Just to provide some balance on this thread, here are some comments from Alzforum on the aducanumab trial. After recognizing the plaque busting ability of aducanumab, Lon Schneider of University of Southern California Keck School of Medecine made these comments:
"Unfortunately, and despite the authors’ disclaimer that “[t]he trial was not powered for the exploratory clinical endpoints, thus the clinical cognitive results should be interpreted with caution,” they nevertheless spend a lot of ink analyzing and discussing clinical efficacy claims from a study that was not designed to do so. There are several problems here:
The sponsor treated the three separate and sequential dosing cohorts (placebo, 1, and 3 mg/kg; placebo and 10 mg/kg; placebo and 6 mg/kg cohorts) as though they were a parallel-group trial by comparing the four dosing groups to a placebo group pooled from the three cohorts. That is, they made the study seem as though patients were randomized contemporaneously to placebo or one of the four doses in a parallel-group, dose-ranging trial. In fact, each cohort was separately randomized: The first cohort was randomized earlier than the second, 10 mg/kg cohort; and the second cohort prior to the third, 6 mg/kg cohort. They called it a “staggered parallel-group design,” but really the cohorts were separate parallel-group studies occurring at different times and differing sites. So, for example, the last cohort, the 6 mg/kg dosing group, was compared to mainly placebo patients acquired nearly a year earlier and from different sites.
The above and play of chance might explain why the pooled placebo group tended to score better on the CDR-sb and FCSRT at baseline than the treatment groups. At best, after covariate adjustments for baseline scores and ApoE, and not adjusting the p value for the multiple comparisons, there was a nominally significant effect for the CDR-sb and the MMSE for the 10 mg/kg dose; and this was accompanied by implausibly large mean differences from placebo, about 1.24 and 2.25 for the CDR-sb and MMSE, respectively. Only three of 16 CDR-sb and MMSE contrasts were nominally significant at the unadjusted 0.05 alpha error level, and the NTB and FCSRT (memory) tasks did not show significant effects (Extended Data Table 1). Outcomes from the Cognitive Drug Research (computerized) battery were not reported.
If the individual dosing cohorts had been presented separately as they were in the very similarly designed
bapineuzumab MAD study (
Salloway et al., 2009), we probably would see substantial variation in the placebo change and clinical effects within each group. Without the display of the cognitive data by dosing cohort, one has to wonder whether the apparent CDR-sb and MMSE benefits at 10 mg/kg had to do with variable baselines between cohorts and sites, statistical corrections, or extreme comparisons.
The enthusiasm for aducanumab should rest on its PK, PD, plaque-busting ability, preclinical biochemical characteristics, and clinical safety. One doesn’t need to invoke implausible clinical and cognitive effects to make a compelling case for the potential for aducanumab."
What do you know copper, Dr Schneider is also comparing the aducanumab trial to a Bapi trial. "If the individual dosing cohorts had been presented separately as they were in the very similarly designed
bapineuzumab MAD study (
Salloway et al., 2009), we probably would see substantial variation in the placebo change and clinical effects within each group." Perhaps you should write him to explain how inappropriate that is
http://www.alzforum.org/news/resear...anumab-phase-1b-study-published#comment-21601
(20min delay)