Patients with mild Alzheimer's disease (AD) who take 800mg of tarenflurbil twice daily show less decline in functional ability than those taking placebo. The findings of this phase II justify phase III studies of tarenflurbil at this dose. These are the conclusions of authors of Article published early Online and in the June issue of The Lancet Neurology.
Deposition of the protein amyloid-Î² (AÎ²) in the brain is a neuropathological hallmark of Alzheimer's disease, and a potential cause of neuronal damage. The molecule believed to initiate this damage is the 42-amino-acid peptide AÎ²42. Tarenflurbil is a drug that reduces production of AÎ²42, and it falls into the category of drugs known as selective AÎ²42 lowering agents (SALAs). In a mouse model of AD, tarenflurbil prevented defects in learning and memory.
Professor Gordon Wilcock, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK and colleagues did a randomised phase II trial of 210 AD patients living in the community, whose score on a scale called the mini-mental state examination (MMSE) of 15-26 gave them a diagnosis of mild to moderate AD. The patients were randomly assigned to receive 400mg tarenflurbil twice per day (69 patients); 800mg tarenflurbil twice per day (70 patients); or placebo (71 patients). Effectiveness of the treatment was assessed using three common scores â€" the AD assessment cognitive subscale* (ADAS-cog); the Alzheimer's Disease Cooperative Study activities of daily living scale** (ADCS-ADL), and the clinical dementia rating sum of boxes*** (CDR-sb /global function). Following the initial 12 months, there was a 12 month extension phase in which some patients who had received tarenflurbil continued on the same dose, and some on placebo were randomised to either the 400mg or 800mg doses of tarenflurbil.
The researchers found that patients with mild AD (MMSE 20-26) and moderate AD (MMSE 15-19) responded differently in terms of ADAS-cog and ADCS-ADL scores, and thus were analysed separately. In the mild AD patients, the 800mg tarenflurbil group experienced a rate of decline 46% lower than placebo patients in the activities of daily living scale; and CDR-sb showed that tarenflurbil also reduced the pace of decline in global function by 36%. In moderate AD patients, tarenflurbil at either dose had no significant effect on ADAS-cog or ADCS-ADL, and a negative effect on CDR-sb (ie, a more advanced decline in global function). The most common adverse advents were diarrhoea, nausea, and dizziness, recorded at similar levels in the three treatment groups. Patients with mild AD who were in the 800mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and either tarenflurbil group for months 12-24.
The authors conclude: "800mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild ADâ€¦.these findings justify phase III studies of tarenflurbil at the 800mg twice daily dose in patients with mild AD."
In an accompanying Comment, Dr Paul Aisen, University of California, San Diego, CA, USA, says: "Are these results sufficient to support continuation of a large phase III development programme" Thankfully, the sponsor's view was affirmative. With the need so enormous, and the potential effect of the benefit suggested (although not proven) by these phase II results, the effort is indeed justified despite the substantial uncertainty. In a few months, we will learn whether tarenflurbil will be the first anti-amyloid intervention to be efficacious in a pivotal trial." He also discusses the substantial number of other promising anti-amyloid drug programmes moving forward.
Notes to editors: *AD assessment cognitive subscale* (ADAS-cog): this assesses cognitive ability, ie memory function and other mental abilities and is part of a larger test protocol. It was designed specially for people with AD and is the most widely used cognitive assessment protocol in trials of new treatments.
**the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL): this assesses a person's ability to undertake normal day to day activities, for instance ranging from basic washing and dressing to more sophisticated tasks like hobbies and discussing current events.
***clinical dementia rating sum of boxes (CDR-sb /global function): this is a more general assessment of the person as a whole, covering domains such as judgement and problem solving, hobbies, orientation and memory
Professor Gordon Wilcock, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK T) +44 (0)1865 221349 / +44 (0)7734 297 334 E) Gordon.Wilcock@ndm.ox.ac.uk
Dr Paul Aisen, University of California, San Diego, CA, USA T) +1 858-622-2028 E) email@example.com