Brendon Binneman

A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression.

OBJECTIVE The corticotropin-releasing hormone (CRH) system is implicated in the pathogenesis of several psychiatric disorders, including major depressive disorder. This study was designed to evaluate the safety and efficacy of CP-316,311, a selective nonpeptide antagonist of corticotropin-releasing hormone type 1 (CRH(1)) receptors, in the treatment of recurrent major depressive disorder. METHOD Of a total of 167 patients with recurrent major depression who were screened, 123 were randomly assigned to receive 400 mg of CP-316,311 twice daily, or 100 mg of sertraline daily, or placebo in a 6-week fixed-dose, double-blind, double-dummy, parallel-group, placebo- and sertraline-controlled trial. The primary efficacy analysis compared the change in score from baseline to endpoint on the 17-item Hamilton Depression Rating Scale (HAM-D) between the CP-316,311 and placebo groups. A group sequential design was used to support early trial termination based on efficacy or futility at a planned interim analysis. RESULTS The evaluable data set for the interim analysis included 28 patients in the CP-316,311 group, 31 patients in the placebo group, and 30 patients in the sertraline group. In the interim analysis, the change from baseline in the HAM-D score at the final visit was not significantly different between the CP-316,311 and placebo groups, while change from baseline between the sertraline and placebo groups was significantly different. Given these results, futility was declared for CP-316,311 and the trial was terminated. CONCLUSIONS Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE PF-04360365 is a humanized IgG(2)Δa anti-amyloid β (Aβ) antibody designed to improve outcome in Alzheimers disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aβ species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

Cerebral metabolic effects of intravenous glycine in healthy human subjects

Enhancing N-methyl-D-aspartate (NMDA) receptor function via increasing synaptic concentrations of glycine is currently investigated as a novel approach to treat schizophrenia. The neural correlates of enhanced NMDA receptor function in humans, however, are unclear to date. The present study determines the effects of intravenous administration of the glycine on regional cerebral metabolic rate of glucose (rCMRGlu) in healthy control subjects by using [18F]fluorodeoxyglucose and positron emission tomography and on neuropsychological behavioral measures. Thirteen healthy volunteers were recruited, and 12 subjects completed the protocol. These individuals participated in 1 magnetic resonance imaging study and 2 [18F]fluorodeoxyglucose positron emission tomography studies. In a double-blind, randomized, controlled, crossover design, participants received on one test day an intravenous glycine infusion and on the other test day a placebo infusion. There were no significant behavioral and neuropsychological effects of glycine compared with placebo. However, there was a significant reduction of whole-brain CMRGlu during administration of glycine compared with placebo (t = 2.60, df = 11, P = 0.023). In the a priori-selected regions of interest, there was a significant reduction in the cerebellum (t = −3.18, df = 11, P = 0.009) and the dorsolateral prefrontal cortex (t = −2.31, df = 11, P = 0.041). When corrected for whole-brain CMRGlu, rCMRGlu differences were not significant. This study suggests that studies of whole-brain cerebral metabolism may be useful for studying glycine-related mechanisms in healthy humans because there is not a clear cognitive or behavioral signal related to glycine administration at doses thought to be important clinically in patient populations.

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

BackgroundSymptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.ResultsAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).ConclusionsSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists.Trial registrationClinicaltrials.gov, NCT01712074. Registered 19 October 2012.

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study

The safety, pharmacokinetics, and effect on peripheral and central amyloid β (Aβ) of multiple doses of ponezumab, an anti‐Aβ monoclonal antibody, were characterized in subjects with mild‐to‐moderate Alzheimers disease treated for 1 year.

Evaluation of the use of the Scale for the Assessment and Rating of Ataxia (SARA) in healthy volunteers and patients with schizophrenia

OBJECTIVE The Scale for the Assessment and Rating of Ataxia (SARA) is a semi-quantitative assessment used to evaluate ataxia. The goal of these studies was to assess and evaluate the utility of this instrument in a Healthy Volunteer (HV) group and subjects with Schizophrenia (SCZ). METHODS Two studies were completed to collect SARA data, in a HV group and in a stable SCZ group. 177 HVs (18-65 years) and 16 SCZs (18-58 years) provided written consent and were assessed using the SARA. Of 177 HV subjects, 88 had 2 SARA assessments (within 2 days of initial visit) while all 16 SCZ had 3 SARA assessments (within 14 days of initial visit). RESULTS For the HV group, the mean score ± Std for the SARA on visit-1 was 0.39 ± 0.72, and 0.34 ± 0.64 for visit-2. The Pearson correlation coefficient between visit-1 and visit-2 was 0.7486 and an ICC of 0.743. For the SCZ group, the mean score for the SARA was 0.63 ± 0.65 on visit-1, 0.84 ± 1.19 on visit-2, and 0.84 ± 0.94 on visit-3. The Pearson correlation coefficient between visit-1 and visit-2 was 0.6545, between visit-1 and visit-3 was 0.6635 and between visit-2 and visit-3 was 0.7613 and an ICC of 0.650. There was no significant difference in baseline SARA scores between the HV and SCZ group p = .063. A statistically significant positive association between age and total SARA scores was observed in HV (r = 0.345) and SCZ (r = 0.676). CONCLUSIONS A strong association was observed in both the HV and SCZ groups in the reassessment of signs of ataxia using the SARA scale. Both groups demonstrated minimal signs of ataxia, with no statistically significant difference between the two groups in their visit-1 scores.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy

Multiple intravenous doses of ponezumab, an anti‐amyloid antibody, were evaluated in subjects with mild‐to‐moderate Alzheimers disease (AD).