Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA;
Commented by , 23 May 2008
Aim of the study
Test the efficacy and safety of the selective Aß42-lowering agent (SALA) tarenflurbil in patients with mild to moderate Alzheimer’s disease (AD).
Method
210 patients with probable AD living in the community in the UK or in Canada with MMSE scores 15-26 were randomized to placebo (n=71), tarenflurbil 400 mg BID (n=69) or 800 mg BID (n= 70) for 12 months.
Most patients were already on a cholinesterase inhibitors. The primary efficacy outcomes were the AD Assessment Scale cognitive subscale (ADAS-cog) the AD Cooperative Study activities of daily living scale (ADCS-ADL), and the Clinical Dementia Rating sum of boxes (CDR-sb).
Exploratory outcomes included the clinician-interview-based impression of change with caregiver input (CIBIC+), the Neuropsychiatric Inventory (NPI), the caregiver distress scale (NPI-CD) and the MMSE. A 12-month extension study followed with patients previously on placebo randomized to tarenflurbil 400 or 800 mg BID.
Results
The primary intent-to-treat analysis for all patients showed no difference between groups on the three efficacy outcomes. A pre-specified interaction analysis showed a differential response based on MMSE scores of 20-26 (mild AD) vs 15-19 (moderate AD).
Patients with mild AD in the 800 mg BID group had lower rates of decline than the placebo group on the ADCS-ADL (∆ 3.98 in slope [95% CI 0.33 to 7.62] points per year) and on the CDR-sb (∆ -0.80 [-1.57 to -0.03] points per year), but not in ADAS-cog (∆ -1.36 [-4.07 to 1.36].
In moderate AD the same dose of tarenflurbil had no significant effects on ADCS-ADL or on ADAC-cog, and a negative effect on CDR-sb. The most common adverse events were diarrhea, nausea and dizziness. Patients with mild AD who received 800 mg BID for 24 months had lower rates of decline for the three primary efficacy outcomes compared to patients who received placebo followed by tarenflurbil.
Professor Gauthier's comments
As commented in the accompanying editorial by Paul Aisen (ref. 1), tarenflurbil as a modulator of γ secretase can reduce the production of Aß42 which may translate into a disease-modifying effect in mild AD, to be confirmed in ongoing Phase III studies.
There are a number of points to be made in this study and publication:
- A well planned analysis for interaction can bring out benefits in a sub-group of responders;
- The most effective dose (800 mg BID for tarenflubil) and stage of disease (mild AD defined by MMSE 20-26) can then be used in Phase III;
- An extension study with randomization of the placebo-group allows for a "delayed start" analysis and data on long-term safety;
- Publication of a Phase II study is a highly respected medical journal allows for rapid diffusion in the scientific community and potentially improve in the design of other drug programs aiming at disease-modification for AD.
References
1. Aisen PS. Tarenflurbil: a shot on goal. Lancet Neurology 2008; 7 (6); 468-469. [Epub 2008 Apr 29]