Eli Lilly and Company recently announced that the monoclonal antibody solanezumab failed to meet primary end points in EXPEDITION3, a phase 3 trial in 2100 patients with mild Alzheimer’s dementia.¹ In comparing outcomes in patients treated with solanezumab vs patients in a placebo group, the researchers found no significant difference in scores on the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS- Cog₁₄). As a result, Eli Lilly announced that they would not pursue regulatory submissions for the drug in this particular patient population.

Experts disagreed about whether the failure signals an end to the line of inquiry based on the “amyloid hypothesis,” which holds that the accumulation of amyloid protein in the brain leads to the development of Alzheimer’s disease (AD). It has been proposed that solanezumab may reduce this accumulation because it “mops up amyloid proteins from the blood and cerebrospinal fluid,” according to an article published in Nature News.²

Groups such as the Alzheimer’s Association expressed disappointment and the hope that separate research efforts focused on solanezumab and other anti-amyloid agents will continue.³ In addition to EXPEDITION3, Eli Lilly has been conducting trials to assess the efficacy of solanezumab in preventing AD in high-risk individuals. For example, one such trial led by Reisa Sperling, MD, MMSc, a professor of neurology and director of the Center for Alzheimer’s Research and Treatment at Harvard University, involves participants with elevated amyloid levels but no signs of dementia.²

The future of these ongoing trials is unclear in light of the latest results. In the press release regarding EXPEDITION3, John C. Lechleiter, PhD, chief executive officer of Eli Lilly, said, “We will evaluate the impact of these results on the development plans for solanezumab and our other Alzheimer’s pipeline assets.” Meanwhile, similar trials using solanezumab and another antibody by Roche Pharmaceuticals in healthy people with high AD risk are being conducted by Washington University researchers. Additionally, 3 current trials by the Banner Alzheimer’s Institute in Phoenix are exploring the effects of an antibody and 2 other treatments aimed at amyloid production in high-risk individuals.²

To explore the broader implications of these negative trial results, Psychiatry Advisor spoke with Ronald Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging in Rochester, Minnesota. (He was not involved in the solanezumab study.)

Psychiatry Advisor: What do you see as possible reasons for the EXPEDITION3 findings?

Dr Petersen: There are at least 2 potential explanations for these results. It is possible that they did not use a sufficiently large dose. Many of the clinical measures were in the anticipated direction, but the magnitude of the effect was not sufficient to produce a positive result.  The other possibility is that they selected participants for the study who were too advanced in their disease state [and that] the compound worked, but it needed to be started earlier in the disease course. These 2 possibilities are not mutually exclusive.

Psychiatry Advisor: What is your take on the implications of these results for the amyloid hypothesis? What should be next steps in this area of research?

Dr Petersen: These data do not defeat the amyloid hypothesis. Again, the drug appeared to do what it was intended to do, but the effect was not sufficiently large. So, considering the 2 possibilities noted above, the amyloid approach may still be viable. I think most investigators are still pursuing this line of treatment. Other studies are using different antibodies or are attacking the process with different approaches such as with beta-secretase inhibitors, which are designed to block the deposition of amyloid.

Psychiatry Advisor: More broadly, what is the importance of negative findings in clinical trials?

Dr Petersen: While the outcomes might be negative, we learn a great deal from each trial, so the design of the next trial is improved. We already have seen that in the field insofar as most amyloid-targeted therapies now require a positive amyloid positron emission tomography (PET) scan for inclusion of participants — we learned this from previous trials.

Psychiatry Advisor: What do these results foretell for the future of biologic therapy?

Dr Petersen: I think the future is still bright. We not only have other approaches to attacking amyloid but we are also entertaining other targets such as tau. This is a complex disease, and ultimately it may take multiple drugs — ie, combination therapy — to address the multiple underlying disease mechanisms.

We cannot slow our attempt to develop therapies; in fact, the opposite is true. We need to accelerate our efforts to deal with the millions of people who have the disease now and the projected many more who will develop the disease in the very near future.