31 January 2020

A new hope for Alzheimer’s – or is it just fool’s gold?

Clinical Drugs Mental Health Neurology

Last March, biotech company Biogen announced it was halting its phase III trials of the amyloid-busting drug aducanumab, which looked unlikely to meet their primary endpoints after a futility analysis.

Now it is gearing up for a launch, hiring talent and talking pricing – even before it files for FDA approval, which it will do any day now.

What happened?

It was just before Halloween when Biogen reanimated aducanumab’s corpse. Further data had rolled in and now the drug worked – not only reducing amyloid-beta plaques as measured on PET scans, and tau in CSF, but also slowing cognitive decline on a range of scores. Biogen was the talk of the CTAD Alzheimer Congress in December.

In short, the monoclonal antibody, which binds to amyloid fibrils and soluble oligomers, showed early promise in a small human trial and was put through two identically designed efficacy trials, EMERGE and ENGAGE, with a combined sample size of more than 3000. Participants with Alzheimer’s disease were given placebo, low dose or high dose monthly for a year and a half. They received less if they carried the Alzheimer’s-predisposing ApoE4 gene variant, for fear of the brain inflammation effect known as ARIA, but the protocol was changed mid-trial to raise their dosage.

A subset of the patients were included in a futility analysis that met its endpoints in December, hence the March announcement. But an even smaller set of patients continued on the drug, and when their results were analysed, Biogen declared victory – despite conflicting results between EMERGE and ENGAGE. 

It’s messy and highly unusual. Details of these convoluted trials can be found in a Lancet article by Dr Lon Schneider, from University of Southern California’s Alzheimer Disease Research Centre. Sounding doubtful, he writes: “Biogen’s slide presentation at the investors’ conference contained sparse information on clinical outcomes, mainly percentage differences and lone p values … Although Biogen claims that the positive results of the EMERGE trial were driven by greater exposure to a higher dose in the larger dataset, the effect could just as likely been due to greater worsening in the placebo group.”

Alzheimer’s drugs have a notorious failure rate. A report in late 2018 by the Pharmaceutical Research and Manufacturers of America counted 146 failed drug trials between 1998 and 2017 (92 more candidates were undergoing trials in 2018). Only four were approved to treat symptoms – there are no disease-modifying drugs currently approved.

So this news should be a triumph. Instead, depending who you ask, the resurrection is either a cause for cautious optimism; an umpteenth chance for a disease hypothesis that after decades has shown no results; or, worse, a cynical grab at the untold wealth that a disease-modifying drug would bring – even one of limited clinical value.

Arguing that the results warranted only a second round of trials, not immediate approval, pharmaceuticals commentator (and amyloid-sceptic) Derek Lowe wrote in October on his Science Translational Medicine blog: “The first actual disease-modifying therapy will very quickly show revenues of over $10 billion a year and rising … There are huge numbers of desperate patients and their families who will immediately demand any such drug, and who could blame them? Meanwhile, there is what I can only describe as a moral hazard for drug developers in this area: if you could only get something approved, it would become the biggest drug in the world even if it doesn’t really help people all that much.”

Even researchers who have pursued amyloid their whole careers are doubtful that the improvements seen in the positive EMERGE trial – amounting to a 23% better performance than placebo – mean the drug is ready for prime time.

The theory behind aducanumab and other drugs like it is that amyloid is the principal cause of and best treatment target for Alzheimer’s. (Amyloid’s partner in crime, tau, is of equal importance, but won’t be properly covered here.) This has been the dominant idea for decades, but skepticism is growing.

Is the criticism fair?

Dr Bill Brooks from NeuRA in Sydney is a veteran clinician and researcher involved with the DIAN-TU trial. This is a longer, earlier intervention in people genetically predisposed to Alzheimer’s, using amyloid-targeting drugs solanezumab and gantenerumab, which have their own rocky histories.

He finds the aducanumab saga encouraging, albeit “unusual”, and defends the amyloid hypothesis against claims that it’s taking too long to produce results.

The question is: “When you start getting symptoms, is it too late to remove amyloid? Has there been too much damage done?”

He says aducanumab quite clearly does remove amyloid, and more importantly has shown a trend towards a slower decline in those on the highest dose.

“They were worthwhile differences,” he says. “They weren’t trivial. People in the early stages who aren’t deteriorating rapidly can still play golf and enjoy things – they may need help with tax returns, but if they have an able spouse they can have a reasonably good time. And if you preserve that by another year you might see your grandchild’s wedding, and that’s worth having.”

Whether amyloid is the main cause, or damage from some other process, is uncertain.

Using a topical analogy – which he stresses is “simplistic and not based in science” – he compares Alzheimer’s to bushfires, saying amyloid “could be the undergrowth, and something else comes along and sets it alight. It could be that it’s not the box of matches, it’s the firewood, and it may be worth removing it. It may be that amyloid is part of the answer but not the full answer.”

Dr Brooks says doubts are entirely legitimate, and by no means new, but that much of the criticism is unfair. For one thing, it is only very recently that we’ve been able to measure Alzheimer’s pathology in living subjects and watch their symptoms progress.

“People say you’ve had these decades to trial it and it hasn’t worked. But in fact it’s only now that we’ve got amyloid imaging, and we’re now doing trials where we can see the amyloid being removed and see what’s happening to people’s memory and thinking.

“I’m a reasonably skeptical person and I’m encouraged by the aducanumab news. I don’t think we should throw out amyloid, we should proceed on as many fronts as we can.

“If these results aren’t replicated and increasing the dose doesn’t work, well yes we’ll have to move on, but we’re just getting to the stage where we’re testing it properly.”

Paul Maruff is a professor at the Alzheimer’s Disease Research Centre at the Florey Institute at Melbourne University, and chief science officer at Cogstate, which specialises in measuring cognition.

Like Dr Brooks, he trained in the orbit of eminent neuropathologist Colin Masters, a professor at the Florey and Australia’s chief amyloid proponent.

While he doubts that Alzheimer’s is a single-factor disease, he, like Dr Brooks, is definitive about the centrality of amyloid: “If you don’t have amyloid, you don’t get Alzheimer’s disease.”

But that said, the disease definition has changed from a clinical phenomenon to a biological one that depends on amyloid, making that statement a tautology.

“The recent staging criteria for Alzheimer’s disease say there has to be pathological confirmation of amyloid,” Professor Maruff says. “So we’re really saying Alzheimer’s disease is amyloidosis.”

He says regardless of whether the drug ends up on the market, the aducanumab trial has been scientifically valuable and illuminating.

“If we stand back and say, from a scientific perspective, does the outcome of the aducanumab trial tell us anything about the pathophysiology of the biology of Alzheimer’s disease? I think yes. I think the trial, despite their stopping and starting, has shown us that lowering amyloid does have an effect on clinical manifestation of the disease.

“And this is not inconsistent with what was found with solenuzumab and gantenerumab, all of those studies which were constrained by the vicissitudes of statistical significance. All of them did show a substantial lowering of amyloid detected by amyloid PET/CSF analysis, and all of them did show that there was consequently improvement in symptoms. Some of them failed to reach statistical significance.”

He doesn’t believe amyloid has worn out its welcome, but says Alzheimer’s poses some unique challenges. First, it’s a very slow-moving disease – a blessing for the patient, a curse for the researcher.

Second, clinical trials have not only been expected to produce treatment options but have borne much of the burden of discovering what the disease is and what causes it.

“In diabetes we understand mechanism, we understand biomarkers, we understand outcomes and we can develop substantial drugs,” Professor Maruff says. “But in Alzheimer’s disease, we have a lot of unknown issues about what stage of the disease is relevant. We still don’t really know the pathology. We still argue about what’s the best way to detect a change, how long you need to study for, what magnitude of change is important. So we are proceeding in a step-by-step, iterative process here.”

As with cancer, he says, some of the Alzheimer’s drug studies have provided information about the biology of the disease even if they haven’t provided a basis for licensing a drug.

“So I wouldn’t say we’ve been at it for 20 years without much to show. I think we actually have developed an enormous amount of knowledge. I think back on my own career … if you want a good laugh, I’ll send you some of the papers I wrote about Alzheimer’s disease before we understood and were able to measure amyloid – we were really boxing at shadows.”

Professor Maruff says the stopping and starting and protocol changes in the Biogen trials, which may look like fiddling or squeezing the data, were in fact completely transparent and conscientious adjustments.

“They were started off on deliberately low doses because they were concerned about side effects, the ARIA. But as they got experience and saw they weren’t as substantial as they thought, they were able to push to higher doses, and the processes and the changes to the trial were all declared, it was not done in secret. They reported to the field: we’re not seeing the ARIA, we’re going to push to the higher dose.

“So if you stand back and look at the evolution of this study, I think from a scientific perspective, it’s great. It’s learn, adjust, refine. And I think they should be commended.

“So I think it’s a bit unfair to throw stones at poor old aducanumab, it’s done such important work.”

But whether the results justify regulatory approval is “an entirely different question from the scientific importance”. Even though CTAD was abuzz with speculation, he says, what the FDA says is ultimately not even the most crucial hurdle.

Given such a small effect size, he says, “the biggest issue for the company is whether insurance companies choose to pay for it. It becomes not about statistical significance, about the magnitude of the effect”.

Asked whether there isn’t a hint of desperation in the rush to market, Professor Maruff says bluntly: “Let me tell you, we are all desperate. And you can’t criticise us for being desperate. That’s a good thing. That’s what we need. What we hope is that our desperation doesn’t lead us to incorrect conclusions.

“We’re working so hard, we really are.”

BEYOND AMYLOID

There are amyloid agnostics in Australia who say they have struggled to have any competing ideas about aetiology taken seriously, though hostilities between them and “amyloidists” have been easing.

Professor Bryce Vissel, from the University of Technology, Sydney, says the adherence to amyloid has not only led to circular thinking about the disease, but has blinkered the research in a way that could end up costing patients.

Professor Vissel says the amyloid hypothesis has been embedded into the disease definition even though amyloid load is a far-from-perfect correlate for Alzheimer’s symptoms. While it is clearly a risk factor, its links with other established genetic and modifiable risk factors are unclear.

“The people who are making these statements about amyloid are good scientists and they’ve done a tonne of work,” he says. “It’s a good, profound body of studies to provide evidence that amyloid is involved with disease.

“One of the problems has been that all data has been interpreted through the amyloid hypothesis, so other hypotheses have not really been given equal airing. And that means there has been a risk of confirmation bias. Because we’re thinking a certain way, we see the answers in a certain way – that’s the nature of human beings.

“Any account of the disease has to account for amyloid, why it’s there, what it’s doing: whether it’s an innocent bystander or a grave marker of disease, we need to understand that.”

He quotes a 2011 paper by the late pathologist Mark Smith, who called the amyloid hypothesis “too big to fail” and said “such a degree of faith would be the envy of any religion”.

In the 2018 paper “Questions concerning the role of amyloid in the definition, aetiology and diagnosis of Alzheimer’s disease”, Professor Vissel and co-authors Ian Clark and Gary P. Morris wrote that while the there was a “plausible clinical rationale for removing” amyloid, “the present data does not prove amyloid-beta has, or will have, a central role in Alzheimer’s disease nosology, aetiology or diagnosis”.

“On the contrary, many would question whether, in the face of the extraordinary accumulation of inconsistencies and controversies … and an accumulation of evidence that supports alternative views of aetiology, amyloid should still be highly regarded as a biomarker that defines Alzheimer’s disease as a unique neurodegenerative disorder.”

While he says the aducanumab trial represents a crossroads for the hypothesis that may leave the amyloidists feeling vindicated, he has some concerns.

One is that in welcoming a positive trial after so many failures, we run the risk of a type II error: “There is actually a random chance if you do enough trials at some point you will get a positive result.”

Then there is the likelihood that once this is on the market, everyone with Alzheimer’s will be put on it, even late-stage patients, even though the results were only shown at early stage.

“The worry about the overuse and the extensive cost and misapplication is so profound because people are so desperate,” he says.

Then there’s the failure to consider that amyloid’s role might actually be protective, rather than disease-causing.

One competing hypothesis, promoted by Harvard researchers Robert Moir and Rudy Tanzi, is that amyloid plaques form as a protection against infection. While he’s not advocating this idea himself, Professor Vissel finds it “an interesting and compelling argument”.

“If that’s the case, then removing it might have a temporary benefit because it might remove inflammation in the brain [but] I wonder, what it does mean longer term if there’s an infection in the brain? Is it really the right thing to be doing?”

Professor Vissel says the aducanumab trial should be independently repeated before it is approved.

“But the pressure on the FDA right now with the Alzheimer’s burden in the States and in Australia, and the urgency for the families and the push by the doctors, the FDA would have to have to be made of titanium to withstand that kind of pressure. They are under pressure from Congress to get stuff out faster and they’ve been seen to be an impediment.

“What do the results really mean? How reversible is it? How specific does the population have to be? All of that really matters, because once this drug gets approved, it will be used in everyone with Alzheimer’s, no matter what phase. I speculate there’ll be a lot of pressure to use it in anyone with Alzheimer’s.

“Reproducibility of that result will be very expensive and hard to enact. But I think a responsibility of the science is to make sure this result is correct.”

FORKING PATHS

Professor Vissel and his colleagues advocate a central role for inflammation in the brain, to which amyloid contributes (others say the inflammation is just a symptom of amyloid damage).

“Amyloid effects activates TLR4, so it wouldn’t surprise us even by that mechanism that this is an important contributor to disease progression,” he says. “It may contribute to TLR4 activation for the very good reason that you want to bring in your innate immune response in the presence of infection – so that would fit with the infection hypothesis as well as the amyloid cascade hypothesis.”

He says anti-TNF drugs like etanercept “should show and have shown evidence of promise in treating Alzheimer’s”.

Other hypotheses are as varied as perturbations in non-coding RNAs, excess iron in the brain, and immune defence against microbes.

A microbe that’s looking especially hot right now is Porphyromonas gingivalis, the gram-negative bacteria that causes gum disease.

A year ago the private company Cortexyme, led by Stephen Dominy and Casey Lynch, published a paper on how the pathogen could drive Alzheimer’s pathology via toxic proteases, called gingipains, and the therapeutic potential of small molecule inhibitors. This mechanism incorporates, rather than replaces, both amyloid and tau.

Cortexyme is currently running a Phase II/III trial of a compound called COR388, which has shown safety and “positive trends” across several cognitive tests in a Phase Ib trial.

The other researchers The Medical Republic spoke to say this theory has acceptance in the wider research community and is being taken seriously – and so is inflammation.

Though all these ideas are apparently in tension, many of them interrelate and it’s possible that one day there’ll be a Grand Unified Theory of Alzheimer’s – or that the Alzheimer’s disease diagnosis will break into subdiagnoses.

Only science can tell us, but whether the science can remain uncontaminated by wishful thinking and profit motive, given the enormous financial implications of an Alzheimer’s drug, is something all three researchers doubt.

Professor Maruff says: “Most of us are just grinding away day after day in the laboratory, trying to find that one glimmer of hope. So Biogen has really provided just a little crack, but we’ve got our fingers in that crack and we’re chiselling away with our fingernails to open it a little bit more.

“[But] as soon as science is conducted by commercial entities, reasons to talk up or talk down a result can have nothing to do with the scientific integrity of the product, but they can be all about the share price.

“When you have science and commerce so directly interlinked, we have to treat the results with even greater care.”

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