Scientists are cautiously optimistic about new data indicating the drug solanezumab can slow the progression of Alzheimer’s disease – if provided early.
The drug’s developer, pharmaceutical company Eli Lilly, this week announced preliminary findings from clinical trials investigating the drug solanezumab. Combining data from several trials, the researchers were able to show that patients who started taking the drug later in clinical trials (i.e. had a delayed start) did not see the same cognitive and functional benefits as those treated with the drug from the start.
The research was presented at the 2015 Alzheimer’s Association International Conference in Washington DC.
Our colleagues at the Aus SMC collected the following expert commentary.
Dr Ian Musgrave, Senior Lecturer in Pharmacology at the University of Adelaide, comments:
“Alzheimer’s disease is a distressing, progressive disease where brain function is lost as nerve cells within the brain die. Typically memory is lost first, then other aspects of brain function.
“Currently we have no therapies that affect the underlying mechanisms of the disease. While we still do not fully understand the cause of the disease, it is believed to be due to two proteins, beta -amyloid, which is toxic to nerve cells, and tau, which affects nerve function. Both are thought to play key roles in the progression of Alzheimer’s.
“Experimental therapies have looked at protecting nerve cells from toxicity, prevention of the formation of the toxic forms of the proteins or removal of beta-amyloid. So far progress has been very disappointing, and drugs that have been promising in early stages of development have failed to be effective in larger studies. One possible reason is that we need to intervene very early to prevent damage.
“Solanezumab and Aducanumab are antibodies that remove the toxic amyloid protein. While they seem to be effective at removing amyloid, they have had less success at preventing memory loss. Trials of Solanezumab in early, mild Alzheimer’s seem to show more effect, and larger clinical trials are going ahead to see if this can be confirmed. Anavex 2-73 acts to protect nerve cells from damage, it seems to be promising in early trials, but it is too early yet to determine if it provides long term protection.”
Dr Bryce Vissel, Head of the Neurodegenerative Diseases Research Laboratory at the Garvan Institute of Medical Research in Sydney, comments:
“We should be encouraged by the enormous amount of research effort in Alzheimer’s disease at present. Alzheimer’s patients and their families should be greatly encouraged that we will achieve a major breakthrough in the next two decades. There is still much work to do and scientists are determined to make a difference to the lives of those who have dementia in any form.
“The recent outpouring of news on Alzheimer’s disease is coming from a range of presentations being made at the annual Alzheimer’s Association International Conference. The big news at present is about three different drugs, called Solanezumab (Eli Lilly), Aducanumab (Biogen) and Anavex 2-73 (Anavex). However, the important point at present is that, while there appears to be some positive news regarding Solanezumab, this is not the time to claim that we have made a breakthrough in slowing the pace of Alzheimer’s. The data being presented at the conference is preliminary. It has occurred in Alzheimer’s research before that exciting preliminary data does not hold up upon further investigation. Next year, when further trial results are due, we will know with higher certainty whether Solanezumab offers the possible breakthrough everyone hopes.
“About the drugs that are in the media today:
“Anavex 2-73 is a drug that is being trialled in early stage clinical trials. It is intended to reduce loss of nerve cells that occurs in Alzheimer’s disease. Many drugs that showed promise early on in a few people failed to show benefit in subsequent studies. There is some early indication that it may be having some benefit in a very early stage small trial. However, this drug is still in early phase testing in humans and it is entirely unclear as to whether this drug will offer the benefit that is hoped.
“Solanezumab and Aducanumab are drugs that have been made, and that are now being tested, by Eli Lilly and Biogen Idec respectively. These drugs are intended to work by clearing a substance called amyloid from the Alzheimer’s brain. The role of amyloid in Alzheimer’s remains controversial, as does the extent to which removing amyloid from the brain will work in people.
“The previous preliminary data for Aducanumab was promising, but an announcement today by the company suggests that, on further study, Aducanumab may not truly help with the memory problems seen in Alzheimer’s disease. More work is needed.
“Solanezumab, on the other hand does appear more promising at this early stage. It appears that, if given to people early in the disease, it may offer some benefit. However we must wait for the results of another large trial before the company can make any clear statement.”
From the UK SMC:
Dr Doug Brown, Head of Research, Alzheimer’s Society’s, said:
“Today’s findings strongly suggest that targeting people in the earliest stages of Alzheimer’s disease with these antibody treatments is the best way to slow or stop Alzheimer’s disease. These drugs are able to reduce the sticky plaques of amyloid that build up in the brain, and now we have seen the first hints that doing this early enough may slow disease progression.
“After a decade of no new therapies for dementia, today’s news is an exciting step forward. We will have to wait for the ongoing trials to finish to know the full risks and benefits of these drugs. If they are positive, these drugs will be the first identified to directly interfere with the disease process and slow the progression of Alzheimer’s.
“It’s good news that some people have been receiving the antibody for over three years and it appears to be having beneficial effects. The current trial has finished recruiting participants, so in just 18 months we may get an exciting first look at the final results.”
Prof John Hardy, Professor of Neuroscience, UCL, said:
“These reports are good news in the same way that a forecast of sunny weather at the weekend is good news. It raises hopes for good weather, but it does not mean good weather is a certainty.”
Prof Peter Roberts, Emeritus Professor of Pharmacology, School of Physiology & Pharmacology, University of Bristol, said:
“I would very cautiously go along with this announcement possibly being significant, though unfortunately in the media this morning we have the usual ‘medical breakthrough’ spin.
“Whether or not solanezumab proves to be disease-modifying will take some time to establish. The published data so far show only a small statistically-significant effect in the subset of mild cases of AD (not all the mild cases). The cognitive benefits are not astounding and are actually little or no better than the currently prescribed anticholinesterases.
“The sooner we move away from the ‘amyloid hypothesis’, or rather the opposing ‘amyloid’ or ‘tau’ causal dogmas, the better. Alzheimer’s is very complicated and combination, multi-target therapies are much more likely to show promise in modifying the disease process. A number of tau-related immunotherapies are entering clinical trials and, if beneficial, point a positive way forward.
“Aside from pharmacological strategies, our ‘epidemic’ of dementia really needs much more investment in prevention, rather than treatment, by identifying and modifying the risk factors for developing AD (atherosclerosis, hypertension and other vascular problems) that are common in western Europe, Australasia and the USA.”
Dr Tara Spires-Jones, Chancellor’s Fellow and Reader, Centre for Cognitive and Neural Systems, University of Edinburgh, said:
“The solenuzemab phase 3 extension trial results indicate that in people with mild Alzheimer’s, drug treatment slows the disease process a small amount. A more thorough phase 3 trial targeting only patients with mild Alzheimer’s is underway to try and confirm these results. Current results show the drug only achieves small improvements in early stages; however if it proves to be disease modifying in the current phase 3 trial and provides long term benefits, it will be a huge step forward from the current treatment options.
“These results also lend hope to other current clinical trials testing similar drugs in people with rare inherited forms of Alzheimer’s at a stage before any clinical symptoms. From a scientific perspective, this study is exciting as it further validates the amyloid hypothesis of disease pathogenesis and will guide scientists working on more effective disease modifying therapeutics.”
Prof Richard Morris, Professor of Neuroscience, University of Edinburgh, said:
“My own judgement is that it is likely to be significant, but it is impossible to comment definitively until the results are actually shown. We don’t yet know how big the effect was, whether the subset of patients was but a fraction or a significant number and so on.
“My grounds for suspecting significance is that the new study constitutes positive evidence for the amyloid hypothesis that has been around for over 20 years, whose co-architect of the idea is the British Scientist – John Hardy (now at UCL).
“Many have been anywhere from sceptical to downright dismissive of the idea given the sheer number of failures of antibody studies, of gamma secretase and BACE inhibitors, and of other compounds targeting aspects of the APP to Abeta pathway. However, a complication in assessing all of these has been that the patients on which the idea has been tested may have been too advanced in their stage of the disease for the treatment, indeed any treatment, to be effective. So early diagnosis such as the DYAN trial and the work on the unusual cohort of families in Colombia (South America) constitute an important shift of focus – one that my group has also pursued in animal studies targeting extremely young animals harbouring human APP mutations. Our own (very) limited animal study published in 2007 showed effectiveness when treatment was given prior to ANY plaque deposition, but NO effectiveness once this had started. We also have a new study in review whose findings, I fear, I cannot yet disclose (but take it that they are positive too!).
“If the industry study has successfully identified very early diagnosis patients and finds that antibody treatment is effective in that subset, my own view is that this would more than vindicate the amyloid cascade idea. More than, as the hypothesis virtually predicts that treatments targeting APP would be ineffective if given too late.
“So I am cautiously optimistic, from the perspective of the audience, they should be too. This is not a mouse study, it’s a people study. And that matters.”
Declared interests
Prof Hardy: I consult on Alzheimer treatment for Eisai Pharmaceuticals and on Alzheimer diagnostics for Cytox
All others: None declared