Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer’s Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized,Double-Blind,Placebo-Controlled Study

Abstract

Background:

ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer’s disease (AD).

Objective:

This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs).

Methods:

Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS-Cog).

Results:

Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, –1.21; standard error, 0.51; p < 0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache.

Conclusions:

Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

Keywords

ABT-126 Acetylcholinesterase inhibitors alzheimer’s disease dementia nicotinic acetylcholine receptors

INTRODUCTION

Degeneration of cholinergic neurons and the associated reduction in cholinergic activity is believed to be partially responsible for cognitive dysfunction associated with Alzheimer’s disease (AD) [1]. However, only 30% –40% of subjects with mild-to-moderate AD respond to first-line acetylcholinesterase inhibitors (AChEIs), and typically with only clinically modest improvements in cognitive function [2]. In addition, memantine, an add-on therapy for treating AD, which might protect against excessive glutamatergic activity, has generally not demonstrated efficacy in subjects with mild disease and yields only a modest benefit for subjects with moderate disease [3]. Given the devastating effects of AD and the low efficacy of available drugs to treat the condition, there is a clear need for new therapies to treat mild-to-moderate AD to be used alone or in conjunction with AChEIs.

Nicotine is a plant-derived alkaloid known to improve memory, attention, and learning [1, 4]. Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels responsible for mediating the effects of nicotine and endogenous acetylcholine. The α7 nAChRs are highly expressed in the hippocampus and prefrontal cortex, which are brain regions involved in learning, memory, and executive function, and which are affected in AD pathology [1]. The α7 nAChRs may play a role in cognitive impairment associated with AD. In fact, data from several groups indicate that subjects with mild AD exhibit significantly lower levels of cortical and hippocampal nAChRs than healthy controls, and levels of cortical and hippocampal nAChRs correlate with the extent of cognitive dysfunction in subjects with AD [5 –7]. Improvements in cognition have been reported in clinical trials in subjects with mild-to-moderate AD or schizophrenia who received an α7 nAChR agonist, including encenicline (EVP-6124) [8, 9], TC-5619 [10], RG3487 [4, 11], and ABT-126 [12].

ABT-126 is a potent, selective α7 nAChR agonist exhibiting high affinity (K_i = 12 to 14 nM) for human, rat, and mouse α7 nAChRs. The pharmacokinetics, safety, and tolerability of ABT-126 were evaluated in single- and multiple-dose phase 1 studies in various populations (e.g., healthy volunteers, subjects with AD, subjects with schizophrenia). Overall, ABT-126 displayed favorable pharmacokinetics for once-daily administration at doses up to 150 mg and was generally well tolerated across all dosing regimens and populations investigated. In a 12-week, phase 2 proof-of-concept study, 25 mg daily doses of ABT-126 monotherapy demonstrated modest procognitive effects, with a magnitude of improvement slightly less than that observed for the active control, donepezil [12]. Exposure-response analyses of data from that study did not identify a clear plateau of the response, warranting investigation of higher doses to examine if higher efficacy could be achieved. In addition, given the widespread use of AChEIs in patients with mild-to-moderate AD, it is important to understand the efficacy and safety profile of ABT-126 when used as an add-on therapy to AChEIs. This randomized, double-blind, placebo-controlled, phase 2 study (NCT01549834) investigated the efficacy and safety of 25 mg ABT-126 and 75 mg ABT-126 administered once daily for 24 weeks in subjects with mild-to-moderate AD who were taking stable doses of AChEIs. A subsequent open-label extension study (NCT01690195) investigated the long-term safety and tolerability of 75 mg ABT-126 in subjects who completed the randomized study.

METHODS

Subjects

Subjects eligible for inclusion in the study were aged 55–90 y, diagnosed with probable mild-to-moderate AD, as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria (NINCDS/ADRDA), and were taking stable doses of oral donepezil (5–10 mg/day), oral rivastigmine (6–12 mg/day), or transdermal rivastigmine (4.6-mg 24-h patch or 9.5-mg 24-h patch) for at least 90 days before screening and throughout the study. With the exception of AD and the presence of any stable medical conditions, subjects were required to be in general good health, have a Mini-Mental State Examination (MMSE) total score of 12 to 24, a Cornell Scale for Depression in Dementia (CSDD) score of ≤10, and a Modified Hachinski Ischemic Scale score of ≤4. Tobacco users were eligible for the study and did not need to alter their tobacco use habits to participate. Subjects who received galantamine, memantine, or any AD medications other than donepezil or rivastigmine within 60 days before screening were ineligible to participate. Subjects and caregivers voluntarily provided written informed consent as approved by an Institutional Review Board at each study site.

Study design and treatment

Randomized study

This was a phase 2, randomized, double-blind, placebo-controlled, multicenter study (NCT01549834) conducted to evaluate the efficacy, safety, and pharmacokinetics of ABT-126 administered for 24 weeks in subjects with mild-to-moderate AD taking stable doses of AChEIs. Subjects were randomly assigned to receive either 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) orally, once daily for 24 weeks. Subjects were randomized in an equal ratio to the three treatment groups using an interactive voice response or web-based system. Subjects and investigators were blinded to the randomized treatment assignments throughout the study and study drugs were identical in appearance.

Open-label extension study

After completing week 24 of the randomized study, medically stable subjects were eligible to participate in an open-label extension study (NCT01690195) for up to 28 weeks to evaluate the long-term safety and tolerability of ABT-126. Subjects were instructed to take 75 mg ABT-126 once daily; investigators were allowed to adjust the dosage downward in 25-mg increments to address any potential safety or tolerability issues.

Both studies were conducted in accordance with the Good Clinical Practice Guideline (US Code of Federal Regulations, 21 CFR parts, 50, 56, and 312) as defined by the International Conference on Harmonisation, The Declaration of Helsinki, and/or all applicable federal and local regulations and Institutional Review Board requirements, as appropriate. The following methods refer to the randomized study unless indicated otherwise.

Assessments

Efficacy

The primary endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS-Cog). Secondary endpoints included the ADAS-Cog 13-item total score, change from baseline to week 24 in Alzheimer’s Disease Cooperative Study– Activities of Daily Living (ADCS-ADL) total score, Neuropsychiatric Inventory (NPI) total score, Clinician Interview-Based Impression of Severity (CIBIS) score (baseline only), and Clinician Interview-Based Impression of Change– Plus (CIBIC-Plus) score. After evaluating data from the double-blind study, the open-label extension study was terminated prematurely and efficacy analyses were not performed.

Safety

Safety evaluations were performed throughout the study, including electrocardiographic (ECG) evaluations, laboratory assessments, vital sign measurements, physical examinations, brief neurological examinations, brief psychiatric assessments, and analysis of CSDD and Columbia-Suicide Severity Rating Scale (C-SSRS) scores. Subjects were also monitored from the time of study drug administration until 30 days after discontinuation of study drug administration for evidence of adverse events (AEs). All AEs were coded by Medical Dictionary for Regulatory Activities primary system organ class and preferred term. The severity, time course, and relationship to study drug were recorded for each AE.

Pharmacokinetic

Blood samples for pharmacokinetic analyses were collected at weeks 2, 4, 8, 12, 18, and 24, as well as at the last visit for subjects who prematurely discontinued.

Medication compliance

Medication compliance was recorded at each scheduled visit. Subjects taking medications at least 70% of the time were considered compliant. Additionally, plasma concentrations of ABT-126 obtained from pharmacokinetic analyses performed after study completion were used to evaluate study drug compliance.

Statistical analysis

A sample size of approximately 140 subjects per treatment group was calculated to yield at least 80% power to detect a treatment difference of –1.95 between each ABT-126 dose group and the placebo group at a one-sided significance level of 0.05 and standard deviation of 6, assuming that 5% of subjects would have no post-baseline ADAS-Cog 11-item assessment. A one-sided significance level was used to assess the hypothesis that ABT-126 was an improvement over placebo; the hypothesis that placebo was an improvement over ABT-126 was not assessed. The intent-to-treat (ITT) and safety data sets included all randomized subjects who took at least one dose of study drug.

The primary efficacy variable– the change from baseline to week 24 of the ADAS-Cog 11-item total score– was analyzed by a likelihood-based, mixed-effects model for repeated measures (MMRM) using factors of treatment, site, visit, and treatment-by-visit interaction, with baseline score and baseline-by-visit interaction as covariates. The primary efficacy variable was also analyzed by baseline MMSE category subgroups (mild, 20–24; moderate, 12–19) using the same MMRM model described above. Pairwise comparisons of efficacy data were performed between each ABT-126 dose group and the placebo group using one-sided tests at the significance level of 0.05. A one-sided significance level was used to assess the hypothesis that ABT-126 was an improvement over placebo; the hypothesis that placebo was an improvement over ABT-126 was not assessed. No comparisons were made between the two ABT-126 treatment groups.

Subgroup analyses were performed to investigate the impact of MMSE scores (mild, 20–24; moderate, 12–19) and apolipoprotein (ApoE)-ɛ4 allele status (ɛ4 + versus ɛ4–) on ADAS-Cog 11-item total scores and ADCS-ADL scores. Change from baseline to the final observation for the ADAS-Cog 11-item total score for the ITT data set was assessed by analysis of covariance including subgroup variable and treatment group as main effects, a subgroup-by-treatment group interaction term, and baseline ADAS-Cog 11-item total score as a covariate.

In the safety data set, comparisons between each ABT-126 dose group and the placebo group were performed with two-sided tests at the significance level of 0.05. The treatment group differences in continuous safety variables were assessed using an analysis of variance model with the term of treatment, whereas binary safety variables and discontinuation rates were evaluated using Fisher’s exact test. In the open-label study, safety was assessed by combining all subjects, regardless of the treatment received in the double-blind study. Baseline for the open-label study was defined as the last visit of the preceding double-blind study.

Plasma concentrations of ABT-126 for each dose level were combined across all visits in the randomized study. The plasma concentrations were categorized on the basis of time since administration of the previous dose of ABT-126 and summarized statistically.

RESULTS

Subjects

A total of 565 subjects were screened at 43 sites located in Canada, France, Germany, Great Britain, Greece, South Africa, and the United States (Fig. 1). Of the screened subjects, 434 (76.8%) were randomized at 41 sites, located in Canada (n = 57), France (n = 49), Germany (n = 40), Great Britain (n = 56), Greece (n = 79), South Africa (n = 44), and the United States (n = 109), and received at least one dose of study drug. A total of 377 subjects (86.9%) completed the study and 57 (13.1%) prematurely discontinued study drug. The most common reason for discontinuation was an AE; 27 subjects across all treatment arms discontinued study drug due to an AE. There were no significant differences among the treatment groups in the reasons for premature discontinuation.

There were no significant differences across the three treatment arms in baseline subject demographics, ApoE-ɛ4 allele status, MMSE score, and ADAS-Cog 11-item and 13-item total scores (Table 1). Most subjects had never used tobacco or were former users of tobacco; 6.5% of randomized subjects were current users of tobacco and these subjects were equally distributed across the three treatment arms. Donepezil was the most commonly prescribed AChEI and was typically given as daily doses of ≥10 mg/day. Most of the subjects who were treated with concurrent rivastigmine received daily doses of ≥9 mg/day. Concomitant AChEI use (drug and dose) was similar between subjects with mild (MMSE ≤19) or moderate (MMSE ≥20) AD.

Assessments

Efficacy

Neither dose of ABT-126 demonstrated significant improvement compared to placebo on the primary efficacy measure, the change from baseline to week 24 of the ADAS-Cog 11-item total score. At week 24, the adjusted mean (the least squares mean change from baseline, adjusted for pre-specified confounders) for ADAS-Cog 11-item total score was 1.37 for placebo compared with 0.57 for 25 mg ABT-126 (p = 0.087, one-sided) and 1.25 for 75 mg ABT-126 (p = 0.416, one-sided). Over the course of the study, the adjusted mean for ADAS-Cog 11-item total score for the 25 mg ABT-126 group was significant compared with placebo at week 4 (–0.54 versus 0.66; p = 0.010, one-sided) and trended toward significance (p < 0.100, one-sided) at weeks 8 (–0.80 versus 0.11), 18 (0.05 versus 0.98), and 24 (0.57 versus 1.37; Fig. 2A). The adjusted mean for the 75 mg ABT-126 group was not significant compared with placebo at any time point during the study (p > 0.100, one-sided; Fig. 2A).

Subgroup analysis controlling for baseline MMSE score categories showed that the adjusted mean for ADAS-Cog 11-item total score in the mild AD population (MMSE≤19) was significantly improved for 25 mg ABT-126 (p < 0.05, one-sided) compared with placebo at weeks 4 (–0.95 versus 0.68), 8 (–1.08 versus 0.41), 12 (–0.96 versus 0.41), and 24 (–0.62 versus 0.82; Fig. 2B); however, the adjusted mean for ADAS-Cog 11-item total score did not improve for 25 mg ABT-126 or 75 mg ABT-126 compared with placebo in the moderate AD population (MMSE≥20; Fig. 2C). Subgroup analyses indicated that gender, age, country, tobacco use status, and ApoE-ɛ4 allele status had no significant effect on the primary efficacy endpoint, the change in ADAS-Cog 11-item total score from baseline to week 24, for any treatment group (data not shown).

Compared with placebo, there were no significant differences in ADAS-Cog 13-item, ADCS-ADL, or NPI total scores for either ABT-126 treatment groups at week 24 (Table 2). In addition, there was no significant difference in ADCS-ADL total scores change from baseline over time for subjects in the ABT-126 treatment groups compared with those in the placebo group (Fig. 3). However, baseline severity of AD, as assessed by the MMSE, had no significant effect on the change from baseline over time in ADCS-ADL total score across treatment groups.

For CIBIC-Plus, moderate or minimal improvement in severity of dementia at week 24 was reported for 11 subjects (8%) in the 25 mg ABT-126 group, 16 subjects (11.7%) in the 75 mg ABT-126 group, and 24 subjects (16.9%) in the placebo group (Fig. 4). No subjects in the study demonstrated a marked improvement in the severity of dementia. Overall, the proportion of subjects with a final CIBIC-Plus assessment of improved, unchanged, or worsened was not significantly different between ABT-126 dose and placebo.

Safety

At least one AE was reported for 294 subjects (67.7%) in the study. The overall incidence of AEs was similar between the ABT-126 groups (67.7%) and placebo group (67.8%). Most AEs (>90%) were mild or moderate in severity, were not serious, and did not result in premature discontinuation. A significantly higher percentage of subjects in the 75 mg ABT-126 dose group had AEs that were considered to have a reasonable possibility of being related to study drug compared with placebo (p = 0.037, two-sided).

Premature discontinuation of study drug primarily due to AEs was reported for seven subjects (4.9%) in the 25 mg ABT-126 group, 11 subjects (7.6%) in the 75 mg ABT-126 group, and nine subjects (6.2%) in the placebo group. Although there was no significant difference in the percentage of subjects reporting premature discontinuation due to an AE between either ABT-126 group and the placebo group, a significantly higher percentage of subjects in the 75 mg ABT-126 group experienced psychiatric disorders that resulted in premature discontinuation compared with the placebo group (3.4% versus 0%, respectively; p = 0.030, two-sided). These included five subjects in total: One subject with moderate agitation; one subject with moderate visual hallucinations and severe agitation; one subject with mild confusional state; one subject with moderate delirium and moderate disorientation; and one subject with moderate agitation, moderate confusional state, and moderate disorientation.

There were no significant differences in the percentage of subjects experiencing a serious AE across treatment groups: Nine subjects (6.3%) the 25 mg ABT-126 group, 10 subjects (6.9%) in the 75 mg ABT-126 group, and 13 subjects (8.9%) in the placebo group. Serious AEs reported for≥2 total subjects included fall (four subjects), urinary tract infection (three subjects), and hip fracture (three subjects). There were no deaths during the study; however, one subject died due to natural causes exactly 30 days after receiving the last dose of 25 mg ABT-126.

The most common AEs reported by≥5% of subjects receiving ABT-126 were agitation, fall, constipation, headache, and diarrhea (Table 3). A significantly higher percentage of subjects treated with 75 mg ABT-126 reported constipation (p = 0.006, two-sided) and nausea (p = 0.011, two-sided) compared with subjects receiving placebo. There was also a trend for more subjects treated with 75 mg ABT-126 to report dizziness compared with subjects receiving placebo (p = 0.085, two-sided). The majority of constipation events reported by ABT-126– treated subjects were mild to moderate in severity and typically began within the first 2 weeks of treatment, lasting anywhere from a few days up to the end of the study. The majority of nausea events began within the first two months of treatment and lasted from one to 21 days. The severity of the reported nausea events was mild for all subjects in the 25 mg ABT-126 and placebo groups, and mild to severe for subjects in the 75 mg ABT-126 group.

Most AEs were assessed as mild or moderate in severity. No consistent, clinically meaningful mean changes or dose-related trends were observed with ABT-126 in laboratory results, vital sign measurements, ECG tracings, CSDD total scores, or C-SSRS scores.

Pharmacokinetics assessments

The observed ABT-126 mean plasma concentrations for each dose group were in agreement with the predicted pharmacokinetic profiles based on the preceding phase 1 studies (data not shown).

Medication compliance assessments

Analysis of ABT-126 plasma concentrations indicated that nearly all subjects were compliant with ABT-126. No subject had consistently non-measurable ABT-126 concentrations.

Medication compliance recorded at each visit indicated that most subjects (93.1%) were compliant with both the study drug and AChEI at least 70% of the time. Of the subjects who were determined to be non-compliant, six (1.4%) were only compliant with the study drug and 23 (5.3%) were only compliant with the AChEI. There were no significant differences among the treatment groups in the percentage of subjects who were compliant at each visit and at all visits.

Open-label extension study

Of the 377 subjects who completed the randomized study, 343 (91%) were enrolled, and 173 (51%) of the treated subjects (n = 342) completed the open-label extension study (Supplementary Fig. 1). The majority of subjects remained on the 75-mg dose of ABT-126 throughout their participation in the open-label extension study, whereas 13 subjects had their study drug dose reduced to 50-mg or 25-mg. The primary reason for premature discontinuation was early study termination due to lack of efficacy in the randomized study. Nineteen subjects discontinued due to an AE, 13 of which cited it as the primary reason and six cited it as the secondary reason.

A total of 196 (57.3%) subjects reported at least one treatment-emergent AE (TEAE) (Supplementary Table 1). Most TEAEs were mild or moderate in severity. Agitation was the most frequent TEAE leading to discontinuation, reported in three subjects. Thirty subjects (8.8%) had serious AEs; the most frequently reported serious AEs were dehydration (n = 3, 0.9%), cerebral hemorrhage, delirium, hypertension, small intestinal obstruction, urinary tract infection, and vomiting (n = 2 for each, 0.6%). Two deaths were reported after study completion: One subject from natural causes on day 147 (post-treatment day 22) and one subject from renal failure after a Clostridium difficile infection on day 80 (post-treatment day 19). Both events were determined to have no reasonable possibility of being related to study drug.

The most frequently (≥5% subjects) reported TEAEs were fall (7.0%), agitation (5.8%), and constipation (5.6%). Subjects who were naïve to ABT-126 treatment had a higher incidence of constipation than did those who had received ABT-126 previously during the randomized study; of the subjects who continued ABT-126 in the extension study, only one had reoccurring constipation. No apparent trends in the results of individual laboratory assessments, vital sign measurements, ECG tracings, CSDD total scores, or C-SSRS scores were observed.

DISCUSSION

This phase 2, multicenter, randomized, double-blind, placebo-controlled study, and subsequent open-label extension study were the first to investigate the efficacy and safety of ABT-126 as add-on therapy to AChEIs for treating AD. Overall, ABT-126 failed to demonstrate meaningful efficacy across cognitive, functional, and global endpoints, but it was generally safe and well-tolerated at the doses evaluated.

In the double-blind study, subjects treated with 25 mg or 75 mg ABT-126 did not exhibit consistently significant improvement in ADAS-Cog 11-item total score at week 24 or over time from baseline to week 24 as compared to the placebo group. In addition, no significant changes were observed in any of the secondary outcome measures of cognition, function, or global improvement in subjects treated with ABT-126 compared with placebo. The 25-mg dose of ABT-126 significantly improved ADAS-Cog 11-item total scores in the mild AD population at weeks 4, 8, 12, and 24. However, the severity of AD as measured by baseline MMSE had no significant effect on changes from baseline to final ADCS-ADL total score across treatment groups. ApoE-ɛ4 allele status had no effect on efficacy, as measured by ADAS-Cog 11-item total score.

ABT-126 was generally well tolerated in this subject population. Agitation, constipation, diarrhea, fall, and headache were the most common AEs for ABT-126 in the randomized study, but constipation and nausea were the only AEs that occurred more frequently in subjects treated with ABT-126 compared with placebo. Fall, hip fracture, agitation, and apathy were the only serious AEs reported for more than two subjects who received ABT-126. Premature discontinuation did not occur more frequently in subjects who received ABT-126, though there was a significant difference between the 75-mg dose group and placebo in the incidence of psychiatric disorders leading to discontinuation. In the open-label extension study, fall, agitation, and constipation were the most common treatment-related AEs for ABT-126. The most frequently reported serious AEs for subjects who received ABT-126 in the open-label study included cerebral hemorrhage, dehydration, delirium, hypertension, small intestinal obstruction, urinary tract infection, and vomiting. Overall, the safety profile for ABT-126 in the double-blind and open-label extension studies was consistent with safety data previously reported in phase 1 studies and in the phase 2 monotherapy study [12].

ABT-126 demonstrated improvement of 1.19 points on the ADAS-Cog 11-item total score (p =0.095, one-sided) at a 25-mg dose compared with placebo in a previously conducted phase 2 monotherapy proof-of-concept trial, and exposure-response analyses did not exclude the potential that higher doses may provide additional efficacy [12]. The 25-mg dose group in this study demonstrated some efficacy compared with placebo, but the magnitude of the increase did not reach statistical significance and was not considered to represent clinically meaningful improvement. Changes in the 75-mg dose over time were very consistent with those observed in the placebo group, clearly demonstrating that this higher dose did not provide additional efficacy. A subgroup analyses showed consistent results for cognitive assessments among current tobacco users and current nontobacco users in the studies (data not shown). The lack of efficacy observed in this study is not due to non-compliance because observed ABT-126 plasma concentrations were consistent with predicted concentrations based on results from previous pharmacokinetic evaluations of ABT-126.

The lack of efficacy of ABT-126 in this study compared with the evidence of efficacy exhibited in the phase 2 monotherapy proof-of-concept study may be a reflection of the difference in study designs. While the initial phase 2 study was a monotherapy study, this study investigated the effects of ABT-126 as an add-on therapy to AChEIs. Although there are differences in the mechanisms of action for ABT-126 and AChEIs, their effects are both mediated through the cholinergic system. The increase in acetylcholine in the synaptic cleft from AChEIs may result in increased activation of many acetylcholine receptor subtypes, including the α7 nAChR. Thus, ABT-126 stimulation at α7 nAChRs could be at least partially redundant with stimulation achieved through AChEIs. This hypothesis raises the possibility that lower doses of ABT-126 would need to be used in combination with AChEIs than when the drug is used as a monotherapy. However, because the 5-mg dose displayed no improvement relative to placebo as a monotherapy in the phase 2 trial and no trend of improved efficacy was observed in subjects with lower than average ABT-126 plasma concentrations in the current study, this possibility seems unlikely.

Several limitations may have affected the results of the current study. The diagnosis of Alzheimer’s dementia was based on NINCDS/ADRDA criteria, and amyloid positron emission tomography data were not obtained to confirm the presence of cerebral amyloid in study participants. In addition, the evaluation of the differences in treatment outcome based on disease severity, as indicated by MMSE score (mild versus moderate), and on other variables such as gender, age, and country, was limited by the number of subjects in these subgroups.

Based on these data, ABT-126 will not undergo further development as a symptomatic add-on treatment to AChEIs for AD. However, results from several studies investigating α7 nAChR agonists suggest evidence of some procognitive effects for this class of agents, including clinical trials for encenicline [8], TC-5619 [10], and RG3487 [11], and preclinical studies for ABT-107 [13, 14], AZD0328 [15, 16], GTS-21 [17, 18], and SSR180711 [19, 20]. Ongoing randomized, placebo-controlled, phase 3 studies of encenicline (NCT01969123 and NCT01969136) will assess the safety and efficacy of high-dose and low-dose encenicline in subjects with mild-to-moderate AD who are currently or were previously taking stable doses of AChEIs. The results from these studies will provide additional evidence about the utility of the α7 nAChR as a drug target for AD.

Footnotes

ACKNOWLEDGMENTS

This study was supported by AbbVie Inc., North Chicago, Illinois. All authors participated in the study design, research, data collection, and analysis and interpretation of data, as well as writing, reviewing, and approving the manuscript for publication. Elizabeth Cartwright, PharmD, of The JB Ashtin Group, Inc., provided medical writing support.

Authors’ disclosures available online ().

Appendix

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