August 31, 2016

expert reaction to amyloid therapy for Alzheimer’s

An antibody therapy for the treatment of Alzheimer’s disease has been described in a paper published in the journal Nature in which the authors report its use in animals and a small number of patients where the treatment was able to reduce amyloid plaques which are thought to contribute to the disease.

Prof. Richard Morris, Professor of Neuroscience, University of Edinburgh, said:

“Given the apparent failure of previous attempts to vaccinate against the progression of Alzheimer’s Disease, it is perhaps natural for the long awaited results of the Biogen trial to be treated with a degree of caution. However, the study’s ingenious use of an antibody based on neo-epitopes present in pathological Aβ aggregates may have successfully got round some of the problems of earlier attempts to develop an appropriate vaccine. What particularly impressed me about this still preliminary study is the dose-response nature of both the clearance of amyloid plaques and the stabilisation of the otherwise worsening cognitive profile of patients enrolled in the study.

“We cannot yet say we have a cure for Alzheimer’s, as this is only a first step.  However, despite being only 165 early-stage patients, these encouraging results will likely help the company enormously to scale up to a full double-blind clinical trial of aducanumab.

“The conclusion that this study supports further development of aducanumab is fully justified and the importance of this first step cannot be understated.. Let’s keep our fingers crossed for success in the next steps.”

Prof. David Allsop, Professor of Neuroscience, University of Lancaster, said:

“This study shows convincingly that it is possible to reduce the extent of amyloid plaque formation in the brains of people with very early signs of dementia, as demonstrated using a brain imaging technique to monitor plaque formation before and after repeated treatment with aducanumab. Encouragingly, this treatment also appeared to slow memory decline, demonstrating that amyloid formation is a direct or indirect cause of memory loss. This has been suspected for some time, but has never been proven in humans. Previous attempts at amyloid therapy have failed, probably because the drugs were tested on people who already have advanced disease, which is too late. Although encouraging, the main problem encountered with this study was the relatively large number of participants who dropped out because of side-effects involving changes in blood vessels that supply the brain. This problem has been encountered previously and will have to be overcome if this type of therapy is to find widespread clinical use. Nevertheless, these findings could be a ‘game changer’ if the effects on memory decline can be confirmed in more extensive follow-on studies.”

Dr David Reynolds, Chief Scientific Officer, Alzheimer’s Research UK, said:

“In continued efforts to develop the first disease-modifying treatment for Alzheimer’s disease, these results provide tantalizing evidence that a new class of drug to treat the disease may be on the horizon. This promising trial data shows that aducanumab is able to clear a key Alzheimer’s protein in people, building on earlier studies in mice. The findings suggest that aducanumab may slow memory and thinking decline in people with early Alzheimer’s and although the analysis is only exploratory in this early trial, it paints a positive picture for ongoing trials with the drug. The ultimate proof of success will be whether aducanumab is safe and effective in large phase 3 trials, which are currently recruiting participants across the UK. Some of the side effects seen in this study are concerning and will need addressing in the current trials, to ensure that people can stay safely on the drug for long periods.

“It has been over a decade since the last drug was licenced for use in people with Alzheimer’s, and there are currently no treatments able to stop the disease in its tracks. Anyone interested in volunteering for dementia research, including the current phase 3 trial of aducanumab, can sign up to Join Dementia Research at www.joindementiaresearch.nihr.ac.uk or by calling Alzheimer’s Research UK on 0300 111 5 111.”

Prof. Gordon Wilcock, Emeritus Professor of Geratology, University of Oxford and Honorary Consultant Physician, said:

“This is preliminary data about another monoclonal antibody targeting amyloid in Alzheimer’s disease, but whether it will really produce meaningful clinical benefit only definitive phase III trials will show, as the researcher themselves state. We have already had previous trials of various anti-amyloid strategies, especially the monoclonal antibodies, that have failed to deliver at phase III.

“Nevertheless these trials are justified by the data and I hope they are successful, despite my feelings of déjà vu!”

Dr James Pickett, Head of Research, Alzheimer’s Society, said:

“These results are the most detailed and promising that we’ve seen for a drug that aims to modify the underlying causes of Alzheimer’s disease.

“The study showed that the drug, aducanumab, was first able to remove clumps of amyloid – a toxic protein associated with Alzheimer’s – from the brain of mice and also, excitingly, in people. What is most compelling is that more amyloid was cleared when people took higher doses of the drug. No existing treatments for Alzheimer’s directly interfere with the disease process – and so a drug that actually slows the progress of the disease by clearing amyloid would be a significant step.

“There is still some work to be done before we know whether this could be a new treatment. Higher doses did cause side effects, like headaches, and this study was not designed to measure whether the drug could slow decline in memory and thinking. While there were hints that it might have an effect on the symptoms of the disease, we need to see the results from further, larger research trials to understand whether this is the case. These larger trials are now underway, including in the UK, and due to finish in 2020.

“To find out your eligibility for this and other studies, you can register to participate in dementia and memory research at www.joindementiaresearch.nihr.ac.uk”

Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:

“This paper looks at the potential of a drug to target and reduce the levels of a toxic peptide called amyloid beta that builds up in the brain of people living with Alzheimer’s.

“The main aim of this study was to look at the safety of this drug in what is called a Phase 1 clinical trial.

“The good news is that by scanning patient brains the researchers show the drug is doing its job in reducing amyloid beta levels within the brain. However, because of the study design, it cannot tell us if there is any improvement in brain function of those that received the drug.

“Therefore caregivers, patients and the scientific community are now keen to see if this drug will provide benefit to people living with Alzheimer’s when the next set of results from ongoing clinical trials are announced.”

Dr Tara Spires-Jones, Interim Director, Centre for Cognitive and Neural Systems, University of Edinburgh, said:

“This study led by scientists at pharmaceutical companies Biogen and Neurimmune is exciting because it shows that an antibody treatment for Alzheimer’s disease robustly reduced amyloid pathology in a small group of people in very early stages of the disease.  I am cautiously optimistic about this treatment, but trying not to get too excited because many drugs make it through this early stage of testing then go on to fail in larger trials. This was a small phase 1 study with 20-30 people in each treatment group. We will have to wait and see whether the promising results reported here are repeated in the larger phase 3 trials of this drug that are currently underway worldwide.”

Prof. John Hardy, Professor of Neuroscience, UCL, said:

“This trial and the reports of it which have appeared since the Alzheimer’s disease/Parkinson’s disease meeting in 2015 have led to renewed hope, which I share, that we are close to having the first effective amyloid based therapies for Alzheimer’s disease.

“It behooves us, however, to be careful since we have been here before with tantalisingly positive phase 1 data.  This was not a phase 3 study: it was not powered or designed to identify treatment effects, and, even in the context of apparently positive data, we need to consider the possibility of selective subject drop out and chance as underlying the positive findings.

“These new data are tantalising, but they are not yet definitive.”

Prof. Robert Howard, Professor of Old Age Psychiatry, UCL, said:

“Although potentially this is an exciting story, it is important to temper any excitement with considerable caution. It would be premature to conclude that this is likely to represent an effective treatment for Alzheimer’s disease (AD), much as those of us who are involved with the care of patients would dearly wish for this.

“This is not the first anti-amyloid vaccine to show molecular target engagement in AD and to have reported promising results from a phase 1 trial. Sadly, we’ve been here before with similar agents which have all failed at the most important (for patients, their families and doctors) phase 3 trial stage when they have shown no efficacy in modifying the symptoms and clinical progression of AD.

“The apparent effects on change in MMSE and CDR-SB scores in the participants who received the highest vaccine doses or achieved the greatest improvements in PET amyloid measures need to be viewed with similar caution. The authors are clear that: “This was a small study designed for assessment of safety and tolerability, and for detecting a pharmacological effect on brain amyloid beta levels measured by PET imaging”. They have certainly achieved these objectives. But it would be premature to conclude that they have gone beyond their stated objectives and have convincingly demonstrated modification of the clinical features of AD. For this, we must patiently await the results of the phase 3 trial that the paper tells us is under development.”

‘The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease’ by Sevigny et al. published in Nature on Wednesday 31^st August. 

Declared interests

Prof. Morris: “I can confirm that I have no conflicts of interest relevant to this paper.”

Prof. Allsop: “We have some of our own amyloid aggregation inhibitors in development that haven’t yet reached clinical trials, and Lancaster University hold a patent on them.”

Dr Reynolds: “None to declare.”

Dr Dallas: “Funded by Al Alzheimer’s Research UK and Neuroscience Theme Lead, The Physiological Society.”

Dr Spires-Jones: “I have no conflicts o interest with this study.”

Prof. Hardy: “Consulting – Eisai Pharmaceuticals”

Prof. Howard: “None to declare.”