24 RESULTS
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COMMENT Another disappointing but not unexpected result. The hope is that we can learn a lot about the clinical trial design with regard to “confounding” parameters. A major underestimated problem is the effect size of the pharmacodynamic interactions between β-a
COMMENT It is easy to forget in the excitement around the amyloid studies that clinical trial results with alternative approaches have been presented, some with impressive results. In particular, the small NA-831 (traneurocin) Phase 2 trial showed an impressive d
COMMENT The sudden discovery of a beneficial effect in one, but not in a second Phase 3 outcome for aducanumab could be due to a combination of a genuine dose-dependent effect and a statistical effect due to an imbalance of a responder genotype. We applied our Qu
COMMENT could have a modest clinical benefit. I acknowledge that this comment falls completely outside of the
COMMENT The negative outcome of any trial in AD is always disappointing, especially since this is a second attempt and it is easy to dismiss this target for symptomatic pro-cognitive enhancement. However as with other examples, the pharmacodynamic interactions wi
COMMENT The latest trial failure with verubecestat /therapeutics/verubecestat underscores why sometimes a linear simple hypothesis is compounded by complex non-linear biology in the human brain. To assess the differential biology of short and long forms of Aβ on
COMMENT Despite these setbacks, I would disagree that the 5-HT6 antagonist concept is dead. Although we don’t have the details, it is likely that the clinical trial design did not take into account the pharmacodynamic (PD) interactions of 5-HT6 antagonists with c
COMMENT The reported premature halt of the BACE inhibitor is a substantial setback, as the field desperately needs some success. Obviously, we need to scrutinize the clinical data in more detail before we can identify possible reasons. However, together with the
COMMENT This is a very noble and timely initiative given the substantial translational issues between current transgene animal models based on familial mutations and the clinical reality with sporadic late-onset AD patients. Demonstrating an effect of a novel dru
COMMENT This project is a major tour de force and likely an excellent example of the implementation of novel guidelines for making preclinical animal research more reproducible (Shineman et al., 2012). It will also provide a good database for preclinical drug met
COMMENT The proposal of combination trials, necessarily with amyloid-modulating interventions, is a substantial challenge, as discussed in an earlier post. Basically the different synthesis rates of Aβ1-40 and Aβ1-42 (Potter et al., 2013) and different aggregatio
COMMENT Besides specific interaction details of the antibody with the amyloid peptide, one also has to consider the larger environment of Aβ synthesis, breakdown, forward and backward aggregation parameters, antibody-mediated microglia-dependent clearance, and im
COMMENT There were some references in this Webinar to the need for more mechanism-based modeling. Someone asked whether modeling and simulation (ever) had been able to identify possible hypotheses for unexpected outcomes in CNS diseases. With the mechanism-based
COMMENT The proposal of combination trials, necessarily with amyloid-modulating interventions (as they are the only disease-modifying drugs close to the clinic), is a substantial challenge, both in terms of selecting drugs and more specifically doses. Based on th
COMMENT Our surprise reaction at this result might have been driven by our amyloid-centric view of Alzheimer’s disease. Effects on amyloid phagocytosis might not be the primary process driving vulnerability to certain TREM2 SNPs. TREM2 does other things besides a
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