Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers.

BACKGROUND: The FG loop peptide (FGL(L)), a novel mimetic of the neural cell adhesion molecule (NCAM), is in clinical development for neurodegenerative disorders such as Alzheimer's disease. Preclinical studies in rats, dogs and monkeys have demonstrated exposure in plasma and cerebrospinal fluid after parenteral or intranasal administration of FGL(L), with no systemic toxicity. This article reports on the results of the first administration of FGL(L) in humans. OBJECTIVE: To determine the tolerability, safety and pharmacokinetics of ascending, single intranasal doses of FGL(L) 25, 100 and 200mg in healthy subjects. METHODS: In an 8-day, open-label, phase I study, 24 healthy male volunteers (mean age 42 [range 24-55] years) received single intranasal doses of FGL(L) (25, 100 and 200mg) in accordance with an ascending dose, sequential-cohort design. RESULTS: All three intranasal doses of FGL(L) were well tolerated and there were no clinical notable abnormalities in ECG recordings, vital signs or laboratory tests. Three subjects (13%) reported five adverse events. A transient (<3 minutes) burning sensation in the nose was reported in two subjects at the 200mg dose level while runny eyes (<2 minutes) were experienced in one subject at 25mg. These events had an onset immediately following intranasal administration, and a relationship to FGL(L) was suspected. One of the latter subjects who had experienced a burning sensation in the nose also experienced dizziness, vomiting and headache with onset >2 days after single-dose administration of FGL(L); no relationship to the study drug was suspected. Quantifiable plasma concentrations of FGL(L) were observed up to 1 hour after intranasal administration of the 100mg dose and up to 4 hours after the 200mg dose (plasma FGL(L) concentrations were undetectable at all timepoints for the 25mg dose). Increasing doses of FGL(L) were associated with higher systemic exposures: mean C(max) 0.52 ng/mL and 1.38 ng/mL (100mg and 200mg, respectively); mean AUC(24) 1.27 ng x h/mL and 4.05 ng x h/mL (100mg and 200mg, respectively). CONCLUSIONS: Intranasal administration of FGL(L) (25, 100 and 200mg) was well tolerated in healthy male volunteers, with no safety concerns and a pharmacokinetic profile that was generally dose related. Further studies are currently being planned to evaluate the effects of FGL(L) in patients with Alzheimer's disease.

Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist.

Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65 years) dosed once daily for 30 days either with 30 mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123.

Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults.

BACKGROUND: Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE: This study examined the safety and immunogenicity in adults of three doses of a pneumococcal single-antigen protein vaccine candidate formulated with aluminum hydroxide adjuvant and recombinantly derived, highly detoxified, genetically mutated pneumolysin protein (PlyD1). METHODS: This phase I, randomized, placebo-controlled, observer-blinded, dose-escalating study enrolled adults (18-50 years). In a pilot safety study, participants received a single injection of 10 µg PlyD1 and were observed for 24 h. Following review of the pilot safety data, participants were randomized (2:1) to receive two injections of PlyD1 at one of three doses or placebo 30 days apart. Assignment of second injection and successive dose cohorts was made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site reactions, solicited systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included geometric mean concentrations of anti-PlyD1 IgG as determined by ELISA and functional assessment in an in vitro toxin neutralization assay. RESULTS: The study included a total of 100 participants, including 10 in the pilot study and 90 in the randomized study. None of the participants in the pilot study had SAEs, allergic reactions, or other safety concerns. Ninety participants received two doses of or placebo (n=30) or active vaccine candidate at 10 (n=20), 25 (n=20), or 50 µg (n=20). No vaccine-related SAE or discontinuation due to an AE occurred. Most solicited reactions were mild and transient. The most frequently reported solicited reactions were pain at the injection site and myalgia. Antigen-specific IgG levels and functional activity showed dose-related increases. When comparing the three dose levels, a plateau effect was observed at the 25 µg dose. CONCLUSIONS: All dose levels were safe and immunogenic. Repeat vaccination significantly increased the level of anti-PlyD1 antibodies. Functional antibody activity was demonstrated in sera from vaccinated individuals (ClinicalTrials.gov no. NCT01444352).

Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults.

BACKGROUND: Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE: To explore safety and immunogenicity of a recombinant protein vaccine candidate against S. pneumoniae composed of adjuvanted pneumococcal histidine triad protein D (PhtD). METHODS: This phase I, exploratory, open-label, single-center clinical study enrolled adults (18-50 years). Participants in a pilot safety cohort received a single intramuscular injection of 6 µg. Following safety review, 3 dose cohorts were enrolled (6, 25, and 100 µg); participants received 2 injections administered approximately 30 days apart. Assignment of the second injection and successive dose cohorts were made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events, serious adverse events, and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD antibodies as measured by ELISA. RESULTS: Sixty-three participants were enrolled and received the pilot safety dose (n=3) or at least 1 dose of PhtD vaccine candidate at 6 µg (n=20), 25 µg (n=20), or 100 µg (n=20). No safety concerns were identified. No vaccine-related serious adverse event was reported. The most common solicited injection site reaction was pain and most common solicited systemic reactions were myalgia and headache; most reactions were mild and transient. Observed geometric mean concentrations (95% CI) were 200.99 ELISA units (148.46, 272.10), 352.07 (193.49, 640.63), and 699.15 (405.49, 1205.48) post-injection 1 in the 6, 25, and 100 µg dose cohorts, respectively, and 378.25 (275.56, 519.21), 837.32 (539.29, 1300.04), and 1568.62 (1082.92, 2272.16) post-injection 2. CONCLUSIONS: All dose levels were safe and immunogenic. The frequency of solicited reactions was highest at the 100 µg dose. Administration of a second injection significantly increased the levels of anti-PhtD antibodies (ClinicalTrials.gov registry no. NCT01444001).

Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine.

BACKGROUND: Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae. OBJECTIVE: To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations. METHODS: This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 µg) or PhtD-PcpA (10 µg each), participants in the main study received AH-adjuvanted PcpA (25 µg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 µg each), unadjuvanted PhtD-PcpA (25 µg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA). RESULTS: Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 µg dose was observed as measured by geometric mean concentrations and by fold increases. CONCLUSIONS: Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339).