A Phase 3 pivotal trial of AGB101 to slow progression in MCI due to Alzheimer's Disease

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A distinctive condition in the patient population with amnestic mild cognitive impairment (aMCI) is overactivity localized to the hippocampus by functional magnetic resonance imaging (fMRI), which longitudinally predicts subsequent cognitive decline/conversion to a dementia diagnosis (Sperling, 2007; Dickerson et al., 2008; Miller et al., 2008) and is significantly correlated with the extent of neuronal injury affecting the brain (Putcha et al, 2011). Such overactivity is most pronounced in MCI due to AD determined by PET amyloid imaging and persists over a three year follow up during which time greater worsening on Clinical Dementia Rating-sum of boxes (CDRsb) is evident in MCI due to AD relative to patients with amyloid negative PET scans (Huijbers et al., 2015). These data, together with preclinical research, provide strong evidence that hippocampal hyperactivity is a driver of neurodegeneration during the aMCI phase of disease, leading to subsequent cognitive decline. To determine whether an intervention to restore hippocampal activity to normal can have a positive therapeutic effect to slow disease progression, we are proposing a Phase 3 randomized placebo-controlled trial with AGB101, a once-a-day formulation of levetiracetam. In Phase 2 levetiracetam demonstrated target engagement by lowering hippocampal hyperactivity in a low dose range that concomitantly improved hippocampal function assessed in a memory task (Bakker et al., 2012; 2015). In a prior meeting (March 2014) the FDA agreed that there are no concerns on safety/toxicity in repurposing this medication given the large amount of safety data for levetiracetam at much higher doses in the treatment of epilepsy. Support under this application will ensure the timely initiation of a Phase 3 trial using a novel therapeutic approach with medication de-risked for adverse effects on patients. At the 2014 pre-IND meeting, the FDA also confirmed that an appropriate measure for efficacy in the pivotal trial would be the use of CDRsb as a sole primary endpoint and that no further preclinical or clinical data would be needed to support such a trial. The end of Phase 2 (EOP2) meeting with the FDA on the Phase 3 protocol is now scheduled for June 14, 2016 with a feasibility study for site selection currently underway. After the EOP2 meeting with the FDA, manufacturing of AGB101 for use in the Phase 3 trial and other activities will be completed prior to first patient enrollment expected in Q1 2017. In addition to the primary FDA regulatory objective of the Phase 3 trial to examine the efficacy of AGB101 on change in the CDRsb at 78 weeks from baseline, much additional data relevant to biomarker development (e.g. EC thickness/volume, hippocampal volume, DNA, resting fMRI, cognitive tests) will be collected under the Phase 3 protocol. Thus this proposal is aligned with the objectives under PAR-16-364 to advance late stage clinical development of therapies in AD. Funds under this application will specifically contribute to support of the costs for conducting the Phase 3 trial at sites in the U.S and partial support for a management team experienced in all Phases of translational and clinical development of therapeutics for AD.