The closely watched med being developed by Wyeth and Elan failed to achieve statistical significance and also raised the risk of a potentially serious side effect, especially in people with a genetic risk of developing Alzheimer's, according to trial data released today at the International Conference on Alzheimer's.
The drugmakers reported that 12 people with mild-to-moderate Alzheimer's who were treated with the drug, called bapineuzumab, developed a build-up of fluid in the brain called vasogenic edema. And 10 of those cases were in people who have the ApoE4 gene, which significantly raises their risk of developing Alzheimer's. The other two patients didn't carry the gene.
"Usually this occurred after the first or second dose," Ronald Black, Wyeth's assistant vp in neuroscience research, tells Reuters. "About half of them had no symptoms at all, and about a third had minor symptoms." He adds that vasogenic edema appeared to be "strongly related" to the dose taken by patients and "the higher doses get more." None of those who received a placebo developed the brain-swelling condition. All those who suffered this side effect recovered, he adds.
What's more, the 234-patient Phase II study did not attain statistical significance on the pre-specified efficacy endpoints in the overall study population - change from baseline in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Disability Assessment Scale for Dementia (DAD). The news sent Elan stock down 17 percent and Wyeth shares fell nearly 10 percent in after-hours trading.
However, the drugmakers are quick to note that post-hoc analyses showed "statistically significant and clinically meaningful benefits in important subgroups," and showed benefit for patients not carrying the ApoE4 gene, according to their statement.
"I think the (drug's) side effects are going to be perhaps significant, but if they are temporary and tolerable and if the drug shows a benefit, the risk-benefit ratio will be worth the side effects," Scott Turner, incoming director of the Memory Disorders Program at Georgetown University Medical Center in Washington, tells Reuters. "This is potentially the first disease-modifying therapy."
When they looked at people do do not carry the gene and who completed the study, "we have absolutely dynamite data," Sid Gilman of the University of Michigan, who helped work on the study and told the IACD meeting in Chicago late today. "There is a very strong signal among non-carriers, suggesting a beneficial effect."
Others were cautious. "You can't conclude anything about the efficacy of the drug from this trial," Ronald Petersen of the Mayo Clinic in Rochester, Minnesota, tells Reuters. "It's a secondary analysis. You have to go with what they pre-specified and what their endpoints were, and they didn't make those." Petersen is incoming chairman of the Alzheimer's Association's scientific board and chairman of a safety monitoring board for a therapeutic vaccine Wyeth and Elan are working on for Alzheimer's.
At issue is whether amyloid plaques in the brains of Alzheimer's patients are a major cause of the disease, if breaking them up can prevent the disease from developing. Another theory holds the plaque is a consequence of Alzheimer's. The results, unfortunately, do not resolve the debate.
A webcast will take place at 7 pm EST. Besides Black, those discussing the results will be Sid Gilman of the University of Michigan, who chairs the bapineuzumab Safety Monitoring Committee; Allison Hulme, Elan's executive vp and head of global development; Dale Schenk, Elan's executive vp and chief scientific officer, and Gary Stiles, Wyeth's chief medical officer. You can watch right here.
4 Comments
With these results on top of Flurizan's failure for Myriad Genetics, I think the theory has been trumped that amyloid plaques are the key to unlocking a treatment for ALZ.
So far (just from Ed's summary) there isn't any new info that wasn't already known. It's interesting to me that the side effects occured most in the apo-E4 set while the benifit was observed in the NON-apo-E4 set. Why isn't more being made of that? Maybe something else will be forthcoming at the 7:00 briefing...
If 30% of the patients in the treatment arm are Apoe4 non-carriers, then about 9 per group (of 30) were non-carriers. In the highest dose (2.0 mg/kg), 2 of the 9 non-carriers had vasogenic edema. That is about 28% and yet they still are going forward with this dose in Phase 3.
The press release from Elan/Wyeth had the title "Elan, Wyeth present encouraging bapineuzumab Phase 2 trial results at ICAD" which makes one wonder what discouraging news would look like.
Couldn't agree more with prior commenters. At the very least, the amyloid theory has a lot of 'splainin' to do. Now all eyes turn to gamma-secretase inhibitors....
The hype with which Wyeth and Elan presented these results was insane. Any time drug companies start promoting post-hoc subgroup analyses, you can almost guarantee that they've got nothing. Because of course they're going to pick a subgroup with some prima facie biological plausibility -- that still doesn't change the fact that they're doing after-the-fact data mining to make these claims in the first place.
I've written more on the subject at BNET Pharma.