A phase III trial of pioglitazone in Alzheimer’s disease has been terminated by Takeda and partner Zinfandel Therapeutics after it became clear the treatment was having no effect.
The TOMORROW study of low-dose pioglitazone – usually used to treat type 2 diabetes – was investigating whether it could delay the onset of mild cognitive impairment in early-stage AD, but an interim test for futility showed that it was not working as hoped.
Pioglitazone was being tested in people considered at high risk of developing AD because of their genetic profiles but who had yet to display any obvious symptoms. Sadly, the drug joins the ranks of dozens of other would-be AD therapies – with multiple mechanisms of action – that have failed to have an impact on the disease in late-stage testing.
Currently-registered drugs such as cholinesterase inhibitors, which boost neurotransmitter levels in the brain, are palliative at best.
Emiliangelo Ratti, head of Takeda’s neuroscience division, said that the partners “will further analyse data from the trial, including the performance of the genetic-based biomarker risk assignment algorithm, with the hope that this information may ultimately help in the global fight against AD”.
Piogliazone is sold by Takeda under the Actos brand and was a $4bn-a-year product before losing patent protection in 2011, after which generic versions entered the market. The decision to develop it for AD stemmed from observations that people with the disease often have compromised insulin function in the central nervous system, as well as suggestions that the drug could reduce inflammation in the brain.
Takeda joined forces with Zinfandel on the project in 2011, licensing rights to an assay (TOMM40) that was used in the study to identify high-risk older adults who would be good candidates for the clinical trials in a deal valued at up to $78m. They started the TOMORROW trial in 2013
It’s not the first time that a glitazone drug has been tested and failed in AD. In 2010 GlaxoSmithKline went down the same path with its Avandia (rosiglitazone) product, although its failed trial used a different biomarker to determine risk based on cerebrospinal fluid sampling.
Meanwhile, other diabetes drugs have also been tested for activity in AD, including Novo Nordisk’s Victoza (liraglutide) which seemed to reduce amyloid plaque formation but had no effect on cognitive impairment. A UK team has started tests of a so-called ‘triple agonist’ treatment based on a drug that can stimulate the growth factors GLP-1, GIP and glucagon that has shown promise in animal studies.