BIIB - Eisai And Biogen's Lecanemab: A Flawed Treatment For Alzheimer's Disease

Summary

• Lecanemab only significantly slows down the progression of Alzheimer's disease in APOE4 carriers.
• Lecanemab is suspected of causing at least three deaths.
• The FDA may still grant approval to lecanemab with a warning label regarding brain bleeds and brain swelling.
• Medicare may deny coverage of lecanemab outside of any further clinical trials based on cost, safety, and efficacy concerns.
• The likelihood of long-term down side pressure on Biogen Inc. and Eisai's stock value seems more likely than long-term positive movement.

The Food and Drug Administration ((FDA)) will soon be considering whether to approve lecanemab for Alzheimer’s disease. If the FDA grants accelerated approval to the drug, Medicare may still not cover lecanemab due to cost, safety, and efficacy concerns. In addition better treatments are likely on the horizon. Given these possibilities, an FDA approval may not have too much positive impact on Eisai Co., Ltd. (OTPCK: ESALY ) and Biogen Inc.’s ( BIIB ) stock value.

Beyond this, however, there are several efficacy and safety issues to consider. At least 3 people have died while on lecanemab which, despite Eisai and Biogen’s protestations to the contrary, was very likely due to the drug itself. One has to wonder if the risk of taking the drug is worth the benefit. The FDA may “dispense” with this issue by adding warning labels in regards to brain bleeds and brain swelling.

In regards to efficacy, Eisai and Biogen reported that lecanemab produced a 41% slower decline in cognition in APOE4 non-carriers versus placebo, whereas APOE4 carriers declined by only 21 percent less as measured by Clinical Dementia Rating scale Sum of Boxes (CDR-SB) ( phase 3 trial results p. 31; limited access). This contradicts all recent Alzheimer’s clinical trials in which only carriers have benefitted from anti-amyloid medications ( Eli Lilly's donanemab , Biogen and Eisai's aducanumab/Aduhelm , p.12, Alzheon ALZ-801/tramiprosate ). This includes the phase 2b clinical trial for lecanemab itself (formerly known as BAN2401). At the highest dose:

APOE carriers declined 63 percent less than those on placebo and noncarriers only 7 percent less [as measured by ADCOMS: Alzheimer’s Disease Composite Score]. ( source of quote ).

Eisai and Biogen were forced to acknowledge this subgroup difference because critics contended that the placebo group saw a sharper rate of decline than the drug group mainly because the placebo group contained more APOE4 carriers who progress more rapidly in Alzheimer’s disease. The reason for this imbalance was that European regulators asked for the suspension of the highest dose in the drug group due to adverse side effects such as brain bleeds and swelling [ source ]. Eisai and Biogen tried to turn the tables on this argument by suggesting that the dearth of APOE participants at the highest dose may have actually worked against lecanemab because this was the subgroup who benefitted most from the drug. It may have been largely a wash.

While discussing the phase 2b clinical trial results, Eisai and Biogen also made the statement that there was no difference between the disease progression in carriers versus non-carriers. However, this was not the case. Carriers in the placebo group declined by an average of .18 points on ADCOMS at 18 months, whereas non-carriers declined by an average of only .146 points. At the highest dose (10mg/kg monthly), carriers declined by .003 points less than those on placebo to .143 whereas carriers declined by .041 points less to .139. The gap grew much wider when the 10mg/kg dose was given bimonthly, but there were not enough participants in this group to draw any firm conclusions ( supplementary table 16 ).

Now that Eisai and Biogen have dismissed the faster progression objections, they are now trying to turn the tables in the opposite direction by arguing that the drug helps non-carriers even more than it helps carriers so that they can obtain approval for all those with “mild” cognitive impairment and “mild” Alzheimer’s. The two companies claim that non-carriers declined -.75 less points from placebo on CDR-SB scores, whereas carriers only declined -.33 points less from baseline. How did this happen when in every other trial only carriers significantly benefitted from anti-amyloid drugs? The answer is that it did not happen.

The mean baseline CDR-SB score was approximately 3.2 (CDR-SB was the primary endpoint in the trial). Those on placebo declined to 4.85 points at 18 months while those on lecanemab declined to 4.4 points at 18 months. So far so good. The problem, however, is that Apoe4 carriers decline about 20 percent more rapidly than carriers ( study and from ADCOMS numbers above), and once this is taken into account the numbers begin to flip. With an approximate 70 to 30 split, carriers in the placebo group would have declined by about 5.1 points whereas non-carriers would have declined by 4.2 points. Non-carriers would have declined by 4.1 points (4.85- .75) versus an expected decline of 4.2 points whereas non-carriers would have declined by 4.52 points (4.85- .33) versus an expected decline of 5.1 points.

These calculation are meant to be illustrative rather than exact, but it is highly likely that only carriers received any benefit from lecanemab.

Amyloid oligomers are only a secondary “cause” of Alzheimer’s disease and only reach a level high enough to contribute to the disease in APOE4 carriers. This is why only carriers derive any benefit from anti-amyloid drugs.

None of this analysis is likely to be of any interest to the FDA, the Alzheimer’s Association, and “amyloid scholars,” all of whom are in one way or another are heavily invested in the amyloid hypothesis for Alzheimer’s disease. After all, the FDA approved aducanumab largely on the basis of amyloid biomarkers and originally used the removal of amyloid to approve the drug for all stages of Alzheimer’s disease, even though the drug was only tested in “mild” cognitive impairment and “mild” Alzheimer’s disease patients. But if the FDA were to listen to the numbers this time, lecanemab would not be approved for use by non-carriers and given the modest reduction in cognitive decline in carriers but with at least three deaths likely tied to the drug not for carriers either.

Better drugs for Alzheimer’s disease likely exist, although the timeline before they eventually reach the market is somewhat murky at this point. Alzheon’s ALZ-801 is a drug that slows down cognitive decline in APOE4 carriers nearly the same as lecanemab without the risks of brain bleeds and swelling (because it inhibits the aggregation of amyloid oligomers rather than removes them). It is currently in phase 3 clinical trials. Anavex ( AVXL ) just completed a phase 2b/3 clinical trial for Anavex 2-73/blarcamesine. At the highest dose, blarcamesine is likely to produce a 3 to 4 point improvement in Alzheimer's Disease Assessment Scale-Cognitive scores in early stage Alzheimer's patients at one year ( earlier trial results ). Anavex 2-73 inhibits the formation of amyloid oligomers and much more importantly it curtails oxidative and nitrostative stress. If approved, lecanemab may be displaced by more effective drugs in a relatively short period of time.

The FDA will probably initially grant acclerated approval to lecanemab for “mild” cognitive impairment and “mild” Alzheimer’s disease early in 2023. Medicare may deny coverage to lecanemab outside of further clinical trials just like it did for aducanumab given that it performs only somewhat better than aducanumab with the same risks. If Eisai and Biogen refuse to substantially drop the price tag for lecanemab under $28,200 a year (the “final” price for Aduhelm), then its case for Medicare approval becomes that much weaker (a very costly Alzheimer’s drug with serious safety issues that is not particularly effective is not what Medicare is looking for).

Investors in Eisai and especially in Biogen have seen this rollercoaster ride before. It is impossible to say whether it will end the same way again, but it probably makes more sense to sell some shares of Eisai and/or Biogen over the coming months than to buy shares in either.

For further details see: