To the patients desperately waiting for a cure for Alzheimer’s disease, the stream of bad news must appear relentless. In the past year Janssen, Pfizer, Merck, AstraZeneca, Eli Lilly and Lundbeck are just some of the pharma companies to have halted Alzheimer’s trials when their once-promising drug candidates failed to deliver good enough results. Although there is still plenty of research ongoing, some of the most promising avenues now appear to have hit a dead-end and there is a real risk that research funding will start to slow.
Many of the recent trial failures have involved beta secretase cleaving enzyme (BACE) inhibitors. These are intended to prevent or reverse the build-up of beta-amyloid, which clumps together to form plaques in the brain that, in turn, appear to be linked to Alzheimer’s. Some early trial results of BACE inhibitors were highly promising. Lanabecestat, a recently-pulled candidate from Eli Lilly and AstraZeneca, went as far as Phase III trials with a fast-track designation from the US FDA. However, hopes that beating the enzyme would prevent the plaques and cure the disease have proven over-optimistic.
For a start, the link between the enzymes and Alzheimer’s is more complex than it first appeared: post-mortem studies reveal that many elderly people die with plaques and tangles in their brains without having shown any signs of dementia. For another thing, even when the plaques are reduced, the relief to the brain appears to be only slight and temporary. Moreover, in some cases BACE inhibitors have worrying side-effects. Janssen’s drug candidate, atabecestat, for example, was linked to elevated levels of harmful liver enzymes.
New avenues
According to Professor Clifford Jack of the Mayo Clinic, one possibility is that BACE inhibitors are tackling the disease too late: the plaques have started doing irreversible damage to the brain long before dementia appears. He argues that Alzheimer’s is the culmination of decades of molecular change, nerve damage and brain degeneration, and that it’s vital to look earlier in the chain of events. So hope rests on one of two options. The first is that researchers can find early biomarkers for the disease and then develop new ways to prevent it from developing in the first place.
Professor Jack and his team are now looking at five biomarkers that may prove significant in the brain’s degeneration. They are not alone. The European Prevention of Alzheimer’s Consortium, for example, is working with 38 research organisations and recently signed up its 800th participant in what is intended to be a global biomarker study. Finding suitable biomarkers is now seen as the preferred route to a cure, although if it proves fruitful it could pose some ethical problems: people with the Alzheimer’s biomarkers may well feel they have to seek immediate treatment, even when they are healthy, in order to ward off the disease.
A second option has also emerged, which is to target the later biological processes in the Alzheimer’s process, those related to the tau and cell dysfunction. Such treatments could include stem cell injections that would aim to regenerate the brain or, more likely, drugs to support neuronal functions so they can continue to work despite the plaques and tangles. But, according to Professor Jack’s hypothesis, such treatments would likely only slow the progress towards dementia or manage the symptoms. Nevertheless, this appears to be where pharma companies are now focusing their research and development (R&D) efforts while they wait to see how the early biomarkers pan out.
The R&D investment
Those that are still in the game, that is. Given the small gains reaped from their investments in Alzheimer’s R&D so far, it is not surprising that many companies are re-evaluating their strategy. In the case of Pfizer, in June it announced that it would discontinue R&D into Alzheimer’s and Parkinson’s disease, cutting around 300 jobs at its facilities in the US states of Massachusetts and Connecticut. As recently as October 2017, the US drugmaker, working in partnership with Germany’s Boehringer Ingelheim, had four experimental Alzheimer’s drugs in play, as well as one for Parkinson’s. But now it will instead launch a new venture fund targeted towards neuroscience research projects.
Others have proved hardier. Eli Lilly was forced to cut 485 jobs following the failure of some of its Alzheimer’s trials, notably a major trial of solanezumab, its prime candidate. Nevertheless, having invested £125m into Alzheimer’s research over the past 25 years, it is determined to carry on with its research, either by going back to basics on the research or by testing its existing candidates on different trial groups with different profiles. Similarly, Merck, despite ending one trial for its candidate verubecestat in February, is poised to complete another on the same drug, targeting those at an earlier stage of the disease.
Their determination is admirable, and may in the end be profitable. After all, according to Alzheimer’s Disease International, the number of people with dementia worldwide is near-doubling every 20 years, suggesting it will reach 75 million by 2030 and 131.5 million by 2050. Alzheimer’s disease is the most common type of dementia, accounting for 62 percent of those diagnosed. And given the amount of care those people need, even those who manage to avoid this debilitating disease will be extremely grateful for any cure.
Ana Nicholls is director, industry operations at the Economist Intelligence Unit
