Dana Hilt

Normalizing effects of EVP-6124, an α-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia.

Cognitive impairment is a cause of significant disability in patients with schizophrenia. To date, no drug has been approved for this indication by the U.S. Food and Drug Administration. This article presents findings suggesting that a medication targeting the alpha-7 nicotinic acetylcholine receptor (&agr;7 nAChR) might meet this need. This single-center, randomized, parallel-group, double-blind,placebo-controlled study examined 21 medically stable patients with schizophrenia or schizoaffective disorder treated with second generation antipsychotics. Patients were treated with a daily dose of either 0.3 mg (n=8) or 1.0 mg (n=9) of EVP-6124, an &agr;7 nAChR partial agonist, or placebo (n=4). Treatment continued for 21 days while patients continued their usual antipsychotic medication: aripiprazole (10–30 mg/day), olanzapine (10–20 mg/day), paliperidone (3–12 mg/day), or risperidone (2–16 mg/day). Cognitive test performance, eventrelated electroencephalographic (EEG) potentials, clinical symptoms, laboratory values, and clinical side effects were measured. EVP-6124 was well tolerated and showed positive, and in some cases, dose-dependent effects on several EEG responses, especially the Mismatch Negativity and P300 potentials. Positive effects were also found in performance on cognitive tests that measured non-verbal learning, memory, and executive function. This study is an example of the type of early proof of concept trial that is done to enable drug developers to evaluate whether to continue research on an agent. Based on the promising findings in this study, larger phase II studies were initiated to further test the pro-cognitive effects of EVP-6124 in patients with chronic schizophrenia. Clinical Trials Registration: Safety, Tolerability, and Pharmacokinetic Study of EVP-6124 in Patients with Schizophrenia, NCT01556763 http://clinicaltrials.gov/ct2/show/NCT01556763?term=NCT01556763&rank=1 (Journal of Psychiatric Practice 2014;20:12–24)

Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Encenicline, a Selective α7 Nicotinic Receptor Partial Agonist, in Single Ascending-dose and Bioavailability Studies

PURPOSE Encenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimers disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. METHODS A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FINDINGS In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (mean range 0.59-100 ng/mL) and AUC0-∞ (mean range 45.6-8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. IMPLICATIONS Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.

Direct binding studies of 125I-α-bungarotoxin and 3H-quinuclidinyl benzilate interaction with axon plasma membrane fragments. Evidence for nicotinic and muscarinic binding sites

Abstract The attachment of 125 I-α-bungarotoxin (BgTx) which is reportedly bound exclusively to “nicotinic” acetylcholine receptors, as well as 3 H-atropine and 3 H-3-quinuclidinyl benzilate (QNB), which reportedly bind exclusively to “muscarinic” receptors, was measured in isolated lobster axon plasma membrane fragments and in the soluble axonal protein fraction. 125 I-α-BgTx binding was also measured in lysolecithin-solubilized fragments. Binding assays were adapted for these studies and are described in detail. High affinity, saturable binding of all three ligands to membrane fragments was observed, as well as binding of BgTx to a macromolecule present in both the soluble fraction and the membrane fragments. These experiments provide the first evidence for the very tight binding of both “nicotinic” and “muscarinic” ligands in peripheral nerve.

Concanavalin A-Sepharose Affinity Chromatography of Axon Plasma Membrane Proteins. Heterogeneity of Cholinergic Binding Sites

Abstract: Lysolecithin‐solubilized proteins from axon plasma membranes of lobster walking leg nerve bundles were chromatographed on concanavalin A (Con A)‐sepharose. Bound glycoproteins were eluted with α‐methyl‐D‐ mannoside. Near quantitative recovery of total protein was observed, 20–30% of the total protein being eluted in the Con A‐binding glycoprotein fraction. A 5‐fold enrichment of acetylcholinesterase (AChE) activity was achieved, demonstrating the glycoprotein nature of the axonal enzyme. The chromatographed fractions were characterized for binding of [3H]quinuclidinyl benzilate (QNB), [3nicotine (Nic), and [1251]α‐bung arotoxin (BgTx) in an attempt to distinguish possible “muscarinic” and “nicotinic” binding sites in axonal membranes. All of the high‐affinity “muscarinic” [3H]QNB binding activity appeared in the non‐Con A‐binding protein fractions, while binding of the two “nicotinic” ligands, [3Nic and 125I‐BgTx, was found in both the glycoprotein and non‐Con A‐binding protein fractions. BgTx interaction with the Con A‐binding glycoproteins could be blocked with dtubocurarine, but BgTx binding in the non‐Con A‐binding proteins was not inhibited by curare. The significance of multiple cholinergic binding sites in axonal membranes is discussed. These data suggest a closer similarity between the cholinergic ligand binding proteins of peripheral nerve membrane and ganglia than between the axonal cholinergic binding sites and the ACh receptor of the neuromuscular junction.

EVP-6124, a selective alpha-7 partial agonist, has positive effects on cognition and clinical function in mild-to-moderate Alzheimer's disease patients: Results of a six-month, double-blind, placebo controlled, dose ranging study

62% were female. 57 participants were evaluated at the 6 week final visit, with 50 participants completing 6 weeks of treatment with study drug. Adherence was very good with 95% of pill bottles returned and 88% of pills being taken according to pill counts. After 6 weeks mean (SD) change in AES scores were -1.9 (1.5) for Met vs. 0.6 (1.4) for Plb (p1⁄40.23). The odds ratio (95% CI) for improvement in CGI-C was 3.7 (1.3, 10.8) (p1⁄40.02), with 21% of Met vs. 3% of Plb rated as moderately or markedly improved. The improvement in NPI Apathy scores was 1.8 points (95% CI 0.3, 3.4) greater in Met vs. Plb (p1⁄40.02). Met treatment was well tolerated with a trend toward greater anxiety and weight loss > 2% in Met vs. Plb. Conclusions: In this proof-of-concept trial Met treatment of apathy in AD was associated with significant improvement in two of three preplanned outcomes, with a third outcome favoring. These results support the efficacy of Met treatment for apathy in AD and warrant a definitive, hypothesis-testing randomized controlled trial.

Validation of a novel cognitive composite assessment for mild and prodromal Alzheimer's disease

PBO and 20 hours post-dose for MOX at the time points of pharmacokinetic sample collection. Standard safety monitoring was conducted throughout the study. Plasma EVP-6124 and metabolite concentrations were determined with a validated assay. Effects of EVP-6124 and MOX on ECG were assessed by central tendency (PBOand baseline-adjusted individual-corrected QT derived from triplicate means; QTcI), categorical, and morphologic analyses. Results: EVP-6124 was well-tolerated and 52 subjects completed the study. The majority of treatment-emergent adverse events were mild in severity and no apparent trends or clinically meaningful changes were observed from baseline in clinical laboratory tests results or vital signs measurements. MOX caused a QT prolongation with the lower bound of the one-sided 95%CI for QTcI change above 5 ms, thereby validating the study design and conduct. The maximum upper bound of the one-sided 95% CI for EVP-6124 change in QTcI was 3.4 ms. Similar results were observed with QTcF analysis. No EVP-6124 effect on categorical or morphologic analyses was observed. No relationship between EVP-6124 or metabolite exposure and QTcI change was observed. Conclusions: EVP-6124 was well-tolerated and did not delay cardiac repolarization in healthy subjects at supratherapeutic exposures.

EVP-6124, an alpha7 nicotinic acetycholine receptor partial agonist, did not delay cardiac repolarization in healthy subjects

Vital signs X X Clinical laboratory X X Clinical measures X 12-lead ECG X X X X X Drug administration X PK blood sampling X X X X X X X X X standardized breakfast X Pupil size X X X X X Neuro-endocrine X X X X X plasma IGF-1/IGFBP3 X X Eye movements X X X X X Adaptive tracking X X X X X Simple reaction time X X X X X Visual analogue scales X X X X X Pharmaco-EEG X X X X X X X X Stroop test X X X X X VVLT-15 X——————————————————X N-back X X X X X Facial recognition task X X

Population pharmacokinetic modeling of EVP-6124 following oral administration

Vital signs X X Clinical laboratory X X Clinical measures X 12-lead ECG X X X X X Drug administration X PK blood sampling X X X X X X X X X standardized breakfast X Pupil size X X X X X Neuro-endocrine X X X X X plasma IGF-1/IGFBP3 X X Eye movements X X X X X Adaptive tracking X X X X X Simple reaction time X X X X X Visual analogue scales X X X X X Pharmaco-EEG X X X X X X X X Stroop test X X X X X VVLT-15 X——————————————————X N-back X X X X X Facial recognition task X X

Circadian rhythms in cognitive functioning: Impact on signal detection in clinical trials of pro-cognitive therapies

(p1⁄40.648). The 3 month difference of PSQI inMT group (-0.716 2.09) was significantly better than control group (1.13 6 1.73)(p1⁄40.011). Further adjusting by gender, age, education level and corresponding baseline measures, we found adjusted differences of MMSE, CASI, NPI and PSQI in MT group were slightly better than those in control group without statistical significance.Conclusions:AD patients usually had poor sleep quality. No apparently additional benefits of this MT were noted on these globally cognitive, neuropsychiatric and sleep quality assessments in AD for 3 months. Potentially, this MT might have promising effects on sleep quality and cognition in AD after 3 more months. It remains further investigation to understand the MT effect on cognition domains and other sleep dimensions in AD.