A Prospective, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Efficacy and Safety Study of Oral ELND005 for Treatment of Agitation and Aggression in Patients With Moderate to Severe Alzheimer’s Disease | C4C

ELND005 (1,3,5/2,4,6-hexahydroxycyclohexane; scyllo-inositol) is an orally bioavailable small molecule with a molecular weight of 180 g/mol (Daltons). To date, ELND005 has been evaluated as a potential disease-modifying treatment of Alzheimer’s disease (AD). Two completed Phase 2 studies (ie, Studies ELND005-AD201 and -AD251) in AD were initiated based on its amyloid anti-aggregation effects in preclinical studies. Multiple lines of evidence from Study AD201 support the potential of ELND005 as a treatment of agitation and aggression in patients with AD, namely: 1) ELND005 decreased the emergence and severity of agitation/aggression in patients with Moderate AD; 2) The dose of 250 mg ELND005 twice daily (BID), which had acceptable long-term safety, decreased brain myo-inositol to levels similar to that reported for therapeutic doses of lithium; and 3) Correlations between ELND005 pharmacokinetic (PK) and neuropsychiatric symptoms (NPS) emergence/severity support this pharmacologic effect. Neuropsychiatric symptoms, including agitation and aggression, are associated with increased morbidity, caregiver burden, and health economic costs. Agitation and aggression are also a major cause of acute care inpatient hospitalizations (Soto et al 2012) and pose a major challenge for AD patient care. Antipsychotics are frequently used, with limited efficacy and associated long-term safety risks. Considering the large number of AD patients, the increasing incidence, and the high prevalence of agitation in later stages of the disease, this unmet need for safe and effective treatments has a major public health impact. A completed Phase 2 program evaluated ELND005 as a potential disease-modifying agent in patients with Mild to Moderate AD. This included two studies, a placebo-controlled Study AD201 (Salloway et al 2011) and its open-label extension Study AD251. In Study AD201, ELND005 showed beneficial effects on NPS, including a decrease in the severity of agitation/aggression that was most prominent in Moderate AD patients. Agitation and aggression are among the most disruptive NPS in AD and increase in severity with disease progression. Neuropsychiatric symptoms in AD are thought to reflect synaptic dysfunction in specific cortical neuronal networks. ELND005 has the potential to improve synaptic activity in these networks via a dual mechanism of action: 1) regulation of brain myo-inositol metabolism and phosphoinositol signaling and 2) protection from oligomer-induced toxicity due to its amyloid anti-aggregation effects. These findings formed the basis for the evaluation of ELND005 as a treatment of agitation and aggression in AD.