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Monday, 16 May 2016

Solanezumab and Alzheimer’s

If you had been sitting in the main room of the 2015 Alzheimer's association international conference, you would have heard a remarkable announcement: a drug - Solanezumab - has been found to delay the course of Alzheimer's disease. Now that is a rare thing - 99.6% of all drugs designed to combat Alzheimer's have failed in trials since 2002. Just four have been approved for use. None of those four target the underlying cause of the disease (they just ameliorate the symptoms). But Solanezumab claims to be different.

Image illustrating the effects of Tau molecules on neurons courtesy NIA
The “plaques” and “tangles” found in the brains of Alzheimer’s patients are caused by two proteins behaving abnormally; beta-amyloid is thought to usually be involved in neuronal development, but in many Alzheimer’s patients the protein is not processed properly. The incorrect processing leads to a build-up of large amounts of beta-amyloid as the protein loses its solubility. The higher concentrations lead to this protein creating large aggregates known as “plaques”. “Tangles” are instead caused by the protein “tau”, which in Alzheimer’s patients has too many phosphate groups added to the protein, this makes tau clump together within the nerve cells.[3] Image credit: National Institute on Aging (public domain)

When given to patients in the early stages of the disease, the drug reportedly slows down disease progression: those taking it scored consistently better on tests of cognition and daily function than those on placebo. But, and this is a big but, the therapeutic effect only becomes statistically significant (the only kind of significant that interests potential investors) in patients with a mild case of the disease. If you start including those with more severe forms of Alzheimer's and that precious significance falls away to nothing.

So why all the fuss? Partly it is down to how the drug works: unlike any of its predecessors, it tackles the underlying pathology of Alzheimer's. A large part of this underlying pathology is the formation of great, sticky, cell-sized lumps of the protein amyloid-beta that start appearing as plaques throughout the Alzheimer's brain[1]. Solanezumab contains an antibody - which reacts with the amyloid beta protein, whilst it is still dissolved in the cerebro-spinal fluid that bathes the brain, allowing it to be cleared [by the body] before it clumps together to form [those] plaques.

On the face of it, this seems reasonably logical - if you help get rid of this obvious brain pathology, you slow down disease progression. The problem is that we're not actually sure if the build-up of amyloid-beta is the cause of the disease, or some knock on effect of the real problem[2]: you wouldn't fix a leak by constantly mopping the floor. There is also evidence that Alzheimer's has various genetic factors as well as other unrelated pathologies, like the build up of intracellular tau protein[1][2]. This drug could be the equivalent of mopping up the water on the floor whilst the rest of the house is falling down.

What's even more puzzling is that various other anti-amyloid strategies have been tried, but have failed: there have been drugs that block its production, chemicals that prevent it aggregating (forming those large, sticky plaques) and even different kinds of antibodies similar to Solanezumab[4]. So why should this drug work and those not? Come to that, why should this drug work this time?

Because Solanezumab has been tested before. Twice. Both times it failed to show a significant positive outcome on patients’ health[4]. But after re-analysing their data, its parent company Eli Lilly claim to have found that it is beneficial for a sub-group of patients - those with mild alzheimer’s disease. One group, given the drug from the beginning of the trial, seemed to do better than those started on it 2 years later. They argue that this shows Solanezumab is beneficial if given early on in cases of mild Alzheimers. It’s not that this isn't a potential game-changer... it's just not clear cut.

Solanezumab might work - although the jury's still out - but even if it does, it sadly won't be much help to those searching for a cure to Alzheimer's disease if it will only delay symptom onset[4]. Attacking amyloid beta build-up in the brain was pretty much the first thing everyone thought of when looking for a therapy, and it's been tried in a myriad ways up until now with no success. The immunological approach used in Solanezumab is so conceptually similar to other failed medicines, that its apparent efficacy in mild cases could be down to a biological quirk rather than by design. Whatever that quirk is, it might be worth looking at - and could even blossom into whole new area of discovery (I hope it does) - but it's not guaranteed.

There is a colossal amount of research going into Alzheimer's research at the moment (read this recent article in Things We Don't Know for an excellent insight) and if the ongoing titanic struggle against cancer can teach us anything, it is that we will make progress. But the unfeeling news storm that surrounds such tenuous advances is cruel and unnecessary. Give it a year, after the next phase of the trials for Solanezumab have been completed, then blow up the twittersphere with outlandish claims of panacea. Science is best when it's slow and steady; despite often being wide of the mark, it gets there eventually.

Dr Alistair Jennings has a PhD in neuroscience from University College London, and is a film-maker and presenter of science-based video content. He can be found on YouTube as Ali Heart Science.

why don't all references have links?

[1] Experimental Alzheimer Drugs Targeting BetaAmyloid and the “Amyloid Hypothesis”. Alzheimer's Association, 2007.
[2] Morris, Gary P., Ian A. Clark, and Bryce Vissel. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta neuropathologica communications 2, no. 1 (2014): 1. DOI: 10.1186/s40478-014-0135-5
[3] Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurology. 2014 April 71;(4):505-8.
[4] Doody, R,S., et al., (2014) Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease. New England Journal of Medicine 370(4):311-321 DOI: 10.1056/NEJMoa1312889