ICAD 2011: Amyloid Targets in Trouble

A number of notable presentations from the ongoing International Conference on Alzheimer's Disease (ICAD) in Paris, most of it ouch-inducing for Lilly.

Dismal news about Lilly's now-defunct semagacestat: Patients with AD who took the company's experimental anti-amyloid gamma secretase inhibitor in a placebo-controlled phase 3 study remain clinically worse 7 months after stopping the drug. The take-home warning from medical pundits is that researchers should stay away from targeting gamma secretase in their zeal to clear beta amyloid, the protein that accumulates in the brains of AD patients. Lilly pulled the plug on semagacestat development in August of last year.

A protein complex, gamma secretase processes amyloid precursor protein, which produces beta amyloid. The tentative conclusion: target beta amyloid (if at all) directly. Bloomberg notes that BMS is also developing a gamma secretase inhibitor, avagacestat (BMS-708163), for the treatment of AD. The compound, in phase 2 development, may or may not be associated with a similar class-effect outcome. But...

Brain edema continues to plague clinical development of anti-amyloid compounds: Regardless of the structure or mechanism of anti-amyloid compounds, one thing appears to be consistent. They all seem to be capable of causing brain edema—probably because they all clear (or facilitate clearing of) amyloid that surrounds cerebral blood vessels. Reuters reports that 3 patients who received the experimental BMS drug developed vasogenic edema. And in January, Lilly's CEO announced that 1 patient in a solanezumab trial had developed brain edema, the adverse effect that has plagued Pfizer/JNJ's anti-amyloid mAb, bapineuzumab. Phase 3 results of Lilly's solanezumab, an anti-amyloid monoclonal antibody, are expected in the 3rd quarter of next year, but The Street isn't sanguine. Les Funtleyder, a NY-based portfolio manager and healthcare strategist, told Bloomberg that he doesn't think the drug will be approved. [A clarification to the parenthetical statement: Lilly would officially argue, if its tracer is approved to rule out amyloid-related dementia, that florbetapir is most useful for distinguishing between clinical AD that is associated with brain amyloid and non-amyloid dementias—like frontotemporal dementia. Presumably the clinical AD patients with very low levels of amyloid in this study do not have pathologically defined AD but some other kind of dementia.]

Lilly continues to put a positive spin on its neuroscience program for AD: While attempting to reassure investors that it hasn't bet everything on the idea that amyloid is the target in AD, Eric Siemers, MD, the senior medical director for the Alzheimer's Disease Team, told Bloomberg, "We haven't put all our eggs in the amyloid basket," and he talked up the company's preclinical efforts to go after tau protein, the component of AD's neurofibrillary tangles.

Nevertheless Lilly is still heavily promoting its not-yet-approved PET amyloid tracer, florbetapir (trade name, Amyvid), through the medical literature generally and the ICAD meeting specifically. The latest from ICAD is that positive scans may predict further cognitive decline in patients with mild cognitive impairment (MCI) on the basis of the existing amyloid burden in the brain. (Although, without a disease-modifying intervention, file this outcome under "What am I supposed to do with this information in practice?")

Lilly bought florbetapir, along with its manufacturer, Avid Pharmaceuticals, in November of last year for $300 million, and will fork over another $500 million if the tracer is FDA approved. In March, the agency said that it would require Lilly to establish a reader-training program to ensure the reliability of scan interpretations. The requirement was made after an FDA advisory committee recommended conditional approval of the tracer (with the indication of ruling out, not ruling in, "pathologically significant levels" of brain amyloid) in January. One month later, Lilly's neuroscience chief, David S. Brendt, MD, PhD, abruptly left the company.*

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

* Update: JNJ "poached" Bredt, said the WSJ Health Blog in March. So it appears that Bredt wasn't ousted from Lilly but was wooed by JNJ (which is developing the troubled bapineuzumab along with Pfizer).