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A goal in mind: Transforming the way Alzheimer’s disease is diagnosed and treated

Published on 20/09/18 at 11:01am
Five patients titrated up to high-dose gantenerumab saw a reduction in florbetapir SUVR of up to 0.75. [Courtesy of Gregory Klein, F. Hoffmann-La Roche.]

Dr Rachelle Doody, Global Head of Neurodegeneration at Roche/Genentech, discusses key learnings from clinical trials in Alzheimer’s disease, and how findings from past and current studies are helping to develop effective new therapies for patients affected by the disease.

Alzheimer’s disease: A health crisis of the 21st century

Alzheimer’s disease is a progressive neurodegenerative disorder, accounting for at least 60–80% of all dementia cases. Dementia currently affects more than 46 million people worldwide, and this figure is expected to rise to 133 million by 2050. This makes dementia, due to Alzheimer’s disease and other causes, one of the greatest public health challenges of our time.

Alzheimer’s disease is characterised by progressive decline in cognitive function, including memory loss, behavioural changes, and impaired ability to perform activities of daily-living. The hallmarks of the disease are the presence of beta-amyloid plaques and neurofibrillary tangles, composed of the hyper-phosphorylated tau protein, deposited in the brain tissue. It is believed that the formation of these plaques and tangles results in damage and disconnection of neurons, and damage to the brain tissue. Alzheimer’s disease starts to develop 20 years or more before any clinical symptoms appear, so patients are not diagnosed until their disease has substantially progressed.

Current drug treatments for Alzheimer’s disease temporarily relieve the symptoms, such as thinking difficulty, communication problems, and trouble performing day-to-day activities. Currently, however, there are no treatments that can prevent, halt, or substantially slow the progression of the disease.

Why Alzheimer’s disease moved me from academia to industry

For the last 25 years, as a practising neurologist and Alzheimer’s Disease Center director, I sat with Alzheimer’s patients and their families as we contemplated their limited options, and addressed the growing needs caused by their disease over time. Our centre conducted extensive research into various aspects of this debilitating disease, including epidemiologic, genetic, and biomarker studies, but we always maintained an array of clinical trials testing new treatments across the stages of disease. I collaborated with many academic and industry groups in trying to advance treatment. My decision to move to Roche was driven by the desire to regain the momentum that we once had when the early symptomatic treatments were approved.

Clinical trials in Alzheimer’s disease: Lessons learned

The treatment era for Alzheimer’s disease began out of scepticism that a reported therapy (tacrine) really had substantial benefit. Industry, academia, the US Alzheimer’s Association and the US National Institutes of Health joined forces to put the drug to the test, eventually leading to the first Alzheimer’s disease drug approval. The past decade has seen significant investment into the development of disease-modifying therapies (DMTs) for Alzheimer’s disease. However, finding an effective treatment has proven challenging.

Drugs targeting beta-amyloid have been at the forefront of clinical research into Alzheimer’s disease. This strategy is driven by the ‘amyloid hypothesis’, which proposes that the overproduction and/or the under-clearance of beta-amyloid in the brain plays a primary role in the disease pathology.

Among the anti-amyloid therapies, monoclonal antibodies (mAbs) targeting beta-amyloid have been the most extensively studied. Pre-clinical and genetic cases of Alzheimer’s disease strongly support beta-amyloid as a target, and mAbs have been developed which target the soluble form of amyloid-beta (preventing its aggregation in the brain), and/or deposited insoluble plaques (plaque removal).

Several anti-beta-amyloid mAbs have been evaluated in trials [(see table)]. While the primary outcomes of these initial studies have been negative, the results have provided valuable learnings, particularly regarding the importance of disease staging, patient selection, and dose.

Overall, these studies suggest that removing brain amyloid substantially is associated with a clinical signal, often on secondary measures, but the clinical signal has been small. One hypothesis for the observed lack of expected benefit in studies that included patients with moderate Alzheimer’s disease (when both cognitive and functional decline is relatively advanced), was that these agents were administered too late in the disease course to provide clinical benefit. Another possible explanation was that some of the agents tested may not have achieved sufficient central or peripheral exposures, raising the question of whether higher doses might have been more effective.

These learnings are now being applied to improve the design of subsequent studies. Current trials are evaluating anti-beta amyloid mAbs in patients with early Alzheimer’s disease (when patients begin to have the very first symptoms, such as mild forgetfulness), or as prevention in individuals with specific genetic mutations, called autosomal dominant mutations, who will develop the disease without intervention. Other studies are evaluating anti-amyloid approaches in people at risk for Alzheimer’s disease because of accumulated brain amyloid and other epidemiologic risk factors, but without specific mutations.

Roche’s commitment to R&D in Alzheimer’s disease

At Roche, we recognise that Alzheimer’s disease is a complex problem requiring a comprehensive solution. We are committed to transforming the way Alzheimer’s disease is diagnosed and treated through development of new diagnostic tools and novel targeted therapies that will enable us to detect, measure, and slow its progression.

We are developing DMTs that target the key neuropathologic features of Alzheimer’s disease: beta-amyloid, as well as tau protein. Our two late-stage mAbs, crenezumab and gantenerumab, are distinct from other anti-beta-amyloid mAbs and from one another, with each targeting different forms of beta-amyloid. Key learnings from past clinical research have been incorporated into these Phase III clinical trial programmes, which use higher dosages and recruit patients with early stages of Alzheimer’s disease.

Crenezumab is being evaluated in patients with early Alzheimer’s disease by two fully recruited Phase III trials (CREAD 1 and 2). We recently reported the results of an earlier Phase II randomised study in patients with mild-to-moderate Alzheimer’s disease (ABBY) in [Neurology], which demonstrated that crenezumab was well tolerated, and showed a potential treatment effect in the subgroup of patients with mild (early) disease who received the higher dose used in this study. Using pharmacokinetic/pharmacodynamic modelling and additional Phase I data, we determined a four times higher dose of crenezumab for our current Phase III trials.

The safety and efficacy of gantenerumab in patients with early Alzheimer’s disease is currently being evaluated in the GRADUATE 1 and 2 Phase III trials. These studies were initiated in August 2017 based on the results from the open-label extensions of two previous Phase III studies (Scarlet Road and Marguerite Road), showing that higher doses of gantenerumab resulted in significantly greater reductions of brain amyloid plaque burden, with an acceptable level of associated Amyloid Related Imaging Abnormalities (ARIA), a side effect common to antibodies targeting deposited amyloid.

Crenezumab and gantenerumab are also being evaluated in two separate Alzheimer’s disease prevention studies (API ADAD and DIAN-TU-001) conducted in people at risk for early onset Alzheimer’s disease caused by autosomal dominant mutations.

Tau protein, in its pathological form of neurofibrillary tangles, represents another important therapeutic target. Roche has a Phase II trial underway to evaluate the efficacy and safety of an anti-tau monoclonal antibody, RG6100, in patients with early Alzheimer's disease.

Accurate and timely diagnosis of Alzheimer’s disease is crucial to enabling earlier interventions and to help patients participate in clinical trials. We have been working on a number of different tests designed to support clinicians in identifying patients on the pathway to Alzheimer’s disease. Our Elecsys cerebrospinal fluid (CSF) assays, which measure beta-amyloid, total Tau, and phosphorylated-Tau concentrations in cerebrospinal fluid are CE certified in Europe, where they are currently being used in standard clinical practice to improve the quality and accuracy of Alzheimer’s disease diagnosis.

Roche’s broader outlook on Alzheimer’s disease

We cannot solve the problem of Alzheimer’s disease with science alone: we also need to examine how society funds research, how governments assess the value of innovative treatments, and how we care for people with dementia. This requires us to work together with the Alzheimer’s community of caregivers and patients, as well as with key thought leaders in policy and other academic researchers, clinicians, and industry peers.

Roche supports several initiatives to raise awareness of the disease, including the Global Alliance on Women’s Brain Health ( whose overarching goal is to put women and dementia on the G20 agenda. Women represent an important group, as they are twice as likely as men to develop Alzheimer’s disease, and worldwide, provide the overwhelming majority of informal and formal care to affected patients. Our prevention studies represent collaborations with public funders of research and academic institutions, and we work with important convenors of multi-stakeholder projects, including patient associations, and the Critical Path for Alzheimer’s disease Consortium (

It is important that we enhance our efforts to learn from and work with others in the Alzheimer’s disease community to truly achieve our common goal, which is to prevent Alzheimer’s from becoming the socially and personally depleting health crisis that is inevitable if we do not impact it substantially and soon.

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