Therapeutics

Nelonicline

Overview

Name: Nelonicline
Synonyms: ABT-126
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Schizophrenia (Inactive)
Company: AbbVie

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

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026
AbbVie NCT00948909
N=274
AbbVie NCT01527916
N=400
AbbVie NCT01549834
N=420
AbbVie NCT01676935
N=350
AbbVie NCT01690195
N=350

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References

News Citations

  1. Clinical Trials Roundup: Four Hits, No Home Runs

Paper Citations

  1. . A phase 2 randomized, controlled trial of the α7 agonist ABT-126 in mild-to-moderate Alzheimer's dementia. Alzheimers Dement: Trans Res Clin Interv. 2015 Jun;1(1):81–90.
  2. . A Phase 2 Trial of the Efficacy and Safety of the Alpha7 Agonist Abt-126 as an Add-On Treatment in Mild-to-Moderate Alzheimer's Dementia. Alzheimers Dement. 2014 Jul;10(4 Suppl):P917-8.
  3. . Efficacy and Safety of the Alpha7 Agonist Abt-126 as a Monotherapy Treatment in Mild-To-Moderate Alzheimer's Dementia: Results of a Phase 2b Trial. Alzheimers Dement. 2014 Jul;10 (4 Suppl):P137.
  4. . ABT-126 monotherapy in mild-to-moderate Alzheimer's dementia: randomized double-blind, placebo and active controlled adaptive trial and open-label extension. Alzheimers Res Ther. 2016 Oct 18;8(1):44. PubMed.
  5. . 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. J Alzheimers Dis. 2016;51(4):1237-47. PubMed.
  6. . The α7 Nicotinic Agonist ABT-126 in the Treatment of Cognitive Impairment Associated with Schizophrenia in Nonsmokers: Results from a Randomized Controlled Phase 2b Study. Neuropsychopharmacology. 2016 Nov;41(12):2893-2902. Epub 2016 Jun 20 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading