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 Since then pioglitazone has come to be prescribed worldwide, but was withdrawn from the market in Germany and France because of concerns that it might increase the risk of bladder cancer.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. 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 (Dec 2012 news story; Yamanaka et al., 2012; Mandrekar-Colucci et al., 2012).

Findings

From 2002 to 2005, a Phase 2 study sponsored by the National Institute on Aging 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; 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 (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 2013-2015, Takeda and Zinfandel Pharmaceuticals conducted "TOMMORROW," a Phase 3 trial that enrolled 3,494 cognitively normal participants in the United States, Australia, Europe, and the U.K. This study was unusual in that it had two separate goals. One was 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 was to evaluate pioglitazone's ability to delay this diagnosis in people deemed high-risk by the diagnostic assay. The assay is being co-developed as a companion diagnostic for preventive treatment. Participants at high risk of developing MCI-AD according to the diagnostic algorithm were randomized to pioglitazone or placebo; participants at low risk received placebo. The primary endpoint for the diagnostic assay was the time to diagnosis for placebo-treated participants in the low-risk group compared with the high-risk group; the primary endpoint for pioglitazone was the time to diagnosis for pioglitazone-treated versus placebo-treated participants in the high-risk group. This trial used 0.8 mg pioglitazone per day, a lower dose than is used to treat diabetes (Moon et al., 2011). Approximately 300 high-risk participants will enter an amyloid-related imaging abnormalities (ARIA) substudy. Each participant was to take a tablet—pioglitazone or placebo—once daily for five years, visit his or her study clinic 14 times, and take a telephone call three months after each visit for a follow-up assessment (Aug 2013 conference story). Approximately 300 high-risk participants entered an ARIA substudy at the request of the FDA. This was later changed to volumetric MRI, on the understanding that low-dose pioglitazone was unlikely to affect brain amyloid.

In early 2018, TOMMORROW was terminated after failing a futility analysis (Jan 2018 news). According to published trial results, pioglitazone did not delay the onset of MCI, after a mean treatment time of about two years. The diagnostic algorithm produced a three-times enrichment of events in the high-risk placebo group compared to the low-risk placebo group, but did not reach a prespecified significance threshold (Burns et al., 2021). The treatment did not alter the rate of change of brain volumes on MRI.

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.

Clinical Trial Timeline