Molecules (Basel, Switzerland) Oct 2020The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the...
The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure-activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.
Topics: Antiviral Agents; Benzimidazoles; Cell Line; Cytomegalovirus; Glycosylation; Humans; Imidazoles; Nucleosides; Pyridines; Ribonucleosides
PubMed: 33022923
DOI: 10.3390/molecules25194531 -
Frontiers in Microbiology 2023Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs... (Review)
Review
Human cytomegalovirus (HCMV) is one of the main causes of serious complications in immunocompromised patients and after congenital infection. There are currently drugs available to treat HCMV infection, targeting viral polymerase, whose use is complicated by toxicity and the emergence of resistance. Maribavir and letermovir are the latest antivirals to have been developed with other targets. The approval of letermovir represents an important innovation for CMV prevention in hematopoietic stem cell transplant recipients, whereas maribavir allowed improving the management of refractory or resistant infections in transplant recipients. However, in case of multidrug resistance or for the prevention and treatment of congenital CMV infection, finding new antivirals or molecules able to inhibit CMV replication with the lowest toxicity remains a critical need. This review presents a range of molecules known to be effective against HCMV. Molecules with a direct action against HCMV include brincidofovir, cyclopropavir and anti-terminase benzimidazole analogs. Artemisinin derivatives, quercetin and baicalein, and anti-cyclooxygenase-2 are derived from natural molecules and are generally used for different indications. Although they have demonstrated indirect anti-CMV activity, few clinical studies were performed with these compounds. Immunomodulating molecules such as leflunomide and everolimus have also demonstrated indirect antiviral activity against HCMV and could be an interesting complement to antiviral therapy. The efficacy of anti-CMV immunoglobulins are discussed in CMV congenital infection and in association with direct antiviral therapy in heart transplanted patients. All molecules are described, with their mode of action against HCMV, preclinical tests, clinical studies and possible resistance. All these molecules have shown anti-HCMV potential as monotherapy or in combination with others. These new approaches could be interesting to validate in clinical trials.
PubMed: 38053548
DOI: 10.3389/fmicb.2023.1321116