Therapeutics

ABT-957

Overview

Name: ABT-957
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: AbbVie

Background

This compound is an inhibitor of the calcium-dependent cysteine protease calpain. This enzyme has long been known to be highly active in Alzheimer’s disease brain (Saito et al., 1993), but its different isoforms, numerous substrates, and pleitropic effects made drug discovery difficult.  More recently, calpain has become an active therapeutic target as more specific inhibitors have become available.

Calpain is thought to play a role in several of the pathophysiological processes underlying neurodegeneration. For example, calpain functions in NMDR signaling cascades that lead to neuronal excitotoxicity, and it has been reported to mediate Aβ-induced synaptic dysfunction by cleaving the synaptic vesicle protein dynamin 1 (e.g., Wu et al., 2004Kelly et al., 2005). Calpain cleaves p35 to release p25, an activating protein for the tau kinase cyclin-dependent kinase 5, and excess calpain activation has been linked to hyperphosphorylation of tau and its subsequent aggregation into neurofibrillary tangles. In a tauopathy mouse model, genetic calpain reduction prevented neurodegeneration (see Noble et al., 2003Rao et al., 2014). 

Preclinical studies with small-molecule calpain inhibitors have shown improvement of behavioral deficits in models of excitotoxicity of the nucleus basalis of Meynert, a brain area involved in AD. This effect was attributed to the inhibitor’s ability to stanch cholinergic neurodegeneration. In hippocampal slice culture, calpain inhibition reportedly prevented both excitotoxic neuronal death and deficits in neurotransmission brought on by Aβ oligomers. In rats, calpain inhibition dose-dependently protected neurons against degeneration caused by Aβ oligomers, and it prevented gliosis (Nimmrich et al., 2008Nimmrich et al., 2010; Granic et al., 2010). 

Findings

In August 2014, AbbVie started enrolling 20 people with mild to moderate Alzheimer’s disease into a Phase 1 trial of ABT-957.  This multicenter study will expose participants to the study drug twice daily for a week and measure pharmacokinetic and safety parameters. It was originally slated to end in March 2015, but after a temporary suspension is now expected to run through February 2016. 

In December 2015, a second Phase 1 study began enrolling 50 people with MCI due to AD or probable AD. This study is being conducted in six U.S. states; it will compare safety and tolerability of multiple doses of ABT-957 given twice daily for 12 weeks. In addition, this study will measure CSF levels of spectrin breakdown product-145. SBDP-145 is considered a biomarker of calpain activity (Warren et al., 2007).

For clinical trials of this compound, see clinicaltrials.gov.  

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References

Paper Citations

  1. . Calpain and caspase proteolytic markers co-localize with rat cortical neurons after exposure to methamphetamine and MDMA. Acta Neuropathol. 2007 Sep;114(3):277-86. Epub 2007 Jul 24 PubMed.
  2. . Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32. PubMed.
  3. . Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J Biol Chem. 2004 Feb 6;279(6):4929-40. Epub 2003 Nov 19 PubMed.
  4. . Beta-amyloid-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J Biol Chem. 2005 Sep 9;280(36):31746-53. PubMed.
  5. . Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron. 2003 May 22;38(4):555-65. PubMed.
  6. . Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice. J Neurosci. 2014 Jul 9;34(28):9222-34. PubMed.
  7. . Inhibition of Calpain Prevents N-Methyl-D-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction. J Pharmacol Exp Ther. 2008 Nov;327(2):343-52. Epub 2008 Aug 13 PubMed.
  8. . Inhibition of calpain prevents NMDA-induced cell death and beta-amyloid-induced synaptic dysfunction in hippocampal slice cultures. Br J Pharmacol. 2010 Apr;159(7):1523-31. Epub 2010 Mar 3 PubMed.
  9. . Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats. Neuropharmacology. 2010 Sep-Oct;59(4-5):334-42. Epub 2010 Jul 23 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Calpain inhibition as a potential treatment of Alzheimer's disease. Am J Pathol. 2012 Aug;181(2):388-91. PubMed.
  2. . Calpain Inhibitor A-705253 Mitigates Alzheimer's Disease-Like Pathology and Cognitive Decline in Aged 3xTgAD Mice. Am J Pathol. 2012 Aug;181(2):616-25. PubMed.
  3. . The novel calpain inhibitor A-705253 prevents stress-induced tau hyperphosphorylation in vitro and in vivo. Neuropharmacology. 2012 Sep;63(4):606-12. PubMed.
  4. . Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest. 2008 Aug;118(8):2796-807. PubMed.
  5. . Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32. PubMed.