Tau-Buster Slows Brain Atrophy in Rare Dementia

by John Gever for Medpage Today:Researchers said they were encouraged by an oral drug targeting tau deposits in Alzheimer's disease and frontotemporal dementia, even though it failed to show clinical benefit in a 1-year trial.The drug, a kinase inhibitor called tideglusib, significantly slowed the rate of brain atrophy in patients with progressive supranuclear palsy (PSP), a form of frontotemporal dementia, said Gunter Hoeglinger, MD, of the German Center for Neurodegenerative Diseases in Munich, Germany.As a result, his research group and the company developing the drug remain optimistic that they are on the right track, despite missing all the prespecified clinical endpoints in the phase II trial, Hoeglinger told attendees at a late-breaking abstract session here at the Alzheimer's Association International Conference.PSP is a rare form of dementia, occurring in about 10 people per 100,000 in the general population. But it has a relative early average onset (mean age 63) and few patients live for as long as 10 years after diagnosis.Pathologically, it's marked by abnormal conglomerations of hyperphosphorylated tau proteins, which form tangles, coiled bodies, and "tuffs" within brain cells.Many enzymes are capable of adding phosphate molecules to normal tau proteins -- which, when done to excess, causes the proteins to assume these toxic forms -- but glycogen synthase kinase-3 (GSK-3) is one of the most common and active, Hoeglinger explained.Consequently, GSK-3 has looked like a promising target for drugs aimed at inhibiting the abnormal tau forms, and the neurodegeneration that follows.Alzheimer's disease also involves "tauopathy," and therefore, a successful drug of this type could be applied to it as well as to PSP. Tideglusib's developer, the Spanish firm Noscira, is now sponsoring a trial in Alzheimer's disease.Hoeglinger and colleagues conducted a multicenter trial in 146 patients in the U.S. and Western Europe, randomized in a 2:2:1 ratio to tideglusib at 800 or 600 mg orally once daily, or to placebo. Treatment lasted 1 year.Patients with mild to moderate disease severity (Golbe stage 1-4) were enrolled. All patients had had MRI scans within the previous 2 years that excluded other causes of their symptoms.The primary outcome measure was change from baseline in the Golbe PSP Rating Scale at the end of the treatment period. Seven other clinical outcome measures, covering motor and cognitive function, functional status, behavior, and quality of life, served as secondary endpoints.Detailed MRI scans were also performed in 37 patients at baseline and at the end of treatment to evaluate brain atrophy.Hoeglinger dealt with the major study outcomes in two sentences: "The treatment was safe and well tolerated. The clinical primary and secondary endpoints were not met," he said. There was no difference at all between either active treatment group and placebo in the clinical measures.But the MRI substudy told a happier story.Those patients also showed no indication of clinical benefit, but rates of brain volume loss in the gray matter overall and in the parietal and occipital lobes were markedly lower with active treatment (all P<0.05 for active drug versus placebo):

• Gray matter: placebo, 3.1%; 600 mg tideglusib, 1.4%; 800 mg tideglusib, 1%
• Parietal lobe: placebo, 4.1%; 600 mg tideglusib, 1.6%; 800 mg tideglusib, 1.4%
• Occipital lobe: placebo, 2.7%; 600 mg tideglusib, 0.4%; 800 mg tideglusib, 0.1%

In addition, there were strong trends toward lower atrophy rates in most other brain regions, including in the cerebrum, cerebellum, and brainstem.Hoeglinger noted that the mid-brain, "the most relevant region for PSP," was among those latter regions with the weaker brain atrophy benefit. He suggested that perhaps tideglusib does not penetrate adequately to that part of the brain.For the future, he added, beginning therapy earlier in the disease, continuing it longer, and perhaps at a higher dose "might lead to measurable clinical effects."Session moderator Ralph Nixon, MD, of New York University, agreed that tideglusib was not a complete washout in the study."It's encouraging enough to investigate further," he told MedPage Today.Nixon said it would be necessary eventually to demonstrate a clinical benefit with tideglusib, that simply proving it prevents brain atrophy would not be adequate.He said that perhaps 1 year was not long enough for a clinical effect to be detected. Nixon also suggested that the clinical outcome measures used in the trial may not have been the right ones to show clinical effects related to the brain regions where the anti-atrophy activity was strongest."In a further analysis, there might be a broader array of measures that would capture the benefits," he said.Source: http://www.medpagetoday.com/MeetingCoverage/AAIC/33822