The Lengthy and Tortured Historical past of Alpha-Synuclein and Parkinson’s Illness – The Well being Care Weblog

By STEVEN ZECOLA

This research tracks the decades-long journey to harness alpha-synuclein as a therapy for Parkinson’s illness. Steven Zecola an activist who tracks Parkinson’s analysis and was on THCB final month discussing it, affords three key adjustments wanted to beat the underlying challenges.

A Fast Begin for Alpha-Synuclein R&D

Within the mid-1990’s, Parkinson’s affected person advocacy teams had turn out to be impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been permitted for Parkinson’s illness (PD).

The Director of Nationwide Institute of Neurological Issues and Stroke (NINDS) arrange a workshop in August 1995 that featured scientists with experience in human genetics who would possibly open novel avenues for PD analysis.

One such scientist, Robert Nussbaum, made the next remarks on the workshop:

“…discovering genes answerable for familial Parkinson’s must be useful for understanding all types of the illness. Strategies now out there ought to permit researchers to seek out the genes answerable for familial Parkinson’s illness in a comparatively quick time.”

Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a serious contributor of irregular clusters of proteins within the mind, not solely in sufferers with synuclein mutations however, extra importantly, in sufferers with sporadic Parkinson’s illness as nicely.

As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union deal with, stated:

“Take into consideration this, your complete retailer of human information now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. It took 9 years. Final yr scientists situated the gene that causes Parkinson’s illness in solely 9 days.”

The NIH is Requested to Take a Management Function

Shortly after President Clinton’s name to motion, a Senate Committee requested the Nationwide Institutes of Well being (NIH) to develop a coordinated effort to make the most of promising alternatives in PD analysis.

In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a serious planning assembly that included all elements of the PD neighborhood. The group’s suggestions fashioned the premise of a five-year PD Analysis Agenda.

The Analysis Agenda was codified in a complete 42-page report that lined all features of analysis from higher understanding the illness, to creating new analysis capabilities, to creating new remedies, and to enhancing the analysis course of.

Noting the “outstanding paradigm shift in Parkinson’s illness analysis” from the invention of the consequences of alpha-synuclein, the report acknowledged that:

“New insights into the function of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of more practical therapies and supply recent analysis alternatives to advance our understanding of Parkinson’s illness”.

NIH invested almost $1 billion from FY 2000 to FY 2004 to implement the PD Analysis Agenda.  A-syn analysis could be funded out of the funds allotted to the classes of Genetics and Epidemiology, with each classes focused to obtain about 15% of the general spending.

Total, there have been 19 broad classes with spending authorizations, together with $32.7 million allotted to Program Administration and Course.

When the PD Analysis Agenda reached the tip of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005.  It introduced collectively an industry-wide consortium to evaluate the progress over the earlier 5 years and to develop future instructions for PD analysis.

The contributors generated greater than fifty particular suggestions.  NIH thought of these plans and the unmet objectives from earlier efforts and developed a 3-year Plan.

A serious focus of that Plan was to determine and intervene with the causes of PD.

As reiterated within the 2006 Plan:

“…Understanding the function of alpha-synuclein might allow methods to selectively block the dangerous results related to this protein as a novel method to therapy of PD”.

NINDS famous that:

“Whereas PD is just not a uncommon or orphan illness, different extra prevalent ailments equivalent to stroke, weight problems and diabetes provide significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical corporations have primarily targeted on medicinal chemistry and alterations of present PD or different neurological medication (e.g., dopamine agonists) fairly than investing in new medication.”

In essence, NINDS acknowledged the monetary conundrum of drug growth for A-syn and different PD therapies, however seemed to academia to resolve the issue by way of its grant program.

Missing success from the efforts of the 2006 Plan, NINDS organized one other convention in January 2014 referred to as: Parkinson’s Illness 2014: Advancing Analysis, Enhancing Lives. The aim of this initiative was to determine vital challenges and to spotlight the best priorities for advancing analysis.

Thirty-one suggestions had been supplied. The abstract of the convention included the High 3 priorities for scientific analysis, translational analysis, and fundamental analysis. Underneath fundamental analysis, priorities 1 and a pair of associated to alpha-synuclein.

On condition that the work specified for A-syn analysis was nonetheless at an early stage of fundamental analysis in 2014, it’s clear that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.

Personal Pursuits Lastly Transfer Ahead with Alpha-Synuclein

Recognizing the persevering with lack of progress and the necessity for funding, the Michael J. Fox Basis introduced a $10-million “Ken Griffin Alpha-synuclein Imaging Competitors” in 2019 to spur growth of a important and elusive imaging analysis device for Parkinson’s illness.

In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Basic Brigham and Merck— made super developments within the growth of various alpha-synuclein tracer strategies.

MJFF awarded Merck an extra $1.5 million to proceed the work and produce its device to life. The primary-in-human scientific trial of its alpha-synuclein PET tracer started in 2023. 

Moreover, after greater than 20 years of fundamental analysis, 5 personal analysis corporations filed purposes with the FDA and have initiated early-stage PD trials.

• Neuropore Therapies and UCB are collaborating on an oral small molecule, which goals to forestall the formation of alpha-synuclein clusters.
• Prothena Biosciences, at the side of Roche, is testing a humanized anti-alpha-synuclein antibody.
• Biogen is investigating one other monoclonal antibody towards alpha-synuclein.
• AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has not too long ago introduced the acquisition of all of AFFiRiS’ property and underlying mental property associated to its vaccine candidates focusing on a-syn.
• Vaxxinity makes use of an immunotherapy candidate codenamed UB–312 to focus on poisonous types of aggregated α-synuclein within the mind to battle Parkinson’s. Its Chairman not too long ago stated that: “Our findings recommend UB-312 may rework Parkinson’s care, providing hope for improved outcomes with a disease-modifying therapy”.

As with all R&D initiatives, there are various remaining challenges within the growth of A-syn therapies earlier than reaching the market. However, assuming that at the least one of many 5 on-going trials might be profitable, we are able to anticipate a remedy using A-syn might be permitted by the FDA inside the subsequent 5-8 years. The web impact is that the general growth window between A-syn’s discovery in 1997 and its software to sufferers could be roughly 35 years – assuming that the analysis goes comparatively easily from right here.

Given its efficiency so far, the view from NIH relating to PD analysis is:

“… Our failures in bringing remedies to the objective line are as a consequence of remaining giant gaps in information of the underlying biology that causes and drives the illness. As we fill in these gaps, the possibilities of success will improve. A few of the gaps we find out about, others we solely discover out about when the science opens one other door”.

Why Has This Analysis Taken So Lengthy?

With the advantage of hindsight, we are able to level to 2 areas that accounted for the best obstacles to progress – focus and sources.

In studying the PD analysis plans and reviews from 2000, 2006 and 2014, it seems that NINDS threw every little thing it knew about PD into the hopper. There have been a whole lot of suggestions, initiatives and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the required abilities, information and considering capacity to resolve a finely-honed query.

There merely are usually not sufficient nice minds to trace down all the “to do’s” within the three NINDS PD analysis plans.  Additionally, communications and networking are vital elements of scientific development, but the aptitude to community with the widespread participation within the small grants program was missing.

The implication of utilizing the time period “focus” is that it comes with the task of accountability and accountability if the precedence doesn’t get carried out. There seems to be little exterior oversight of the effectivity and effectiveness of the analysis {dollars} that had been utilized on A-syn or different PD analysis initiatives. If something, NIH appears content material with the output.

Lastly, NIH/NINDS knew there was a funding downside in crossing the Valley of Demise from fundamental analysis to scientific trials, however these organizations fell again to their consolation zone, specifically small grants to academicians. This technique didn’t produce the required outcomes.

A Higher Strategy

In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for extra funds because the challenge progressed out of fundamental analysis and thru the requisite scientific trials.

To deal with the shortcomings so far, the Division of Well being and Human Providers (HHS) ought to step in and 1) slim the PD analysis precedence listing to the highest candidates, 2) require the institution of a sturdy communications community for sharing info and three) loosen up the FDA rules for PD to assist degree the fund-raising enjoying subject.

Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies equivalent to A-syn include very excessive dangers and people dangerous funding {dollars} get to decide on between healthcare therapies that undergo 15+ years of fundamental analysis and costly scientific trials and different alternatives that may be launched in lower than a yr.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious results on fund-raising. First, the FDA overhang has dried up curiosity in angel and enterprise capital investing in potential therapies equivalent to A-syn. The consequence has been a Valley of Demise between fundamental analysis and drug growth. Second, even when the preliminary Valley may be crossed by way of authorities grants or non-profit donations, the FDA regulatory scheme places an unlimited burden on corporations to boost scores of thousands and thousands of {dollars} for prolonged scientific trials that face an unsure regulatory end result.

NIH/NINDS haven’t acknowledged that even with none direct function in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D relies on claims tied to regulatory milestones. Buyers are well-aware of the challenges of the FDA approval course of and it curbs investor curiosity.

Even in fundamental analysis, the FDA has had a big affect on scientific progress. For the tutorial entrepreneur, early growth of an efficient regulatory plan may be the distinction between success and failure. Subsequently, regulatory technique turns into a important element of the innovation course of.

HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome relating to any proposed adjustments to its processes.

The answer to those challenges, partially, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA must be excludedfrom Part 1 and Part 2 trials and from offering any steerage to researchers previous to Part 3 scientific trials. Such a change will pace growth, unleash innovation, and enhance early-stage fund-raising.

Second, to enhance efficiency of the analysis endeavors, NINDS must be tasked to develop and handle a proper, hub-and-spoke, communications community amongst all stakeholders concerned in PD analysis. ClinicalTrials.gov doesn’t fulfill this requirement as a result of it comprises deceptive info.

Facilitating common exchanges of knowledge, information sharing, and collaboration ought to assist to maximise the impression of analysis efforts and keep away from duplication of labor. For the funding neighborhood, a partition within the hub with investment-related info would assist to construct a bridge over the Valley of Demise and produce extra funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications workplace ought to typically be housed by MBAs (fairly than by Ph.D.’s) who’re targeted on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to take into account hiring an funding banking agency to help in organising the investor-related element of this info community.

The third advice for change is that NIH ought to convene a really small group of consultants engaged on PD analysis to determine the three most-likely-to-succeed paths to a remedy. It ought to make sure that these paths have enough personnel and adequate analysis {dollars} for completion.  Progress must be monitored frequently.

Lastly, I ought to point out that the Michael J. Fox Basis has carried out a wonderful job on plenty of vital points and must be a serious a part of any restructure going ahead. For instance, HHS may outsource the communications hub to MJFF.

The underside line is that each one elements of the PD {industry}, together with the FDA, have to be on the identical web page by way of discovering a remedy for PD inside an inexpensive period of time given present sources whether or not or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn so far, and equally, now we have witnessed that your complete analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.

The Lengthy and Tortured Historical past of Alpha-Synuclein and Parkinson’s Illness

Preface

This research tracks the decades-long journey to harness alpha-synuclein as a therapy for Parkinson’s illness. The creator affords three key adjustments wanted to beat the underlying challenges.

A Fast Begin for Alpha-Synuclein R&D

Within the mid-1990’s, Parkinson’s affected person advocacy teams had turn out to be impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been permitted for Parkinson’s illness (PD).

The Director of Nationwide Institute of Neurological Issues and Stroke (NINDS) arrange a workshop in August 1995 that featured scientists with experience in human genetics who would possibly open novel avenues for PD analysis.

One such scientist, Robert Nussbaum, made the next remarks on the workshop:

“…discovering genes answerable for familial Parkinson’s must be useful for understanding all types of the illness. Strategies now out there ought to permit researchers to seek out the genes answerable for familial Parkinson’s illness in a comparatively quick time.”

Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a serious contributor of irregular clusters of proteins within the mind, not solely in sufferers with synuclein mutations however, extra importantly, in sufferers with sporadic Parkinson’s illness as nicely.

As Nussbaum had predicted, progress had occurred quickly. President Clinton in his 1998 State of the Union deal with, stated:

“Take into consideration this, your complete retailer of human information now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. It took 9 years. Final yr scientists situated the gene that causes Parkinson’s illness in solely 9 days.”

The NIH is Requested to Take a Management Function

Shortly after President Clinton’s name to motion, a Senate Committee requested the Nationwide Institutes of Well being (NIH) to develop a coordinated effort to make the most of promising alternatives in PD analysis.

In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a serious planning assembly that included all elements of the PD neighborhood. The group’s suggestions fashioned the premise of a five-year PD Analysis Agenda.

The Analysis Agenda was codified in a complete 42-page report that lined all features of analysis from higher understanding the illness, to creating new analysis capabilities, to creating new remedies, and to enhancing the analysis course of.

Noting the “outstanding paradigm shift in Parkinson’s illness analysis” from the invention of the consequences of alpha-synuclein, the report acknowledged that:

“New insights into the function of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of more practical therapies and supply recent analysis alternatives to advance our understanding of Parkinson’s illness”.

NIH invested almost $1 billion from FY 2000 to FY 2004 to implement the PD Analysis Agenda.  A-syn analysis could be funded out of the funds allotted to the classes of Genetics and Epidemiology, with each classes focused to obtain about 15% of the general spending.

Total, there have been 19 broad classes with spending authorizations, together with $32.7 million allotted to Program Administration and Course.

When the PD Analysis Agenda reached the tip of its 5-year span, NINDS sponsored a second PD Summit which was held in June 2005.  It introduced collectively an industry-wide consortium to evaluate the progress over the earlier 5 years and to develop future instructions for PD analysis.

The contributors generated greater than fifty particular suggestions.  NIH thought of these plans and the unmet objectives from earlier efforts and developed a 3-year Plan.

A serious focus of that Plan was to determine and intervene with the causes of PD. As reiterated within the 2006 Plan:

“…Understanding the function of alpha-synuclein might allow methods to selectively block the dangerous results related to this protein as a novel method to therapy of PD”.

NINDS famous that:

“Whereas PD is just not a uncommon or orphan illness, different extra prevalent ailments equivalent to stroke, weight problems and diabetes provide significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical corporations have primarily targeted on medicinal chemistry and alterations of present PD or different neurological medication (e.g., dopamine agonists) fairly than investing in new medication.”

In essence, NINDS acknowledged the monetary conundrum of drug growth for A-syn and different PD therapies, however seemed to academia to resolve the issue by way of its grant program.

Missing success from the efforts of the 2006 Plan, NINDS organized one other convention in January 2014 referred to as: Parkinson’s Illness 2014: Advancing Analysis, Enhancing Lives. The aim of this initiative was to determine vital challenges and to spotlight the best priorities for advancing analysis.

Thirty-one suggestions had been supplied. The abstract of the convention included the High 3 priorities for scientific analysis, translational analysis, and fundamental analysis. Underneath fundamental analysis, priorities 1 and a pair of associated to alpha-synuclein.

On condition that the work specified for A-syn analysis was nonetheless at an early stage of fundamental analysis in 2014, it’s clear that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.

Personal Pursuits Lastly Transfer Ahead with Alpha-Synuclein

Recognizing the persevering with lack of progress and the necessity for funding, the Michael J. Fox Basis introduced a $10-million “Ken Griffin Alpha-synuclein Imaging Competitors” in 2019 to spur growth of a important and elusive imaging analysis device for Parkinson’s illness.

In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Basic Brigham and Merck— made super developments within the growth of various alpha-synuclein tracer strategies.

MJFF awarded Merck an extra $1.5 million to proceed the work and produce its device to life. The primary-in-human scientific trial of its alpha-synuclein PET tracer started in 2023. 

Moreover, after greater than 20 years of fundamental analysis, 5 personal analysis corporations filed purposes with the FDA and have initiated early-stage PD trials.

• Neuropore Therapies and UCB are collaborating on an oral small molecule, which goals to forestall the formation of alpha-synuclein clusters.
• Prothena Biosciences, at the side of Roche, is testing a humanized anti-alpha-synuclein antibody.
• Biogen is investigating one other monoclonal antibody towards alpha-synuclein.
• AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has not too long ago introduced the acquisition of all of AFFiRiS’ property and underlying mental property associated to its vaccine candidates focusing on a-syn.
• Vaxxinity makes use of an immunotherapy candidate codenamed UB–312 to focus on poisonous types of aggregated α-synuclein within the mind to battle Parkinson’s. Its Chairman not too long ago stated that: “Our findings recommend UB-312 may rework Parkinson’s care, providing hope for improved outcomes with a disease-modifying therapy”.

As with all R&D initiatives, there are various remaining challenges within the growth of A-syn therapies earlier than reaching the market. However, assuming that at the least one of many 5 on-going trials might be profitable, we are able to anticipate a remedy using A-syn might be permitted by the FDA inside the subsequent 5-8 years. The web impact is that the general growth window between A-syn’s discovery in 1997 and its software to sufferers could be roughly 35 years – assuming that the analysis goes comparatively easily from right here.

Given its efficiency so far, the view from NIH relating to PD analysis is:

“… Our failures in bringing remedies to the objective line are as a consequence of remaining giant gaps in information of the underlying biology that causes and drives the illness. As we fill in these gaps, the possibilities of success will improve. A few of the gaps we find out about, others we solely discover out about when the science opens one other door”.

Why Has This Analysis Taken So Lengthy?

With the advantage of hindsight, we are able to level to 2 areas that accounted for the best obstacles to progress – focus and sources.

In studying the PD analysis plans and reviews from 2000, 2006 and 2014, it seems that NINDS threw every little thing it knew about PD into the hopper. There have been a whole lot of suggestions, initiatives and so-called priorities. However a key issue of success in analysis is having a workforce of motivated scientists with the required abilities, information and considering capacity to resolve a finely-honed query.

There merely are usually not sufficient nice minds to trace down all the “to do’s” within the three NINDS PD analysis plans.  Additionally, communications and networking are vital elements of scientific development, but the aptitude to community with the widespread participation within the small grants program was missing.

The implication of utilizing the time period “focus” is that it comes with the task of accountability and accountability if the precedence doesn’t get carried out. There seems to be little exterior oversight of the effectivity and effectiveness of the analysis {dollars} that had been utilized on A-syn or different PD analysis initiatives. If something, NIH appears content material with the output.

Lastly, NIH/NINDS knew there was a funding downside in crossing the Valley of Demise from fundamental analysis to scientific trials, however these organizations fell again to their consolation zone, specifically small grants to academicians. This technique didn’t produce the required outcomes.

A Higher Strategy

In 1998 and thereafter, alpha-synuclein wanted a swat workforce of top-flight researchers together with a dedication for extra funds because the challenge progressed out of fundamental analysis and thru the requisite scientific trials.

To deal with the shortcomings so far, the Division of Well being and Human Providers (HHS) ought to step in and 1) slim the PD analysis precedence listing to the highest candidates, 2) require the institution of a sturdy communications community for sharing info and three) loosen up the FDA rules for PD to assist degree the fund-raising enjoying subject.

Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies equivalent to A-syn include very excessive dangers and people dangerous funding {dollars} get to decide on between healthcare therapies that undergo 15+ years of fundamental analysis and costly scientific trials and different alternatives that may be launched in lower than a yr.

Of paramount concern, the FDA’s regulatory scheme has had two deleterious results on fund-raising. First, the FDA overhang has dried up curiosity in angel and enterprise capital investing in potential therapies equivalent to A-syn. The consequence has been a Valley of Demise between fundamental analysis and drug growth. Second, even when the preliminary Valley may be crossed by way of authorities grants or non-profit donations, the FDA regulatory scheme places an unlimited burden on corporations to boost scores of thousands and thousands of {dollars} for prolonged scientific trials that face an unsure regulatory end result.

NIH/NINDS haven’t acknowledged that even with none direct function in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D relies on claims tied to regulatory milestones. Buyers are well-aware of the challenges of the FDA approval course of and it curbs investor curiosity.

Even in fundamental analysis, the FDA has had a big affect on scientific progress. For the tutorial entrepreneur, early growth of an efficient regulatory plan may be the distinction between success and failure. Subsequently, regulatory technique turns into a important element of the innovation course of.

HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome relating to any proposed adjustments to its processes.

The answer to those challenges, partially, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA must be excludedfrom Part 1 and Part 2 trials and from offering any steerage to researchers previous to Part 3 scientific trials. Such a change will pace growth, unleash innovation, and enhance early-stage fund-raising.

Second, to enhance efficiency of the analysis endeavors, NINDS must be tasked to develop and handle a proper, hub-and-spoke, communications community amongst all stakeholders concerned in PD analysis. ClinicalTrials.gov doesn’t fulfill this requirement as a result of it comprises deceptive info.

Facilitating common exchanges of knowledge, information sharing, and collaboration ought to assist to maximise the impression of analysis efforts and keep away from duplication of labor. For the funding neighborhood, a partition within the hub with investment-related info would assist to construct a bridge over the Valley of Demise and produce extra funding to potential therapies such alpha-synuclein.

This investor-related partition of the communications workplace ought to typically be housed by MBAs (fairly than by Ph.D.’s) who’re targeted on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to take into account hiring an funding banking agency to help in organising the investor-related element of this info community.

The third advice for change is that NIH ought to convene a really small group of consultants engaged on PD analysis to determine the three most-likely-to-succeed paths to a remedy. It ought to make sure that these paths have enough personnel and adequate analysis {dollars} for completion.  Progress must be monitored frequently.

Lastly, I ought to point out that the Michael J. Fox Basis has carried out a wonderful job on plenty of vital points and must be a serious a part of any restructure going ahead. For instance, HHS may outsource the communications hub to MJFF.

The underside line is that each one elements of the PD {industry}, together with the FDA, have to be on the identical web page by way of discovering a remedy for PD inside an inexpensive period of time given present sources whether or not or not it’s with alpha synuclein or different therapies. Such has not been the case with A-syn so far, and equally, now we have witnessed that your complete analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.

Steve Zecola bought his net software and internet hosting enterprise when he was recognized with Parkinson’s illness twenty three years in the past.  Since then, he has run a consulting apply, taught in graduate enterprise college, and exercised extensively