Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h4064 (Published 24 July 2015) Cite this as: BMJ 2015;351:h4064
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Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
Much appreciated appraisal. As a possible addition, if I read correctly, the carrying-on of the significant group to see if they stay significant has no statistical basis. If I gave ten groups of patients a bag of chips from ten different shops.....then found by chance that shop B's chip-group had less Dementia than shop F's chip-group; I couldn't prove the difference WASN'T by chance by giving the F-group some of the B-chips and showing it didn't help them.....
JL
PS My findings in a pilot study were once heralded as "The Breakthrough" in a newspaper headline. The article lauded my boss and his "crack team". I looked around me and realised......I was a crack team.
Competing interests: No competing interests
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
letter enclosed as pdf
Competing interests: I wrote the article, competing interests at bottom of column.
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
Margaret McCarthey’s article is correct to be cautious about the effectiveness of this drug for Alzheimer’s disease which she says might be a chance finding.. But this is not due to the relatively small size but due to the nature of testing for subgroups within an overall negative trial. If the overall trial showed no effect but a subgroup did then it is important to interpret these findings cautiously.
Firstly, if those with a mild disease benefited then it follows that those with severe disease got worse (as the overall trial did not show anything). Is this likely to be true? If not then it is likely to be a chance finding. A similar thing happened in another trial of a drug from Eli Lilly of raloxifine (1). In this large trial there was no impact of raloxifine on cardiovascular events. However, among a subgroup of women with increased risk of cardiovascular disease at baseline raloxifene appeared to show a 40% reduction in cardiovascular events. In a replication study of raloxifine solely among women with pre-existing cardiovascular disease there was no effect.
Whilst it is tempting to look for effectiveness among subgroups when the overall trial shows no effect these can often be misleading and, at best, are pointers to replication trials. Consequently, until a trial has been completed among patients with mild disease then the results are not believable.
(1) Barrett-Connor et al. JAMA. 2002;287(7):847-857. doi:10.1001/jama.287.7.847
(2) Barrett-Connor et al. N Engl J Med 2006; 355:125-137
Competing interests: No competing interests
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
It's a gold rush, and they are chasing fool's gold. When I was a consultant to pharmaceutical corporations I used to joke that my main value was in dissuading them from wasting money on illusions or fads.
Competing interests: No competing interests
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
Dr McCartney knows much more about this story than I do, because I merely vaguely followed the 'press coverage'.
My feelings were mixed: dementia is a horrible illness, and a cure would be fantastic. But even without some of the doubts raised by Dr McCartney, what I picked up on, was that this wasn't a 'cure' but that it slowed down the progression of dementia, and only in the very early stages of dementia. Cynically, I was thinking to myself 'So if this turns out to be developed into something with few claimed side effects, and if early-stage dementia is hard to identify, will this become 'so everyone over 65 should be taking the tablets' ?'
Of course, if it is developed into something which halts the progression of dementia at all stages, or even better reverses the illness, then my thought is ' wonderful' !
Competing interests: No competing interests
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
While Margaret McCartney’s article raises some important points about the media reporting of this week’s solanezumab trial results, the real significance of the trial data is not fully explained in this piece.
The article references a comment from my interview with the BBC, which explained that “these findings are hugely significant, in the sense that it’s the first data that we’ve had which is consistent with the drug actually slowing down the course of the disease.” It is unfortunate that the analysis that follows does not explore this crucial point.
Currently, the only available treatments for Alzheimer’s(1) help to manage the symptoms of the disease. They do not act on the underlying disease process, and damage to the brain continues unabated until these symptomatic treatments are no longer able to have any effect. At Alzheimer’s Research UK, we have long argued that a therapy capable of changing the course of the disease would have real significance. Research that we commissioned from the Office of Health Economics last year estimated that, for example, a treatment capable of slowing progression of the disease could help to reduce the numbers of people living with the more debilitating, severe form of Alzheimer’s(2) .
It’s important to understand the design and purpose of the extension study (EXPEDITION-EXT), from which results were reported on Wednesday. With no placebo control group in the extension period, this study was neither able, nor designed, to provide insights into the magnitude of the drug’s efficacy. As part of a ‘staggered-start’ design, this study was instead intended to reveal the drug’s mechanism of action. To do this, it aimed to determine whether the difference in cognitive decline in mild Alzheimer’s disease – already revealed during a pooled analysis of the placebo-controlled EXPEDITION and EXPEDITION 2 trials – was maintained when all participants were either continued on, or switched to, solanezumab. If the drug acted purely on symptoms, the two groups would coalesce and the difference would be lost – as the drug would not have deflected the trajectory of the disease during the initial trials. Instead, however, the difference between the two groups was sustained for a further two years: a result consistent with the drug having had a disease-modifying effect during the trials’ placebo-controlled phase.
In some of this week’s media reports, this key difference between the aims of the different trials was not always fully explained. It was not always clear that the 34% slowing of decline that EXPEDITION and EXPEDITION 2 reported in 2012 was not new data, and it’s therefore understandable that some people may have missed the true significance of these new results.
Dr McCartney is correct that these previously reported results on efficacy show only a modest benefit in real terms for patients with mild Alzheimer’s, whose symptoms are by definition less pronounced to begin with. But if the treatment has in fact altered the course of the disease, this raises the question of whether the magnitude of the effect would increase over time compared to a placebo group. This question still remains to be answered, as Alzheimer’s Research UK was careful to point out in media interviews, in our full written comment(3) on the research and in our blog post(4) about the results. Of course we must still also wait for the completion of EXPEDITION 3, an ongoing placebo-controlled trial in mild Alzheimer’s disease, to confirm the results seen in this group in the first two trials.
Is this level of efficacy all we would wish for? No, but slowing a disease process as complex as Alzheimer’s by 34% with a single agent is a good start. These latest results are also a test of the amyloid cascade hypothesis, which posits that deposition of amyloid in the brain drives the disease, at least in its early stages. With many other drugs in late-stage clinical development also targeting amyloid, it could be that these drugs provide greater benefit than solanezumab, or that combinations of different drugs could provide greater relief.
If solanezumab is acting on the disease process, this is highly significant. This extension study could be providing the first evidence that the course of Alzheimer’s can be slowed, and that the major hypothesis in Alzheimer’s research may be correct. It tells us that in future, we may be able to offer hope to people with Alzheimer’s beyond the symptomatic treatments currently available: we may begin to be able to tackle the disease at its root cause. We very much hope that in the coming years Dr McCartney will be able to offer better drugs to her patients with Alzheimer’s disease. While there is much more work to be done to reach this stage, this first step could be a real turning point for research into this devastating disease.
1 - http://www.nice.org.uk/guidance/ta217
2 - Lewis et al (2014), The Trajectory of Dementia in the UK – Making a Difference, report produced by OHE for Alzheimer’s Research UK http://www.alzheimersresearchuk.org/wp-content/uploads/2015/01/OHE-repor...
3 - http://www.alzheimersresearchuk.org/solanezumab-trials/
4 - http://www.dementiablog.org/solanezumab/
Competing interests: No competing interests
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
Dr McCartney asks: "This is no breakthrough. How did this paper score such extraordinary publicity?".
As a former Fleet St specialist correspondent, I may be able to cast some light on this specific question - and on the more general issue of how patently feeble research garners so much publicity.
It is, I feel, not sufficiently recognised that journalists are hired to report stories of general interest, not necessarily ones they believe in. It should also be borne in mind that repeated failure to report such stories - especially if they are picked up by rival outlets - leads to dismissal on the grounds of "lack of news judgement".
In the specific case of the Alzheimer's research, announcements about this condition are always potentially of widespread interest, but only sometimes also well-founded.
Journalists then face a judgement call. Will their rivals - by whose coverage they are judged - decide that the "newsworthiness" of the story outweighs its "thinness" and "go big" with the story ? In the case of the AD story, most clearly decided not to take the risk of being the only ones turning their noses up at the story - resulting in blanket coverage.
Many reporters will, I suspect, have had distinct qualms about their decision, however - not least because, like GPs (but unlike news editors), they are likely to be contacted directly by carers anxious to find out more about this "breakthrough" .
As a result, some will have attempted "reputational hedging", in which they write the story, but include caveats. Whether these survive the sub-editing process, or lead to a slightly less shrill headline, is not, however, something they have any control over - despite their names being on the story.
Please note I am not condoning such practices. I am hoping simply to provide some insight into what I know is a constant source of perplexed annoyance for knowledgeable readers.
Competing interests: No competing interests
Re: Margaret McCartney: The “breakthrough” drug that’s not been shown to help in Alzheimer’s disease
Combination of Monocloinal Antibodies,
β-Secretase inhibitor and a Anti-Tau agent with or without a Cholinesterase inhibitors for Alzheimer 's Disease .
In Alzheimer 's disease amyloid accumulation likely starts many years before the onset of symptoms. There are many pathways involved in amyloid synthesis and deposition cascade in the
Pathogenesis of Alzheimer ' s disease. so using of modified versions of monoclonal antibodies such as Solanezumab may not give a successful outcome. So along with monoclonal antibodies a combination of an another drug that decreases deposits of amyloid, for example, a β-secretase inhibitor, which targets an earlier step on the amyloid pathway, might have superior results. Addition of one more drug that target tau might also provide much more benefit along with above combination.
So a combination of Monocloinal antibodies, a β-secretase inhibitor and a anti-tau agent with or without a Cholinesterase inhibitors is ideal treatment strategy for prevention and progression of Alzhemier' s disease .
As far as Solanezumab is concern it may be well tolerated and without evidence of meningoencephalitis, microhemorrage or vasogenic edema. It can produce physiological changes in the amount of amyloid beta concentrations in the plasma and CSF, but Solanezumab in recent study shows no evidence of cognitive or functional improvement in patients with Alzheimer’s disease
Competing interests: No competing interests