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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

Additional Comments on the CTAD annual conference

In the four previous reports presented this week at the Clinical Trials in Alzheimer’s Disease (CTAD) annual conference in San Francisco, we had focussed on rather positive data from the large study performed with Eisai’s lecanemab, Eli Lilly’s donanemab and the odd ones of TauRx with HMTM. At this stage it is also of more than passing interest to comment on Roche’s gantenerumab failure and report some relevant comments made by key opinion leaders and some analysts.

In early November Roche had already disclosed that gantenerumab, its anti-amyloid beta antibody, had failed to reach the primary endpoints which had been set. At the CTAD meeting more details have been provided by the Swiss company. After one year of treatment, gantenerumab reduced amyloid plaque in Alzheimer’s brain patients only half as well as expected from previous clinical trials. Moreover, not a single patient tested negative for amyloid reduction after one year of treatment and only half of the treated population became negative over the two years course of the trial. It is still not clear why gantenerumab underperformed Roche’s expectation. Two hypotheses have been forwarded: the drug was given subcutaneously rather than intravenously, and the trial had a 36-week run-up schedule to reach the maximum dose. Could the combination of the two factors have limited its potency? Roche said it is starting a phase 1b/2a trial where it will use a “brain shuttle technology” to improve concentrations of gantenerumab in the brain.

The recent results reported at CTAD still raise a series of important questions.

1. Is there a consistent correlation between the reduction of amyloid plaque and the slowing down of decline in patients cognitive function? Lecanemab results at 18 months are an indicator. “I am uncomfortable with saying that we have the surrogacy of amyloid established” said Chris Van Dyck, director of the Yale Alzheimer’s Disease Research Center, which led the lecanemab study when he was referring to the idea that amyloid clearance is predictive of clinical benefit.
2. Can one coin the term “disease modifier” to drugs which just slightly slow down a decline but don’t stop the disease?
3. Is a 20-30% reduction in slowing down cognitive function at 18 months clinically relevant? Not according to a quote of Madhav Thambisetty, a neurologist at the National Institute on Aging, when he stated: “From the perspective of a physician caring for Alzheimer’s patients, the difference between lecanemab and placebo is well under what is considered to be a clinically meaningful treatment effect.”
4. Is the amyloïd plaque the cause of Alzheimer’s disease?  “I am uncomfortable with amyloid as a unitary thing. We still need to think about the subtypes” said Van Dyck.

The statement which we found most original, and which has been our own motto for many years, came from Howard Fillit, co-founder of the Alzheimer’s Drug Discovery Foundation, when he wrote: “The mixed data shows that while anti-amyloids are a promising starting point, we will need a combination of drugs aimed at different targets informed by the biology of aging to effectively treat this disease.”

Like many other observers and analysts, we are eager to see how regulatory bodies will handle the above issues in the first quarter of 2023.

Paris, December 3, 2022.

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