Solanezumab: Missed Endpoints, Some Hope Regardless

Eli Lilly’s investigational monoclonal antibody failed to reach its primary endpoints, but it was associated with a significant slowing of cognitive decline in patients with mild Alzheimer’s disease.

Progressive neurodegenerative Alzheimer's disease (AD) affects more than 5.4 million Americans, and the numbers are growing ever higher as the Baby Boomers move into their older years. The condition’s incidence is expected to reach approximately a million people each year by 2050, doubling or even tripling the overall number of affected people. Effective disease-modifying treatments are sorely needed, but are unavailable because we have only a partial understanding of AD’s pathophysiology.

We do know some basics—that the intracellular protein process in AD is abnormal and characterized by the presence of intraneuronal protein clusters (neurofibrillary tangles, or NFTs). NFTs are paired helical filaments of the hyperphosphorylated tau protein and extracellular beta-amyloid aggregates (senile plaques, or SPs). Researchers remain unsure about how NFTs and SPs work together or cause neuronal death.

One theory—the amyloid cascade hypothesis—suggests that SPs develop first, causing NFTs to develop with oligomeric forms of amyloid beta (Aβ)—dimers, trimers and other multimers—causing neuronal death and Aβ-derived diffusible ligands (ADDLs), which in turn causes cognitive decline. (Normal Aβ is monomeric.) Immunotherapy in the form of conformation-specific monoclonal antibodies targeted to oligomeric Aβ species and ADDLs might ameliorate cognitive effects without altering normal monomeric Aβ physiology.

Several clinical trials are investigating active and passive immunotherapy approaches. On August 24, 2012, Eli Lilly and Company announced that 2 Phase 3 studies of its investigational monoclonal antibody solanezumab failed to meet their primary cognitive and functional endpoints. These trials enrolled patients with mild-to-moderate AD.

Despite the setback, Eli Lilly found encouragement in a secondary pooled analysis of the studies. Administered at the test dose, solanezumab was associated with a statistically significant slowing of cognitive decline in patients with mild AD, although not in patients with moderate AD. These results suggest that more study is needed to determine if an Alzheimer’s therapy targeting Aβ can improve cognitive abilities in people with mild-to-moderate Alzheimer’s. The company is supporting a continuing open-label extension study of solanezumab.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.