We now know quite a bit about the 2b/3 trial and, by extension, how blarcamesine does and doesn't fit into the ordinary paradigm of an Alzheimer's drug. These differences, on balance, present obstacles to an easy approval -- not because the drug isn't effective, but because it doesn't fit all the pre existing regulatory boxes.
Here are my thoughts:
1. Dose response. Blarcamesine has not adequately demonstrated dose response. Instead, what matters most is the pre existing S1R genotype. Consequently, a higher dose to an S1R mutated patient will be less useful than a lower dose to an S1R WT carrier. That will confound an ordinary drug response analysis that assumes all patients will respond equivalently to a drug.
2. Reported endpoint statistics.The interaction of the S1R and COL24A1 genotypes, which dominate dose response, also create a multi-modal response curve. This, in turn, adversely affects the reported co-primary efficacy results, which are measured using statistical tools (standard deviations, in particular) that assume a standard distribution. Having half of your 30 mg showing an 84.7 percent reduction in decline in ADAS-Cog 13, yet having an over 36.3 percent ADAS-Cog13 reduction in decline outcome is not something you would see with a standard distribution. Blarcamesine also would have shown an even lower p value for ADAS-Cog13 for a 36.3 percent reduction in decline if there were a classical response curve.
3. Biomarkers. The accepted A/T/N biomarkers are oriented toward amyloid plaque reduction. This is not surprising, given that the disease has historically been defined as that symptom. However, blarcamesine is far upstream of plaque reduction, instead aiming at more basic neuronal functions. The ADAS-Cog13 graph does not even show a significant diversion between the dosed and placebo groups until the last twelve weeks of the 48 week trial. The relatively delayed drug effect is inconsistent with the symptomatic relief indirectly measured by the traditional biomarkers.
All these eccentricities are explainable, but having to explain means having to defend, and having to defend is not the best dynamic for a drug approval process. There is really nothing Anavex could have done to avoid these complications; the existing AD trial paradigm is just not a good fit for this first in class drug.
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