By STEVEN ZECOLA
This examine 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, gives 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 grow to be impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorized 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 liable for familial Parkinson’s ought to be useful for understanding all types of the illness. Methods now obtainable ought to permit researchers to search out the genes liable for familial Parkinson’s illness in a comparatively brief time.”
Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a significant 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 handle, mentioned:
“Take into consideration this, all the retailer of human data now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. IT took 9 years. Final 12 months 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 Health (NIH) to develop a coordinated effort to reap the benefits of promising alternatives in PD analysis.
In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a significant planning assembly that included all elements of the PD group. The group’s suggestions shaped the idea of a five-year PD Analysis Agenda.
The Analysis Agenda was codified in a complete 42-page report that coated all elements of analysis from higher understanding the illness, to creating new analysis capabilities, to growing new therapies, and to enhancing the analysis course of.
Noting the “exceptional paradigm shift in Parkinson’s illness analysis” from the invention of the consequences of alpha-synuclein, the report said that:
“New insights into the position of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of more practical therapies and supply contemporary 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 top 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 individuals generated greater than fifty particular suggestions. NIH thought of these plans and the unmet targets from earlier efforts and developed a 3-year Plan.
A significant focus of that Plan was to establish and intervene with the causes of PD.
As reiterated within the 2006 Plan:
“…Understanding the position of alpha-synuclein could allow methods to selectively block the dangerous results related to this protein as a novel strategy to therapy of PD”.
NINDS famous that:
“Whereas PD just isn’t a uncommon or orphan illness, different extra prevalent illnesses corresponding to stroke, weight problems and diabetes provide significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical firms have primarily centered on medicinal chemistry and alterations of current PD or different neurological medicine (e.g., dopamine agonists) fairly than investing in new medicine.”
In essence, NINDS acknowledged the monetary conundrum of drug improvement for A-syn and different PD therapies, however seemed to academia to unravel 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 known as: Parkinson’s Illness 2014: Advancing Analysis, Enhancing Lives. The aim of this initiative was to establish vital challenges and to spotlight the very best priorities for advancing analysis.
Thirty-one suggestions had been offered. The abstract of the convention included the Prime 3 priorities for scientific analysis, translational analysis, and fundamental analysis. Underneath fundamental analysis, priorities 1 and a couple 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 is evident that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.
Non-public 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 improvement of a essential and elusive imaging analysis instrument for Parkinson’s illness.
In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Normal Brigham and Merck— made great developments within the improvement of various alpha-synuclein tracer strategies.
MJFF awarded Merck an extra $1.5 million to proceed the work and convey its instrument to life. The primary-in-human scientific trial of its alpha-synuclein PET tracer started in 2023.
Moreover, after greater than twenty years of fundamental analysis, 5 personal analysis firms filed functions 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, together with Roche, is testing a humanized anti-alpha-synuclein antibody.
- Biogen is investigating one other monoclonal antibody in opposition to alpha-synuclein.
- AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has just lately introduced the acquisition of all of AFFiRiS’ belongings 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 just lately mentioned that: “Our findings recommend UB-312 may remodel Parkinson’s care, providing hope for improved outcomes with a disease-modifying therapy”.
As with all R&D initiatives, there are numerous remaining challenges within the improvement of A-syn therapies earlier than reaching the market. However, assuming that at the least one of many 5 on-going trials will likely be profitable, we will anticipate a remedy using A-syn will likely be authorized by the FDA throughout the subsequent 5-8 years. The online impact is that the general improvement 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 to this point, the view from NIH relating to PD analysis is:
“… Our failures in bringing therapies to the purpose line are as a result of remaining giant gaps in data of the underlying biology that causes and drives the illness. As we fill in these gaps, the possibilities of success will enhance. A number of the gaps we learn 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 will level to 2 areas that accounted for the best obstacles to progress – focus and sources.
In studying the PD analysis plans and stories from 2000, 2006 and 2014, IT seems that NINDS threw all the pieces 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 crew of motivated scientists with the required abilities, data and considering means to unravel a finely-honed query.
There merely aren’t sufficient nice minds to trace down all the “to do’s” within the three NINDS PD analysis plans. Additionally, communications and networking are necessary elements of scientific development, but the potential 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 duty 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 Dying 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 Method
In 1998 and thereafter, alpha-synuclein wanted a swat crew of top-flight researchers together with a dedication for added funds because the undertaking progressed out of fundamental analysis and thru the requisite scientific trials.
To handle the shortcomings to this point, the Division of Health and Human Providers (HHS) ought to step in and 1) slender the PD analysis precedence checklist to the highest candidates, 2) require the institution of a sturdy communications community for sharing Information and three) loosen up the FDA laws for PD to assist degree the fund-raising enjoying discipline.
Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies corresponding 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 12 months.
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 corresponding to A-syn. The end result has been a Valley of Dying between fundamental analysis and drug improvement. 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 firms to boost scores of hundreds of thousands of {dollars} for prolonged scientific trials that face an unsure regulatory consequence.
NIH/NINDS haven’t acknowledged that even with none direct position in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D is predicated 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 educational entrepreneur, early improvement of an efficient regulatory plan may be the distinction between success and failure. Due to this fact, regulatory technique turns into a essential element of the innovation course of.
HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome when IT involves any proposed adjustments to its processes.
The answer to those challenges, partly, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA ought to be excludedfrom Part 1 and Part 2 trials and from offering any steering to researchers previous to Part 3 scientific trials. Such a change will pace improvement, unleash innovation, and enhance early-stage fund-raising.
Second, to enhance efficiency of the analysis endeavors, NINDS ought to 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 accommodates deceptive Information.
Facilitating common exchanges of Information, information sharing, and collaboration ought to assist to maximise the influence of analysis efforts and keep away from duplication of labor. For the funding group, a partition within the hub with investment-related Information would assist to construct a bridge over the Valley of Dying and convey extra funding to potential therapies such alpha-synuclein.
This investor-related partition of the communications workplace ought to usually be housed by MBAs (fairly than by Ph.D.’s) who’re centered on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to think about hiring an funding banking agency to help in establishing the investor-related element of this Information community.
The third advice for change is that NIH ought to convene a really small group of specialists engaged on PD analysis to establish the three most-likely-to-succeed paths to a treatment. IT ought to be sure that these paths have satisfactory personnel and adequate analysis {dollars} for completion. Progress ought to be monitored frequently.
Lastly, I ought to point out that the Michael J. Fox Basis has carried out a wonderful job on a lot of necessary points and ought to be a significant a part of any restructure going ahead. For instance, HHS may outsource the communications hub to MJFF.
The underside line is that every one elements of the PD {industry}, together with the FDA, should be on the identical web page by way of discovering a treatment for PD inside an affordable period of time given current sources whether or not IT be with alpha synuclein or different therapies. Such has not been the case with A-syn to this point, and equally, now we have witnessed that all the 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 examine tracks the decades-long journey to harness alpha-synuclein as a therapy for Parkinson’s illness. The writer gives 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 grow to be impatient by the absence of any main therapeutic advances within the 25 years since L-dopa had been authorized 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 liable for familial Parkinson’s ought to be useful for understanding all types of the illness. Methods now obtainable ought to permit researchers to search out the genes liable for familial Parkinson’s illness in a comparatively brief time.”
Two years later in 1997, Spillantini et al. confirmed that alpha-synuclein (A-syn) was a significant 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 handle, mentioned:
“Take into consideration this, all the retailer of human data now doubles each 5 years. Within the 1980’s, scientists recognized the gene inflicting cystic fibrosis. IT took 9 years. Final 12 months 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 Health (NIH) to develop a coordinated effort to reap the benefits of promising alternatives in PD analysis.
In response, the NIH and the Nationwide Institute of Neurological Illness and Stroke (NINDS) held a significant planning assembly that included all elements of the PD group. The group’s suggestions shaped the idea of a five-year PD Analysis Agenda.
The Analysis Agenda was codified in a complete 42-page report that coated all elements of analysis from higher understanding the illness, to creating new analysis capabilities, to growing new therapies, and to enhancing the analysis course of.
Noting the “exceptional paradigm shift in Parkinson’s illness analysis” from the invention of the consequences of alpha-synuclein, the report said that:
“New insights into the position of synucleins within the pathobiology of Parkinson’s illness would speed up discovery of more practical therapies and supply contemporary 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 top 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 individuals generated greater than fifty particular suggestions. NIH thought of these plans and the unmet targets from earlier efforts and developed a 3-year Plan.
A significant focus of that Plan was to establish and intervene with the causes of PD. As reiterated within the 2006 Plan:
“…Understanding the position of alpha-synuclein could allow methods to selectively block the dangerous results related to this protein as a novel strategy to therapy of PD”.
NINDS famous that:
“Whereas PD just isn’t a uncommon or orphan illness, different extra prevalent illnesses corresponding to stroke, weight problems and diabetes provide significantly bigger “markets” for drug therapies than does PD. Thus, pharmaceutical firms have primarily centered on medicinal chemistry and alterations of current PD or different neurological medicine (e.g., dopamine agonists) fairly than investing in new medicine.”
In essence, NINDS acknowledged the monetary conundrum of drug improvement for A-syn and different PD therapies, however seemed to academia to unravel 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 known as: Parkinson’s Illness 2014: Advancing Analysis, Enhancing Lives. The aim of this initiative was to establish vital challenges and to spotlight the very best priorities for advancing analysis.
Thirty-one suggestions had been offered. The abstract of the convention included the Prime 3 priorities for scientific analysis, translational analysis, and fundamental analysis. Underneath fundamental analysis, priorities 1 and a couple 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 is evident that a big hole existed between the earlier NINDS priorities for A-syn and what was delivered.
Non-public 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 improvement of a essential and elusive imaging analysis instrument for Parkinson’s illness.
In March 2023, MJFF introduced that the three preliminary Alpha-synuclein imaging competitors groups — AC Immune, Mass Normal Brigham and Merck— made great developments within the improvement of various alpha-synuclein tracer strategies.
MJFF awarded Merck an extra $1.5 million to proceed the work and convey its instrument to life. The primary-in-human scientific trial of its alpha-synuclein PET tracer started in 2023.
Moreover, after greater than twenty years of fundamental analysis, 5 personal analysis firms filed functions 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, together with Roche, is testing a humanized anti-alpha-synuclein antibody.
- Biogen is investigating one other monoclonal antibody in opposition to alpha-synuclein.
- AFFiRiS, an Austrian biotech firm, is testing an alpha-synuclein vaccine. AC Immune has just lately introduced the acquisition of all of AFFiRiS’ belongings 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 just lately mentioned that: “Our findings recommend UB-312 may remodel Parkinson’s care, providing hope for improved outcomes with a disease-modifying therapy”.
As with all R&D initiatives, there are numerous remaining challenges within the improvement of A-syn therapies earlier than reaching the market. However, assuming that at the least one of many 5 on-going trials will likely be profitable, we will anticipate a remedy using A-syn will likely be authorized by the FDA throughout the subsequent 5-8 years. The online impact is that the general improvement 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 to this point, the view from NIH relating to PD analysis is:
“… Our failures in bringing therapies to the purpose line are as a result of remaining giant gaps in data of the underlying biology that causes and drives the illness. As we fill in these gaps, the possibilities of success will enhance. A number of the gaps we learn 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 will level to 2 areas that accounted for the best obstacles to progress – focus and sources.
In studying the PD analysis plans and stories from 2000, 2006 and 2014, IT seems that NINDS threw all the pieces 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 crew of motivated scientists with the required abilities, data and considering means to unravel a finely-honed query.
There merely aren’t sufficient nice minds to trace down all the “to do’s” within the three NINDS PD analysis plans. Additionally, communications and networking are necessary elements of scientific development, but the potential 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 duty 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 Dying 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 Method
In 1998 and thereafter, alpha-synuclein wanted a swat crew of top-flight researchers together with a dedication for added funds because the undertaking progressed out of fundamental analysis and thru the requisite scientific trials.
To handle the shortcomings to this point, the Division of Health and Human Providers (HHS) ought to step in and 1) slender the PD analysis precedence checklist to the highest candidates, 2) require the institution of a sturdy communications community for sharing Information and three) loosen up the FDA laws for PD to assist degree the fund-raising enjoying discipline.
Particularly, HHS/NIH/NINDS should acknowledge that investments in new healthcare therapies corresponding 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 12 months.
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 corresponding to A-syn. The end result has been a Valley of Dying between fundamental analysis and drug improvement. 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 firms to boost scores of hundreds of thousands of {dollars} for prolonged scientific trials that face an unsure regulatory consequence.
NIH/NINDS haven’t acknowledged that even with none direct position in fundraising, the FDA dominates the fund-raising course of. For instance, roughly 90% of fundraising for R&D is predicated 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 educational entrepreneur, early improvement of an efficient regulatory plan may be the distinction between success and failure. Due to this fact, regulatory technique turns into a essential element of the innovation course of.
HHS should additionally acknowledge that the FDA has safety-first tradition and a not-invented-here syndrome when IT involves any proposed adjustments to its processes.
The answer to those challenges, partly, entails HHS imposing a relaxed regulatory scheme for PD. For instance, the FDA ought to be excludedfrom Part 1 and Part 2 trials and from offering any steering to researchers previous to Part 3 scientific trials. Such a change will pace improvement, unleash innovation, and enhance early-stage fund-raising.
Second, to enhance efficiency of the analysis endeavors, NINDS ought to 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 accommodates deceptive Information.
Facilitating common exchanges of Information, information sharing, and collaboration ought to assist to maximise the influence of analysis efforts and keep away from duplication of labor. For the funding group, a partition within the hub with investment-related Information would assist to construct a bridge over the Valley of Dying and convey extra funding to potential therapies such alpha-synuclein.
This investor-related partition of the communications workplace ought to usually be housed by MBAs (fairly than by Ph.D.’s) who’re centered on speaking excessive worth analysis endeavors with the not-so-subtle intent of fomenting an curiosity in investments. NIH ought to think about hiring an funding banking agency to help in establishing the investor-related element of this Information community.
The third advice for change is that NIH ought to convene a really small group of specialists engaged on PD analysis to establish the three most-likely-to-succeed paths to a treatment. IT ought to be sure that these paths have satisfactory personnel and adequate analysis {dollars} for completion. Progress ought to be monitored frequently.
Lastly, I ought to point out that the Michael J. Fox Basis has carried out a wonderful job on a lot of necessary points and ought to be a significant a part of any restructure going ahead. For instance, HHS may outsource the communications hub to MJFF.
The underside line is that every one elements of the PD {industry}, together with the FDA, should be on the identical web page by way of discovering a treatment for PD inside an affordable period of time given current sources whether or not IT be with alpha synuclein or different therapies. Such has not been the case with A-syn to this point, and equally, now we have witnessed that all the analysis effort for PD has underperformed – and can proceed to underperform – within the absence of corrective motion.
Steve Zecola offered his internet 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 observe, taught in graduate enterprise faculty, and exercised extensively