Two Alzheimer’s immunotherapy drugs flunk in four studies

Although they provided valuable insight, the four failed immunotherapy trials didn’t adequately test the theory that clearing amyloid – whether by dissolving plaques or preventing further aggregation – could benefit Alzheimer’s patients, Eric Karran, Ph.D., and John Hardy, Ph.D., wrote in an accompanying editorial (N. Engl. J. Med. 2014;370:377-8).

During the first bapineuzumab study, its upper dosing range was limited by the occurrence of brain edema, and sometimes microhemorrhages, associated with higher doses, the authors said. And the inclusion of patients with "mild Alzheimer’s," who probably had non-Alzheimer’s dementia, may have tainted the study pool and subsequent results of both trials.

"A common finding in the trials of bapineuzumab and solanezumab was that approximately 25% of patients with mild Alzheimer’s disease tested negative by means of PET amyloid imaging; they most probably did not have Alzheimer’s disease. In EXPEDITION 3, positivity on PET amyloid imaging is an inclusion criterion, and this will greatly increase the potential to show efficacy," they wrote.

Although bapineuzumab research is dead, work on solanezumab continues. Building on a signal of possible benefit in patients with mild disease, EXPEDITION 3 will focus solely on those patients. Investigators hope to reconcile the drug’s dichotomy – a hint of clinical effect in the absence of biomarker evidence.

"Possibly, in mild Alzheimer’s disease, solanezumab reduces the process of ongoing Abeta aggregation, and it is this – rather than the presence of plaques – that triggers downstream pathologic processes that later become Abeta-independent ... . We advocate continuing to investigate ways to modulate Abeta levels in the brain while accepting that we lack clarity on the roles that different forms of Abeta play in the disease," the authors wrote.

Dr. Karran is the director of research at Alzheimer’s Research UK, the country’s leading dementia research charity. He was previously chief scientific officer at Janssen Pharmaceuticals in Belgium. He had nothing to disclose. Dr. Hardy is a geneticist and molecular biologist at University College London. He first posited the amyloid cascade theory of Alzheimer’s pathophysiology. He has received fees for serving on a speakers bureau for Eli Lilly and consulting for Eisai.