EANpages has the honor and the pleasure to introduce this virtual Round Table, composed by some members of the EAN Scientific Panel on Dementia and Cognitive Disorders, who are discussing the Paper of the Month, in addition to the comments of the Presidential Page. We thank the Panel for their enthusiastic participation and we invite all EAN members to participate with sending their comments.
Prof. Reinhold SCHMIDT (Chair of the SP on Dementia and CD, Austria):
The most important and remarkable finding of the PRIME study and its preclinical investigations is that aducanumab selectively reacts with Aβ oligomers including soluble oligomers and insoluble fibrils and that it clears amyloid deposits in a dose-dependent manner. The clinical data are certainly of interest, but caution is advised. The size of the different dose groups was small (in the range of 25 subjects), there was no clear dose-effect relationship, and as stated in the paper the trial was not powered to assess clinical efficacy. Previously, the literature has reported Alzheimer trials with antibodies against Aß that reduced the amyloid load of the study participants and found clinical effects at least in subgroups of the phase II studies with no clinical efficacy in phase III. In this aspect it is of note that the placebo group of PRIME showed a marked decline at week 52 on the CDR-sb and MMSE, with a high chance for lower figures when larger numbers of patients are included. With respect to safety, the main concern was the dose-dependent ARIA-E, which predominantly affected carriers of the ApoE4 allele. Forty-one per cent of patients on 10 mg/kg aducanumab developed ARIA-E and it was the 10 mg group that had the greatest drop-out rate (38 percent). It is unclear if this was due to the larger number of ARIA-E cases in that group. It seems that ARIA-E did not cause a major problem in the trial conduct despite its high incidence. The case for the potential for aducanumab to modify the course of AD is compelling, but the results of two ongoing Phase 3 trials, powered to finally determine the possible clinical benefits are to be awaited.
Prof. Philip SCHELTENS (Management group member of the SP on Dementia and CD, The Netherlands):
For me the most convincing part of this study is the dose-response effect on amyloid PET and to a lesser degree and only after 52 weeks on MMSE and CDR. We have seen other studies showing amyloid removal on PET but never in such a dose-response manner. This, combined with the low rate of side effects, and being a fully human antibody, makes me optimistic to the future. There are issues with using SUVr because of the flow sensitivity; hence it may still be a flow effect of the compound itself in areas specifically affected by AD and not in the reference region, or the reverse even, but again the dose response curve and the clinical effect render these objections less important. I do however would have liked to see a phase 2 study in between, showing lowering of absolute volume of amyloid using quantitative PET.
Dr. Daniela GALIMBERTI (Secretary of the SP on Dementia and CD, Italy):
Data on aducanumab are promising but yet to be considered cautiously. The scientific rationale at the basis of the treatment has been definitely proven by PET data. On the other hand, still there are adverse events to be considered and phase III trial results on clinical endpoints are needed to prove the efficacy in real life. Issues to be considered for the future include a better definition of the treatment window (secondary preventions in at risk subjects versus treatment in mild symptomatic people) and efficacy of the treatment over time to determine the best treatment duration.
