It has been announced that Solanezumab, an experimental Alzheimer’s treatment from Eli Lilly & Co, failed to slow the progression of the neurodegenerative disease.
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Prof. Roxana Carare, Professor of Clinical Neuroanatomy, University of Southampton, said:
“It is saddening that the latest solanezumab trial has failed, but that may in part be because we need to deal with the problem of removing amyloid, not just breaking it down. The brain is not equipped with lymph vessels as other organs have. Instead fluid and waste are eliminated from the brain along very narrow pathways that are embedded within the walls of blood vessels (perivascular pathways). These pathways change in composition and fail in their function with increasing age and with the risk factors for Alzheimer’s disease, resulting in the buildup of amyloid in the walls of blood vessels. When a vaccine such as solanezumab is administered, the sticky plaques of amyloid from the brain break down, but the excess waste and fluid (soluble amyloid) is unable to drain along the already compromised drainage pathways.
“In order for further immunisation trials to yield success, they need to be administered early, before the perivascular pathways are compromised. Furthermore, we need to invest in efforts in identifying how we can detect the health of the perivascular drainage pathways in people in order to determine the right treatment strategy.”
Prof. Gordon Wilcock, Emeritus Professor of Geratology, University of Oxford and Honorary Consultant Physician, The 2gethger NHS Foundation Trust, Cheltenham, said:
“The failure of solanezumab in this trial to meet its endpoints is disappointing and is similar to previous trials of this strategy. However it is a very important result and has implications for other anti-amyloid related strategies that use this antibody approach, but I need to see the data before coming to a firm conclusion. Nevertheless I would be surprised if other monoclonal antibody strategies are going to be more successful, even if their target is a different part of the amyloid molecule, but only time will tell.
“It may be that anti-amyloid strategies are not the best way of treating Alzheimer’s disease but before drawing this conclusion we need more data on the efficacy of other approaches, including BACE inhibitors which may reduce amyloid formation, rather than targeting its removal like the antibody strategies.
“These results emphasise the need to explore other approaches, not just those relating to amyloid but also other targets such as preventing or removing the tangles that develop in brain cells.”
Dr Tara Spires-Jones, Interim Director of the Centre for Cognitive and Neural Systems at the University of Edinburgh, said:
“The news today that Solanezumab treatment did not slow progression of dementia symptoms in people with mild Alzheimer’s disease is disappointing. This drug aims to lower levels of amyloid beta, which is a toxic molecule that accumulates very early in the disease process, beginning long before any symptoms appear. There is still hope that this type of treatment will be beneficial if given to people before symptoms begin.”
Prof. Peter Roberts, Emeritus Professor of Pharmacology, University of Bristol, said:
“I am not in the least surprised by the solanezemab data, despite Lilly’s seeming optimism just a short while ago. The problem, to my mind, is completely fundamental. There is still no convincing evidence that shows a clear relationship between amyloid deposition and deficits in cognition in humans. All we really know is that evidence of amyloid deposition begins up to maybe 20 years before the onset of Alzheimer’s disease. This might be a good indicator, but does not prove causality.
“There is still a polarisation of the scientific ‘camps’ with beta-amyloid versus tau hyperphosphorylation, right down to the chicken and egg arguments on which precedes the other. Tau has received nothing like the attention that amyloid has by big pharma – they all jump on the bandwagon, unfortunately. There are studies progressing with tau as a target, but it will be a while before clear evidence emerges.
“Of course, the possibility remains that neither tau nor amyloid are responsible for the development of AD and their changes are consequences of other underlying neuropathological events.
“One very good question is whether focus will now shift to BACE inhibitors. Lilly’s BACE inhibitor LY2886721 failed due to its causing liver abnormalities, as has been reported for several other early stage BACE1 inhibitors. Others have been reported as being well tolerated – however, in the absence of any positive clinical data, it could just be that the doses tested have been at sub-therapeutic levels.
“Although the drug companies would love to have a drug that you could take like statins against hypercholesterolaemia, to give long term protection against Alzheimer’s disease, the problem is that BACE is not a nice selective target. BACE1 null mice exhibit highly complex neurological abnormalities including seizures, neurodegeneration, cognitive deficits and hypomyelination. It is completely unclear whether BACE could be targeted in a manner to affect amyloid processing in a therapeutic manner, without serious long term side effects.”
Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:
“While this is disappointing news, we will have to wait for the full dataset to see if there are any nuggets of information that provide insight into the lack of effect of solanezumab. It’s another setback for the Alzheimer’s community, however the information we obtain from these setbacks is vital in our common goal of generating a novel treatment to tackle Alzheimer’s disease. There are other drugs in the pipeline that are targeting the amyloid beta peptide from another angle (the so-called BACE inhibitors) and these may prove more fruitful endeavours. What we are currently struggling with is converting our biological targets into druggable targets and indeed to see if this will combat disease symptoms or progression. Therefore our research efforts must continue. There are interesting pipeline programs looking at targeting other cells within the brain to offer protection to the nerve cells which are lost in Alzheimer’s disease.”
Jeremy Hughes, Chief Executive of Alzheimer’s Society, said:
“After positive news last summer we had high hopes for this drug to become the first to slow down Alzheimer’s disease. It’s extremely disappointing to learn that it hasn’t delivered a meaningful change for people living with dementia, when the need is clearly so great.
“Dementia is society’s biggest health challenge – and we’ve seen time and again that developing effective treatments is incredibly difficult. This is only one drug of several in the pipeline and they aim to tackle dementia in different ways, so we should not lose hope. Dementia can and will be beaten.
“Dementia is our leading cause of death, touching the lives of millions. There will be concern that investment in dementia research may drop as a result of another failure -neither families nor the NHS can afford for this to happen. We must and will redouble our efforts and investment into dementia research.”
Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:
“Our 15-year wait for a new Alzheimer’s drug does not end today, but we shouldn’t view this setback as the end of the line – the journey towards a new treatment can and will continue. It’s very disappointing that solanezumab has not shown benefit for people with mild Alzheimer’s and will no doubt trigger important debate within the research community. We only have headline information today, so we’ll need to see the full data to understand why solanezumab didn’t show benefits and what researchers must learn from the findings.
“Solanezumab is designed to mop up amyloid protein – a key hallmark of Alzheimer’s – and is the result of years of development based on the concept that this protein is a central driver of the disease. While today’s results are a setback for the amyloid hypothesis, there are several other anti-amyloid drugs still in clinical trials that work in different ways, some of which are being tested even earlier in the disease process than solanezumab. We can’t disregard these ongoing trials and their findings will now be more important than ever in shaping the search for disease-modifying treatments for Alzheimer’s.
“Today is undoubtedly a set-back for people with Alzheimer’s and their families, and highlights the ongoing importance of drug discovery efforts into other aspects of the biology of Alzheimer’s. Our understanding of the biology of Alzheimer’s is expanding and with it are our approaches for improving the lives of those with the disease. Alzheimer’s Research UK is already supporting millions of pounds of treatment research taking place in labs around the country today, including our pioneering Drug Discovery Alliances, to ensure that this hard work continues.”
Dr James Warner, Consultant Old Age Psychiatrist and Honorary Reader in Psychiatry, Faculty of Medicine, Imperial College London, said:
“This is disappointing. To my knowledge, solanezumab is the first ‘next generation’ Alzheimer’s treatment to have concluded phase 3 trials. It was a potentially ground breaking approach to treatment – regular injections of a compound designed to scavenge the protein called amyloid that is deposited in the brains of people with Alzheimer’s disease. Amyloid is a hallmark of the condition and thought to be involved in the process that causes Alzheimer’s.
“I think this does represent a failure. The non-significant trend outlined in the press release probably means that any effects are too small to make the treatment worthwhile. I know many patients with dementia and their relatives will be very disappointed.”
Dr Elizabeth Coulthard, Consultant Senior Lecturer in Dementia Neurology, University of Bristol, said:
“This is very disappointing. Again there seems to be a hint that Alzheimer’s is modifiable, but solanezumab does not appear to work well enough to recommend as a treatment. Fortunately there are multiple other therapeutic approaches including BACE inhibitors that will report in coming years. This is probably not the end for amyloid approaches as there are other types of amyloid that other drugs can target, for example, aducanumab targets aggregated amyloid and is currently being tested in a phase 3 clinical trial.”
Prof. Robert Howard, Professor of Old Age Psychiatry at UCL, said:
“This is disappointing but not a great surprise. Like other agents in this class, the drug engages with the target in terms of demonstrably reducing brain amyloid but this doesn’t appear to reverse or slow cognitive and functional decline. Whether this approach is likely to be more effective earlier in the disease – say at the stage of identification of biomarker evidence of Alzheimer’s disease pathology in the brain but before the onset of any symptoms – is unclear. What we have learned from several decades of research and hundreds of failed Alzheimer’s disease trials is that no matter how promising the basic and early phase data, all that really matters is the results of these late phase effectiveness trials.”
Prof. John Hardy, Professor of Neuroscience, UCL, said:
“The focus will shift to BACE inhibitors. It will be important to look in detail at these results to understand why solanezumab failed to move forward constructively.”
Prof. Carare: “None to declare”
Prof. Wilcock: “I am an adviser to TauRx who are developing an anti-tau strategy”
Dr Spires-Jones: “I am on the Grant Review Board for Alzheimer’s Research UK and collaborate with pharmaceutical company Cognition Therapeutics.”
Prof. Roberts: No interests to declare
Dr Dallas: “Receive funding from Alzheimer’s Research UK and The Alzheimer’s Association.”
Mr Hughes: None declared
Dr Reynolds: “No interests to declare”
Dr Warner: No conflict of interest to declare”
Dr Coulthard: “No interests to declare”
Prof. Howard: “No declarations of interest”
Prof. Hardy: “I consult for Eisai”