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.).

A randomized, placebo-controlled phase I trial of live, attenuated herpes zoster vaccine in subjects with end-stage renal disease immunized prior to renal transplantation.

BACKGROUND: Solid organ transplant recipients are at increased risk for reactivation of herpes zoster, or shingles, and have a higher frequency of serious complications including post-herpetic neuralgia. A live, attenuated shingles vaccine is effective and approved for individuals 50 years and older. The vaccine is contraindicated following transplantation, but may be used in patients with renal failure. Utilization of the vaccine has been poor in patients with end-stage renal disease, including those awaiting transplant, owing to concerns for safety, efficacy, and potential sensitization prior to transplant. METHODS: We conducted a phase I, randomized, placebo-controlled study of the safety and immunogenicity of live, attenuated Oka strain shingles vaccine in subjects prior to or awaiting renal transplant at 3 US centers. Subjects received vaccine a minimum of 4 weeks prior to transplant. RESULTS: The vaccine was safe and well-tolerated. There were no cases of herpes zoster or rash illness. There was no change in donor-specific antibody or calculated panel reactive antibody after vaccination during the follow-up period. There were no rejection episodes. There was a significant 2.1-fold rise in geometric mean titer of anti-VZV antibody at 5 weeks post-vaccine. CONCLUSIONS: The data suggest that the shingles vaccine is safe in subjects with ESRD awaiting transplant. Antibody responses were similar to those seen previously in adults >50 years of age and are consistent with a protective response.

An observer blinded, randomized, placebo-controlled, phase I dose escalation trial to evaluate the safety and immunogenicity of an inactivated West Nile virus Vaccine, HydroVax-001, in healthy adults.

BACKGROUND: West Nile virus (WNV) is the most common mosquito-borne infection in the United States. HydroVax-001 WNV is a hydrogen peroxide inactivated, whole virion (WNV-Kunjin strain) vaccine adjuvanted with aluminum hydroxide. METHODS: We performed a phase 1, randomized, placebo-controlled, double-blind (within dosing group), dose escalation clinical trial of the HydroVax-001 WNV vaccine administered via intramuscular injection. This trial evaluated 1 mcg and 4 mcg dosages of HydroVax-001 WNV vaccine given intramuscularly on day 1 and day 29 in healthy adults. The two dosing groups of HydroVax-001 were enrolled sequentially and each group consisted of 20 individuals who received HydroVax-001 and 5 who received placebo. Safety was assessed at all study days (days 1, 2, 4 and 15 post dose 1, and days 1, 2, 4, 15, 29, 57, 180 and 365 post dose 2), and reactogenicity was assessed for 14 days after administration of each dose. Immunogenicity was measured by WNV-specific plaque reduction neutralization tests (PRNT50) in the presence or absence of added complement or by WNV-specific enzyme-linked immunosorbent assays (ELISA). RESULTS: HydroVax-001 was safe and well-tolerated as there were no serious adverse events or concerning safety signals. At the 1 mcg dose, HydroVax-001 was not immunogenic by PRNT50 but elicited up to 41% seroconversion by WNV-specific ELISA in the per-protocol population (PP) after the second dose. At the 4 mcg dose, HydroVax-001 elicited neutralizing antibody responses in 31% of the PP following the second dose. In the presence of added complement, PRNT50 seroconversion rates increased to 50%, and 75% seroconversion was observed by WNV-specific ELISA. CONCLUSIONS: The HydroVax-001 WNV vaccine was found to be modestly immunogenic and well-tolerated at all dose levels.

Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

BACKGROUND: Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development. METHODS: CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens. RESULTS: 402 CMV seronegative subjects were vaccinated (195 vaccine, 207 placebo). The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group. The vaccine induced gB antibody in all vaccine recipients with a gB geometric mean titer of 13,400 EU; 95%CI 11,436, 15,700, after 3 doses. Overall, 48 CMV infections were detected (21 vaccine, 27 placebo). In the per protocol population (124 vaccine, 125 placebo) vaccine efficacy was 43%; 95%CI: -36; 76, p=0.20. The most significant difference was after 2 doses, administered as per protocol; vaccine efficacy 45%, 95%CI: -9; 72, p=0.08. CONCLUSION: The vaccine was safe and immunogenic. Although the efficacy did not reach conventional levels of significance, the results are consistent with a previous study in adult women (Pass et al. N Engl J Med 2009;360:1191) using the same formulation.