Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers.

Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.).

Innate, T-, and B-Cell Responses in Acute Human Zika Patients.

Background: There is an urgent need for studies of viral persistence and immunity during human Zika infections to inform planning and conduct of vaccine clinical trials. Methods: In 5 returned US travelers with acute symptomatic Zika infection, clinical features, viral RNA levels, and immune responses were characterized. Results: Two pregnant, flavivirus-experienced patients had viral RNA persist in plasma for >44 and >26 days. Three days after symptom onset, transient increases in proinflammatory monocytes began followed at 5 days by transient decreases in myeloid dendritic cells. Anti-Zika virus immunoglobulin M was detected at day 7 after symptom onset, persisted beyond 103 days, and remained equivocal through day 172. Zika virus-specific plasmablasts and neutralizing antibodies developed quickly; dengue virus-specific plasmablasts and neutralizing antibodies at high titers developed only in flavivirus-experienced patients. Zika virus- and dengue virus-specific memory B cells developed in both flavivirus-naive and -experienced patients. CD4+ T cells were moderately activated and produced antiviral cytokines after stimulation with Zika virus C, prM, E, and NS5 peptides in 4/4 patients. In contrast, CD8+ T cells were massively activated, but virus-specific cells that produced cytokines were present in only 2/4 patients assessed. Conclusions: Acute infections with Zika virus modulated antigen-presenting cell populations early. Flavivirus-experienced patients quickly recalled cross-reactive MBCs to secrete antibodies. Dengue virus-naive patients made little dengue-specific antibody but developed MBCs that cross-reacted against dengue virus. Zika virus-specific functional CD4+ T cells were readily detected, but few CD8+ T cells specific for the tested peptides were found.