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Holding on to hope for Alzheimer’s advances

Despite another late-stage failure, now is not the time to give up on the disease

Holding on to hope for Alzheimer’s advances

In many ways 2016 was as unpredictable a year as you can get, but the failure once again of yet another potential Alzheimer’s disease treatment in the clinic was sadly all too predictable.

Both analysts and academics had been getting excited about the Expedition 3 trial of Eli Lilly’s solanezumab, which has been developed to target amyloid-beta - the protein that clumps together in the brains of Alzheimer’s sufferers. The excitement was a bit surprising given that the Expedition 1 and 2 trials had crashed and burned.

However, pooled data from the studies had suggested to some observers that Expedition 3, which recruited patients with mild Alzheimer’s who were amyloid positive, might succeed where so many others have failed. There was no such luck.

Solanezumab setback
Patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to those on placebo. Lilly said that while the study results, ‘including many secondary clinical endpoints, directionally favoured solanezumab, the magnitudes of treatment differences were small’.

All highly disappointing for Lilly (which saw its stock sink), for academics that backed the amyloid hypothesis and for patients. What was supposed to be a celebration turned into a wake as the full data set was presented at the Clinical Trials in Alzheimer’s Disease meeting in San Diego in December, where Lilly confirmed it will not pursue regulatory submissions for solanezumab for mild dementia.

Lawrence Honig of the Columbia University Medical Center and principal investigator of Expedition 3, presented the data at the meeting. He said that although: “Alzheimer’s is a challenging disease…now is not the time to give up. While the outcome of this study is not what we had hoped for, it is reasonable to believe that disease-modifying therapies to slow down the progression of Alzheimer’s disease will be discovered.”

The failure of solanezumab has led to renewed attacks on the amyloid hypothesis and whether targeting the protein with a drug is actually going to do anything. Professor Peter Roberts at the University of Bristol is one of those who feels that the amyloid card has been overplayed.

There are fears that the constant failures are going to lead to a drop in investment

“I am not in the least surprised by the solanezemab data, despite Lilly’s seeming optimism just a short while ago,” he said. “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.”

Amyloid hypothesis not dead
While the solanezumab results are clearly a setback for the amyloid hypothesis, ie that the protein is a central driver of Alzheimer’s, the theory is not dead. At the CTAD meeting, data was presented on other anti-amyloid drugs which their makers hope will end the search for disease-modifying treatments for the disease.

Data was presented from a Phase Ib study on Biogen’s aducanumab which showed statistically significant reductions in amyloid plaques in the brain compared with placebo among 31 early-stage Alzheimer’s patients given titrated dosing. Biogen has begun enrolment in two phase III trials of aducanumab but those results are not likely before 2020.

The response to the early-stage data in some quarters was optimistic. Thomas Shrader, an analyst at Stifel, said “it’s extremely clear aducanumab both gets into the brain and removes existing plaque” but he acknowledged that “this removal of plaque remains somewhat controversial with respect to disease relevance”.

There was also some enthusiasm in San Diego for Roche and AC Immune’s crenezumab. Positive results from a phase Ib dose-escalation study were presented and Roche’s Genentech unit is pushing on with its 60 mg/kg dose in a phase III trial of 750 people with prodromal to mild Alzheimer’s; that too is scheduled to complete in 2020.

Prof Roberts remains unconvinced, believing that the faith pharmaceutical companies have put into the amyloid hypothesis has had a highly detrimental effect on research in other areas, notably the role of tau protein. He says that there is still a polarisation of the scientific ‘camps’ with amyloid versus tau, “right down to the chicken and egg arguments on which precedes the other”.

He believes that “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 Alzheimer’s disease and their changes are consequences of other underlying neuropathological events”.

Prof Gordon Wilcock at the University of Oxford said: “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 beta secretase cleaving enzyme (BACE) inhibitors which may reduce amyloid formation, rather than targeting its removal like the antibody strategies.”

He believes the 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”.

Big pharma backing BACE
A number of experts in the field believe that the research focus could indeed shift to BACE inhibitors. Leading the pack are Merck & Co’s verubecestat, pivotal data on which is due in mid-2017, Lilly and AstraZeneca’s LY3314814 and Eisai/Biogen’s E2609.

In terms of BACE, Prof Roberts said: “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.” Noting that knocking out the gene for BACE1 in mice causes a variety of “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”.

Funds need to keep flowing
There are fears that the constant failures in the clinic are going to lead to a drop in investment for Alzheimer’s research. However, given that dementia was recently recognised in a statistical bulletin from the Office of National Statistics as the leading cause of death in England and Wales, and with a globally ageing population, it is more urgent than ever to accelerate efforts - the price is too high not to do so.

So 2017 begins and hopes rise again, not least with the creation in the UK of its new Dementia Research Institute. The project is a joint £250m investment into dementia research led by the Medical Research Council, alongside the Alzheimer’s Society and Alzheimer’s Research UK.

In December, the UK DRI unveiled the University of Leuven’s Professor Bart De Strooper as its director, who will lead the initiative from University College London. He said: “Right now, our understanding of these diseases is not dissimilar to what we knew, or thought we knew, about cancer several decades ago. What we need is a paradigm shift in the way we think about dementias.”

Prof Strooper, who was selected after a competitive international search, noted: “Just as we realised that a whole range of factors is responsible for how cancers occur and progress in an individual, we now need to take a more holistic view of dementia and accept that a wide range of approaches may be needed in order to be successful. We have a huge amount of discovery science to do - and I want to see real surprises.”

He is not the only one. We still have no drugs that have demonstrated that they can stop or even slow down the progression of Alzheimer’s. Headlines in the mainstream press about ‘breakthroughs’ or ‘cures’ are unhelpful but hope springs eternal in the hunt for treatments.

Article by
Kevin Grogan

is a freelance journalist who has covered healthcare for over 20 years

3rd March 2017

Article by
Kevin Grogan

is a freelance journalist who has covered healthcare for over 20 years

3rd March 2017

From: Research



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