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
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 Since then pioglitazone has come to be prescribed worldwide, but was withdrawn from the market in Germany and France because of concerns that it might increase the risk of bladder cancer.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 story; Yamanaka et al., 2012; Mandrekar-Colucci et al., 2012).
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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- Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011 Sep;32(9):1626-33. PubMed.
- Hanyu H, Sato T, Kiuchi A, Sakurai H, Iwamoto T. 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.
- Moon JH, Kim HJ, Yang AH, Kim HM, Lee BW, Kang ES, Lee HC, Cha BS. 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.
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- Large Study Questions Tomm40’s Effect on AD Age of Onset
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- Orlando: Early Results Hint That Insulin-Sensitizing Drug Improves Cognition
- Honolulu: Tomm40 Reported to Track With Brain Atrophy, Cognition
- Las Vegas: AD, Risk, ApoE—Tomm40 No Tomfoolery
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