Background

ABT-126 is an α-7 nicotinic acetylcholine receptor (α7-nAChR) allosteric modulator that was being developed to treat cognitive deficits in schizophrenia and Alzheimer's disease. Cholinergic function declines in Alzheimer's, and currently approved acetylcholinesterase-inhibitor therapies modestly improve cognitive deficits in patients with AD by way of boosting cholinergic transmission. The rationale of α7-nAChR agonists was that they will enhance cognition without causing side effects associated with overactivation of other nAChRs or muscarinic AChRs. ABT-126 was initially developed by Abbott Laboratories. In January 2013, Abbott spun out its pharmaceuticals business into a new company called AbbVie.

Findings

ABT-126 was in Phase 2 development for Alzheimer's disease in the United States, Canada, South Africa, and Eastern European countries, and in Phase 3 development for cognitive symptoms in schizophrenia in the United States and Europe. 

For Alzheimer's disease, Phase 1 research for safety and pharmacology parameters started in healthy volunteers in 2009, and in patients with mild to moderate Alzheimer's in 2011. Also in 2009, a 12-week Phase 2 study in 274 people with mild to moderate AD compared 5 mg and 25 mg of ABT-126 to placebo and to donepezil, but without co-administration of ABT-126 and donepezil. This trial ended in 2010, and in 2013 preliminary data was reported to have shown good tolerability for ABT-126, with side effects similar to donepezil. A cognitive benefit for the higher dose similar to that seen with donepezil was reported as well. The cognitive signal correlated with blood measures of exposure to ABT-126 (see Aug 2013 conference news). Full data were subsequently published open-access (Gault et al., 2015). 

In 2012, AbbVie started two 24-week Phase 2b trials in 400 patients each, comparing doses ranging from 25 to 75 mg. One trial compared ABT-126 added on to treatment with an acetylcholinesterase inhibitor to placebo, the other compared ABT-126 monotherapy to placebo. Preliminary results were published, suggesting that efficacy at these higher doses was insufficient to continue further development (Gault et al., 2014, and Othman et al., 2014). Each trial offered a 28-week, open-label extension to people who had completed the blinded portion of the study. These studies were due to read out in 2014, but have been terminated. In January 2016, results of the add-on study were formally published, showing insufficient efficacy to continue development; similarly, in October, a peer-reviewed paper on the results of the monotherapy trial showed no significant improvement with any of the ABT-126 doses tested (Florian et al., 2016, Gault et al., 2016).

In schizophrenia, a 2009 Phase 1 trial evaluated safety and pharmacokinetics in 16 adult patients who were receiving treatment with an atypical antipsychotic.  In 2010, a Phase 2 study compared two undisclosed doses to placebo in 207 adults with the disease. Two additional Phase 2 trials were added, one to compare two doses to placebo in 150 patients for 12 weeks at sites in the United States; the other as an international trial to compare 25, 50, and 75 mg doses to placebo in 430 patients for 24 weeks, with a one-year open-label extension. In November 2016, a peer-reviewed paper reported no statistically significant treatment benefit for ABT-126 in the larger trial (Haig et al., 2016).

For a listing of ABT-126 trials, see clinicaltrials.gov.

Clinical Trial Timeline