Clinical Trials: Leqembi

Lane Simonian

An FDA advisory board is going to provide input on the anti-amyloid drug Leqembi in June. For aducanumab the FDA statistician showed that the drug had almost no affect on non-APOE4 carriers, which may have impacted the FDA advisory board's decision not to recomment its approval, although the FDA later approved it anyway.

The phase 2b trial for lecanemab/Leqembi also showed the drug had almost no affect on non-carriers and yet the phase 3 trial seemed to indicate that this was the group who benefitted most from the drug. How could two trials with the same medicine diverge so radically?

In the phase 3 trial, Biogen and Eisai compared each group (those with two copies of the APOE4 gene, those with one copy of the the APOE4 gene, and non-carriers) against a combined mean score for those on the placebo. The results were as follows (as measured by Clinical Dementia Rating-Sum of Boxes scores):

4.83-.75=4.08 in non-carriers on Leqembi

4.83-.5=4.33 in those with one copy of the APOE4 gene

4.83 + .28= 5.11 in those with two copies of the APOE4 gene.

If these were the true results then the simple solution would be not to approve the drug for those with two copies of the APOE4 gene as they are the ones most likely to suffer from brain swelling and brain bleeds.

However, when you compare the effects of the drug against the mean placebo scores for each group the figures change dramatically because carriers decline more rapidly than non-carriers during the early stages of Alzheimer's disease. Note, though, these figures are based on decline rates in previous anti-amyloid trials and on charts for historic decline in all three groups. The following then is not perfect in terms of exact scores but indicative of the effects of Leqembi on different groups of patients.

4.18-.1=4.08 in non-carriers on Leqembi

4.93-.6=4.33 in those with one copy of the APOE4gene

5.71-.6=5.11

The results for Leqembi are neither statistically nor clinically significant for non-carriers. For carriers, the effects of the drug are statistically significant, but probably not clinically significant.

We will see if the FDA has learned anything from the aducanumab debacle.