Prof. Bart De Strooper: We saw this coming for a long time – aducanumab is one of the many antibodies that have been and are being tested against amyloid. People often call the previous trials failures, but I think they were learning exercises. We made several mistakes in the past and in these trials, but the antibody is more specific in clearing amyloid and the patient groups were much better characterized than before.

Prof. Rik Vandenberghe: We now know that antibodies against amyloid need to be given in sufficiently high doses, and that they can successfully break down the amyloid accumulations in the brain, to levels that are even lower than in healthy control people. This is a crucial insight. Ten years ago, no one thought it was possible to completely ‘wash away’ the amyloid in the brain.

Prof. Vandenberghe: The evaluation of the clinical trials did not really follow the classic rules. Usually the primary outcome parameters, on the basis of which you decide whether a drug is successful, are precisely determined in advance. In the case of aducanumab, those primary outcomes were improvements in cognition and activities of daily living. In only one of two clinical studies was a small clinical benefit observed after 1.5 years of treatment in the subgroup who received the highest dose. Nevertheless, the FDA approved the drug based on its clear ability to remove amyloid, a secondary outcome.

Prof. De Strooper: For the first time, the FDA has given the message that it is ready to accept Alzheimer’s drugs based on biomarker evidence, a hypothesized underlying disease mechanism, and a minimum of clinical evidence of efficacy. The approval went through an accelerated procedure, but is conditional: within the next 9 years, the drug’s clinical benefit needs to be demonstrated by a Phase 4 clinical trial. This will bring new challenges, such as carefully designing the trials and selecting the right patients, at the right stage of disease, in a real-life setting.

Prof. Vandenberghe: Several of my patients in Leuven participated in the EMERGE study and some are still actively using aducanumab in the ongoing EMBARK study. For them, this is a hopeful message: after years of pursuing amyloid-based strategies and partly thanks to their own personal efforts, there is finally some positive result. But I would not say that the patients in Europe and elsewhere in the world who do not currently have access to the drug, are missing out: the clinical benefit seems too small to really make a difference, while the drug is very expensive. Moreover, several similar drugs are currently on their way to being approved through the same accelerated route. Aducanumab also has side effects, some of which are serious but manageable when patients are regularly monitored with MRI scans. It’s not clear whether all of these conditions will be easily met in real life, outside the context of a clinical trial.

Prof. De Strooper: These events remind me of what happened in the AIDS field: the first drugs fast tracked by the FDA for use in humans, all didn’t have big clinical effects. But by approving them, a market was created and this attracted the pharma/biotech industry to further invest in research and bring new, improved drugs to patients. Within two decades, almost curative therapies for AIDS have been developed. The FDA is now giving us a huge opportunity to learn and develop new ways to treat dementia. We now have a great tool to answer some of the most pressing open questions in well-designed studies. Which patient subgroup(s) will benefit most from anti-amyloid treatment? At which disease stage is this therapy most cost-effective? Will it also be effective for people with mixed forms of dementia? I hope to see a new phase of Alzheimer's drug development with an explosion of experimental studies, new drugs and clinical trials, to finally end the dementia pandemic.

Prof. Vandenberghe: I agree that this positive news can spark renewed interest, but it is difficult to predict the extent to which it will stimulate further research. Some investigators worry that the amyloid-lowering strategy will become the preferred treatment and that fewer patients will be willing or eligible to participate in other types of trials. It will be interesting to see how this evolves further in the US. But overall, it’s a good thing that we now have a revolutionary new way of looking at drug development for Alzheimer’s disease. I think it is critical that we focus on measurable biomarkers of the underlying disease processes and on determining the optimal time window for intervention. There are still several important steps forward to be made, but we are starting to see the light at the end of the tunnel.