Solanezumab: Learning Lessons from Recent Therapeutic Disappointment

January brought the publication of negative trial results for the hopeful Alzheimer’s therapy solanezumab. We ask Lewis Killin, Clinical Studies Officer for the Neuroprogressive and Dementia Research Network, what these findings mean for Alzheimer’s disease research and what lessons can be learned from this latest setback.

In the ongoing search for effective treatments for Alzheimer’s dementia, much hope has been placed in those investigational drugs targeting amyloid-beta, a protein which can clump together in the brain to form the hallmark plaques associated with Alzheimer’s disease. Although initially unsuccessful, previous trials of the experimental amyloid-targeting treatment solanezumab hinted at a trend towards a treatment benefit in those participants with the mildest disease severity. A large international trial was therefore initiated to evaluate whether solanezumab could improve particular memory and thinking measures in over a thousand volunteers at this early stage of dementia.

The trial failed to yield a positive outcome. Here, our guest Lewis Killen reflects on how we can move forwards using the knowledge gained from this recent disappointment.

‘Research in treatment for Alzheimer’s Disease has been described as experiencing a “14 year losing streak.”  This January, Eli Lily published their study of solanezumab to declare that it did not make people perform significantly better on their outcome measure than people taking a placebo.

Clinical research progresses through three phases of questions:  is this new treatment safe; does it work at all, and if so, does it work better than what’s out there already?

Treatments can fail during any of these phases; solanezumab faded at the third.

The description of research as going through a losing streak is telling. It suggests that the progression of treatment through phases is something like a gamble, and eventually we will experience a lucky break. But research does not progress like this. Progress is made through careful adjusting and refining. It is made by picking apart failures and investigating their causes.

In Phase III trials, the definition of failure is singular and definitive. However, the causes of failure are multifaceted and opaque. When a scientist looks at a failed trial, they should be asking:

  • What would we change if we could do this again?
  • Is this treatment attacking the most fundamental aspect of Alzheimer’s Disease?
  • At what point in the disease should we be thinking about intervention; could we have been earlier?
  • Was the outcome measure appropriate?
  • Was it good at picking up whether someone was getting better or worse?
  • Do we need to use something better?’

In relation to this third point; going in earlier, trials of solanezumab remain ongoing in people at increased risk for Alzheimer’s dementia but who are yet to overtly show any symptoms. Final results are not expected before 2021.

‘This process takes time. For the public health crisis that is Alzheimer’s Disease, time is of the essence. For this reason, we need swathes of studies run in parallel; a divide and conquer strategy against the causes of failed trials. Every study and piece of evidence that is revealed matters, because our current failures are telling us something that we don’t yet understand.’