In 2016, Rachelle Doody switched from academia to industry when she left Baylor College of Medicine for Roche/Genentech in Basel, Switzerland. At this year’s Clinical Trials on Alzheimer’s Conference, held November 1–4 in Boston, Doody used a keynote address to call for more balanced reporting of clinical trials in Alzheimer’s disease, and for more optimism all around.

After four cholinesterase inhibitor drugs were approved between 1993 and 2001, AD trials research entered a dry spell that was tallied and highlighted recently in a review article. In it, the authors counted 413 trials of 244 unique compounds tested between 2002 and 2012, of which only Namenda—an old drug previously in use in Europe—garnered FDA approval (Cummings et al., 2014). This amounted to an overall failure rate of 99.6 percent, which was widely reported in the press and indeed keeps haunting the field of AD research. “The media really keyed in on that 99.6 percent number,” Doody told the CTAD audience. She quoted Fox News, BBC News, and Scientific American; Fortune, Genetic & Engineering News, FierceBiotech, and other outlets had also reported it.

Painting AD research with a broad, negative brush is at odds with a general sense of scientific progress among the research community; what’s worse, a “failure number” creates a downward spiral, Doody cautioned. In media stories citing this number, the general public hears that Alzheimer’s is hopeless and trial participation pointless. Academic investigators see a devaluation of their work on shared multicenter trials. Within industry, overly negative headlines drive down internal calculations of a metric called probability of technical success. The PTS, in turn, influences another internal metric called net present value, by which a given investigational AD therapy competes for investment with candidate drugs in other disease areas perceived to be “easier” or more likely to generate marketing approval, such as cancer.

Citing 2016 numbers from the Biotechnology Innovation Organization (BIO), Doody acknowledged that far fewer investigational drugs progress through the clinical trial phases and to regulatory approval in Alzheimer’s than in the pharmaceutical industry overall. The reasons, however, are manifold and changing.

For example, comparing oncology, a field that has seen much progress in the past decade, with AD, Doody noted that AD trials are not only fewer but also far larger. An AD trial enrolls hundreds to thousands of participants in Phases 2 and 3, respectively, versus an average 20 to 30 participants per oncology trial in all phases. Moreover, AD drugs span a range of targets and approaches, from active and passive immunotherapies, various receptor agonists or antagonists, inhibitors of different enzymes, to growth factors, repurposed drugs, hormones, even nutraceuticals. Each one of these had its own reason for having failed, and distilling them all into a single failure number is counterproductive, Doody argued.

Both internal postmortems and reporting to the general public should focus on what each failure has taught the field, and what is being done differently in the next attempt. Some drugs failed because they never reached their pharmacodynamics targets, or the trial included no robust measure of target engagement in the brain. In other trials, the mechanism of action was vague or not central to AD progression. Some drugs foundered under dose-limiting side effects, others because their studies were statistically underpowered. Some trials stumbled because the placebo group did not decline or large variability between the participating sites precluded analysis. Yet other drugs were tested in heterogeneous, insufficiently characterized patient populations. And so on. The point is that the field is learning from every trial setback, Doody said.

So what has been learned? For one, it appears that drugs that modify risk factors of AD belong in prevention trials. Drugs targeting neuropathology, which  begins years before symptoms start, belong in very early-stage trials. For another, it appears that the most established Aβ/tau CSF biomarkers help identify patients with AD pathology but poorly predict progression or measure drug response. The field needs additional markers that change dynamically as people develop symptoms and get worse; for this purpose, research-grade tests, such as neurofilament light, neurogranin, and tau PET, are coming along rapidly. 

And what is different today? Many aspects of AD trials are changing. New trials incorporate criteria for prodromal AD, anti-amyloid trials verify amyloid positivity for inclusion and increasingly incorporate PET as outcome measures, and tau PET is entering therapeutic trials. Trialists and regulators together agree that, for the time being, trials at the prodromal stage won’t aim for surrogate biomarkers as approvable outcome measures, but instead will work out sensitive measures of subtle cognitive decline (see Part 1 of this series). Regulators support the field’s deepening understanding of the AD preclinical period by focusing on composite measures and accepting a single Phase 3 trial.

On anti-amyloid antibodies and BACE inhibitors, at least it is now clear that they can remove amyloid from the human brain, or slow its accumulation there. While this has not helped people with symptomatic AD, earlier intervention may well do so, Doody said.

She called on her colleagues in both academia and industry to include lessons learned when discussing a negative trial, and to encourage both investment and enthusiasm for new trials. “We need to work together to send a positive message to patients about participating in clinical trials. We also need to help trial sites maintain respect for what they are doing, and to offer clinical trials as options for all patients,” Doody concluded. —Gabrielle Strobel


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News Citations

  1. 10th CTAD: Finally, Alzheimer’s Field Is Serious About Prevention Trials

Paper Citations

  1. . Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37. Epub 2014 Jul 3 PubMed.

Further Reading