Lilly Not So Nuts to Cling to Solanezumab?
Results of the two phase 3 trials of Lilly’s solanezumab and the two phase 3 trials of Pfizer/JNJ’s bapineuzumab in mild-moderate Alzheimer disease have finally been peer reviewed and published (in the NEJM). My take-aways:
1. Maybe (maybe) it’s no so crazy of Lilly to pursue further clinical investigation of solanezumab in early AD, MCI, and/or (especially) prodromal AD.
While the MAb failed to statistically significantly alter cognition, there were statistical trends toward improvement in the second trial (EXPEDITION-2), the design of which was altered after the fact to assess subtler cognitive changes in milder disease (by incorporating the ADAS-14 scale). There were also, very importantly, biomarker changes suggesting that solanezumab mobilized the soluble version (Lilly consistently makes a big point of this) of amyloid (Aβ), the sticky protein that accumulates in the brains of patients with AD.
The study authors contended that solanezumab shouldn’t be categorized with other failed (we’re looking at you, bapineuzumab) anti-amyloid compounds in AD. “The results of the current study argue for carefully differentiating among these therapeutic approaches according to the underlying mechanism, rather than for grouping all antiamyloid treatments together,” they concluded.
Solanezumab is currently being assessed in 3 studies of individuals with early disease or those at risk of AD: EXPEDITION-3, a DIAN trial (as one of 2 anti-amyloid MAbs), and the A4 Study (estimated primary completion dates: December 2016, July 2014, and April 2019, respectively). Notably EXPEDITION-3 and the A4 Study will “enrich” for enrollees with evidence of abnormal accumulations of brain amyloid (via PET or CSF).
2) Pfizer/JNJ’s bapineuzumab (like Francisco Franco) is still dead because it a) provided no clinical benefit; and b) was associated with dose-related brain edema and/or hemorrhages, phenomena that were most probably caused by the MAb’s effect on amyloid and its mobilization/removal from the central nervous system.
An interesting outcome from the bapineuzumab trials was that the MAb (in dose-related fashion) was also associated with changes in a “downstream” AD biomarker (CSF phospho-tau) in carriers of APOE ε4 (an allele that increases the risk of AD and abnormal amyloid deposition in the brain). To explain the negative clinical results, the authors offered,
It is…possible that Aβ may not be the best target for therapeutic intervention, that too little amyloid was removed, that an important species of Aβ was insufficiently affected, or that other aspects of neurodegeneration were inadequately affected.
Overall, they contended,
Amyloid accumulation probably starts many years before the onset of symptoms, and initiation of anti-amyloid treatment only after dementia develops may be too late to affect the clinical course of the disease.
Notably the bapineuzumab study authors did not make a point of how anti-amyloid MAbs may target soluble versus insoluble (plaque) amyloid (or both) and how this characteristic may affect clinical or biomarker outcomes. It remains to be seen whether Lilly’s emphasis on targeting soluble (aka free-roaming Aβ) is really mechanistically important in the treatment of AD or just a marketing ploy to distinguish solanezumab from the now-defunct bapineuzumab.