Bioclinica scientists David Scott and Katarzyna Adamczuk contributed to a recent publication summarizing volumetric MRI findings from a phase III clinical trial of Merck’s BACE inhibitor verubecestat. The trial did not meet its primary clinical endpoint, though significant reduction in brain amyloid load was observed. Volumetric MRI changes were also significant, though paradoxically the treated groups appeared to demonstrate an increase in volume change (i.e. atrophy), compared to placebo.

The phenomenon was observed throughout the brain and could be seen following only 13 weeks of treatment. VBM analysis revealed the effect was a broadly distributed pattern throughout the cortex, and these findings were discussed at the recent CTAD conference.

VBM Results: Main Effect of Visit


Compared to placebo, verubecestat exposure was associated with a highly significant reduction in GM tissue density for both dose groups at both week 13 (top) and week 78 (bottom) visits. 

The EPOCH trial of verubecestat in early AD patients revealed BACE inhibition is associated with an acute change of brain tissue contrast as detected by volumetric MRI. This apparent “pseudo-atrophy” has been reported for other CNS compounds, including those that do not target beta-amyloid plaques. What could explain the phenomenon, and are there implications for CNS trial design?

The EPOCH trial of verubecestat in early AD patients revealed BACE inhibition is associated with an acute change of brain tissue contrast as detected by volumetric MRI. This apparent “pseudo-atrophy” has been reported for other CNS compounds, including those that do not target beta-amyloid plaques. What could explain the phenomenon, and are there implications for CNS trial design?

  1. Why is this considered “pseudo-atrophy” and not outright tissue loss?
    The apparent volume change is unlikely to reflect a neurodegenerative or neurotoxic process. For example, relevant biomarkers like CSF NfL concentrations did not differ between groups. Further, volume change trajectories in treated groups became parallel with placebo after week 13. Less convincingly, the sites of largest acute change do not overlap with sites of active, ongoing neurodegeneration as seen in the placebo group.
  2. Is this a consequence of the amyloid pathway?
    Yes and no. BACE inhibition does not actively clear amyloid, but reduced production could facilitate overtaxed clearance mechanisms. In the case of EPOCH, volume change was primarily observed within amyloid-rich brain regions. But, regional vMRI changes were not correlated with regional amyloid load at baseline. And the change in amyloid load at week 78 was actually negatively correlated with degree of volume change.
  3. What else could explain the phenomenon?
    Altered neuritic dystrophy and/or inflammation could induce fluidic shifts detectable by vMRI. The reports of similar findings with non-amyloid compounds suggests this process may not be about BACE inhibition in particular. Rather, it’s possible many other CNS drugs induce similar acute effects.
  4. What are the implications for future clinical trials?
    The clinical significance of the volume change appeared weak, especially considered against the impact of ongoing disease-related neurodegeneration. However, there was some evidence of early-onset cognitive worsening in EPOCH, possibly mirroring the acute effect seen in MRI. Future clinical trials should consider accounting for the acute effect of onboarding the CNS agent. Evidence of therapeutic efficacy may become more obvious once this acute “clouding” phenomenon is accounted for.

Read the article here:

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer’s disease brain