Tag: Parkinson’s Disease

The Long and Tortured History of Alpha-Synuclein and Parkinson’s Disease

Mar 29, 2024

By STEVEN ZECOLA

This study tracks the decades-long journey to harness alpha-synuclein as a treatment for Parkinson’s disease. Steven Zecola an activist who tracks Parkinson’s research and was on THCB last month discussing it, offers three key changes needed to overcome the underlying challenges.

A Quick Start for Alpha-Synuclein R&D

In the mid-1990’s, Parkinson’s patient advocacy groups had become impatient by the absence of any major therapeutic advances in the 25 years since L-dopa had been approved for Parkinson’s disease (PD).

The Director of National Institute of Neurological Disorders and Stroke (NINDS) set up a workshop in August 1995 that featured scientists with expertise in human genetics who might open novel avenues for PD research.

One such scientist, Robert Nussbaum, made the following remarks at the workshop:

“…finding genes responsible for familial Parkinson’s should be helpful for understanding all forms of the disease. Techniques now available should allow researchers to find the genes responsible for familial Parkinson’s disease in a relatively short time.”

Two years later in 1997, Spillantini et al. showed that alpha-synuclein (A-syn) was a major contributor of abnormal clusters of proteins in the brain, not only in patients with synuclein mutations but, more importantly, in patients with sporadic Parkinson’s disease as well.

As Nussbaum had predicted, progress had occurred rapidly. President Clinton in his 1998 State of the Union address, said:

“Think about this, the entire store of human knowledge now doubles every 5 years. In the 1980’s, scientists identified the gene causing cystic fibrosis. It took 9 years. Last year scientists located the gene that causes Parkinson’s disease in only 9 days.”

The NIH is Asked to Take a Leadership Role

Shortly after President Clinton’s call to action, a Senate Committee asked the National Institutes of Health (NIH) to develop a coordinated effort to take advantage of promising opportunities in PD research.

In response, the NIH and the National Institute of Neurological Disease and Stroke (NINDS) held a major planning meeting that included all components of the PD community. The group’s recommendations formed the basis of a five-year PD Research Agenda.

The Research Agenda was codified in a comprehensive 42-page report that covered all aspects of research from better understanding the disease, to creating new research capabilities, to developing new treatments, and to enhancing the research process.

Noting the “remarkable paradigm shift in Parkinson’s disease research” from the discovery of the effects of alpha-synuclein, the report stated that:

“New insights into the role of synucleins in the pathobiology of Parkinson’s disease would accelerate discovery of more effective therapies and provide fresh research opportunities to advance our understanding of Parkinson’s disease”.

NIH invested nearly $1 billion from FY 2000 to FY 2004 to implement the PD Research Agenda. A-syn research would be funded out of the funds allocated to the categories of Genetics and Epidemiology, with both categories targeted to receive about 15% of the overall spending.

Overall, there were 19 broad categories with spending authorizations, including $32.7 million allocated to Program Management and Direction.

When the PD Research Agenda reached the end of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005. It brought together an industry-wide consortium to assess the progress over the previous five years and to develop future directions for PD research.

The participants generated more than fifty specific recommendations. NIH considered these plans and the unmet goals from previous efforts and developed a 3-year Plan.

A major focus of that Plan was to identify and intervene with the causes of PD.

A New Day for Parkinson’s Disease Research Is Near

Feb 6, 2024

By STEVEN ZECOLA

The U.S. Department of Health and Human Service (“HHS”) is responsible for a wide range of activities relating to medical and public health. It has 60,000 employees and a $1.7 trillion annual budget with approximately $140 billion for discretionary spending. For the past 13 years, HHS has been spearheading a National Plan for addressing Alzheimer’s disease – with some notable successes.

Given its resources, expertise and charter, HHS should launch a National Plan to cure Parkinson’s disease patterned after its approach on Alzheimer’s disease.

Legislation, or Not

The U.S. House of Representatives has passed H.R.2365, the National Plan to Cure Parkinson’s Disease.

The bill would establish HHS as the central point for strategic direction and coordination of PD research. It would require formation of a broad-based Advisory Panel to provide strategic advice and any on-going course corrections.

There is nothing preventing HHS from putting the structure of H.R. 2365 into effect now, and it should do so without waiting for Senate action or inaction. There is no incremental funding required to implement this National Plan, nor is any Congressional approval necessary. This approach would mark an important step towards finding a cure for Parkinson’s disease, and is well within HHS’s charter.

A Cross-Section of Policy and PD Research

For those who have studied the application of regulatory policies to Parkinson’s disease research, it does not provide a productive narrative.

Levodopa was first discovered in 1910. In 1975, after 14 years of its “miraculous” treatment of PD symptoms, the FDA approved the drug. Levodopa does not cure or delay the progression of the disease. Yet, it has remained the gold standard of treatment of PD for the past fifty years. That is not to say there has been insufficient research or inadequate FDA approvals. Rather, it’s a question of where the research dollars have been funneled. It turns out that levodopa becomes less effective over time and eventually produces uncontrolled shaking. Therefore, research dollars have been targeted toward drugs that delayed the need for levodopa or controlled its side effects.

An exception to this approach was Geron, which became a leader in embryonic stem cell research. It had raised $100 million to conduct clinical trials. However, most of that money was consumed by undertaking thousands of experiments on mice under the “guidance” of the FDA. Nevertheless, Congress saw the potential of embryonic stem cells, and passed the Stem Cell Research Enhancement Act.

While Congress cheered, the Evangelical movement viewed embryonic stem cell research as barbaric and akin to murdering a human life. It didn’t matter that embryonic stem cells could not become a living being unless they were implanted in a woman’s womb, and this step wasn’t part of the research efforts. Notwithstanding, the Evangelicals convinced George W. Bush to veto the legislation, and a promising path for PD research was shut down.

More recently, the House has passed bills for a National Plan to Cure Parkinson’s in its last two sessions, but the Senate has failed to act, despite a myriad of sponsors of a bill with similar provisions.

Building Upon Lessons from the Past

In 2011, Congress passed legislation establishing a National Plan to Address Alzheimer’s disease (“NAPA”). Thirteen years later, there are many lessons to be learned from that effort that can be applied in a National Plan for PD. Of particular note, the original plan had five objectives including to “Prevent and Effectively Treat AD/ADRD by 2025”.

The first report by the Advisory Council specified that the current “level of resource commitment falls drastically short of the funding needed to accelerate the pace of research on prevention, cures, and treatments for AD”. It also recommended that the Secretary examine “[h]ow HHS uses existing authorities to reduce drug development barriers and accelerate development of new therapies” and specifically called for recommendations to “accelerate the FDA review process”.

What happened? While funding was increased substantially and hundreds of potential treatments have been identified, only two drugs have been approved by the FDA under an “accelerated” review process.

While HHS may express pride in the accomplishments from the Alzheimer’s National Plan, it should conclude that the process to get an effective treatment identified and approved takes too long. For example, the FDA provides “guidance” to researchers even before clinical trials are submitted. It also regulates the provision of genetic tests. These actions needlessly slow development and reduce innovation.

Similarly, the FDA’s regulation of Phase 1 and Phase 2 trials slows down development and does little to benefit the public interest. The FDA points to multiple ways that it has accelerated the drug approval process. But the reality is that progress from PD research has been lacking.

On the other hand, in 2019, researchers issued a report – based on real-world observations — that Terazosin resulted in a lower incidence of PD and a slower development of the disease when it did occur. Terazosin has been used for over 35 years to treat other maladies. Yet the drug underwent a 13-person Phase I trial to determine if it is safe. This phase 1 trial took several years to complete. This approach was a distraction that caused unnecessary delay and cost under the FDA’s regulatory regime.

The FDA will say that its rules do not require 3 (or more) trials nor does it mandate a particular trial design. This is disingenuous. Companies spending hundreds of millions of dollars on research cannot afford the risk of shirking the FDA’s standard procedures.

Taken as a whole, the HHS should limit the FDA’s involvement in PD research to approval of Phase 3 trials. Such an approval process will speed development and foster innovation yet maintain adequate safety controls by the FDA. Research organizations would be less constrained in developing their strategies and would be held to more responsibility for their approach to research.

A Multivariate Solution Is Likely to be Required

PD is a complex disease that has different manifestations when looked at from a genetic, diet, exercise, environmental (pesticides/pollution/solvents), vitamin, drug, electronic, radiation and possibly other perspectives. As such, a multivariate solution is likely to be required to successfully treat PD.

Such a solution will not be well accommodated by the current FDA review process, with each different combination of therapies being subjected to regulatory review and intervention. The process could drag on for decades.

HHS should recognize the need for a multivariate solution and plan accordingly, as described below.

Data Collection to Identify Multivariate Solutions

In 2010, The Michael J. Fox Foundation launched the Parkinson’s Progression Markers Initiative (PPMI) to find the biological markers of Parkinson’s onset and its progression. That study led to the impressive finding of a tool that can detect pathology not only of people diagnosed with Parkinson’s, but also in individuals that are at a high risk of developing it. However, after ten years, that study has only a few thousand participants. HHS should endorse and expand the scope of that study.

The “second version” of PPMI should be an overlay study designed with the end game in mind. That is, it should produce a mapping of individual people’s PD “score” over time against all relevant explanatory variables that could possibly impact PD for each individual. Such an approach is superior for identifying multivariate solutions.

To accomplish this objective, each participant would establish and maintain a unique portal for his/her own explanatory PD variables. The portal would include a series of hard-coded entry requirements covering scores of inputs. The initial set-up could be completed in piece-part (with the availability of outside assistance) and would auto-populate with each quarterly update (allowing for input of any changes that occurred after the initial set-up). The portal would interface with the growing number of portals of individual healthcare providers and would collect the diagnostic information from those systems. Personal “meters” of this sort are now actively being deployed in the field of Alzheimer’s disease given that certain therapies and drugs have shown progress against that disease.

As the above information from participants is collected over time, artificial intelligence software would be used to identify combinations of diet, exercise, supplements, genetics, sleep habits, therapies, electronics, radiation and drugs that point towards promising results. New treatments such as those undertaken in clinical trials would be added to the participant’s portal as they as are pursued by those individuals. All of the patient’s existing drugs would be analyzed in the context of all other relevant explanatory variables for that participant – over time.

As importantly, a comparative, quantifiable measurement of PD over time for each individual is required. The PPMI was originally focused on identifying a marker for PD and therefore uses a series of qualitative questions to gauge the patient’s development of PD symptoms over time. In contrast, the emphasis for this data collection effort should shift to the explanatory variables affecting PD progression over time.

In terms of the participant’s PD score, I believe a modified version of the Fitness program currently designed for the computer game “Wii” (which provides a quantitative estimate of an adult’s age based on how that person performed on certain activities) would provide more reliable results. Each participant would provide his/her own age estimator from the computer program on a quarterly basis as well as provide any updates for the various explanatory variables.

Once this revised format is established, the HHS should establish a goal of enrolling 100,000 PD participants into the study within two years.

A Better Approach for PD Research Is Available Now

HHS can – on its own accord – dramatically improve the efficiency and effectiveness of Parkinson’s research by: 1) adopting the industry-wide structure it utilized for Alzheimer’s disease, 2) embracing and expanding upon the current PPMI study and 3) limiting the FDA’s involvement in research to the approval of Phase 3 clinical trials.

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

The FDA’s Culture: Should Safety Dominate All Practices?

Aug 26, 2021

By STEVEN ZECOLA

An organization’s culture is an internal set of shared values, attitudes and practices. The cohesiveness of the organizational culture will affect whether the entity will meet its vision, purpose, and goals.

One type of organizational culture is hierarchical in nature. Unlike a risk-taking culture, this structure features policy, process and precision. It is best suited for mature and stable organizations.

The disadvantage of a hierarchal culture is that its stability and control can turn into rigidity. In many cases, the organization develops a negative attitude towards ideas supplied by third parties. It paints itself as having the perfect answer for every issue, no matter how large or small.

My interactions with the FDA suggest that its cultural practices are focused on safety, seemingly to the exclusion of all other issues. This practice may be appropriate in the regulation of food, but not for drug research where flexibility and creativity are required to cure complex diseases.

Over the past decade, I have witnessed an excessive adherence to its existing practices in the context of BRCA1-related breast cancer, metastatic cancer, precision medicines, “Big Data” and Parkinson’s disease. While the rulings were directed at me, the FDA’s position on these issues has impacted millions of people for the worse.

The Case to Realign Parkinson’s Disease Research

Jul 15, 2021

By STEVEN ZECOLA

If asked, the leaders of the research organizations working on Parkinson’s disease would say that they have made tremendous progress and are optimistic on finding a cure for the disease.

In truth, this viewpoint understates the magnitude of the challenge and results in insufficient resources being devoted to PD. Given the size of the challenge versus the available resources, most research studies today don’t even include finding a cure for PD as part of their objective.

The time is ripe to get everybody on the same page when it comes to the objectives, resources, and timelines for PD research.

What We Know About Parkinson’s Disease

Parkinson’s disease (PD) is a chronic, progressive movement disorder that affects the lives of almost one million Americans. Roughly 50,000 of the inflicted people die each year, often by injuries from falling. The incidence of PD is expected to expand to 1.6 million in the U.S. by the year 2037.

The characteristic motor symptoms of PD are tremors, stiffness, slowed movement and impaired balance. Over time, people with PD also experience non-motor symptoms including changes in mood, problems with attention and memory, sleep disturbances, fatigue, and changes in bowel and bladder function. PD has a considerable impact on the quality of life.

The cost to treat PD has been estimated to be $50 billion a year, split equally between the direct cost of care and the indirect costs of lost opportunities for the patients and caregivers.

PD is a complex disease which is thought to result from an interaction between genetic and environmental risk factors. More than 20 genes have been identified as having an impact on the onset of PD. However, genetic variation is estimated to contribute only about 25% to the overall risk of developing PD. Moreover, like the majority of neurodegenerative disorders, little insight is available on how specific sequence variations contribute to disease development and progression.

In short, the exact cause of PD is unknown. However, we know that that there is more than one manifestation of the disease. We can also reasonably conclude that more than one single element or therapy will be required to cure the disease.

What We Know About Parkinson’s Disease Research

PD was first discovered and described by James Parkinson in 1817 in London, England.

In 1911, the efforts of Kazimierz Funk, a Polish biochemist, paid off with the identification of Levodopa as a potential treatment.

By 1970, the FDA approved the use of Levodopa combined with Carbidopa for the treatment of PD. Since then, this combination has remained the gold standard for treatment.

During the last 50 years, many attempts have been made to improve this treatment and avoid its long-term complications. While several enhancements have been approved by the FDA and have helped patients, no treatment has cured or slowed the progression of the disease.

The Perfect Storm: When Parkinson’s Patients Enter the Hospital

Jan 23, 2019• 4

By HOOMAN AZMI MD, FAANS

When a patient enters a hospital either in an elective or more urgent manner, the main focus of the care team is to address the chief complaint. Other diagnoses, while important, may not receive as much attention. While this may not affect patients in most circumstances, it can be very impactful in patients who have Parkinson’s disease (PD). Studies have demonstrated that when patients with Parkinson’s disease enter the hospital, they are more susceptible to developing hospital related complications. Patients with Parkinson’s disease have a higher length of stay (LOS) than those entering the hospital for the same diagnosis without PD and can develop complications such as dysphagia, confusion and falls, impacting their outcomes and increasing their LOS.

Awareness about PD and its treatment and implications thereof are critical in ensuring reduced risks for this patient population. People with PD are very dependent on their medication, and timing of this medication is critical to maintaining good symptomatic control. In the outpatient setting, the main goal of medication management for these patients is to provide as much ON time as possible while minimizing side effects of the medications, such as dyskinesia. ON time describes a period of time when the medications are working and symptoms are controlled. Patients with advanced PD may have considerable difficulty with motor fluctuations if they transition from the ON state to an OFF state when the medication effect has worn off and they are symptomatic. The fine tuning of the medication regimen is pain-staking and often the result of multiple office visits and telephone calls to arrive at the best schedule customized for the patient. This can often result in seemingly unconventional timings (sometimes on the quarter after the hour) and at time q3 or even q2 intervals. Deviations from these regimens, even as little as 15 minutes delays, can have deleterious effects on patients with PD, as detailed above.

When patients with PD enter the hospital, attention is seldom paid to the exact timing of medication administration. If a patient takes a particular medication six times daily, ordering the medication six times daily in the hospital defaults to standard timings that often are different from the patients’ own regimen, causing timing errors. Almost 75% of PD patients who enter the hospital have delays in their medications and more than 60% of these patients can have complications during their hospitalization because of these delays.