Conference Coverage
Subanalysis spurs continued study of solanezumab for Alzheimer's
Major finding: Solanezumab decreased cognitive decline by 34% and functional decline by 17% in a group of patients with mild Alzheimer’s disease....
Dr. Aisen presented results that compared the early-start and delayed-start subgroups by four different measures of efficacy, and each of the four analyses showed that the separation between the outcomes of the two treatment subgroups remained fairly constant during follow-up of as long as 2 years, findings consistent with the hypothesis of disease modification according to the statistical tests developed by researchers at Lilly, the company that sponsored the EXPEDITION studies and is developing solanezumab. “The curves are consistent across measures and over time. The late-start group did not appear to catch up. The shape of the curves supports disease modification,” Dr. Aisen said.
“This is the first time that a delayed start methodology has been analyzed in an Alzheimer’s disease clinical trial,” he noted.
The FDA’s view
Several staffers from the FDA who formed a panel at the session to discuss the results and the delayed-start trial design as a way to try to prove disease modification expressed skepticism about the validity and relevance of this analysis.
Mitchel L. Zoler/Frontline Medical News
Dr. Lisa LaVange
“The delayed-start design is a clever idea, but it is tough to establish disease modification,” said Lisa LaVange, Ph.D., director of biostatistics in the FDA’s Center for Drug Evaluation and Research. “The new methods [for analyzing delayed-start outcomes] are intriguing, but you want to show that the difference doesn’t deteriorate with time, and that requires the first difference [at the end of the placebo-controlled phase] to be significant and meaningful. You need to show first one thing, and then another, and that’s complicated.”
Dr. LaVange also highlighted the issue of many patients dropping out from the extended-treatment phase. “One of the biggest problems with delayed start is the missing-data problem. We need to be very careful when imputing missing data for dropouts. The missing data aspect of delayed start needs more attention.”
Another concern voiced by the FDA staffers who commented on delayed-start trials and trying to prove disease modification was the paramount importance of showing efficacy during the placebo-controlled phase of the trial.
Mitchel L. Zoler/Frontline Medical News
Dr. William Dunn
“We want to modify the disease, but the prize is clearly a large treatment effect. Disease modification is absolutely not required for drug approval,” said Dr. William Dunn, director of the division of neurology products for the FDA’s Center for Drug Evaluation and Research. “What we are after is a treatment effect.”
The EXPEDITION trials and the delayed-start analysis for disease modification effects were funded by Lilly, the company developing solanezumab. Dr. Aisen has received research support from Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. Dr. Knopman said he has no other disclosures. Dr. LaVange and Dr. Dunn had no disclosures.
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