Neuropsychopharmacology (2016) 41, 2893–2902 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org The ɑ7 Nicotinic Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia in Nonsmokers: Results from a Randomized Controlled Phase 2b Study ,1 1 1,2 1 George Haig* , Deli Wang , Ahmed A Othman and Jun Zhao 1 2 Abbvie Inc., North Chicago, IL, USA; Faculty of Pharmacy, Cairo University, Cairo, Egypt A double-blind, placebo-controlled, parallel-group, 24-week, multicenter trial was conducted to evaluate the efficacy and safety of 3 doses of ABT-126, an α7 nicotinic receptor agonist, for the treatment of cognitive impairment in nonsmoking subjects with schizophrenia. Clinically stable subjects were randomized in 2 stages: placebo, ABT-126 25 mg, 50 mg or 75 mg once daily (stage 1) and placebo or ABT-126 50 mg (stage 2). The primary analysis was the change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score for ABT-126 50 mg vs placebo using a mixed-model for repeated-measures. A key secondary measure was the University of California Performance-based Assessment-Extended Range (UPSA-2ER). A total of 432 subjects were randomized and 80% (344/431) completed the study. No statistically significant differences were observed in either the change from baseline for the MCCB neurocognitive composite score (+2.66 [ ± 0.54] for ABT-126 50 mg vs +2.46 [ ± 0.56] for placebo at week 12; P40.05) or the UPSA-2ER. A trend for improvement was seen at week 24 on the 16-item Negative Symptom Assessment Scale total − ± − ± = score for ABT-126 50 mg (change from baseline 4.27 [0.58] vs 3.00 [0.60] for placebo; P 0.059). Other secondary analyses were generally consistent with the primary end point results. Adverse event rates were similar for ABT-126 and placebo. ABT-126 did not demonstrate a consistent effect on cognition in nonsmoking subjects with schizophrenia; however, a trend toward an effect was observed on negative symptoms. ClincalTrials.gov registration: NCT01655680. Neuropsychopharmacology (2016) 41, 2893–2902; doi:10.1038/npp.2016.101; published online 10 August 2016 INTRODUCTION The nicotinic acetylcholine receptor (nAChR) system has been studied as a possible target to improve cognition in Nearly all patients with schizophrenia are compromised in schizophrenia and other cognitive disorders. The procogni- their ability to function in the community due to cognitive tive effects of nicotine have been known for some time; impairment (Keefe et al, 2005). This is in addition to the however, addictive properties, short duration of action, and effects associated with positive, negative, and mood symp- development of tachyphylaxis limit its utility as a therapeutic toms. Whereas the severities of other core symptoms of the agent (Harris et al, 2004). Of the possible nAChR targets, the disease vary and are typically episodic, cognitive impairment α7 receptor has been one of particular interest in terms of is persistent throughout the course of illness, with a fairly drug development for the treatment of schizophrenia-related consistent level of severity. Cognitive impairment com- cognitive impairment. People with schizophrenia have mences prior to the onset of the other symptom domains decreased expression of brain α7 nAChRs, and these deficits and, with the exception of focused remediation therapy, is are most prominent in the hippocampus, frontal cortex, and not amenable to treatments in the long term (Bowie and thalamus (Freedman et al, 1995; Guan et al, 1999; Levin and Harvey, 2005; Green et al, 2004). Rezvani, 2007). The decreased expression of α7 receptors has led to speculation that smoking is self-medication for *Correspondence: Dr G Haig, AbbVie Inc., R48B/Bldg. AP4-1, 1 North cognitive impairment (Levin and Rezvani, 2007). Waukegan Rd., North Chicago, IL 60064, US, Tel: +847 938 1900, Fax: A number of α7 nAChR agonists have been developed and +847 937 0745, E-mail: [email protected] tested in the clinic, including GTS-21, encenicline, TC-5619, Previously presented at the International Congress on Schizophrenia and RG3487, with positive or mixed results (Keefe et al, 2015; Research, Colorado Springs, CO March 28—April 1, 2015. Work was performed at AbbVie Inc., 1 North Waukegan Rd., North Chicago, Lieberman et al, 2013; Olincy et al, 2006; Umbricht et al, IL 60064, USA. 2014). A possible interaction between nicotinic receptor Received 9 March 2016; revised 23 May 2016; accepted 12 June 2016; ligands such as α7 agonists and nicotine has been observed. accepted article preview online 20 June 2016 First reported by Freedman et al (1995), it was thought that ABT-126 for cognition in schizophrenia nonsmokers G Haig et al 2894 chronic exposure to nicotine results in nicotinic receptor Figure S1). Subjects returned at weeks 1, 2, 4, 6, 8, 10, 12, 14, desensitization (Freedman et al, 1995). Many of the trials 16, 18, 20, 22, and 24. There were 2 stages of randomization involving nicotinic compounds either excluded patients who in the study. During stage 1, 279 subjects were randomized in smoke or, if allowed to participate, required smoking a 1 : 1 : 1 : 1 ratio to ABT-126 25 mg, 50 mg, 75 mg, or restrictions during the cognition testing period (AhnAllen matching placebo. Using pre-established decision rules that et al, 2008; Freedman et al, 2008; Harris et al, 2004; Myers considered estimated effect sizes and their predictive et al, 2004; Smith et al, 2006). probabilities of success as well as safety/tolerability for each ABT-126 is a potent and selective α7 nAChR agonist that dose group, an independent, unblinded efficacy data has exhibited high affinity for the α7 nAChR in nonclinical monitoring committee (DMC) used interim data to select studies, and demonstrated efficacy in animal models relevant the dose of ABT-126 for use in stage 2 of the study. An to cognitive impairment associated with schizophrenia. additional 153 subjects were subsequently randomized in a ABT-126 was well tolerated in phase 1 studies, has a 1 : 1 ratio to ABT-126 or placebo. Randomization was pharmacokinetic half-life that supports once-daily dosing, conducted via an interactive voice-response/web-based and is virtually devoid of drug-drug interaction liabilities. We system using a randomization schedule provided by the have previously reported the results of a 12-week, placebo- sponsor. controlled study of ABT-126 in 207 subjects with schizo- phrenia who were clinically stable (Haig et al, 2016). In the Subjects overall analysis, a dose-related trend toward an effect of ABT-126 on cognitive improvement was observed. In a Eligible subjects were men and women between 20 and 65 subgroup analysis by smoking status, we observed that years of age with a current diagnosis of schizophrenia who ABT-126 10 and 25 mg once daily had an apparent dose- were receiving stable doses of 1 to 2 allowed antipsychotics. related effect on the primary end point, the Measurement Subjects were clinically stable and had a diagnosis of and Treatment Research to Improve Cognition in Schizo- schizophrenia for ⩾ 2 years prior to screening. Stability phrenia (MATRICS) Consensus Cognitive Battery (MCCB) criteria included no psychiatric inpatient hospitalization or (Kern et al, 2008; Nuechterlein et al, 2008) composite score, destabilization within the previous 4 months, no symptom- in nonsmokers, with a Cohen’s d effect size of 40.80 in the related changes in psychotropic medications within 8 weeks highest dose group. In smokers, there was no treatment effect prior to baseline, no changes in medications within 4 weeks observed at any dose. A trend toward significance was also prior baseline, core positive symptoms no worse than noted among nonsmokers on the University of California moderate in severity, extrapyramidal symptoms (EPS) no San Diego Performance-based Skills Assessment (UPSA-2) worse than mild in severity, and no evidence of a major (Patterson and Goldman, 2005). depressive episode. Eligible subjects were current nonsmo- As a follow-up to that study, we conducted a dose-ranging kers, meaning they had not smoked on a regular basis for study in nonsmokers with schizophrenia that utilized higher ⩾ 3 months. Nonsmoking status was confirmed with urine ABT-126 doses to better understand the dose-response cotinine tests prior to and at several visits following relationship and assess the durability of effect. Estimates on randomization. Participants were otherwise healthy based smoking rates in the schizophrenia population vary, but the on their medical history, physical examination, vital signs, consensus is that the majority of them smoke (de Leon and laboratory testing, and a 12-lead electrocardiogram (ECG). Diaz, 2005). Nevertheless, a treatment to improve cognition Subjects with potential or known risk factors for Torsades de in a subset of the patient population would be considered a Pointes, a clinically significant abnormal ECG, or an ECG major advancement. with a prolonged QT interval were excluded. Other major exclusion criteria included a history of substance abuse, evidence of suicidality or violent ideation, hepatitis or HIV MATERIALS AND METHODS infection, and body mass index (BMI) 445 kg/m2 or body 4 Study Design weight 145 kg. Participants remained on their baseline antipsychotic The objective of this study was to evaluate the efficacy and regimen during the entire study. Most typical and atypical safety of ABT-126 in treating cognitive impairment in antipsychotics were permitted. Anticholinergics were al- subjects with schizophrenia who were clinically stable, lowed during the study; however, they had to be at stable receiving antipsychotic medications, and did not currently doses and were not to be taken within 12 hours prior to smoke. Protocols, amendments, and informed consent forms protocol-specific cognitive testing. Mood stabilizers, sertin- were approved by institutional review boards and indepen- dole, iloperidone, chlorpromazine, pimozide, thioridazine, dent ethics committees.