EXPEDITION 3 Study: Is It Really a Failure?


Solanezumab did not significantly affect cognitive decline compared with the placebo in subjects with mild Alzheimer's, but there are still takeaways.

Alzheimer’s disease is a condition characterized by progressive dementia affecting cognition, behavior, and functional status. Symptoms tend to appear gradually and progressively. The exact etiology of Alzheimer's is unknown, and therefore, no cure exists.The CDC estimates that Alzheimer's was the sixth-leading cause of death in the US in 2015, and in 2014, 50.4% of nursing home residents were diagnosed with the disease.Tools, such as imaging studies (computed tomography scan, magnetic resonance imaging, and positron emission tomography), laboratory tests (thyroid function and vitamin B12 test), and neurological examination (ADAS-cog14, ADCS-iADL, CDR-SB, FAQ, and MMSE, per the American Academy of Neurology), are used to diagnose Alzheimer's and prescribe drug therapy.

Pharmacotherapy focuses on improving cognition, behavioral symptoms, and functional ability. FDA-approved therapies include NMDA receptor antagonist and cholinesterase inhibitors in order to slow the progression of Alzheimer's and symptomatic management.The American Academy of Family Physicians and the American College of Physicians suggest that memantine has modest benefits in patients with moderate to severe Alzheimer's. In advanced Alzheimer's, a combination of AChEI (donepezil, galantamine, and rivastigmine) and memantine is suggested.Scientists have discovered that Alzheimer's is characterized by the formation of beta amyloid plaques, gliosis, and neurofibrillary tangles.

Therefore, there has been an increasing effort to target such properties via pharmacotherapy. Solanezumab is an investigational humanized monoclonal antibody that works by binding and increasing the clearance of the beta amyloid from one’s brain. Solanezumab has failed to significantly affect cognitive decline compared with the placebo in subjects with mild Alzheimer's.4


2 identically designed randomized control, double-blind, phase 3 trials studied solanezumab in 2052 subjects. Both studies failed to demonstrate significant improvement in cognition or functional ability in subjects with mild to moderate Alzheimer's.5 However, the secondary pooled analysis showed that subjects who received solanezumab had less cognitive decline by about 34% (measured using ADAS-Cog14 and MMESE) and functional decline by 18% (measured using ADCS-iADL) compared with the placebo. Based on the findings of the pooled analysis, EXPEDITION 3 trial was initiated.6

Study Overview

EXPEDITION 3 Trial was a randomized, multicenter, double-blind, parallel, placebo-controlled study. 2129 subjects were randomly assigned in solanezumab or the placebo group to receive 400 mg of solanezumab intravenous infusion every 4 weeks for 76 weeks.4 This is an extended duration compared with 400 mg of intravenous solanezumab every 4 weeks for 72 weeks from the EXPEDITION 1 and EXPEDITION 2 studies. Subjects were authorized to receive concomitant standard of care therapy (achetylcholinesterase inhibitor or memantine alone or in combination) during the 76-week period. 79.9% of the solanezumab group and 77.8% of the placebo group were concomitantly taking the standard therapy. The primary outcome of the study was to test if solanezumab would slow the cognitive decline of Alzheimer's compared with the placebo (assessed using ADAS-Cog14). Subjects who completed the 76-week period were given an option to participate in an optional 24-month open-label period. However, only the double-blind period was published.

The statistical analysis was conducted on the basis of modified intention-to-treat principle and included only subjects who had outcome measurements both at and after the baseline. Tests of effects were conducted at a 2-sided alpha level of 0.05. The primary outcome measure (ADAS-Cog14) was analyzed, and there was no significant difference in the change of score from baseline (solanezumab 6.65 ± 0.36 vs placebo 7.44 ± 0.36, P=0.10).


Although the EXPEDITION 3 trial failed to achieve the primary outcome, there are several takeaways. Because solanezumeb works by increasing the clearance of beta amyloid, people with a relatively high level of beta amyloid at baseline could experience a greater clinical benefit than those who have lower levels of beta amyloid at baseline. Therefore, using screening methods, such as enzyme-linked immunosorbent assay, to establish additional inclusion criteria (eg, baseline beta amyloid level) may potentially affect the study outcome. During the EXPEDITION 3 trial, 400 mg of solanezumab was intravenously administered every 4 weeks, which resulted in poor central nervous system (CNS) penetration.4 Developing a strategy to increase solanezumab’s concentration in the CNS could potentially lead to a clinically meaningful outcome.

For further coverage from the fields of Alzheimer’s disease and dementia, check out PharmacyTimes' sister site, NeurologyLive. The site's condition-specific page serves as a resource for the latest clinical news, articles, videos, and the most recently released data.


  • Slattum PW, Peron EP, Hill A. Alzheimer's disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014.
  • CDC. Alzheimer's disease. cdc.gov/nchs/fastats/alzheimers.htm. Updated October 16, 2016. Accessed April 4, 2018.
  • Qaseem A, Snow V, Cross JT, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148(5):370—8.
  • Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321-330. doi:10.1056/NEJMoa1705971.
  • Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311-21. doi: 10.1056/NEJMoa1312889.
  • Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimers disease patients. Alzheimers Dement. 2016;12(2):110-120. doi:10.1016/j.jalz.2015.06.1893

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