Abstract
BackgroundResults from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer’s dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25–75 mg) and an open-label extension study (75 mg).MethodsThe randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10–24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale—Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.ResultsA total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (−2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, −0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, −0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, −1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.ConclusionsIn the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.Trial registrationClinicalTrials.gov NCT01527916, Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935. Registered 29 August 2012 (open-label extension study).Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0210-1) contains supplementary material, which is available to authorized users.
Highlights
Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer’s dementia (AD)
A novel approach to symptomatic treatment for AD is modulation of the α7 nicotinic acetylcholine receptors, acetylcholine-gated cation channels found in areas of the brain that are important for learning and memory [2]
The mechanism of action of α7 Nicotinic acetylcholine receptor (nAChR) agonists is expected to differ from marketed compounds such as Acetylcholinesterase inhibitor (AChEI) that inhibit the enzyme which degrades acetylcholine in the synaptic cleft, resulting in an increased effect from acetylcholine at all receptor subtypes
Summary
Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer’s dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. A novel approach to symptomatic treatment for AD is modulation of the α7 nicotinic acetylcholine receptors (nAChRs), acetylcholine-gated cation channels found in areas of the brain that are important for learning and memory [2]. The mechanism of action of α7 nAChR agonists is expected to differ from marketed compounds such as AChEIs that inhibit the enzyme which degrades acetylcholine in the synaptic cleft, resulting in an increased effect from acetylcholine at all receptor subtypes. Several α7 nAChR partial agonists have shown potential in the treatment of AD [6, 7] but either the procognitive effects were not reproducible [8] or the trials are currently on clinical hold, apparently due to safety concerns related to gastrointestinal side effects [9]
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