Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients.

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.

Maribavir: Mechanism of action, clinical, and translational science.

Maribavir is an oral benzimidazole riboside for treatment of post-transplant cytomegalovirus (CMV) infection/disease that is refractory to prior antiviral treatment (with or without resistance). Through competitive inhibition of adenosine triphosphate, maribavir prevents the phosphorylation actions of UL97 to inhibit CMV DNA replication, encapsidation, and nuclear egress. Maribavir is active against CMV strains with viral DNA polymerase mutations that confer resistance to other CMV antivirals. After oral administration, maribavir is rapidly and highly absorbed (fraction absorbed >90%). The approved dose of 400 mg twice daily (b.i.d.) achieves a steady-state area under the curve per dosing interval of 128 h*µg/mL and trough concentration of 4.90 µg/mL (13.0 µM). Maribavir is highly bound to human plasma proteins (98%) with a small apparent volume of distribution of 27.3 L. Maribavir is primarily cleared by hepatic CYP3A4 metabolism; its major metabolite, VP44669 (pharmacologically inactive), is excreted in the urine and feces. There is no clinically relevant impact on maribavir pharmacokinetics by age, sex, race/ethnicity, body weight, transplant type, or hepatic/renal impairment status. In phase II dose-ranging studies, maribavir showed similar rates of CMV viral clearance across 400, 800, or 1200 mg b.i.d. groups, ranging from 62.5-70% in study 202 (NCT01611974) and 74-83% in study 203 (EudraCT 2010-024247-32). In the phase III SOLSTICE trial (NCT02931539), maribavir 400 mg b.i.d. demonstrated superior CMV viremia clearance at week 8 versus investigator-assigned treatments, with lower treatment discontinuation rates. Dysgeusia, nausea, vomiting, and diarrhea were commonly experienced adverse events among patients treated with maribavir in clinical trials.

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 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 follow-up. Primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of non-inferiority margin of 7.0%). 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 non-inferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference [95% confidence interval (CI)]: -7.7% [-14.98, -0.36]; 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 [95% CI]: 4.4% [-3.91, 12.76]). With maribavir (versus 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 non-inferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified non-inferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. CLINICAL TRIALS REGISTRATION: NCT02927067 [AURORA].

Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial.

BACKGROUND: Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase. METHODS: In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16. RESULTS: 352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs. CONCLUSIONS: Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).

A Phase 3 open-label study of the efficacy, safety and pharmacokinetics of buccally administered midazolam hydrochloride for the treatment of status epilepticus in pediatric Japanese subjects.

BACKGROUND: In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE. METHODS: A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed. RESULTS: The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation. CONCLUSIONS: The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.

Epidemiology of status epilepticus in the United States: A systematic review.

OBJECTIVES: Convulsive status epilepticus (CSE) is a life-threatening neurologic emergency, which is defined by the International League Against Epilepsy (ILAE) as bilateral tonic-clonic seizure activity lasting longer than 5 min, while absence status epilepticus (SE) and focal SE are specified as exceeding 10 min. Epidemiological evidence on SE is currently lacking, and the incidence is not well-known, especially in light of changes in the ILAE criteria for SE. The objectives of this systematic literature review were to describe the epidemiology of SE in the US population and the associated burden of illness. METHODS: A systematic review, including literature and pragmatic searches, was conducted. Literature searches were performed using MEDLINE, Embase, BIOSIS, and Web of Science electronic databases from inception to February 2019. Pragmatic searches of the gray literature were carried out using Google, Google Scholar, conference proceedings, and ClinicalTrials.gov to identify additional sources. Only US-based studies or multinational studies reporting US data of interest were included. RESULTS: In total, 69 sources were identified. The incidence of all SE in patients of all ages in the USA ranged from 18.3 to 41 per 100,000 people per year. Incidence of all-age CSE rose from 3.5 (1979) to 12.5 (2010) per 100,000 people per year. Status epilepticus incidence followed a bimodal (U-shaped) distribution, with the highest estimates in the first years of life (0-4 years) and after 60 years. Mortality associated with SE varied from 21% over 30 days to 31.2% over 10 years. For CSE, two studies reported similar in-hospital mortalities (9.2% and 10.7%). Median healthcare costs related to SE admission were approximately US$14,500 per adult (17-45 years) and US$8000 per child (0-16 years). CONCLUSIONS: There is a lack of recent data on the epidemiology and healthcare burden associated with SE. Reports of SE incidence in the USA are highly variable and predate the 2015 ILAE definition of SE. However, the available data suggest a high burden of illness.

Burden of disease in patients with a history of status epilepticus and their caregivers.

OBJECTIVE: Status epilepticus (SE) is a life-threatening neurological emergency with the potential for wide-ranging impact on patients and caregivers. In this study, the burden of disease in patients with a history of SE and their caregivers was assessed. METHODS: Adult patients as well as caregivers of children, adolescents, and adults who had experienced ≥1 SE event in the past 24 months completed an online survey. Functional, social, emotional, and economic burden in patients and caregivers was assessed. Burden was measured through concept-targeted questionnaires, including the US Centers for Disease Control and Prevention (CDC) Health-Related Quality of Life 4 (HRQoL-4) and the Work Productivity and Activity Impairment (WPAI) instruments. RESULTS: The 198 respondents comprised 49 adult patients, 51 caregivers of children, 47 caregivers of adolescents, and 51 caregivers of adults. Most patients (93.9%) were diagnosed with epilepsy. Patients' daily activities were highly affected, and many respondents reported a substantial long-term physical and mental impact on patients. The mean CDC HRQoL-4 score for unhealthy days per month ranged from 11.1 for caregivers of adults to 16.9 for caregivers of children. WPAI scores demonstrated a substantial impact on the ability of adult patients and all caregivers to work. Among respondents, caregivers of children reported the highest absenteeism from work (20%) and the lowest employment rate (33%). Proportions of caregivers reporting that their daily social life was impacted at least 'some of the time' ranged from 80% to 92%, with nearly half (47%) of caregivers of children responding that their social life was impacted 'all the time'. CONCLUSIONS: Status epilepticus episodes place a high burden on patients and caregivers. Notably, the burden appeared high across a variety of domains. This study highlights that the burden of disease is pronounced and wide-reaching and goes beyond the immediate physical and medical impact of an SE episode.