The third time unfortunately was not the charm in the case of solanezumab, Eli Lilly’s antibody against soluble Aβ. This week, investigators led by Lawrence Honig, Columbia University, New York, formally published results of the EXPEDITION3 trial. This was the third Phase 3 test of the antibody, and one focused on people with mild AD. As it has all along, the antibody consistently moved endpoints in the right direction, but only by tiny degrees and, in this trial, not enough to reach statistical significance.
- Trial marks third Phase 3 miss for solanezumab.
- The antibody did not slow cognitive decline in mild AD.
- Primary and secondary prevention trials are ongoing.
Alzforum has covered the trial results extensively (Nov 2016 news; Dec 2016 conference news), including a postmortem dissection of the biomarker data and its lessons for future work (Jan 2017 conference news). Based on the results, in 2016 Lilly announced it would not pursue FDA approval for the antibody for mild AD.
The first two EXPEDITION trials, though overall negative, gave investigators cause for hope when solanezumab slowed cognitive decline by 33 percent in the subset of participants with mild AD (Aug 2012 news). The effect was small but significant. To replicate that result, EXPEDITION3 enrolled 2,129 people with mild dementia, who received IV infusions of placebo or 400 mg antibody every four weeks for 80 weeks. In the previous trials, about 25 percent of participants turned out to be amyloid-negative; the new trial required biomarker confirmation of amyloid accumulation. The primary endpoint was difference in change on the 14-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog); secondary outcomes included additional measures of cognition and function.
At the end of treatment, the solanezumab recipients once again declined less on the ADAS-Cog than the placebo group, but the 11 percent difference was not statistically significant. The direction of the effects on all six secondary outcomes also favored treatment, but because the primary endpoint had failed, the investigators reasoned the secondary outcomes were descriptive and did not include statistical analysis for the paper, but that has been presented in conferences. The antibody continued to show good safety, with a very low incidence of adverse amyloid-related imaging abnormalities (ARIAs).
Now, the antibody’s prospects rest on two prevention trials that are using solanezumab at higher doses for extended times in asymptomatic people. The DIAN and A4 studies are treating cognitively healthy people at risk for AD, either due to dominantly inherited mutations or brain amyloid deposition. Participants are receiving up to 1,600 mg antibody monthly for four or more years. Unfortunately, the results will not emerge until then.
Solanezumab does not reduce brain amyloid, in contrast to the antibody aducanumab, which binds fibrillar Aβ. It’s not clear yet whether plaque clearance is required to improve cognition.
Although it is too early to give up on Aβ immunotherapies, scientists would be foolish to ignore the continued failures of anti-amyloid approaches, wrote M. Paul Murphy, University of Kentucky, Lexington, in an editorial accompanying the paper. “We may very well be nearing the end of the amyloid hypothesis rope, at which point one or two more failures will cause us to loosen our grip and let go,” he wrote, stressing the need for innovative ideas for new treatments.—Pat McCaffrey
- Lilliputian Effect Size Fells Phase 3 Trial of Solanezumab, Leaving Its Future Uncertain
- CTAD: Solanezumab Seen to Nudge AD Ever so Slightly
- Solanezumab: Did Aβ ‘Reflux’ From Blood Confound Target Engagement in CSF?
- Phase 3 Solanezumab Trials "Fail"—Is There a Silver Lining?
No Available Further Reading
- Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):321-330. PubMed.
- Murphy MP. Amyloid-Beta Solubility in the Treatment of Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):391-392. PubMed.