Marie-Emmanuelle Riviere

Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy

OBJECTIVE This was the first proof of principle clinical trial assessing the efficacy and safety of rufinamide as adjunctive therapy in epileptic patients. The pharmacokinetic (PK) profile of rufinamide was also determined. METHODS Fifty patients with diagnoses of partial or primary generalized tonic-clonic seizures were enrolled in this 28-day double-blind, placebo-controlled, weekly rising dose (400-1600 mg/day) trial. PK profiles were obtained after administration of single-dose rufinamide prior to and after the Double-blind phase. RESULTS In the evaluable patient population, seizure frequency decreased by 41% in the rufinamide group and increased by 52% in the placebo group (P=0.040). Thirty-nine percent (39%) of rufinamide-treated and 16% of placebo-treated patients experienced reduction in seizure frequency of at least 50% relative to baseline (P=0.096). SAFETY Treatment-emergent adverse events (AEs) consisted mainly of neurologic signs and symptoms commonly associated with antiepileptic drugs (AEDs). PHARMACOKINETICS At steady state, rufinamide reached a peak plasma concentration with a mean time (Tmax) of 3.4 h and a mean half-life (t1/2) of 7.3 h. No autoinduction of rufinamide metabolism occurred. Rufinamide did not influence the plasma concentration of carbamazepine, phenytoin or valproate when added to these single AED regimens. CONCLUSION Rufinamide has been shown, in this proof of principle trial, to be safe and effective in reducing seizure frequency in epileptic patients with no relevant influence on the metabolism of other AEDs.

Active immunotherapy options for Alzheimer's disease.

Alzheimer’s disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Aβ) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Aβ-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Aβ-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Aβ accumulation and prevent downstream pathology in preclinical models. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach.

PSYCHOSOCIAL OUTCOMES OF APOE E4 GENOTYPE DISCLOSURE IN THE GENERATION STUDY

O4-08-03 PSYCHOSOCIAL OUTCOMES OF APOE E4 GENOTYPE DISCLOSURE IN THE GENERATION STUDY Angela R. Bradbury, Jason Karlawish, J Scott Roberts, Brian L. Egleston, Linda Patrick-Miller, Elisabeth McCarty Wood, Scott YH. Kim, Jan Jaeger, Neeraja Reddy, Cara Cacioppo, Dare Henry-Moss, Stephanie Jideama, Demetrios Ofidis, Fonda Liu, Angelika Caputo, Marie-Emmanuelle Riviere, Mauritz Bezuidenhoudt, Carolyn Langlois, Eric M. Reiman, Pierre N. Tariot, Jessica B. Langbaum, University of Pennsylvania, Philadelphia, PA, USA; University of Michigan, Ann Arbor, MI, USA; Fox Chase Cancer Center, Philadelphia, PA, USA; Independent Consultant, Chicago, IL, USA; National Institutes of Health, Bethesda, MD, USA; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Novartis Pharma AG, Basel, Switzerland; Novartis Pharma, Basel, Switzerland; Banner Alzheimer’s Institute, Phoenix, AZ, USA; Arizona Alzheimer’s Consortium, Phoenix, AZ, USA. Contact e-mail: angela.bradbury@uphs.upenn.edu