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Repairing the Parkinsonís Pipeline

By Robin Elliott

(This story was first published in the Summer 2008 issue of News & Review).

A decade ago, hopes were high in the Parkinson’s disease (PD) community. We were riding a new wave of research opportunities and many people — including scientists — were anticipating not only new treatments, but were also speculating that there could be a cure in as little as five to 10 years.

In contrast, today’s seemingly widespread feelings of disappointment — in the pace of progress toward treating and understanding PD — make it difficult to remember the optimism of the 1990s.

To understand today’s discontent; we must look backwards and ask: Why were we so confident then? There were several reasons.

Increased funding for medical research in general. Thanks to the efforts of a visionary bipartisan group in Congress and an effective coalition of universities and disease-advocacy groups, the budget of the National Institutes of Health (NIH) more than doubled in seven years — from $11.9 billion in 1996 to $27 billion in 2003.

Increased funding for Parkinson’s research specifically. In 1997, President Clinton signed the Morris K. Udall Act for Parkinson’s Research, which authorized up to $100 million a year for PD research. Three years later, NIH issued the first Parkinson’s Disease Research Agenda. These events increased federal funding for PD research from about $72 million in the mid-1990s (as estimated by the Parkinson’s Action Network) to $230 million in 2003.

The not-for-profit sector played its own part in the rise of research investments. A new foundation created by Michael J. Fox in 2000 began injecting millions into PD research, while the established foundations (the Parkinson’s Disease Foundation, the American Parkinson Disease Foundation and the National Parkinson Foundation), more than doubled their collective research investments between 1996 and 2006.

Advances in Parkinson’s science and treatments. A new generation of dopamine agonists (pramipexole and ropinirole) and a new surgery — deep brain stimulation (DBS) — promised more effective relief of several PD symptoms. In addition, impressive strides were made in the basic science of Parkinson’s. Just one example: the first gene to be linked to PD appeared in 1997. A decade later, we had as many as 12 genes.

The activities of a powerful group of celebrities with Parkinson’s. Muhammad Ali, US Attorney General Janet Reno and actor Michael J. Fox were ready not just to “go public,” but to roll up their sleeves for the fight to support PD research.

Setbacks and Slowdowns

Today, our optimism in new treatments seems to have waned. We have observed treatment breakthroughs become few and far between, seen that new drugs that do move through the pipeline are fewer and less successful, and watched funding for basic and translational science drop. Our observations are supported by a startling statistic: the number of new molecular entities approved by the US Food and Drug Administration (FDA) fell from 53 in 1996 to just 18 a decade later.

In 2004, the trial of GDNF, a promising growth factor, was abruptly halted for what its sponsors and investigators said was failure to show efficacy. In the same year, a trial of CEP-1347 was abandoned for similar reasons. In 2006, two other potential treatments were dropped — first Sarizotan, an anti-dyskinesia medication, and then GPI 1485, a treatment that the developer hoped would help regenerate damaged nerve cells.

In February of this year, the manufacturer of istradfeylline, another experimental treatment, received a “Not Approvable” letter from the FDA and the company thereupon issued a letter indicating that it was suspending further development of the drug. On March 20, a long-awaited dopamine-agonist patch had to be recalled by its manufacturer because of production errors that reduced its efficacy.

We all know that the progress of science is checkered with setbacks, disappointments and blind alleys, but it does seem that there has been a string of them lately, and people are understandably disappointed. Certainly there remain some very interesting potential Parkinson’s treatments making their way through the pipeline — including three separate gene therapy initiatives — but definitive results remain years away.

While disappointments in drug development accumulate, we have seen federal support of basic and translational research falter. At the NIH, after five years of unprecedented growth, funding first flattened out, then — corrected for inflation — actually dipped. The NIH budget in FY2008 is $29.465 billion — an increase of less than one-half of one percent above the level of the previous year. Meanwhile, funding for Parkinson’s research at the Department of Defense was cut from $26.5 million in 2007 to $20 million in 2008.

One result of the decline in NIH funding has been a sharp drop in the number of PD applications that get funded. The success percentage among grant applicants to the National institute of Neurological Disorders and Stroke (NINDS) — where most PD research is funded — dropped from 25 percent in 2003 to just nine percent in 2007.

Looking Ahead

How do we turn this situation around? Just as the process of drug development is multi-dimensional, so is its solution. It is not just a matter of spending more money, or reengineering the philosophy of research, or changing the political culture in which it operates; it is all of these, and more.

On the level of basic research, we need to give the NIH resources to build the knowledge infrastructure on which drug development depends. Unfortunately, in the current presidential campaign, other than a good statement of principle on the website of Senator Barack Obama, discussion of medical research, and in particular funding for NIH, has been virtually nonexistent.

Moving further along the pipeline, we need to “bridge the gap” — that stretch between basic science discoveries and successful drug development, where such discoveries get stuck on the shelf rather than explored by biotech and pharmaceutical companies.

Therefore, we need to both encourage NIH to reach forward in the process (that is, to fund more translational research) and to identify incentives to encourage biotech and pharmaceutical companies to reach back (that is, investing in earlier stages of drug development). Encouraging companies to do so may include exploring ways of subsidizing their risk (as the Fox Foundation is trying to do). Part of this may involve taking a hard look at tort law and assessing the role that class actions — not all certainly, but those of the nuisance variety — may play in increasing risk aversion among companies, that in turn can slow drug development.

We need to ensure that medications that do make it to market are both safe and available by insuring that the FDA has sufficient funding to do its job effectively and that the regulatory process properly balances the protection of public health with the expeditious testing and processing of potentially lifesaving treatments.

We need to re-examine the way we go about chasing cures, beginning by reviewing the very philosophy of the drug development process. As Greg Simon, CEO of Faster Cures, has written: we should be “more strategic about how resources are used; address the growing gap in the research continuum between basic discovery and commercial development; foster collaborations; and apply some management to the science that can help drive progress along the continuum.”

We need to improve the clinical research enterprise, by raising levels of awareness, trust and participation in the process — among doctors as well as people with PD. Current barriers include low levels of public awareness of what trials are available, and where; the failure of doctors to educate people with PD about the opportunity to participate in clinical research; and the breakdown in trust that can occur when industry sponsors exhibit cavalier behavior towards trial participants. (These and related issues are the focus of PDF’s Advancing Parkinson’s Therapies Programs (APT)). A key concept in this thinking is to see the person with PD as a central agent of change in the clinical research process.

And we need to expect that private foundations like PDF take advantage of their natural nimbleness to build boldly on traditional commitments (for example, the long-term support of Columbia University and other leading research centers that is the core of PDF’s research funding) to fund important new research in innovative new ways — especially in the areas where government and businesses, for whatever reasons, are not providing the support that is needed.

The revolution in molecular biology, genetics and other areas of science has revealed opportunities for new treatments that would have been almost unimaginable a half-century ago. Now we need to muster the political will, capitalist ingenuity and social imagination to take advantage of them.

Robin Elliott is the Executive Director of the Parkinson’s Disease Foundation.