Biomarker Data for Lilly’s Solanezumab Less Than Impressive
Despite overly optimistic press reports, a closer look of an independent analysis of Lilly’s pooled phase 3 biomarker data for solanezumab is warranted.
According to an audio recording of Dr. Paul Aisen‘s presentation at the recent CTAD meeting in Monaco, the anti-amyloid MAb showed “clear evidence of target engagement” through a “huge rise in total plasma [amyloid beta]”—meaning that the MAb hooked up with its intended target. Fine. Moreover there was evidence that the MAb altered CSF levels of total amyloid beta (the important 1-40 and 1-42 species), showing that there was some MAb activity in the central nervous system. Also fine. But even more intriguing and more important was evidence that solanezumab reduced levels of free amyloid beta; although this finding only applied to the 1-40 species, not the sticky 1-42 species. Dr. Aisen offered a purely speculative reason for the discrepancy: the 1-42 species of amyloid beta, as opposed to the 1-40 species, is somehow preferentially tied up in amyloid plaques. Perhaps. Although both amyloid species are major components of mature amyloid plaques.
With respect to other recognized AD biomarkers, solanezumab did not statistically significantly alter amyloid deposits seen via PET imaging, CSF tau levels (either total or phosphorylated), or brain volume (either whole or hippocampal) via MRI. However, there was a trend toward a statistically significant treatment difference in subgroups—specifically patients with milder disease or those with evidence of amyloid positivity (the latter group making up 79% of enrollees). Lilly and other investigators would argue that these modest/trending biomarker data compliment the previously reported, modest/trending cognitive benefits of solanezumab seen in mildly impaired patients. Others, like me, may view the results as simply negative, given the lack of consistent statistical significance. Also head scratching was the fact that there was a statistical trend toward a reduced hippocampal volume in solanezumab-treated, amyloid-positive patients.
Overall I’m inclined to conclude that these results provide little support for further trials of solanezumab—including studies of patients with milder AD or those at risk of AD.* If you’re clinging to the amyloid hypothesis of AD, I would think you’d have to show a more robust and clear-cut effect on amyloid biomarkers, before investing the necessary millions and time in additional clinical trials of solanezumab.
In other CTAD news, TauRx Therapeutics announced that it’s (finally) moving forward with phase 3 study of its anti-tau agent, a variant of methylene blue, in AD. The 12- and 18-month studies (here and here) are expected to be completed in December of 2014 and July of 2015, respectively. BTW, the first time methylene blue was ever used therapeutically was more than 100 years ago. German scientist Paul Ehrlich tried the compound in 1891 as an anti-malarial therapy. It was mildly successful and well tolerated, but it turned patients’ urine green (yellow + blue make…). To maintain blinding of the TauRx trials, placebo-treated patients will receive a very small dose of the agent to color their urine.
CSF = cerebrospinal fluid; CTAD = Clinical Trials on Alzheimer’s Disease; MAb = monoclonal antibody; MRI = magnetic resonance imaging; PET = positron emission tomography.
* Unless, of course, you’re desperate. And maybe, you are.