The Next Steps in Parkinson’s Disease Research

By STEVEN ZECOLA

Steven Zercola is back with his latest insights into research in Parkinson’s disease. You can say previous part of this series here

In its latest report, the National Institute of Health (NIH) references 508 active Parkinson’s disease (PD) projects as the recipients of $243M in grants.

A few caveats are warranted about these numbers:

1. The information is not as precise as it seems.  The NIH report states that: “NIH does not expressly budget by category”. Rather, it “categorizes diseases, conditions, and other research based on a computerized process that it uses at the end of each fiscal year”.
2. NIH alludes to $74 million of the overall budget as indirect costs without an explanation of this distinction.
3. Only about half of the aforementioned research grants are available to review. The NIH report specifies that “{t}he minimum reporting threshold for a specific disease/condition is $500,000”.
4. NIH isn’t the only federal government agency providing grants for PD research.  For example, the Department of Defense also maintains a budget for PD research, albeit much smaller.

Generally speaking, one can categorize basic research into having exploratory, explanatory or diagnostic objectives.  Given that basic research for PD has gained some important insights over the past several decades, I have added some PD-specific categories to the more general categories of research, as shown in the chart below.

Once these additional categories were identified, I assigned each of the reported studies and associated costs to the corresponding categories as follows:

As you can see from the activity on explanatory and exploratory research, NIH is still very much in a discovery mode when it comes to PD research.  From my perspective as a patient, only about 25% of these identified grants are in a position to produce game-changing results within the 10-year window of the legislation (namely, tools, biomarkers and alpha-synuclein).

In terms of clinical research, clinicaltrials.gov provides a listing of all trials, broken down into phases, including those that are completed, recruiting or terminated.  However, the inputs are not reviewed by an independent party, and the overall numbers are not reliable and do not reflect the funding status of the trials.

Nevertheless, there are a series of individual trials that show promise.

• A dozen or so trials target alpha-synuclein either by 1) reducing alpha-synuclein by immunization; 2) blocking misfolding of alpha-synuclein; 3) blocking alpha-synuclein aggregation; or 4) reducing alpha-synuclein synthesis. For example, Prasinezumab is designed to block the transmission of the aggregated forms of alpha-synuclein.
• The PROPEL Study tests a one-time gene therapy drug for people with Parkinson’s disease and a GBA1 gene mutation.
• Johns Hopkins is studying the safety and tolerability of RO-7486967, a small molecule designed to inhibit inflammation in Parkinson’s disease.
• Ambroxol is in a phase 3 clinical trial to test its long-term efficacy in slowing the progression of the disease.

The above examples are provided for illustrative purposes only and by no means are near complete.

Nevertheless, the two most important areas for PD research right now are 1) finding an easily administered biomarker for the disease and 2) finding a way to stop or reverse the clumping of the alpha-synuclein protein in the brain.  

Finding an easily administered biomarker would enhance the pursuit of a cure by providing a quick and definitive cause and effect relationship of certain approaches.  In the case of alpha-synuclein, research has shown a direct correlation between clumping of alpha-synuclein protein in the brain and the death of dopamine producing cells.  Therefore, if the effects of alpha-synuclein can be halted or reversed, the Holy Grail of PD research can be reached.

Separately, Terazosin deserves a special mention.  Several scientists found that those people who took Terazosin over an extended period of time had a lower incidence of PD and a slower progression of the disease if it manifested itself.  The drug had been approved by the FDA thirty-five years ago for other uses.  Yet it has taken years and millions of dollars for the drug to go through a Phase 1 trial to determine if it is safe.  This is a good example of unnecessary regulation at its worst.

A New Approach

Significantly, in July of this year, the President signed into law the National Plan to Cure Parkinson’s Disease.  In essence, the legislation requires HHS and other funding federal agencies to become more efficient and effective with respect to PD research.

The HHS Secretary with advice provided by an Advisory Council has been tasked by the legislation with sorting out the strategic direction for PD research. As this program kicks off, there are several steps that can be taken to improve the effectiveness of PD research.

First, all federal PD grants should be administered under one agency and coordinated with oversight by one person/office on a dedicated basis.

Second, at this point in the research cycle, grants for basic PD research should be more limited in scope and increased in dollar value.  For example, additional tools such as provided by Artificial Intelligence as well as having an easily-administered biomarker for the disease will have disproportionate positive effects.  Therefore, the amount and size of commitments to these projects should be increased provided that the specific project is not being pursued in the private sector.

Third, grants for physical therapies such as exercises, music and various forms of brain or body stimulation should be wound down and left to the private sector. The payback period on this research is comparatively short and the potential benefits are more limited compared to the other categories.

Fourth, unless the Advisory Council finds a high degree of uncertainty from the ongoing clinical trials, basic research in exploratory and explanatory matters should be scaled back while research for specific diagnostic efforts should continue, where such diagnostic research aims to understand “why” something is happening by investigating and addressing the potential cause. This research could become important if a multivariant approach to the disease is required.

Fifth, to the extent that any well-constructed clinical trials regarding alpha-synuclein are not fully funded, NIH should divert funds from basic research to this key area of clinical research.

Sixth, an increase in efficiency alone will not cause a fundamental change in 50 years’ worth of lackluster research results. Rather, HHS must change the FDA-approval process to shorten the research cycle for both basic and clinical research.

A simple yet effective solution would be to eliminate all FDA involvement in pre-clinical research, in Phase 1 clinical trials, and in Phase 2 clinical trials of PD.  The FDA would review the Phase 3 results for safety and effectiveness.

Conclusion.

As of today, progress remains slow. HHS has not taken any observable actions in terms of implementing the PD legislation.  

Nevertheless, by kick-starting the program with strong leadership and dedicated resources that are focused exclusively on PD, a cure to PD is achievable within five years with adoption of the six changes recommended herein.   While overall leadership changes abound with the new Administration, a tiger team of experts can be identified and sequestered to drive progress on conquering PD.  If necessary, the tiger team can be composed of outside experts hired for a short period of time to kick-start the new program during the transition.

Simply put, a one-billion-dollar investment in a well-organized and less regulated PD research program over the next several years will yield $25+ billion in savings per year for Medicare and Social Security — in perpetuity. That’s an approach worth pursuing for both patient well-being and economic soundness.

Steve Zecola sold his web application and hosting business when he was diagnosed with Parkinson’s disease twenty three years ago.  Since then, he has run a consulting practice, taught in graduate business school, and exercised extensively