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Title: Tarenflurbil Provides Increasing Benefits Over Time in Alzheimer's Disease: Presented at EFNS

"Tarenflurbil Provides Increasing Benefits Over Time in Alzheimer's Disease: Presented at EFNS"

By Chris Berrie BRUSSELS, BELGIUM -- August 30, 2007 -- Tarenflurbil, a selective Abeta42-lowering agent (SALA), is well tolerated for up to 2 years and provides increasing benefits over time for patients with mild Alzheimer's disease (AD), according to study findings. The results of an international, multicentre, randomised, double-blind, placebo-controlled phase 2 study were presented here on August 28th at the 11th Congress of the European Federation of Neurological Societies (EFNS) by Gordon K. Wilcock, MD, DM, Principal Investigator and Professor in Gerontology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, on behalf of these Alzheimer's Disease Phase 2 Study Investigators. "Tarenflurbil is a selective Abeta42-lowering agent, both in vitro and in vivo, which works by allosterically modulating, rather than inhibiting, gamma-secretase," said Dr. Wilcock. It also reduces insoluble amyloid in mouse brains, leading to improvements in spatial reference learning and memory performance. Effective concentrations are achievable in humans at clinically safe doses, so the present study was designed to investigate the effectiveness of tarenflurbil as a SALA in patients with mild-to-moderate AD (Mini Mental State Examination [MMSE] 15-26). The study was designed for 12 months, with an optional 1-year follow-up available to Canadian participants. Three treatment groups (N = 207) were randomised to placebo or tarenflurbil at 400 or 800 mg BID. However, a prespecified primary analysis for no interactions between disease severity at baseline and active treatment was not met, and so mild (MMSE <20) and moderate (MMSE <20) patient data was handled separately. Due to the consequent low numbers in the moderate group, Dr. Wilcock only presented data from patients with mild AD. Primary outcomes were efficacy measures according to the Alzheimer's Disease Assessment Scale - cognitive (ADAS-cog), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), and Clinical Dementia Rating - sum of boxes (CDR-sb). Concomitant exploratory analyses looked at lower tarenflurbil dosing and drug concentration effects. A total of 130 patients with mild AD received placebo (n = 46; mean age, 76 years) or tarenflurbil 400 mg BID (n = 36; mean age, 75 years) or 800 mg BID (n = 48; mean age, 76 years). For baseline clinical characteristics, no significant differences were noted across these groups for percent acetylcholinesterase inhibitor (AChEI) use (97%, 94%, 94%, respectively); mean duration of AChEI use at baseline (16.0, 19.7, 16.9 months); MMSE (22.9, 23.1, 22.8); ADAS-cog (27.5, 28.6, 28.3); ADCS-ADL (58.9, 61.4, 59.8); and CDR-sb (5.7, 5.0, 6.0). With all further analyses carried out on an intent-to-treat basis, all primary analyses showed declining levels that were generally positively affected by treatment. As such, analyses for significance were based upon the slopes of the time courses of the changes seen. For patient cognition according to changes in ADAS-cog, with the combined data (UK plus Canada) at 12 months, there were no significant differences in the approximate 3-point loss seen (800 mg vs placebo, [P =.109). However, the continuation trial to 2 years in Canada showed a significant (approximately 4-point) benefit of tarenflurbil 800 mg over 400 mg by 2 years (P =.013). This was also the situation for the exploratory analysis of MMSE, with significant (approximately 3.5-point) benefit only seen at 2 years, but apparent benefit for tarenflurbil 800 mg over both placebo (P =.001) and tarenflurbil 400 mg (P <.001).

The ADCS-ADL demonstrated significant (approximately 4-point) benefit for tarenflurbil 800 mg over placebo within the 12-month analysis (P =.015) that, despite some slope changes around months 15 to 20, was also indicated for tarenflurbil 800 mg versus 400 mg at 2 years.

Similarly, for global function with CDR-sb, significant (approximately 0.8-point) benefit was seen for tarenflurbil 800 mg over placebo at 12 months (P =.0005), with similar slope variations in the later data prior to tarenflurbil 800 mg versus 400 mg benefit at 2 years.

In the exploratory study of plasma tarenflurbil concentrations, although only the ADCS-ADL was illustrated, there was significance for all efficacy measures; patients who achieved higher maximum plasma concentrations of tarenflurbil showed better responses (P =.027 for ADCS-ADL). A post-hoc analysis of time to psychiatric event also showed significant benefits for tarenflurbil 800 mg over placebo, both for number of patients with events (7 vs 18, P =.02) and median time to event (>333 vs 106 days, P =.011).

For the safety summary (n = 207) over the first 12 months, tarenflurbil was well tolerated and discontinuations due to AEs were comparable with placebo and tarenflurbil 800 mg (respectively): gastrointestinal, 4.5% versus 2.9%; metabolism and nutrition, 1.5% versus 2.9%; and psychiatric, 4.5% versus 2.9%.

Overall, there were some differences in the AEs across placebo and tarenflurbil 800 mg, with active treatment seeing more transient eosinophilia, mild anaemia, blood pressure elevation, lower respiratory tract infection, and rash, and less urinary incontinence and fewer psychiatric events.

In the tarenflurbil 800-mg treatment group, patients with mild AD showed significant benefit for daily living activities and global function, with a beneficial trend for cognition. Furthermore, Dr. Wilcock said, "Over a period of time, the effect sizes and the statistical significances increase, and this is consistent with this being a beta-amyloid lowering, an Abeta42-lowering strategy." Finally, this tarenflurbil treatment was well tolerated to 2 years.

This study was sponsored by Myriad Pharmaceuticals.

[Presentation Title: Efficacy and Safety of Tarenflurbil (Flurizan), A Selective Abeta42-Lowering Agent, in Alzheimer's Disease: A Phase 2 Trial of Up to 24 Months of Treatment. Abstract SC306]

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