ABT-126 monotherapy in mild-to-moderate Alzheimer’s dementia: randomized double-blind, placebo and active controlled adaptive trial and open-label extension

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.

Curcumin intervention for cognitive function in different types of people: A systematic review and meta‐analysis

“…Furthermore, according to docking calculations, curcuminoids glucuronide showed no obvious inhibitory effects against AD‐related acetylcholinesterase and β‐amyloid precursor cleavage enzyme (Shen et al, ). Acetylcholinesterase inhibitors are efficacious in improving cognitive function of mild‐to‐moderate AD (Gault et al, ). And pharmacological β‐amyloid precursor cleavage enzyme inhibition has found slow progressive β‐amyloid deposition and associated synaptic pathology in a transgenic AD model (Peters et al, ).…”

The current agonists and positive allosteric modulators of α 7 nAChR for CNS indications in clinical trials

“… AD Phase II (terminated in 2014) K i : 12–14 nmol/L (in h α 7, r α 7 and m α 7) 93. , 94. (AbbVie) Schizophrenia Phase II (terminated in 2014) (AbbVie) AZD0328 Partial agonist Binding affinity: Mice: NOR in normal mice 96.…”

Metabolism and Disposition of a Novel Selective α7 Neuronal Acetylcholine Receptor Agonist ABT-126 in Humans: Characterization of the Major Roles for Flavin-Containing Monooxygenases and UDP-Glucuronosyl Transferase 1A4 and 2B10 in Catalysis

“…ABT-126 is a potent and selective a7 nAChR agonist with high binding affinity (K i = 12-14 nM) to a7 nAChRs (human, rat, or mouse cortex) (Gault et al, 2016). ABT-126 shows significantly less affinity (.140-fold) toward other nAChR subtypes and muscarinic receptor and therefore is expected to eliminate the dose-limiting toxicity associated with acetylcholine esterase inhibitors.…”

“…ABT-126 was evaluated in single-dose and multiple dose phase 1 studies, and doses up to 150 mg once daily or up to 40 mg twice a day were generally well tolerated (AbbVie internal data). The results of a phase 2a trial indicated that treatment with ABT-126 was associated with a trend for improvement in cognition in subjects with mild to moderated AD (Gault et al, 2015); however, the subsequent phase 2b trial encompassing a broader dose range did not demonstrate statistically significant improvement versus a placebo control (Florian et al, 2016;Gault et al, 2016). In another phase 2a trial in subjects with schizophrenia, ABT-126 demonstrated a precognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention (Haig et al, 2016b).…”