Professor Frank Jessen, M.D.
Department of Psychiatry and Psychotherapy

University of Cologne, Medical Faculty
German Centre for Neurodegenerative Disorders (DZNE), Bonn

The end of yet another Alzheimer’s drug

On 21 March 2019 the company Biogen announced that they stopped the clinical development of the anti-amyloid antibody Aducanumab after an interim analysis of two large ongoing trials (ENGAGE, EMERGE). The results of the analysis suggested a lack of efficacy. Worldwide, this was a big disappointment for people with dementia, carers and researchers. This particular antibody had raised high expectations for a disease-slowing treatment because in a previous smaller study it not only lowered amyloid deposition (plaques) in brain but also attenuated the progression of the disease. These initial findings were not confirmed in the current trial.

A series of setbacks

The significant setback shares the fate of other anti-amyloid antibodies including Bapineuzumab, Solanezumab and most recently Crenezumab. They were all abandoned because of lack of efficacy. Currently, only two anti-amyloid antibodies are still being evaluated in large patient groups (Gantenerumab of Roche; BAN2401 of Eisai). In parallel to the halt of the antibody trials the development of two inhibitors of the enzyme beta-secretase (it cuts the amyloid fragment out of a larger precursor protein) was terminated, also because they did not meet efficacy expectations (Verubecestat of Merck; Lanabecestat of Astra Zeneca and Eli Lilly). Unlike the antibodies, these compounds do not remove amyloid from the brain but lower its production. The two enzyme inhibitors were even suspected to worsen the condition of the study participants as compared with a sham compound (placebo).

Why do the novel compounds fail?

There are several reasons for the recent series of setbacks. The drug development strategies of pharmacological companies, driven by economical pressure and competition, may be too hasty. Several large trials have been launched on the basis of incomplete and unclear data from preliminary studies. Also, treatments may start too late. The participants of the failed clinical trials had mild cognitive impairment or mild dementia. Although at this stage symptoms are mild, key parts of the brain are severely damaged, so that experimental compounds can achieve little. Would it be possible to initiate treatment earlier - in people who have no symptoms? This actually happens, however only in the context of research on individuals with either a very high genetic risk of dementia or imaging evidence of amyloid deposits in brain. It is highly questionably whether this approach can be applied in clinical practice.

Is amyloid the right target?

There are several arguments why amyloid is an appropriate treatment target. All genetic changes that result in Alzheimer’s disease are associated with a particularly intense amyloid load in brain. People with mild memory problems who have amyloid deposits are at high risk of developing dementia within a few years. Moreover, the presence of amyloid increases the formation of tau protein aggregates inside of nerve cells – the second histological hallmark of Alzheimer’s disease. In recent years it has become obvious, however, that removing amyloid from the brain is not enough to slow down or even arrest the disease. The development of novel treatments for Alzheimer’s disease is now turning to the tau protein aggregates (neurofibrillary tangles). They are much more closely linked to severity of symptoms than amyloid. Soon it will be seen whether compounds that interfere with tau agglutination are more effective than anti-amyloid antibodies.

No magic pill on the horizon

There will be no magic pill for Alzheimer’s disease in the near future. It may be that a combination of several compounds can achieve greater effects than current drugs. Possible, novel treatment approaches need to be developed that address chronic inflammatory events associated with neurodegenerations or basic processes of nerve cell ageing which are not specific to any disease. Whatever the future may hold, managing medical risk factors and comorbidities, as well as adopting an active lifestyle is the best everyone can do to keep the brain healthy.