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.

As reiterated in the 2006 Plan:

“…Understanding the role of alpha-synuclein may enable strategies to selectively block the harmful effects associated with this protein as a novel approach to treatment of PD”.

NINDS noted that:

“While PD is not a rare or orphan disease, other more prevalent diseases such as stroke, obesity and diabetes offer considerably larger “markets” for drug therapies than does PD. Thus, pharmaceutical companies have primarily focused on medicinal chemistry and alterations of existing PD or other neurological drugs (e.g., dopamine agonists) rather than investing in new drugs.”

In essence, NINDS recognized the financial conundrum of drug development for A-syn and other PD therapies, but looked to academia to solve the problem through its grant program.

Lacking success from the efforts of the 2006 Plan, NINDS organized another conference in January 2014 called: Parkinson’s Disease 2014: Advancing Research, Improving Lives. The purpose of this initiative was to identify significant challenges and to highlight the highest priorities for advancing research.

Thirty-one recommendations were provided. The summary of the conference included the Top 3 priorities for clinical research, translational research, and basic research. Under basic research, priorities 1 and 2 related to alpha-synuclein.

Given that the work specified for A-syn research was still at an early stage of basic research in 2014, it is clear that a large gap existed between the previous NINDS priorities for A-syn and what was delivered.

Private Interests Finally Move Forward with Alpha-Synuclein

Recognizing the continuing lack of progress and the need for funding, the Michael J. Fox Foundation announced a $10-million “Ken Griffin Alpha-synuclein Imaging Competition” in 2019 to spur development of a critical and elusive imaging research tool for Parkinson’s disease.

In March 2023, MJFF announced that the three initial Alpha-synuclein imaging competition teams — AC Immune, Mass General Brigham and Merck— made tremendous advancements in the development of different alpha-synuclein tracer methods.

MJFF awarded Merck an additional $1.5 million to continue the work and bring its tool to life. The first-in-human clinical trial of its alpha-synuclein PET tracer began in 2023. 

Additionally, after more than two decades of basic research, five private research companies filed applications with the FDA and have initiated early-stage PD trials.

• Neuropore Therapies and UCB are collaborating on an oral small molecule, which aims to prevent the formation of alpha-synuclein clusters.
• Prothena Biosciences, in conjunction with Roche, is testing a humanized anti-alpha-synuclein antibody.
• Biogen is investigating another monoclonal antibody against alpha-synuclein.
• AFFiRiS, an Austrian biotech company, is testing an alpha-synuclein vaccine. AC Immune has recently announced the acquisition of all of AFFiRiS’ assets and underlying intellectual property related to its vaccine candidates targeting a-syn.
• Vaxxinity uses an immunotherapy candidate codenamed UB–312 to target toxic forms of aggregated α-synuclein in the brain to fight Parkinson’s. Its Chairman recently said that: “Our findings suggest UB-312 could transform Parkinson’s care, offering hope for improved outcomes with a disease-modifying treatment”.

As with all R&D projects, there are many remaining challenges in the development of A-syn therapies before reaching the market. Nevertheless, assuming that at least one of the five on-going trials will be successful, we can expect a therapy utilizing A-syn will be approved by the FDA within the next 5-8 years. The net effect is that the overall development window between A-syn’s discovery in 1997 and its application to patients would be approximately 35 years – assuming that the research goes relatively smoothly from here.

Given its performance to date, the view from NIH regarding PD research is:

“… Our failures in bringing treatments to the goal line are due to remaining large gaps in knowledge of the underlying biology that causes and drives the disease. As we fill in these gaps, the chances of success will increase. Some of the gaps we know about, others we only find out about when the science opens another door”.

Why Has This Research Taken So Long?

With the benefit of hindsight, we can point to two areas that accounted for the greatest obstacles to progress – focus and resources.

In reading the PD research plans and reports from 2000, 2006 and 2014, it appears that NINDS threw everything it knew about PD into the hopper. There were hundreds of recommendations, projects and so-called priorities. But a key factor of success in research is having a team of motivated scientists with the necessary skills, knowledge and thinking ability to solve a finely-honed question.

There simply are not enough great minds to track down all of the “to do’s” in the three NINDS PD research plans.  Also, communications and networking are important components of scientific advancement, yet the capability to network with the widespread participation in the small grants program was lacking.

The implication of using the term “focus” is that it comes with the assignment of responsibility and accountability if the priority doesn’t get done. There appears to be little outside oversight of the efficiency and effectiveness of the research dollars that were utilized on A-syn or other PD research projects. If anything, NIH seems content with the output.

Finally, NIH/NINDS knew there was a funding problem in crossing the Valley of Death from basic research to clinical trials, but these organizations fell back to their comfort zone, namely small grants to academicians. This strategy did not produce the necessary results.

A Better Approach

In 1998 and thereafter, alpha-synuclein needed a swat team of top-flight researchers along with a commitment for additional funds as the project progressed out of basic research and through the requisite clinical trials.

To address the shortcomings to date, the Department of Health and Human Services (HHS) should step in and 1) narrow the PD research priority list to the top candidates, 2) require the establishment of a robust communications network for sharing information and 3) relax the FDA regulations for PD to help level the fund-raising playing field.

In particular, HHS/NIH/NINDS must recognize that investments in new healthcare therapies such as A-syn come with very high risks and those risky investment dollars get to choose between healthcare therapies that go through 15+ years of basic research and expensive clinical trials and other opportunities that can be launched in less than a year.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious effects on fund-raising. First, the FDA overhang has dried up interest in angel and venture capital investing in potential therapies such as A-syn. The result has been a Valley of Death between basic research and drug development. Second, even if the initial Valley can be crossed through government grants or non-profit donations, the FDA regulatory scheme puts an enormous burden on companies to raise scores of millions of dollars for lengthy clinical trials that face an uncertain regulatory outcome.

NIH/NINDS have not recognized that even without any direct role in fundraising, the FDA dominates the fund-raising process. For example, approximately 90% of fundraising for R&D is based on claims tied to regulatory milestones. Investors are well-aware of the challenges of the FDA approval process and it curbs investor interest.

Even in basic research, the FDA has had a large influence on scientific progress. For the academic entrepreneur, early development of an effective regulatory plan can be the difference between success and failure. Therefore, regulatory strategy becomes a critical component of the innovation process.

HHS must also recognize that the FDA has safety-first culture and a not-invented-here syndrome when it comes to any proposed changes to its processes.

The solution to these challenges, in part, entails HHS imposing a relaxed regulatory scheme for PD. For example, the FDA should be excludedfrom Phase 1 and Phase 2 trials and from providing any guidance to researchers prior to Phase 3 clinical trials. Such a change will speed development, unleash innovation, and improve early-stage fund-raising.

Second, to improve performance of the research endeavors, NINDS should be tasked to develop and manage a formal, hub-and-spoke, communications network among all stakeholders involved in PD research. ClinicalTrials.gov does not satisfy this requirement because it contains misleading information.

Facilitating regular exchanges of information, data sharing, and collaboration should help to maximize the impact of research efforts and avoid duplication of work. For the investment community, a partition in the hub with investment-related information would help to build a bridge over the Valley of Death and bring more funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications office should generally be housed by MBAs (rather than by Ph.D.’s) who are focused on communicating high value research endeavors with the not-so-subtle intent of fomenting an interest in investments. NIH should consider hiring an investment banking firm to assist in setting up the investor-related component of this information network.

The third recommendation for change is that NIH should convene a very small group of experts working on PD research to identify the three most-likely-to-succeed paths to a cure. It should ensure that those paths have adequate personnel and sufficient research dollars for completion.  Progress should be monitored on a regular basis.

Lastly, I should mention that the Michael J. Fox Foundation has done an excellent job on a number of important issues and should be a major part of any restructure going forward. For example, HHS could outsource the communications hub to MJFF.

The bottom line is that all components of the PD industry, including the FDA, must be on the same page in terms of finding a cure for PD within a reasonable amount of time given existing resources whether it be with alpha synuclein or other therapies. Such has not been the case with A-syn to date, and similarly, we have witnessed that the entire research effort for PD has underperformed – and will continue to underperform – in the absence of corrective action.

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

Preface

This study tracks the decades-long journey to harness alpha-synuclein as a treatment for Parkinson’s disease. The author 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. As reiterated in the 2006 Plan:

“…Understanding the role of alpha-synuclein may enable strategies to selectively block the harmful effects associated with this protein as a novel approach to treatment of PD”.

NINDS noted that:

“While PD is not a rare or orphan disease, other more prevalent diseases such as stroke, obesity and diabetes offer considerably larger “markets” for drug therapies than does PD. Thus, pharmaceutical companies have primarily focused on medicinal chemistry and alterations of existing PD or other neurological drugs (e.g., dopamine agonists) rather than investing in new drugs.”

In essence, NINDS recognized the financial conundrum of drug development for A-syn and other PD therapies, but looked to academia to solve the problem through its grant program.

Lacking success from the efforts of the 2006 Plan, NINDS organized another conference in January 2014 called: Parkinson’s Disease 2014: Advancing Research, Improving Lives. The purpose of this initiative was to identify significant challenges and to highlight the highest priorities for advancing research.

Thirty-one recommendations were provided. The summary of the conference included the Top 3 priorities for clinical research, translational research, and basic research. Under basic research, priorities 1 and 2 related to alpha-synuclein.

Given that the work specified for A-syn research was still at an early stage of basic research in 2014, it is clear that a large gap existed between the previous NINDS priorities for A-syn and what was delivered.

Private Interests Finally Move Forward with Alpha-Synuclein

Recognizing the continuing lack of progress and the need for funding, the Michael J. Fox Foundation announced a $10-million “Ken Griffin Alpha-synuclein Imaging Competition” in 2019 to spur development of a critical and elusive imaging research tool for Parkinson’s disease.

In March 2023, MJFF announced that the three initial Alpha-synuclein imaging competition teams — AC Immune, Mass General Brigham and Merck— made tremendous advancements in the development of different alpha-synuclein tracer methods.

MJFF awarded Merck an additional $1.5 million to continue the work and bring its tool to life. The first-in-human clinical trial of its alpha-synuclein PET tracer began in 2023. 

Additionally, after more than two decades of basic research, five private research companies filed applications with the FDA and have initiated early-stage PD trials.

• Neuropore Therapies and UCB are collaborating on an oral small molecule, which aims to prevent the formation of alpha-synuclein clusters.
• Prothena Biosciences, in conjunction with Roche, is testing a humanized anti-alpha-synuclein antibody.
• Biogen is investigating another monoclonal antibody against alpha-synuclein.
• AFFiRiS, an Austrian biotech company, is testing an alpha-synuclein vaccine. AC Immune has recently announced the acquisition of all of AFFiRiS’ assets and underlying intellectual property related to its vaccine candidates targeting a-syn.
• Vaxxinity uses an immunotherapy candidate codenamed UB–312 to target toxic forms of aggregated α-synuclein in the brain to fight Parkinson’s. Its Chairman recently said that: “Our findings suggest UB-312 could transform Parkinson’s care, offering hope for improved outcomes with a disease-modifying treatment”.

As with all R&D projects, there are many remaining challenges in the development of A-syn therapies before reaching the market. Nevertheless, assuming that at least one of the five on-going trials will be successful, we can expect a therapy utilizing A-syn will be approved by the FDA within the next 5-8 years. The net effect is that the overall development window between A-syn’s discovery in 1997 and its application to patients would be approximately 35 years – assuming that the research goes relatively smoothly from here.

Given its performance to date, the view from NIH regarding PD research is:

“… Our failures in bringing treatments to the goal line are due to remaining large gaps in knowledge of the underlying biology that causes and drives the disease. As we fill in these gaps, the chances of success will increase. Some of the gaps we know about, others we only find out about when the science opens another door”.

Why Has This Research Taken So Long?

With the benefit of hindsight, we can point to two areas that accounted for the greatest obstacles to progress – focus and resources.

In reading the PD research plans and reports from 2000, 2006 and 2014, it appears that NINDS threw everything it knew about PD into the hopper. There were hundreds of recommendations, projects and so-called priorities. But a key factor of success in research is having a team of motivated scientists with the necessary skills, knowledge and thinking ability to solve a finely-honed question.

There simply are not enough great minds to track down all of the “to do’s” in the three NINDS PD research plans.  Also, communications and networking are important components of scientific advancement, yet the capability to network with the widespread participation in the small grants program was lacking.

The implication of using the term “focus” is that it comes with the assignment of responsibility and accountability if the priority doesn’t get done. There appears to be little outside oversight of the efficiency and effectiveness of the research dollars that were utilized on A-syn or other PD research projects. If anything, NIH seems content with the output.

Finally, NIH/NINDS knew there was a funding problem in crossing the Valley of Death from basic research to clinical trials, but these organizations fell back to their comfort zone, namely small grants to academicians. This strategy did not produce the necessary results.

A Better Approach

In 1998 and thereafter, alpha-synuclein needed a swat team of top-flight researchers along with a commitment for additional funds as the project progressed out of basic research and through the requisite clinical trials.

To address the shortcomings to date, the Department of Health and Human Services (HHS) should step in and 1) narrow the PD research priority list to the top candidates, 2) require the establishment of a robust communications network for sharing information and 3) relax the FDA regulations for PD to help level the fund-raising playing field.

In particular, HHS/NIH/NINDS must recognize that investments in new healthcare therapies such as A-syn come with very high risks and those risky investment dollars get to choose between healthcare therapies that go through 15+ years of basic research and expensive clinical trials and other opportunities that can be launched in less than a year.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious effects on fund-raising. First, the FDA overhang has dried up interest in angel and venture capital investing in potential therapies such as A-syn. The result has been a Valley of Death between basic research and drug development. Second, even if the initial Valley can be crossed through government grants or non-profit donations, the FDA regulatory scheme puts an enormous burden on companies to raise scores of millions of dollars for lengthy clinical trials that face an uncertain regulatory outcome.

NIH/NINDS have not recognized that even without any direct role in fundraising, the FDA dominates the fund-raising process. For example, approximately 90% of fundraising for R&D is based on claims tied to regulatory milestones. Investors are well-aware of the challenges of the FDA approval process and it curbs investor interest.

Even in basic research, the FDA has had a large influence on scientific progress. For the academic entrepreneur, early development of an effective regulatory plan can be the difference between success and failure. Therefore, regulatory strategy becomes a critical component of the innovation process.

HHS must also recognize that the FDA has safety-first culture and a not-invented-here syndrome when it comes to any proposed changes to its processes.

The solution to these challenges, in part, entails HHS imposing a relaxed regulatory scheme for PD. For example, the FDA should be excludedfrom Phase 1 and Phase 2 trials and from providing any guidance to researchers prior to Phase 3 clinical trials. Such a change will speed development, unleash innovation, and improve early-stage fund-raising.

Second, to improve performance of the research endeavors, NINDS should be tasked to develop and manage a formal, hub-and-spoke, communications network among all stakeholders involved in PD research. ClinicalTrials.gov does not satisfy this requirement because it contains misleading information.

Facilitating regular exchanges of information, data sharing, and collaboration should help to maximize the impact of research efforts and avoid duplication of work. For the investment community, a partition in the hub with investment-related information would help to build a bridge over the Valley of Death and bring more funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications office should generally be housed by MBAs (rather than by Ph.D.’s) who are focused on communicating high value research endeavors with the not-so-subtle intent of fomenting an interest in investments. NIH should consider hiring an investment banking firm to assist in setting up the investor-related component of this information network.

The third recommendation for change is that NIH should convene a very small group of experts working on PD research to identify the three most-likely-to-succeed paths to a cure. It should ensure that those paths have adequate personnel and sufficient research dollars for completion.  Progress should be monitored on a regular basis.

Lastly, I should mention that the Michael J. Fox Foundation has done an excellent job on a number of important issues and should be a major part of any restructure going forward. For example, HHS could outsource the communications hub to MJFF.

The bottom line is that all components of the PD industry, including the FDA, must be on the same page in terms of finding a cure for PD within a reasonable amount of time given existing resources whether it be with alpha synuclein or other therapies. Such has not been the case with A-syn to date, and similarly, we have witnessed that the entire research effort for PD has underperformed – and will continue to underperform – in the absence of corrective action.

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

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.

My first interaction with the FDA came when my fiancée was diagnosed with breast cancer and received the news that she had a BCRA1 mutation.  As is the case for most BCRA1 carriers, she was also diagnosed as Triple-Negative, implying a more aggressive form of cancer with fewer approved pathways for treatment.

She reluctantly accepted the recommendation to undergo a double mastectomy and a chemotherapy regime consisting of Adriamycin, Cytoxan and Taxol (ACT).

ACT is a powerful concoction that has a deleterious effect on many parts of the body, including one’s hair. Patients wonder out loud if it is worth the bother.

Hearing that feedback, I began looking into the research to see if there were any alternatives in the pipeline. At the time, there was some encouraging news coming out of the early trials with PARP inhibitors and platinum-based drugs for BRCA1 victims.

Additionally, I realized that only one trial had been designed to show the effect of ACT on BRCA1 cancer victims as opposed to the broader class of Triple-Negative victims.  Looking at raw data, BRCA1 victims were worse off than non-BRCA1 victims when receiving ACT.

I then Petitioned the FDA to change its approach.  My fiancée was up to her third bout of metastatic cancer and it seemed that ACT was the culprit, and even if not, it was causing much pain without much benefit.

Luckily, she managed to get into a trial featuring Olaparib. Within months, the tumors completely disappeared.   However, the potency of Olaparib wears off after a couple of years and the bouts of metastatic cancer returned. She died at the age of 57 from her eighth bout of cancer that had metastasized to the brain.  It was the same age that her mother had died of the same cause.

Meanwhile, the FDA was busy defending its approach. It produced a 12-page letter rejecting my petition. It contained several non sequiturs and outright falsehoods to support its position, including:

“But the prognostic significance of having a BRCA mutation is not clear” and “it is not completely understood how similar BRC1-related breast cancers are to non-BRCA1 breast cancers”. FDA Letter, page 6.

“There are side effects with all chemotherapeutic agents (not just ACT).  In addition, you have not presented any evidence suggesting that side effects are more deleterious in BRCA1 patients being treated with ACT drugs than in other patients”.  FDA Letter, page 7.

“Given that adjuvant treatment was not assigned, it is not statistically valid to compare the survival rates of the 24 BRCA-1 patients who received chemotherapy and the 17 patients who did not receive chemotherapy”. FDA Letter, page 7.

“There is no evidence, however, that the deleterious effect of ACT on DNA in BRCA1 mutations is greater than the deleterious effect caused by other agents (e.g., platinum-based chemotherapy agents).”  FDA Letter, page 8.

“We do not agree with your claim that the results of any clinical trial of TNBC cannot be applied with statistical validity to the BRCA1 subcategory of TNBC unless that subcategory is specifically separated out and monitored.” FDA Letter, page 9.

I believe that all of these statements have been proven to be false.  Certainly, the author’s understanding of multivariable statistics is lacking. More importantly, the drug Lynparza® (Olaparib) has since been approved by the FDA for patients with metastatic breast cancer who have inherited mutations in the BRCA1 gene.

In reality, there was enough information for the FDA to be flexible and responsive to BRCA1 cancer victims before Lynparza was approved.   Over 500,000 women would have lived longer and with less pain if the FDA did not rigidly apply its cultural norms to the situation.

My second encounter with the FDA unsurprisingly involved metastatic cancer.  I noticed that only 8% of government spending on cancer research was directed to metastatic cancer but that 90% of the deaths from cancer were from metastatic cancer.  I suggested that the FDA champion an increase to 15% of the funding and to establish a separate center to raise the visibility and focus on this very efficient killer. I also suggested a modification of the standard FDA approval process for metastatic cancer.

The FDA responded with a seven-page letter denying my request.

The FDA wrote that their regulations “do not prescribe any particular type of trial design” and “nothing…requires that drugs undergo testing in distinct phases”.  

The FDA said: “in addition to flexibility in designing clinical trials, FDA has various other programs to expedite development and review of new drugs including…metastatic cancer”.

It added: “The Agency reorganized its oncology review office in 2011….and does not believe that its current structure lacks ‘sufficient organizational structure’ on metastatic disease, is inefficient, or otherwise impedes the conduct of clinical trials for…. metastatic cancer”.

These statements reflect an Agency that is in denial of reality. The reality is that eight years after this letter was written, the goal posts for metastatic cancer have not moved appreciably. Virtually all drug candidates go through multiple phases before approval. It is a long and costly process.

The budgets for metastatic cancer remain underfunded in general and in relation to other cancer targets. Metastatic cancer continues to be bad news no matter how you slice it.  Whatever the FDA is doing for metastatic cancer, it is far from perfect and hardly enough.

My third encounter with the FDA relates to precision medicines. In his 2015 State of the Union address, President Obama announced the launch of the Precision Medicine initiative “to revolutionize how we improve health and treat disease”. The White House subsequently specified that the Initiative “will include reviewing the current regulatory landscape to determine whether changes are needed to support the development of this new research and care model”. White House Fact Sheet: January 30, 2015.

On September 17, 2015, under the leadership of the NIH Director, the Precision Medicine Initiative Working Group recommended the creation of a national research participant group (a cohort) that would lead to trials of precision therapies, among other things.

In February 2016, I filed a Petition for the FDA to initiate a rulemaking seeking, legal, economic, scientific input on how best to analyze and approve new Precision Medicine Initiatives.

In March 2020, I received a letter denying my Petition.  The FDA said that “between 2013 and 2018, 76 out of 240 novel new drugs approved (31.7%) would likely be considered precision medicines…Additionally, we note that FDA currently employs many vehicles and authorities to encourage drug development”.

The FDA relies upon a serious case of tunnel vision to miss the point. There are likely to be several breakthrough findings emanating from the data in the cohort, but the sponsors of the research findings will need to deal with the FDA’s existing regulatory process.   I don’t think that is what President Obama had in mind when he said the PMI would: “revolutionize how we improve health and treat disease”.  The ensuing applications will take years if not decades to gain FDA approval at a cost of over $1 billion per approved drug. 

My fourth entanglement with the FDA revolved around “Big Data”.  More specifically, researchers collaborating between China and Iowa had found a correlation between Terazosin and Parkinson’s disease.  This was not a trial.  It was what actually happened in the real world. Terazosin had been approved 30 years ago for prostate issues.  The researchers then tracked what effect Terazosin had on the incidence of Parkinson’s and the progression of the disease.  The results were noticeably beneficial on both scores.  This is exactly the type of breakthrough that “Big Data” had promised (presuming the results are not fraudulent).

Despite this fantastic news, I saw little activity around Terazosin so I filed a Freedom of Information Act request with the FDA to determine if the FDA was putting unwarranted burdens on Terazosin before it could be used in the filing of an IND.

I received a phone call denying my request.  The caller said my request would be rejected orally so that no processing fee would be applied.

As a point of reference, FDA’s website says that “if a request for records is denied, a letter of explanation will be sent to the requester, who has the right to appeal the denial”.  This language reflects the wording of federal law.  No such letter was sent.

My fifth and less formal interaction with the FDA transpired with a senior executive to whom I had suggested that not much progress had been made in finding a cure for Parkinson’s disease since I had been diagnosed with the disease over twenty years ago.

I was told that: “Parkinson’s disease research is a very vibrant scientific field. There are a number of different streams of research that are ongoing that we hope will lead to highly impactful therapies…We have frequent communications with all of the U.S. Parkinson’s disease organizations, the Parkinson’s Study Group, academic investigators, and we coordinate on a variety of projects. The NIH system of funding the most meritorious projects has substantially increased our knowledge of Parkinson’s. Our failures in bringing treatments to the goal line are due to remaining large gaps in knowledge of the underlying biology that causes and drives the disease. As we fill in these gaps, the chances of success will increase. Some of the gaps we know about, others we only find out about when the science opens another door”.

While these remarks are sincere, the reality is that there is no plan with tangible steps to find a cure for Parkinson’s disease by a reasonably attainable target date.  The agency appears to be tone deaf to the negative impact that it perpetuates upon the cost and delays of research.

Do these instances provide a basis for concluding the nature of the FDA’s culture?  I think not, but I believe that The House Committee on Oversight and Reform should investigate the FDA’s culture and its practices to determine if the behavior described herein is the exception or the rule.  If the Committee members get answers to their questions that suggest what the FDA is doing is perfect or near perfect, they will have the answer.  The end-result will be that the FDA will not listen to outside ideas or change its practices.  This is particularly harmful in the area of drug research.

My view is that the FDA ignores the “big picture” of the massive hurdles to research it has created by its practices. The rigidity surrounding the practice of safety has overwhelmed the flexibility and creativity needed to cure complex diseases. The cultural trait of believing it has the perfect approach produces results that are nowhere near perfect and its practices – if left unchecked — will continue to bog down progress in the healthcare industry.

Steven Zecola is the managing director of Competitive Strategies and has held executive positions in large companies and the federal government.

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 U.S. Federal Government’s National Institute of Health is the largest funder of Parkinson’s research at roughly $250 million per year, with the National Institute of Neurological Disorders and Strokes (NINDS) funding about half of that amount.

A typical Funding Opportunity Announcement (FOA) by NINDS would invite applications for program funding. According to its website, “the overarching goal of this program is to support specialized research Centers that work collaboratively as well as independently to define the causes of and discover improved treatments for Parkinson’s disease”.  This goal doesn’t address finding a cure.

A number of other organizations also fund Parkinson’s research through grants. For example:

Michael J Fox Foundation (MJFF) – $1 billion since inception

Parkinson’s Foundation – $350 million since 1957

Aligning Science Across Parkinson’s (ASAP) – $161M over three years

American Parkinson Disease Association – $51 million over the past decade

Very few of the independent Foundation Grants are focused on finding a cure to PD, with the exception of the MJFF.

The ClinicalTrials.gov website lists 2959 clinical trials of Parkinson’s disease with 534 trials actively recruiting.

The vast majority of these trials are either unfunded or do not address the issue of finding a cure for Parkinson’s disease.

Moreover, the report simply does not pass the numerical “smell test”.  First, there aren’t enough PD volunteers in the United States or elsewhere to support 534 on-going clinical trials.  Second, there are not enough funds to support 534 ongoing trials.  The average Phase 1 trial costs about $5 million in out-of-pocket costs.

It would require at least $2.5 billion to support 534 trials. The annual research spending on Parkinson’s disease is about $350 million.  The numbers don’t jive and therefore the report is misleading, at best.

The typical FDA drug approval process requires three phases of successful testing with increasing patient enrollment.

On average, getting the approval of one drug from the FDA costs over $1 billion in research and results in over 12 years of regulatory scrutiny.  To make matters worse, this delay does not include FDA’s involvement in pre-clinical research such as what occurred with embryonic stem cells or with the tests of gene variations (of which there are many).

The large pharmaceutical companies support this regulatory structure because it reduces competitive entry from new drugs and helps to maintain high prices for drugs. On the other hand, as smaller companies show success in Phase 1 and/or Phase 2 trials, Big Pharma often provides resources for completing the trials in exchange for an ownership interest, or they simply acquire the company. This dynamic has been at play for decades to the immense benefit of Big Pharma, and not to many others.

The FDA’s objective in this process is to prevent harm to the public, not to find a cure for costly diseases – and it does a very good job at achieving its objective.

What’s Wrong with the Current Research Approach?

There are several problems with the current research approach for PD.

First, after 50 years of trying, there is no clear path to a cure. In fact, it is hard to find any condition that makes it easier to cure PD.  The people in charge of PD research must acknowledge that there is something wrong with this picture.  Without that acknowledgement, their organizations will have no incentive to change what they are comfortable doing.

Second, the “numbers” related to PD research reflect a large disconnect.  On the current course, there will over $650 billion in costs incurred by society from Parkinson’s disease over the coming decade.  Out of the NIH’s $40+ billion annual research budget, about $250 million is allocated each year to research for PD. If that amount were doubled and resulted in a cure being identified within 5 years, the payback on the incremental funding would be $520 for every incremental $1 invested.  What business would not invest $1 now to achieve $520 in cost-savings in the not-to-distant future?  Obviously, there is an imbalance between opportunity and investment when it comes to funding PD research.  It appears that the NIH allocates research dollars based, in large part, on the number of deaths from a disease (of which PD is not a high producer) and not from the overall cost to society of the various diseases (for which PD ranks relatively higher).

Third, most researchers are testing only one element (e.g., a protein, a drug, a genetic correction) in clinical trials.  However, there is likely to be a combination of elements required to cure the disease. Getting the right combination could take ten or more tries after the initial approval.  Each try would be subject to the FDA’s costly and time-consuming processes.  In other words, the present course is likely to entail several decades of additional research before achieving an FDA approval of a multi-faceted cure.

Fourth, even if the current research budget were significantly increased, there is no guarantee that the funds will be used effectively and efficiently in pursuit of a cure.  While there is a smattering of communications and collaboration in the field, PD research endeavors are not well coordinated.  For example, many funded programs are directed to basic research, while promising approaches from the lab face “The Valley of Death” due to a lack of funding.

A Better Approach to Finding a Cure for PD

The first step to finding a cure is to recognize that a change in approach is needed.  At the top of the list is that PD is likely to require a combination of therapies to enable a cure. As with other fields, the leaders should look to “technology” to give significant improvements in productivity to address this challenge.

In fact, improvements in DNA sequencing, genome editing based on the microbial CRISPR-Cas adaptive immune system, human pluripotent stem cell technology, and genome-wide association studies (GWAS) have opened the possibility of finding a complex solution to a complex problem.  Further progress will require an increased focus on the tools needed to make that happen.

Second, Parkinson’s disease research needs an industry-wide organization to enhance communications, collaboration and focus. As an important component, there should be a Parkinson’s Research Council (PRC) that sets the direction of research and approves the funding initiatives of its five members for PD projects above $2 million.

The Research Council should be composed of one member elected from each of the NINDS, the Parkinson’s Foundation, the Michael J. Fox Foundation, Aligning Science Across Parkinson’s and an annual rotating seat elected by a university with an expertise in PD. A representative from the FDA should hold a non-voting seat.

Additionally, a newly-formed virtual organization under the PRC should be created with an appointee from each accredited PD research organization. There would be regular communications of PD research findings, and an annual meeting held via video conference to address performance versus expectations for the prior year, lessons learned, and plans for the coming year.

The third step to finding a cure for PD on an expeditated basis is to change the FDA regulatory paradigm. The FDA should be foreclosed from involvement in pre-clinical PD research.  Also, the FDA should be removed from its self-imposed position of approving genetic health and carrier information. Finally, FDA’s role in Phase 1 and Phase 2 PD trials should be limited to observation.

Conclusion

PD research is spread out in many directions, but after 50 years of trying, it is still decades away from finding a cure.  That realization must sink in to its participants before a change in approach is accepted.

The requisite changes are: 1) a focus on multivariate solutions; 2) an overlay industry structure that coordinates the focus and funding of PD research and tracks performance and 3) a modified approach to FDA regulation.  Once these changes are put in place, the funding of PD research should be increased substantially over the next several years with the singular objective of finding a cure.

Steven Zecola is the managing director of Competitive Strategies and has held executive positions in large companies and the federal government.

Most people would agree that the number of cures for debilitating and costly illnesses such as Alzheimer’s disease, Parkinson’s disease and cancer have been too few and far between.

To address this issue, the U.S. House of Representatives recently passed the 21st Century Cures Act, which now resides in the U.S. Senate for action.  The main thrusts of the Act are to increase government funding for research and to improve several regulatory processes.

Unfortunately, the Act does not address the root cause of the dearth of cures; namely, the inhospitable investment climate for research and development (“R&D”) culminating in the “Valley of Death” for most health-related discoveries.

II. Overview of the 21st Century Cures Act

The 21st Century Cures Act mandates a 3% real increase in the NIH budget per year for three years after enactment. It also provides an additional $1.86 billion a year in the form of an “innovation” fund that would primarily support young scientists and precision medicine.

The bill also provides for changes to the current approval processes including provisions for making data from NIH-funded clinical trials more easily available to researchers, facilitating collaborative research, speeding up the review of new vaccines by the Advisory Committee on Immunization Practices, requiring a strategic plan every five years to identify research opportunities and strategic focus areas, reducing administrative burdens on researchers, and limiting the term of office of directors of centers and institutes to five years (with reappointment by the NIH director possible). The bill also requires the directors of each institute to “establish programs to conduct or support research projects that pursue innovative approaches to major contemporary challenges in biomedical research that involve inherent high risk, but have the potential to lead to breakthroughs” and “set aside a specific percentage of funding, to be determined by the Director of NIH for each national research institute, for such projects.”

III. Critique of the Act

While the provisions of the 21st Century Cures Act are admirable, the Act does not address the underlying reason for the dearth of cures.  That is, the regulatory process adds excessive and unpredictable risk, cost, and delays to research and development that result in a “Valley of Death” where most scientific discoveries remain unfunded.

An approach to overcome this obstacle is summarized here and explained in more detail in a position paper posted at www.thevalleyofdeath.info .  In a nutshell, Congress needs to create an environment that provides for increased incentive for private capital formation to fund R&D without compromising consumer safety.

IV. Summary of Proposed Amendment to Address the Valley of Death in Research and Development

The following five provisions summarize the approach to improve private capital formation for research and development in health-related initiatives.

To ease any concerns between the balance of benefits and public safety with this program, the following recommendations could be rolled out in one or two areas such as Alzheimer’s disease, Parkinson’s disease and/or metastatic cancer where patients have more suffering and less hope for a cure.

The proposed approach is as follows:

1) Congress would limit the FDA’s role in preclinical research to surveillance.

2) Each pre-approved, qualified professional research organization filing a Phase 1 drug application would receive a provisional license from the FDA within 60 days from the time it provided the details of its trial and put a corresponding deposit into an escrow account.

Likewise, applications for Phase 2 and Phase 3 trials would also be subject to a 60 day review cycle and would require additional funds to be deposited into an escrow account, the amount of which would be subject to the size of the trials. A sample deposit schedule follows:

Phase 1 – $250,000 per trial participant
Phase 2-  $100,000 per trial participant
Phase 3 –   $50,000 per trial participant

The above schedule would produce escrowed deposits as follows:

Number of Participants       Incremental Deposit   Cumulative Deposit
Phase 1 20 – 40                       $5M – $10M                 $5M – $10M
Phase 2 100 – 200                   $10M – $20M                $15M -$30M
Phase 3 1000 – 3000                $50M – $150M             $65M – $180M

The FDA would have the authority to reduce the above deposits for special considerations.

3) An industry organization would be required to provide regular reports to the FDA for purposes of oversight (along with the reports provided by individual research organizations with the results of each phase of its trial). This industry organization would have the authority and responsibility to audit individual trial results and to maintain a secure whistle blower system.  A reward would be paid to whistle blowers whose efforts led to the successful prosecution of fraud by a licensee.

4) The FDA would have authority to seek injunctions from the U.S. Court of Appeals to stop any new drug, procedure or device that it believed was unfit for human application.  If a company were found to be in violation of the FDA’s safety guidelines, the company would lose its license and forfeit its escrowed funds.

5) Research organizations would be required to maintain and submit relevant health statistics on patients for one year from commercial launch.  Sixty days after such filings, the FDA would issue a commercial license and the escrowed funds would be returned to the licensee if a Court had not granted an injunction.

Likewise, if the research organization voluntarily abandoned its program during development, the deposit would also be refunded.

Such an approach would place the risk, pace and costs of both pre-clinical research and clinical trials principally under the control of qualified research organizations.  The effect would be greater funding opportunities for the private sector to pursue promising research opportunities.

In addition, the Amendment would strengthen the FDA’s surveillance and enforcement powers for purposes of protecting consumer safety, and put the proper incentives and penalties in place to forestall the introduction of unsafe products to the public.

V. Conclusion

While the 21st Century Cures Act recognizes and addresses a significant issue in the health and welfare of our country, it does not solve the underlying problem causing the lack of significant health-related cures.

Congress could jumpstart private funding for research and development of promising discoveries by adopting the above recommendations in an Amendment to the 21st Century Cures Act.

To minimize concerns for public safety, the approach recommended here could be achieved with an Amendment that would apply only to specific research areas such as Alzheimer’s disease, Parkinson’s disease and/or metastatic cancer where suffering is the greatest and hope is fleeting.

Out of an even further abundance of caution, Congress could implement this Amendment on an optional basis, thereby letting research organizations choose between this approach and the more traditional approach outlined by the Act and the FDA.