Therapeutics

Pioglitazone

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Overview

Name: Pioglitazone
Synonyms: AD4833, Actos®, Glustin™, Piozone®
Chemical Name: 2,4-Thiazolidinedione
Therapy Type: Small Molecule
Target Type: Inflammation, Other
Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Phase 3)
Company: Takeda Pharmaceutical Company, Zinfandel Pharmaceuticals Inc.
Approved for: Type 2 diabetes mellitus

Background

Pioglitazone is an insulin sensitizer of the thiazolidinedione class of peroxisome-proliferator activated receptor γ (PPARγ) agonists. Takeda developed pioglitazone as a once-daily treatment of type 2 diabetes. The FDA approved it in 1999 as an adjunct to diet and exercise for the control of blood sugar in adults with this disease. Since then pioglitazone has come to be prescribed worldwide, but was withdrawn from the market in Germany and France because of concerns that it might increase the risk of bladder cancer. The issue remains under review in the United States, though in its update issued in August 2013, the FDA did not conclude that pioglitazone increased the risk of bladder cancer (see FDA Webinar). Generic tablet versions became available starting in 2012.

In recent years, PPARγ has come to be a target of interest for Alzheimer's drug development, both because of a general overlap of metabolic disease and Alzheimer's disease risk factors and because cell-based and animal studies have implicated PPARγ, in particular, to play a role in neuroinflammatory processes in Alzheimer's and other neurodegenerative conditions. For example, PPARγ activation has been shown to modulate the microglial response to amyloid deposition in such a way that it increases Aβ phagocytosis and decreases cytokine release (see Dec 2012 news storyYamanaka et al., 2012Mandrekar-Colucci et al., 2012).

Findings

From 2002 to 2005, a Phase 2 study sponsored by the National Institute on Aging (NIA) evaluated the safety and tolerability of pioglitazone in patients with AD and gathered pilot data on whether this drug might affect measures of cognition, daily function, and behavior. Twenty-nine patients with mild to moderate AD but without diabetes took up to 45 mg per day of pioglitazone or placebo for 18 months. Consistent with the known side effects of pioglitazone, about a fourth of participants developed peripheral edema; other than that they tolerated the drug well. No indications for a clinical benefit arose from this trial (see Geldmacher et al., 2011; see Sep 2010 news story).

A Japanese open-label study of 42 patients who had both mild Alzheimer's and diabetes suggested a benefit for both diseases after six months of treatment with 15 to 30 mg/day of pioglitazone, as did a previous pilot study in patients who had mild AD or mild cognitive impairment and diabetes (see Sato et al., 2011; Hanyu et al., 2009).

In 2012, Takeda conducted a Phase I trial in the United States to evaluate the effects of two weeks of pioglitazone treatment on blood flow in brain areas important for cognition in 61 healthy older participants (NCT01456117). Results are unpublished.

In August 2013, Takeda and Zinfandel Pharmaceuticals began "Tommorrow," a Phase 3 trial that is to enroll 5,800 cognitively normal participants in the United States, Australia, Europe, and Russia. This study is unusual in that it has two separate goals. One is to evaluate how accurately a diagnostic algorithm based on the genes ApoE and TOMM40, developed by Zinfandel, predicts a person's risk of developing mild cognitive impairment due to AD (MCI-AD) within five years. The other is to evaluate pioglitazone's ability to delay this diagnosis in people deemed high-risk by the diagnostic assay. The assay is being codeveloped as a companion diagnostic for preventive treatment. Participants at high risk of developing MCI-AD according to the diagnostic algorithm are randomized to pioglitazone or placebo; participants at low risk receive placebo. The primary endpoint for the diagnostic assay is the time to diagnosis for placebo-treated participants in the low-risk group compared with the high-risk group; the primary endpoint for pioglitazone is the time to diagnosis for pioglitazone-treated versus placebo-treated participants in the high-risk group. This trial uses an undisclosed but lower dose of pioglitazone than is used to treat diabetes (see Moon et al., 2011). Approximately 300 high-risk participants will enter an amyloid-related imaging abnormalities (ARIA) substudy. Each participant will take a tablet—pioglitazone or placebo—once daily for five years, visit their study clinic 14 times, and take a telephone call three months after each visit for a follow-up assessment (see Aug 2013 conference story).

For trials of pioglitazone in Alzheimer's disease, see clinicaltrials.gov.

In addition, pioglitazone was evaluated in a Phase 1 study in patients with multiple sclerosis, but development for this indication stopped.

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References

News Citations

  1. Trial Updates: B Vitamin Back in Vogue? Diabetes Drug Less Sweet
  2. Can Phagocytosis, Memory Effects Revive Diabetes Meds?

Paper Citations

  1. . A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol. 2011 Jan;68(1):45-50. PubMed.
  2. . Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011 Sep;32(9):1626-33. PubMed.
  3. . Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus. J Am Geriatr Soc. 2009 Jan;57(1):177-9. PubMed.
  4. . The effect of rosiglitazone on LRP1 expression and amyloid β uptake in human brain microvascular endothelial cells: a possible role of a low-dose thiazolidinedione for dementia treatment. Int J Neuropsychopharmacol. 2011 Nov 1;:1-8. PubMed.
  5. . PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci. 2012 Nov 28;32(48):17321-31. PubMed.
  6. . Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci. 2012 Jul 25;32(30):10117-28. PubMed.

Other Citations

  1. Aug 2013 conference story

External Citations

  1. National Institute on Aging (NIA)
  2. clinicaltrials.gov
  3. FDA Webinar

Further Reading

Papers

  1. . Using genetics to enable studies on the prevention of Alzheimer's disease. Clin Pharmacol Ther. 2013 Feb;93(2):177-85. PubMed.
  2. . Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease. Ann Pharmacother. 2011 Nov;45(11):1416-24. PubMed.
  3. . Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathology. PLoS One. 2013;8(7):e68612. PubMed.
  4. . Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2012;30(4):943-61. PubMed.
  5. . The Nuclear Receptor PPARgamma as a Therapeutic Target for Cerebrovascular and Brain Dysfunction in Alzheimer's Disease. Front Aging Neurosci. 2010;2 PubMed.
  6. . Effects of long-term pioglitazone treatment on peripheral and central markers of aging. PLoS One. 2010;5(4):e10405. PubMed.
  7. . Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer's disease and decreases it in wild-type mice. Diabetologia. 2006 Sep;49(9):2153-61. PubMed.