Avoiding future controversies in the Alzheimer's disease space through understanding the aducanumab data and FDA review

Abstract

Key points of disagreement between the aducanumab FDA statistical review, which had primarily negative conclusions, and the clinical review, which had primarily positive conclusions, were investigated. Results from secondary endpoints in positive Study 302 were significant and these endpoints provided meaningful additional information. Findings indicate the statistical review of the aducanumab data was incorrect in a number of key areas. Greater placebo decline was not responsible for the significant results in Study 302. Correlations did exist between reduction in β-amyloid and clinical outcomes. Missing data and functional unblinding did not likely bias results. In contrast, the clinical review went too far in saying the negative results in Study 301 did not detract from the positive results in Study 302, as all clinical data should be considered in the evaluation, and the clinical review accepted the company's explanation for divergence of the results between the studies although much of the divergence remained unexplained. Interestingly, both the statistical review and the clinical review considered the available efficacy evidence despite both studies being terminated early. Implications of these findings include that the divergence in results seen in the two phase 3 aducanumab studies can be expected in other studies with similar design and analysis. Therefore, further research is needed to determine if analysis methods other than MMRM and/or optimized outcomes will provide more consistent results across studies.

Keywords: Alzheimer’s disease; Clinical trials.

Fig. 1

Forest plot of key endpoints in Study 301 and Study 302 with GSTs combining endpoints within the studies and between studies. The assumed correlation between endpoints within studies was 0.3, while correlation between studies was assumed to be 0 due to the independent populations

Fig. 2

Aducanumab-related biomarker changes are associated with slowing in clinical decline (Study 302). Correlations between biomarkers and clinical outcomes. All associations are partial Spearman correlation of change from baseline to week 78 between each variable

Fig. 3

Study 301 high-dose group diverged from an otherwise consistent association between Aβ reduction and slowing of clinical decline. Associations between changes in Aβ and changes in CDR-SB by randomized treatment groups in Studies 103, 301, and 302

Fig. 4

No trend in placebo decline over enrollment time (Study 301 and 302). Trends in placebo group mean changes by enrollment cohorts in Studies 301 and 302

Fig. 5

No systematic effect of PV4 in treatment arms that did not have a dose change (Study 301 and 302). Pre- and post-PV4 mean change from baseline in the placebo and low-dose groups

Fig. 6

Treatment difference of change from baseline in CDR‐SB, MMSE, ADAS-Cog 13, and ADCS‐ADL-MCI at week 78 grouped by study, dose, and ApoE carrier status and including or excluding post‐ARIA observations (× – Study 302, ο – Study 301, C – carrier, NC – non‐carrier; solid line is the line of unity)