On the 23rd of July, the British newspapers interpreted Eli Lilly’s most recent data on Solanezumab presented at the Alzheimer’s Association International Conference in Washington DC ranging from a circumspect “Dementia Drug Shows Promise” (the i), through “Jab Will Halt Alzheimer’s” (Daily Express) to “Alzheimer’s Miracle Drug Has Saved My Life” (Daily Mirror). The BBC was at the less excitable end of the spectrum claiming that there were “Early signs that drug ‘may delay Alzheimer’s decline”. Within the scientific literature opinion was likewise divided as to whether Solanezumab does not help in Alzheimer’s disease (McCarthey, M. BMJ 2015), has “questionable potential” (Reardon, S Nat Rev Drug Discov, 2015) and or actually does demonstrate disease modifying effects (Karran, E. BMJ, 2015). So, what’s going on here? Well, the recent debate relates to data from a two-year extension study, EXPEDITION-EXT from the two earlier 18-month Phase 3 studies of Solanezumab (EXPEDITION 1 and EXPEDITION 2) that we discussed previously (Amyloid in Alzheimer’s Disease – The End of the Beginning or the Beginning of the End?). Questions can be raised about the clinical trial design, in which patients and caregivers knew that they were on the drug on the extension trial as well as the effect size (Reardon, S Nat Rev Drug Discov, 2015). Nevertheless, the key observation, which is consistent (but not proof of) a disease modifying rather than symptomatic effect, is that change in the ADAS-Cog score for subjects that were previously on placebo but then given Solanezumab in the extension trial ran parallel rather than converged with the group that received drug during the original 18-month Phase 3 study (see figure below, taken from see Reardon, S Nat Rev Drug Discov, 2015).
Better placed than most to comment on the matter is Dr Eric Karran, currently the director of research at Alzheimer’s Research UK but formerly head of neuroscience research at Eli Lilly when Solanezumab first progressed into development. Dr. Karran, who recently authored an excellent article reviewing the preclinical and clinical data on a variety of Phase 3 Alzheimer’s disease drugs (Karran E. Annals of Neurology, 2014), told the BBC; “If this gets replicated, then I think this is a real breakthrough in Alzheimer’s research. Then, for the first time, the medical community can say we can slow Alzheimer’s, which is an incredible step forward. These data need replicating, this is not proof, but what you can say is it is entirely consistent with a disease-modifying effect”. The Solanezumab replication study, EXPEDITION 3, involves 2,100 patients with mild Alzheimer’s disease with results due in October 2016 and as Dr. Karran comments “if it doesn’t work, we will all be very disheartened” although the next drug stepping up to the crease/plate (depending on whether you prefer your sporting analogies with a British or American flavour) will be Merck’s B-secretase inhibitor, MK-8931 which he described as “a superlative molecule” (Karran, E. Nat Rev Drug Discov, 2015). And so, following the flurry of excitement and hyperbole we settle back down to awaiting the data from rigourously-conducted, placebo-controlled Phase 3 studies with predefined end-points and can best describe the EXPEDITION-EXT data as very interesting without making any extrapolation to the patient benefit and ultimate regulatory approval (or otherwise) of Solanezumab. However, from the patient point of view, it is perhaps best to keep our collective fingers crossed.
Blog written by John Atack