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Failed Clinical Trials, Monday Morning Quarterbacking and Where We Go from Here

Failed Clinical Trials, Monday Morning Quarterbacking and Where We Go from Here

It’s been a tough few weeks for Alzheimer’s drug development. Last Monday, we learned of disappointing results from the first Phase 3 trial of bapineuzumab, or “bapi,” a compound being tested by Pfizer, Johnson & Johnson and Elan to target beta amyloid clumps — the pathological hallmark of Alzheimer’s. This followed closely on the heels of an unsuccessful Phase 2 trial of bapi, announced on July 24. As The New York Times reported then, “the failures have raised questions about whether beta amyloid really is the culprit behind Alzheimer's disease.”

Online chatter ramped up too, both in the Twitterverse and on the blogs. Here’s what Nate Sadeghi-Nejad had to say over at

“We don’t know enough about Alzheimer’s disease to bet half a billion dollars on a failed Phase II trial and post hoc data mining. The money for bapi’s pivotal trials should have been reallocated to enhancing our understanding of the disease’s etiology, which remains painfully limited.”

Here at The Michael J. Fox Foundation, we appreciate the critical need for ongoing discovery science to understand the mechanisms underlying disease onset and progression. But speaking as an impatient, ambitious and patient-focused stakeholder in Parkinson’s drug development, we don’t believe we have the luxury of waiting to start testing promising compounds till we know everything about the natural history of a disease — and in our experience, few patients believe that either. The Parkinson’s community is all too familiar with risky clinical trials and the immense frustration and disappointment that follow when they fail. Yet even failures have value — they get us closer to understanding what does work, and how to better focus future efforts. So we can’t help wondering what good is done by lambasting drugmakers and fault-finding after the fact.

“We are hoping to encourage some degree of risk-taking in the industry and it isn’t really that helpful for them to get so slammed when a trial didn’t work,” notes our CEO, Todd Sherer, PhD. “I agree that bapi was risky, but still — easy to say after the fact.”

A big bet was made in Alzheimer’s: that clearing beta amyloid alone would be enough to bring functional and cognitive improvement to those living with the disease. Because drug development is “stinkin’ expensive” (in the words of our co-founder and executive vice chairman, Debi Brooks), that bet necessarily absorbed billions of dollars in R&D. And now, according to the commentariat, it was folly and an abject failure.

Yet, characteristically of the maddening business that is biology, the case on bapi isn’t really closed. In fact, it’s just as likely that this generation of Alzheimer’s drugs (Eli Lilly & Co.’s solanezumab is next up at bat) has simply been tested in the wrong population of patients. While a successful trial would likely yield results to benefit people at all stages of disease, emerging research suggests it is critical to conduct clinical testing in the newly diagnosed or at-risk populations. Reports Reuters’ Julie Steenhuysen:

“[Scientists] believe the best hope now is testing drugs much earlier in this process, before the disease has done too much damage. But some fear that companies like Pfizer and J&J may balk over the long haul after spending billions on failed experiments.

“ ‘Even though the scientific rationale might still be valid and strong and not adequately tested in the phase of the disease where you might expect the therapy to work, that may be lost to investors,’ said Dr. Ronald Petersen, director of the Mayo Clinic Alzheimer's Disease Research Center in Rochester, Minnesota. ‘I hope that is not the case.’ ”

The insights we’re gaining on trial populations come in large part from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, launched in 2004 to identify and validate biomarkers of Alzheimer’s disease. In spite of Internet pessimism, ADNI is opening up a new appreciation of the etiology of Alzheimer’s, including critical insights into how and in whom we should be testing Alzheimer’s drugs.

So here’s the question: Did the bapi trials start too early, or did ADNI start too late? Either way, we in the Parkinson’s community are fortunate to benefit from lessons learned the hard way by our Alzheimer’s counterparts — count that as one positive outcome from the trials. Our Foundation, together with 24 clinical sites around the globe and 11 industry partners, is two years into the Parkinson’s Progression Markers Initiative (PPMI), a biomarker effort in Parkinson’s disease, for which ADNI was the scientific precedent. We launched it in 2010. Some felt we were on the early side, but we’re more convinced than ever that we made the right move at the right time. And while we’re incredibly optimistic about what PPMI will make possible, we’re not halting investment in promising targets while we wait for the better imperfect information it will yield.

Another lesson learned from ADNI: Open-source science not only works, it’s critical to speed progress. Like ADNI, PPMI is structured to make data and biosamples available to the research community at large in real time.  To date, nearly 25,000 scientists around the globe have accessed the data and 16 applications have been submitted for biomarker validation studies using our biosamples. Speaking to Chemical & Engineering News this week, Todd underscored the compelling case for companies to “share as much of the data from these failed trials available to the research community to try to understand what didn’t work, and what the results really mean. ‘It’ll be a goldmine of information for other Alzheimer’s trials, but also for other genetic diseases like Parkinson’s disease and Huntington’s disease.’ ”

It would be ironic — and tragic — if industry decision-makers let themselves be convinced there’s no business case for investing in risky targets just when the science is getting as exciting as it’s ever been and an aging population tumbles headlong into its golden years. Our social media manager, Stephanie Startz, says: “Rule of thumb: It’s rarely good when people are tweeting your stock symbol.” Several of our industry research partners’ symbols festooned page after page of tweets in the past weeks. That’s not going to help anyone’s cause, least of all patients’, in an already risk-averse funding environment.

With apologies to Beckett: Fail. Fail again. Fail better. Drug development is a risky and costly business, but it’s also an urgent one, and cooling our heels waiting for 360 degrees of information on any target is simply never going to be an acceptable option. Instead, let’s keep dreaming big about what we can accomplish when scientists collaborate instead of compete, when data is shared early and often, when we project-manage the best science and lay the groundwork for promising trials at the same time as we validate the most promising targets. We’re not naïve; we’re sober about the work remaining to be done. But we’re also optimistic. Smart, well-timed investments to shore up scientific and business challenges will pay off in the end. We won’t get there overnight, but we will get there.


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