I don’t disagree that blarcamesine’s MoA is upstream and longer-horizon compared to the plaque-focused mAbs. But amyloid and tau aren’t “mAb biomarkers” — they’re core A/T/N biology of Alzheimer’s itself.
And the company’s own slides repeatedly say SIGMAR1 activation leads to improved autophagy and proteostasis upstream of both the amyloid and tau pathways.
If that’s the case, mechanistically, then Aß42/40, p-tau, and NfL are still valid downstream biomarkers to show disease modification, even for an upstream drug. Regulators are not asking for mAb-level effects — just internally consistent A/T/N signals in the same subgroup where the clinical effect is claimed.
So I agree blarcamesine shouldn’t be expected to drop plaques like a mAb, but if ABCLEAR3 is the key efficacy subgroup, the absence of clearer A/T/N support is still something CHMP will look at carefully.
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