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Alzheimer’s: the search for a cure

Will Biogen’s aducanumab re-energise the hunt for pharma’s white whale?

Alzheimer's disease

One year ago, it looked as though Biogen and Eisai’s aducanumab had joined the long list of failed Alzheimer’s disease drugs. To some people, the setback encountered by aducanumab marked the moment to call time altogether on efforts to treat the disease by targeting amyloid beta.

However, the situation has changed dramatically since then, with Biogen preparing for a drug launch that could make aducanumab a blockbuster and reinvigorate interest in amyloid beta.

The whiplash turnaround is the result of Biogen’s analysis of data from two phase 3 trials. In March 2018, Biogen revealed the phase 3 programme had failed a futility analysis, dragging confidence in the amyloid hypothesis down to a new low.

Yet, months after the apparent setback, Biogen said the result of the futility analysis was wrong and outlined plans to file for approval of aducanumab.

Resurrecting aducanumab

Biogen committed to seeking approval after factoring in additional data from patients who received the higher dose of its anti-amyloid beta antibody.

The analysis of the expanded data set for one of the phase 3 trials, EMERGE, linked aducanumab to improvements on a clinical dementia scale. Despite the unconventional route by which Biogen came to that finding, some experts hailed the result as a big breakthrough for a field that has been beset by years of failures.

“Clearly the EMERGE final analysis is positive... and the analysis of all the key secondaries was consistent and positive. As important, the biomarker evidence supports the mechanism, with significant amyloid reduction leading to... reduction in tauopathy,” said Paul Aisen, director of the Alzheimer’s Therapeutic Research Institute, at the Clinical Trials on Alzheimer’s Disease meeting where Biogen presented its data.

However, even Aisen acknowledges that the “data is complex”. Other observers have more critical ways of describing the data. The case against aducanumab is underpinned by the fact that in the other phase 3 trial, ENGAGE, placebo performed numerically better than the high dose of the antibody on the clinical dementia scale and as a measure of cognitive function.

Biogen thinks the differences between the results of the two trials can be explained by the mid-study modifications it made and the timing of enrolment. Even so, the clinical data package is imperfect, at best.

A more sceptical reading of the package is that it lacks even one successful trial, given that the failed futility analysis forced Biogen to rely on post-hoc analyses. Baird analyst Brian Skorney is among the people who have a dim view of Biogen’s prospects.

‘The preponderance of the data indicates aducanumab doesn’t provide a clinical benefit,’ Skorney wrote in a note to investors. ‘The bottom line is, the FDA standard of approval is substantial evidence of efficacy and the cumulative data for aducanumab falls really far off this standard.’

A lot is resting on the US Food and Drug Administration’s (FDA) interpretation of the data. If, after receiving input from an advisory committee, the FDA decides to approve aducanumab, it will provide an immediate fillip to Biogen.

While analysts are divided on the chances of aducanumab winning approval, there is a consensus that the antibody will sell well if it comes to market, given the demand for new Alzheimer’s drugs. Canaccord Genuity analysts forecast peak sales of $9.9bn (£7.6bn).

In late February, Biogen also made another big investment play in Alzheimer’s disease with a $350m upfront agreement with gene-editing specialist Sangamo for rights to tau-targeting drug ST-501 as part of a broader R&D alliance. Tau is emerging as a target for drug development in Alzheimer’s, as well as other disorders like frontotemporal dementia.

The changing pipeline

If aducanumab is approved and subsequent studies lessen doubts about its efficacy, the drug could give the industry renewed confidence that amyloid beta is a worthwhile target. While years of work on the target have yielded scant reward, it is possible that with aducanumab as a way-post, scientists will develop better amyloid beta drugs.

A clutch of drugs with anti-amyloid mechanisms are in phase 2 and 3 trials. Roche’s crenezumab is perhaps the closest analogue to aducanumab, but companies including Araclon Biotech, AriBio and Cognition Therapeutics are also aiming to reduce amyloid via other approaches.

The shortlist of companies with amyloid-focused Alzheimer’s drugs in development points to two big changes in the search for the cure. Firstly, the presence of Araclon, AriBio and Cognition on the list shows how biotechs have filled the vacuum created by the retreat of big pharma from neuroscience. In 2018, venture capitalists invested almost $1.5bn (€1.4bn) in neuroscience biotechs, an increase of more than 500% over funding levels in 2011.

Secondly, the limited number of companies with amyloid drugs in mid- and late-phase development is testament to the diversification of the Alzheimer’s pipeline.

Amyloid drugs dominated the pipeline as recently as January 2018, accounting for 54% of drugs in phase 3 at that time. However, by February 2019 amyloid’s share of the phase 3 pipeline had fallen to 32%. Analysis of the phase 2 pipeline suggests the trend will continue. In 2019, amyloid drugs accounted for 24% of the phase 2 pipeline, down from 30% one year earlier.

No one mechanism has filled the gap created by the decline in the number of amyloid assets. Rather, the pipeline has diversified as small numbers of drugs with neuroprotective, antioxidant, metabolic and other mechanisms of action have entered the clinic. The upshot is there are more approaches being pursued than in the past, when the industry pipeline was heavily skewed toward amyloid.

Organisations including the Alzheimer’s Drug Discovery Foundation (ADDF) think combinations of molecules with these different approaches will yield the best results. Many clinical trials already give experimental molecules on top of standard of care but the combination studies envisaged by groups such as ADDF differ.

The goal is to target distinct drivers of the disease, for example, by administering one drug to tamp down inflammation and another to address vascular issues. The diversification of the pipeline creates opportunities to pair drugs with different mechanisms for modifying the disease or addressing its symptoms.

While explorations of such combinations are yet to yield a breakthrough, with Eli Lilly dropping an N3pG/BACE combination in 2018, trials of multiple other combinations are ongoing.

Pharma’s return?

Positive data on one of the combinations or approval of aducanumab could spark renewed interest in treating Alzheimer’s. In recent years, companies such as Amgen and Pfizer have exited neuroscience research in response to the high failure rate and a perception that our understanding of the causes of the big diseases in the field, such as Alzheimer’s, is too limited to make near-term success likely.

Dave Reese, head of R&D at Amgen, touched on those issues to explain Amgen’s exit from neuroscience research.

“Based on what we felt was the state of the art in terms of understanding the pathogenesis of major diseases, especially neurodegenerative diseases, and our overall portfolio, we made that decision to end our early neuroscience research efforts,” Reese told investors.

However, the history of other areas of drug development shows companies could quickly return to Alzheimer’s and neuroscience if perceptions of the returns offered by the field changed. Such a shift has recently happened in the gene therapy space, which was a backwater pursued largely by biotech until the progress of companies such as Spark Therapeutics led Novartis, Roche and others to spend billions of dollars to buy their way into the field.

The willingness of venture capitalists to continue investing in neuroscience means there is a body of biotechs that larger companies could acquire to quickly return to the sector.

History suggests there is a good chance the money invested in neuroscience R&D, and in Alzheimer’s in particular, will fail to deliver a financial return or safe, effective therapies, but there are well-placed people who think the renaissance of the sector is just around the corner.

“We think neuroscience has the potential in the ‘20s to be what oncology has been in the last decade,” Roche Pharmaceuticals CEO Bill Anderson said at the J.P. Morgan Healthcare Conference.

Nick Taylor is a journalist specialising in the life sciences industry

19th March 2020

Nick Taylor is a journalist specialising in the life sciences industry

19th March 2020

From: Research

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