Therapeutics

ABT-288

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Overview

Name: ABT-288
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: AbbVie

Background

Abbott, now AbbVie, was developing this histamine H3 receptor antagonist for the treatment of cognitive deficits in Alzheimer's and schizophrenia. The rationale was to boost release in the brain of histamine, acetylcholine, noradrenaline, and dopamine in an attempt to enhance cognitive processes. In particular, the approach has been proposed to increase cholinergic signaling, which wanes with neurodegeneration in AD (Passani and Blandina, 1998; Bembenek et al., 2008; Bitner et al., 2011, Brioni et al., 2011).  Blocking the receptor has been a target of several small-molecule therapeutic programs for cognition disorders at other companies as well, e.g. GSK239512, S 38093.

Findings

Three clinical trials are registered on this compound. A single- and multiple-ascending dose study in healthy volunteers was reported to have been generally safe and well-tolerated, with the most frequent side effects being related to sleep, nausea, and dizziness. The 1 and 3 mg per day doses were subsequently evaluated in Phase 2 (Othman et al., 2012).

A subsequent Phase 2 trial of adjunct treatment with ABT-288 in 242 people with mild to moderate Alzheimer's disease who were on stable donepezil treatment ended early. It met futility criteria when the ADAS-cog outcome was statistically significantly improved on donepezil but not on ABT-288 (Haig et al., 2014). A third Phase 2 trial was conducted in schizophrenia. ABT-288 development appears to have been discontinued.

For details on clinical studies, see clinical trials.gov.

Last Updated: 15 Jan 2016

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References

Therapeutics Citations

  1. GSK239512
  2. S 38093

Paper Citations

  1. Othman AA, Haig G, Florian H, Locke C, Zhang J, Dutta S. Safety, Tolerability and Pharmacokinetics of the Histamine H(3) Receptor Antagonist, ABT-288, in Healthy Young Adults and Elderly Volunteers. Br J Clin Pharmacol. 2012 Sep 28; PubMed.
  2. Haig GM, Pritchett Y, Meier A, Othman AA, Hall C, Gault LM, Lenz RA. A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer's dementia. J Alzheimers Dis. 2014;42(3):959-71. PubMed.
  3. Passani MB, Blandina P. Cognitive implications for H3 and 5-HT3 receptor modulation of cortical cholinergic function: a parallel story. Methods Find Exp Clin Pharmacol. 1998 Oct;20(8):725-33. PubMed.
  4. Bembenek SD, Keith JM, Letavic MA, Apodaca R, Barbier AJ, Dvorak L, Aluisio L, Miller KL, Lovenberg TW, Carruthers NI. Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling. Bioorg Med Chem. 2008 Mar 15;16(6):2968-73. Epub 2007 Dec 25 PubMed.

External Citations

  1. clinical trials.gov
  2. Bitner et al., 2011
  3. Brioni et al., 2011

Further Reading

Papers

  1. Haig GM, Pritchett Y, Meier A, Othman AA, Hall C, Gault LM, Lenz RA. A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer's dementia. J Alzheimers Dis. 2014;42(3):959-71. PubMed.